GB2162840A - Sterospecific process for preparing azetidinones - Google Patents

Abstract

Chiral azetidinones II (R1 optionally substituted phenyl, R2 = C1-C4 alkyl or aryl, R3 = H or an N-protecting group) are prepared by reacting compound III (R4 = carboxy protecting group) with an organometallic derivative and treating the resultant dianion with a compound IV. The azetidinones II are stereospecifically prepared by the above process and may be converted to azetidinones VIII (R5 = hydroxy protecting group), useful in the preparation of penems. <IMAGE>

Description

SPECIFICATION Stereospecific process for preparing Azetidinones Description The invention relates to a stereospecific process for the preparation of chiral azetidinones. The azetidinones prepared according to the invention are useful as intermediates for the preparation of known and new p-lactam compounds, including 8R,6S,5R penems and carbapenems having the general formula I

wherein R2 represents a lower alkyl group or an aryl group, R represents an organic group and X represents a sulphur atom (such compounds being described in British Patent Specification No. 2043639) or a -CH2- residue (such compounds being the known antibiotic thienamycin and its derivatives). These compounds show high antibacterial activity.

The invention provides a process for the preparation of a chiral azetidinone having the general formula

wherein R1 represents an optionally substituted phenyl group, R2 is as defined above and Ra represents a hydrogen atom or an N-protecting group. Many attempts to prepare optically active azetidinones II have failed, see for example D.J. Hart et al. J. Org. Chem. 48, 289 (1983). Now we have surprisingly found that an optionally N-protected imine treated with a S(-) hydroxy ester in the presence of an organometallic compound affords goods yields of optically pure (3S) compounds II.

More particularly, the process of the invention comprises reacting a compound of the general formula Ill

wherein R2 is as defined above and R4 represents a carboxy protecting group with an organometallic derivative and treating the resultant dianion with a compound of the general formula IV

wherein R, and R3 are as defined above.

Suitable organometallic derivatives include di-(trimethyl- silyl)-amino lithium, di-(isopropyl)-amino lithium, n-butyllithium, t-butyllithium, methyllithium and phenyllithium. The reaction of compound Ill with the organometallic derivative is preferably carried out in an inert solvent such as tetrahydrofuran, benzene, toluene or hexane, at a temperature of from -100" to -70"C for a period of from 10 minutes to 3 hours. The treatment of the resultant dianion with the compound IV may be effected in the same reaction mixture at a temperature of from -100" to 30 C, for a period of from 3 to 24 hours. The crude compound II obtained may be purified by conventional methods.

In this specification, the term "lower alkyl" means a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Preferred groups which R, may represent include phenyl, p-methoxyphenyl and pchlorophenyl groups. R2 is preferably a methyl group. R3 preferably represents a tri-(lower alkyl)-silyl group such as a t-butyldimethylsilyl or trimethylsilyl group, a phenyl group or a substituted phenyl group such as a p-methoxy-phenyl group. The term "a carboxy protecting group" means any group conventionally used for the protection of a carboxy function during chemical reactions.Such groups include lower alkyl groups (e.g. methyl, ethyl, isopropyl and t-butyl), lower haioalkyl groups (e.g. 2-iodoethyl and 2,2,2-trichloroethyl), lower alkoxymethyl groups (e.g. methoxymethyl, ethoxymethyl and isobutoxymethyl), lower alkanoyloxymethyl groups (e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl), 1-(lower alkoxycarbonyloxy)-ethyl groups (e.g. 1-methoxycarbonyioxyethyl and 1ethoxy-carbonyloxyethyl), optionally substituted arylmethyl groups (e.g. benzyl, p-methoxybenzyl, o-nitrobenzyl and p-nitrobenzyl), benzhydryl and phthalidyl groups and tri-(lower alkyl)-silyl groups (e.g. trimethylsilyl and t-butyldimethylsilyl).

The azetidinones II provided by the process of the invention may be easily transformed into useful azetidinones Vlil by well established procedures as illustrated by the following reaction scheme:

(R1,R2,R3 are as defined above, Rs represents a hydroxy protecting group).

The compounds II are reacted with formic acid in the presence of triphenyl phosphine and the resultant inverted formate esters are transformed into the compounds of formula (V) by alkaline hydrolysis, as described in more detail hereinbelow in preparation A.

Cleavage of the -CH=CH-R1 side chain to give the corresponding compounds VII may be accomplished by conversion of the compounds V into their hydroxy protected derivatives VI which are reacted with sodium periodate in aqueous acetone in the presence of ruthenium trichloride, for example as described by A.K. Bose et al. J. Org. Chem. 47, 4075 (1982). The compounds VII are processed without purification to give, as single products, the (4R) acetate VIII by treatment with lead tetracetate in acetonitrile in the presence of catalytic amounts of copper acetate.

Alternatively, the compounds VII may be obtained from compounds VI by ozonization in methylene dichloride at -78"C followed by reduction of the ozonide with zinc in acetic acid, and oxidation of the crude aldehyde IX so obtained by a new polymer-bound chloride reagent. The chiral starting materials Ill are known compounds or may be prepared from the corresponding free carboxylic acids by methods well known to the skilled chemist. The imine derivatives IV may be prepared from an appropriate aldehyde derivative and a primary amine in a conventional manner, or by other methods well known to the skilled chemist, according to the substitution pattern of the compounds IV.

Since pharmacologically active 8R, 6S, 5R penems and carbapenems I may be obtained from axetidinones VIII having the 1'R,3R,4R configuration by known reactions and methods as described, inter alia, in our British Patent Specification No. 2111496 for penems, and in Tetrahedron Lett. 2293 (1982) for carbapenems, the process of the invention is very useful in providing optically active azetidinones which are key intermediates in the synthesis of biologically active penems and carbapenems. Although some processes to give azetidinones have been reported, none leads to total asymmetric induction, therefore the process of the invention is surprisingly advantageous.In accordance with the process of the invention, a starting chiral hydroxy-ester Ill having the S configuration will lead univocally to azetidinones II having only the 1'S,3S configuration, so providing a novel and practical route to pharmacologically active penems and carbapenems. The following Example and Preparations illustrate the invention.

Melting points are uncorrected. Infrared spectra (IR) were recorded as film on a Perkin Elmer 710 B spectrometer and the frequences are given in reciprocal centimetres. tH NMR spectra and 13C NMR spectra were determined in CDC13 or C6D6 solutions on Varian EM 390 and Varian FT 80 apparatus respectively, and the chemical shifts are expressed in parts per million from internal standard (TMS). Mass spectra were taken on a Varian Mat 111 instrument (70 eV). U.V. spectra were recorded on a 402 UVS Perkin Elmer instrument. Thin layer chromatography (TLC) was performed on silica gel sheets (1B2F Baker) and column chromatography on Chromatospac Prep. 10 (Jobin-lvon instrument) using silica gel (H 60 Merck). Optical rotations were measured on a Perkin Elmer Model 241. Tetrahydrofuran (THF) was obtained anhydorus and oxygen free by distillation over sodium benzophenone ketyl under argon. Meth ylene dichloride was distilled over phosphorus pentoxide. Diisopropylamine was refluxed over molecular sieves (Type 4A, Fluka) and distilled at atmospheric pressure.

Example {3S,4RS)-3-/lS-Hydroxyethyl)-4-{ss-styrylJ-2-azetidinone (II, R1=Ph, R2 = C Ha, Ra H To a stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (9.6 ml, 46 mmol) in 70 ml of tetrahydrofuran at room temperature was added 31 ml (46 mmol) of 15% n-butyl- lithium in hexane.The solution was stirred for 15 minutes and cooled to -70 C. Addition of 3 ml (23 mmol) of (S)-3-hydroxy ethyl butyrate (II1, Rz=CH3 R4=C2Hs) in 10 ml of tetrahydrofuran followed at a rate such that the internal temperature did not exceed -70DC. To the resulting solution of ester enolate was added a solution of N-(trimethyl- si- lyl)cinnamaldimine (IV, R,=Ph, R3=Si-(Me)3) (prepared by addition of 2.89 ml (23 mmol) of cinnamaldehyde to a solution of 23 mmol of lithium bis (trimethylsilyl)amide in 20 ml of tetrahydrofuran/hexane at 25"C for 1 hour) at a rate that kept the internal temperature at -70 C. The resulting mixture was stirred while the cold bath reached room temperature and for a further 12 hours at room temperature. The solution was diluted with 50 ml of diethyl ether and washed with three 40 ml portions of 1.0 M aqueous hydrochloric acid, 50 ml of saturated aqueous sodium bicarbonate and 50 ml of brine. The organic phase was dried (anhydrous magnesium sulphate) and concentrated in vacuo. The residual solid was chromatographed by flash-chromatography (ethyl acetate as eluting solvent) to give the title compound (2.5 g, 50%).

I.R. 3550, 3400, 1750; 60 MHz 1H NMR (CDCla) 7.3 (5H Ar); 6.7 (d, J=16Hz, 1H); 6.6 (N-H); 6.3 (1H, dd, J=6Hz; 16Hz); 4.4 (C4H, dd, J=6Hz, J=7Hz, 1H); 4.1 (C5H, q, J=6Hz); 3.33 (dd, J=6Hz; J=7Hz, C3H, 1H); 2.8 (OH); 1.25 (3H, d, J=6Hz); 13C NMR (Varian FT 80 MHz, CDCl3) 170.0 C2; 135.9; 128.7; 128.2; 126.6; C-Ar; 134.3 C8; 125.6 C7; 53.4 C4; 61.5 C; 64.8 Ca; 21.8 C4.

Preparation A (3S,4RSJ-3-( 1R- -HydroxyethylJ-4-(P-styryl)-2-azetidin one (V, R,=Ph, R2=CH3, Ra=H) A solution of the azetidinone prepared in Example 1 (2.37 g, 11 mmol) and triphenylphosphine (5.51 g, 21 mmol) in dry tetrahydrofuran (100 ml) was cooled in an ice-bath. Formic acid (98%, 1.62 ml, 43 mmol) and diethyl azodicarboxylate (3.29 ml, 21 mmol) were successively added to the stirred solution. Stirring was continued at room temperature for 30 minutes. The solution was partitioned between ethyl acetate and sodium hydrogen carbonate. The organic phase was separated off, washed with water and brine and dried. The solution was evaporated to small volume at reduced pressure and applied to a column of silica gel, which was eluted with ethyl acetate/hexane (6:4 by volume).The crude formate ester obtained from the chromatographic column was dissolved in 20% aqueous 1,4-dioxan (100 ml) and cooled in an ice-bath. Potassium hydroxide (137.5 ml, 0.8M solution) was added and the solution was stirred at this temperature for 10 minutes. Ethyl acetate (200 ml) was then added and the organic solution was washed with water and brine, and dried. Removal of the solvent under reduced pressure gave a pale yellow solid, which was chromatographed over silica-gel. Elution with ethyl acetate afforded the title compound (1.88 g 79% yield).

I.R.(film) 3500, 3400,1740; 13C NMR: 168.7 C =0, 135.8, 128.3, 127.6,126.2 126.2 C-Ar, 132.5 C4, 125.9 C7, 63.6 C4, 62.1 C5, 52.8 C2, 21.2 C6.

Preparation B F3S,4RS)-3-{1R-Hydroxyethyl)-4(ss-stryryl)-2-azetidínone bis t-butyldimethylsilyl derivative (Vl,Ri='Ph,R2=CHa, R3=Rs=Si(tBUt)Me2 A solution of the compound of Preparation A (1.08 g, 4.9 mmol) in 50 ml of dichloromethane at 0 C was treated with 2.26 g (15 mmol) of t-butyldimethylsilyl chloride and DMAP (2.44 g, 20 mmol). The temperature was allowed to reach room temperature and the solution was stirred under inert gas, for an additional 12 hours. To the solution was added 100 ml of dichloromethane. The solution was washed with brine, the organic phase was dried over Na2SO4 and the solvent was evaporated off. Flash-chromatography of the residue gave 1.81 g of title compound (84% yield).

Preparation C (3R, 4R)-3-(lR-h ydroxyeth yl)-4-acetoxy-2-azetidinone, bis t-butyldimethyl silyl derivative (Vlil, R2=CH3, R3=R5=Si(tBut)Me2) A solution of the compound of preparation B (1 g, 2.2 mmol) in dichloromethane was treated at -78"C with a stream of 0a0a in suitable apparatus until the solution was a deep blue colour. The resulting mixture was allowed to reach room temperature while a stream of nitrogen was passed through. Zinc dust was added, followed by acetic acid (3 ml). The mixture was stirred at room temperature for 1 hour, treated with sodium hydrogen carbonate until neutrality, washed with brine and dried over anhydrous magnesium sulphate.The resulting residue (IX, R2=CH3, R3=Rs=Si(tBut)Me2) was suspended in tetrahydrofuran and Polymer bound chloride (20 ml) was added followed by acetic acid (4 ml). The solution was stirred for an additional 1 hour at room temperature and filtered. The solvent was removed at reduced pressure. The residue (VII, R2=CH3, R3=Rs=Si(tBut)Me2) was dissolved in acetonitrile (10 ml) and treated with cupric acetate (5 mg) and lead tetraacetate (1.159, 2.6 mmol) (dried in vacuo to remove acetic acid).

The slurry was immersed in a 65"C oil bath and stirred with a stream of nitrogen bubbling through the slurry. After TLC showed the complete formation of the target compound (2-4 hours), the slurry was filtered and the solid washed with ethyl acetate. The combined filtrate and washings were evaporated in vacuo and the residue taken up in 100 ml each of ethyl acetate and aqueous sodium hydrogen carbonate.

The pH was adjusted to 7. The ethyl acetate layer was separated off, dried and evaporated to give, after flash-chromatography (six,, Hexane:diethyl ether 85:15 by volume), 0.397 g of the title compound as a single enantiomer. (45% yield). l.R (film) 1760, 1750, 1250; 60 MHz 1NMR (CDCI3): 0.33 (12H, m), 0.95 (18H, m), 1.35 (3H, d, J=6Hz), 2.1 (3H, s), 3.2 (1H, broad d, J=6Hz), 4.2 (1H, quintet, J=6Hz), 5.85 (1H, broad 5), laC NMR 170.9 C7, 169.4 OC=0, 63.9 Ca, 76.2 C4, 67.3 Cs, 21.0 C6.

Claims (10)

1. A process for the preparation of a chiral azetidinone having the general formula II

wherein R1 represents an optionally substituted phenyl group, Ra represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms or an aryl group and Ra represents a hydrogen atom or a Nprotecting group, the process comprising reacting a compound of the general formula Ill

wherein Ra is as defined above and R4 represents a carboxy protecting group with an organometallic derivative and treating the resultant dianion with a compound of the general formula IV

wherein R1 and Ra are as defined above.

2. A process according to claim 1 in which the reaction of the compound Ill with the organometallic derivative is carried out in an inert solvent, at a temperature of from -100" to -70"Cfor a period of from 10 minutes to 3 hours.

3. A process according to claim 2 in which the treatment of the resultant dianion with the compound IV is effected in the same reaction mixture at a temperature of from -100" to 30"C for a period of from 3 to 24 hours.

4. A process according to claim 2 or claim 3 in which the inert solvent is tetrahydrofuran, benzene, toluene or hexane.

5. A process according to any preceding claim in which the organometallic derivative is di-(trimethylsilyl)- amino lithium, di-(isopropyi)-amino lithium, n-butyllithium, t-butyllithium, methyllithium or phenyllithium.

6. A process according to claim 1, the process being substantially as described herein with reference to the Example.

7. A process for the preparation of an azetidinone having the general formula VIII

wherein Ra and R3 are as defined in claim 1 and R5 represents a hydroxy protecting group, the process comprising reacting a compound II as defined in claim 1 with formic acid in the presence of triphenyl phosphine, transforming by alkaline hydrolysis the resultant inverted formate ester into a compound of the general formula V

wherein R1, Ra and Ra are as defined in claim 1, protecting the free hydroxy group of the compound V to give a compound of the general formula VI

wherein R1, Ra and Ra are as defined in claim 1 and Rs is as defined in this claim, cleaving the 4-substituent of the compound VI to give a compound VII

wherein R7 and R3 are as defined in claim 1 and R5 is as defined in this claim, and treating the compound VII with lead tetraacetate in acetonitrile in the presence of a catalytic amount of copper acetate.

8. A process according to claim 7 in which the cleavage of the 4-substituent of the compound VI is effected by reaction of the compound VI with sodium periodate in aqueous acetone in the presence of ruthenium trichloride.

9. A process according to claim 7 in which the cleavage of the 4-substituent of the compound VI is effected by ozonisation of the compound VI in methylene dichloride at -78"C, reduction of the resultant ozonide with zinc in acetic acid, and oxidation of the resultant compound of the general formula IX

wherein Ra and R are as defined in claim 1 and R5 is as defined in claim 7 with a polymer bound chloride reagent.

10. A process according to claim 7, the process being substantially as described herein with reference to preparations A to C.