Inversion of the 3.alpha.-amino group attached to the .beta.-lactam ring

Abstract

A process for preparing 3.beta.-amino-4.beta.-substituted-2-azetidinones, which comprises condensing a 3.alpha.-amino-4.beta.-substituted-2-azetidinone with a trihalogenoacetaldehyde or the reactive derivative thereof to give a 3.alpha.-(2,2,2-trihalogenoethylidene)amino-4.beta.-substituted-2-azetidinones, treating the latter with a base to give a 3-(2,2-dihalogenovinyl)imino-4.beta.-substituted-2-azetidinone, reducing the latter with a metal hydride to give a 3.beta.-(2-halogenovinyl)amino-4.beta.-substituted-2-azetidinone, and hydrolyzing the latter to give the objective compound.

Description

This invention relates to intermediates useful in the preparation of penicillins and cephalosporins and the preparation thereof. In another aspect, this invention relates to the inversion of the 3.alpha.-amino group attached to the .beta.-lactam ring.

In the course of penicillin or cephalosporin total synthesis, 6.alpha.-aminopenicillanic acid derivatives or 7.alpha.-aminocephalosporanic acid derivatives are sometimes produced. In order to obtain useful penicillins or cephalosporins, it is usually necessary to convert the above 6.alpha.- or 7.alpha.-amino group into the useful 6.beta.- or 7.beta.-amino group. The inversion processes have been investigated and described in, for example, Japanese published patent application Nos. 49-125,389 and 50-106,993, Journal of the American Chemical Society 99, 5505 (1977) and Tetrahedron Letters 1973, 4649. These well-known methods, however, provide low yield, and cannot be applied to compounds having an unstable group because of the strong reaction conditions. The present inventors have investigated in order to overcome the above defects of the well-known methods and have found the present novel inversion process of a 3.alpha.-amino group attached to the .beta.-lactam ring.

The novel process of this invention can be represented as follows by the reaction scheme: ##STR1## [wherein

R.sup.1 is a group of the formula: ##STR2## (wherein R.sup.3 and R.sup.4 are same or different lower alkyls; and

COB.sup.1 is carboxy or protected carboxy);

R.sup.2 is alkenyloxy, alkynyloxy, alkanoyloxy, or alkylthio; or

R.sup.1 and R.sup.2 taken together represent a group of the formula: ##STR3## (wherein

Y.sup.1 is hydrogen, halogen, lower alkoxy, or lower alkyl which may be substituted by halogen, acyloxy, or heteroaromatic thio;

Y.sup.2 is alkylidene; and

COB.sup.2 is carboxy or protected carboxy);

Hal is halogen.]

In the above formulae, the dotted lines represent the .alpha.-configuration and the bold lines represent the .beta.-configuration. The expressions ".alpha." and ".beta." mean relative steric configuration. That is to say, in the formula (I), the 3-amino and the 4-R.sup.2 groups are in the trans position and the 3-hydrogen and the 4-R.sup.2 group are in the cis position. This invention also includes the inversion of the 3.beta.-amino to 3.alpha.-amino.

The explanation of the each reaction process is as follows:

(First step)

This process is a condensation reaction and may be readily carried out by reacting a 3.alpha.-amino-4.beta.-substituted-2-azetidinone [I] with an equimolar or excess amount of an aldehyde [II] or the reactive derivatives thereof in a suitable solvent under heating.

Representatives of the solvent are alcohols (e.g. methanol, ethanol, propanol, butanol, t-butanol, benzyl alcohol, ethylene glycol), ethers (e.g., diethyl ether, glyme, diglyme, tetrahydrofuran), hydrocarbons (e.g., benzene, toluene, xylene, methylene chloride), or the like or a mixture of two or more of them.

This reaction proceeds under the same condition as in the original formation reaction of Schiff bases, but it is preferred to carry it out while removing the water produced during the reaction by means of a molecular sieve or the like.

(Second step)

This step is a dehydrohalogenation reaction, and may be carried out by reacting the Schiff Base (II) prepared in the 1st step with an equimolar or excess amount, preferably 1.1 to 2 equivalents, of a base in a suitable solvent.

The utilizable solvents are the same as the solvents exemplified in Example 1.

Representatives of bases are tertiary amines (e.g., triethylamine, ethyl diisopropylamine), alkoxide of alkali metals (e.g. lithium methoxide, potassium t-butoxide), pyridine, quinoline, or the like organic bases.

The reaction may be carried out under cooling, preferably at -50.degree. to 0.degree. C., more preferably at -40.degree. to -20.degree. C. However, this reaction proceeds enough even at room temperature. The reaction is ordinarily complete within several tens of minutes, but the reaction runs often slower depending on varying reaction temperature, kinds of base, and other reaction conditions.

(Third step)

This process is a reduction of the imino group, and is carried out by reducing the imine compound (IV) prepared in the 2nd step with a reducing agent in a suitable solvent. The exemplified solvents in the 1st step may be also employed in this step. Among them, diethyl ether, tetrahydrofuran, and diglyme are more preferable.

Represenatives of the said reducing agents are metal hydrides such as sodium borohydride, potassium borohydride, lithium aluminium hydride, sodium cyano borohydride, lithium aluminium trialkoxyhydride, aluminium diisobutylhydride and the like.

This reaction may be carried out at room temperature under stirring, but depending on the reaction species, this reaction is carried out under cooling, even at -50.degree. to 0.degree. C.

(Fourth step)

This process is a hydrolysis reaction and may be carried out by treating an enamine compound (V) prepared in the 3rd step with an acid.

Representatives of the acid are inorganic acids such as hydrochloric acid, sulfuric acid, and the like and organic acids such as formic acid, acetic acid, oxalic acid, and the like.

This reaction is carried out in the presence of protic solvents such as water or an alcohol.

This reaction proceeds enough under ice-cooling or at room temperature, but if required, the reaction may be accelerated by warming.

The above 1st to 4th steps may be successively carried out in one vessel, or may be discontinuously carried out in order to isolate the desired intermediates. The intermediates (IV) and (V) are novel compounds.

This inversion process can be applied to the preparation of the strongly active antibacterial agents e.g. 1-oxacefalothin [J. A. C. S., 96; 24, 7582 (1974)] and 1-oxa-cefamandole [J. Med. Chem., 20, 551 (1977)]. In order to prepare these antibacterial agents, it is necessary to introduce stereospecifically the oxygen group in the .beta.-configuration at the 4-position of the azetidinone ring. This operation was very difficult, however, the present inventors have found that this difficult problem might be solved by carrying out this operation after converting the 3.beta.-acylamino of the starting materials into the 3.alpha.-acylamino (Japanese Unexamined Patent Publication No. 53-98951). The produced 3.alpha.-acylamino on the 2-azetidinone: must be converted back to 3.beta.-acylamino on the 2-azetidinones in a suitable step. This invention is applicable to this operation.

Compounds prepared by the process of this invention have the following general formula: ##STR4## (wherein R.sup.1 and R.sup.2 each has the same meaning as mentioned above.)

In the above definition of each symbol, preferable Hal is chloro, bromo, or iodo. Lower alkyl as R.sup.3 or R.sup.4 may be C.sub.1 to C.sub.3 alkyl. Alkenyloxy and alkynyloxy as R.sup.2 may be C.sub.2 to C.sub.4 alkenyloxy and alkynyloxy, respectively, and alkanoyloxy and alkylthio as R.sup.2 may be C.sub.1 to C.sub.4 alkanoyloxy and alkylthio, respectively. Lower alkoxy and lower alkyl as Y.sup.1 may be C.sub.1 to C.sub.7 alkoxy and lower alkyl, respectively. Alkylidene as Y.sup.2 may be C.sub.1 or C.sub.2 alkylidene. COB.sup.1 and COB.sup.2 may be a conventional carboxylic ester group, for example, diphenylmethyl ester, 2,2,2-trichloroethyl ester, p-nitrobenzyl ester, p-methoxybenzyl ester, phthalidyl ester, acetoxymethyl ester, pivaloyloxymethyl ester, t-butyl ester, phenyl ester, indanyl ester, or the like group.

Representatives are compounds of which R.sup.1 and R.sup.2 are selected from the following groups:

______________________________________R.sup.1 R.sup.2______________________________________ ##STR5## ##STR6## ##STR7## SCH.sub.3 ##STR8## SCH.sub.3 ##STR9## ##STR10## ##STR11## ##STR12## ##STR13## ##STR14## ##STR15##______________________________________

Intermediates of this invention have the following general formulae: ##STR16##

Representatives are compounds of which Hal, R.sup.1 and R.sup.2 are selected from the following groups:

______________________________________Hal R.sup.1 R.sup.2______________________________________Cl ##STR17## ##STR18##Cl ##STR19## SCH.sub.3Cl ##STR20## SCH.sub.3Cl ##STR21##Cl ##STR22##Cl ##STR23##Cl ##STR24##Cl ##STR25##Cl ##STR26##Cl ##STR27##______________________________________

The following examples are provided to further illustrate this invention.

Ph represents phenyl and Tetr represents 1-methyltetrazol-5-yl.

EXAMPLE 1-A

Diphenylmethyl 7.alpha.-(2,2,2-trichloroethylidene)amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate ##STR28##

To a solution of 4.1 g of diphenylmethyl 7.alpha.-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate 1 in 130 ml of benzene are added 6.85 ml of trichloroacetaldehyde and 13.5 g of 3 A Molecular Sieves, and the mixture is stirred for 2.5 hours under nitrogen atmosphere and filtered. The filtrate is concentrated under reduced pressure and the residue is chromatographed on prepacked silica gel column [Merck AG; size C/benzene-ethyl acetate (1:1)] to give 2.566 g of the title compound 2 as yellow crystals in 50% yield.

mp. 146.degree.-149.degree. C.

IR: .nu..sub.max.sup.CHCl.sbsp.3 1788, 1723 cm.sup.-1.

NMR: .delta..sup.CDCl.sbsp.3 3.85(s,3H), 4.33(s,2H), 4.75(s,2H), 4.88(d,J=2 Hz,1H), 5.20(s,1H), 6.97(s,1H), 7.32-7.80(m,10H), 8.15 (d,J=2 Hz,1H).

EXAMPLE 1-B

Diphenylmethyl 7-(2,2-dichlorovinyl)imino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate ##STR29##

To a solution of 2.363 g of diphenylmethyl 7.alpha.-(2,2,2-trichloroethylidene)amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate 2 in 25 ml of dichloromethane is added 772 .mu.l of ethyl-diisopropylamine at -40.degree. C. under nitrogen atmosphere, and the mixture is stirred for 20 minutes, poured into ice-cooled 2 N hydrochloric acid, and extracted with dichloromethane. The extract is washed with aqueous sodium hydrogencarbonate and water, dried, and evaporated. The residue is crystallized from ether to give 2.110 g of the title compound 3 in 95% yield.

mp. 186.degree.-189.degree. C.

NMR: .delta..sup.CDCl.sbsp.3 3.83(s,3H), 4.33(s,2H), 4.73(s,2H), 5.47+5.50 (2s,1H), 6.97(s,1H), 7.13-7.83(m,10H), 8.03(s,1H).

EXAMPLE 1-C

Diphenylmethyl 7.beta.-(2,2-dichlorovinyl)amino-3-(1-methyltetrazol-5-yl)thiometyyl-1-oxadethia-3-cephem-4-carboxylate ##STR30##

To a solution of 440 mg of diphenylmethyl 7-(2,2-dichlorovinyl)imino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate 3 in 8 ml of tetrahydrofuran is added a solution of 48 mg of potassium borohydride in 12 ml of 50% tetrahydrofuran, and the mixture is vigorously stirred for 3 minutes and treated in a conventional manner to give the title compound 4.

NMR: .delta..sub.ppm.sup.CDCl.sbsp.3 2.30(s,3H), 4.28(s,2H), 4.50(d,J=3 Hz,1H), 4.68(s,2H), 5.03(d,J=3 Hz,1H), 5.31(s,1H), 6.93(s,1H), 7.2-7.7(m,10H).

EXAMPLE 1-D

Diphenylmethyl 7.beta.-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate ##STR31##

To the resulting solution containing diphenylmethyl 7.beta.-(2,2-dichlorovinyl)amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate 4 in Example 1-C are added 12 ml of cooled 2 N hydrochloric acid and 6 ml of acetonitrile and the mixture is stirred for 2.5 hours under ice-cooling, poured into an aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The extract is washed with water, dried, and evaporated. The residue is triturated with ether and the resulting powder is chromatographed on a prepacked silica gel column (Merck Ag; size B/ethyl acetate) and crystallized from ethyl acetate-ether to give 154 mg of the title compound 5.

mp. 151.degree.-154.degree. C.

NMR: .delta..sub.ppm.sup.CDCl.sbsp.3 1.87(s,2H), 3.77(s,3H), 4.25(s,2H), 4.47(d,J=4 Hz,1H), 4.63(s,2H), 4.95(d,J=4 Hz,1H), 6.90(s,1H), 7.13-7.67(m,10H).

EXAMPLE 2

(Continuous operation)

Diphenylmethyl 7.beta.-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate ##STR32##

To a solution of 205 mg of diphenylmethyl 7.alpha.-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate 1 and 0.343 ml of trichloroacetaldehyde in 7 ml of anhydrous benzene is added 680 mg of 3 A molecular Sieves and the mixture is refluxed for 2.5 hours and filtered. The filtrate is concentrated under reduced pressure. The residue is dissolved in 2 ml of tetrahydrofuran and mixed with 76.3 .mu.l of ethyl-diisopropylamine at -40.degree. C. under nitrogen atmosphere. After 20 minutes, the reaction mixture is warmed to 0.degree. C. and mixed with 3 ml of a solution of 51 mg of potassium borohydride in 50% tetrahydrofuran and after 3 minutes, mixed with 3 ml of 2 N hydrochloric acid and 1.5 ml of acetonitrile. The mixture is stirred for 2 hours under ice-cooling, poured into an aqueous sodium hydrogencarbonate solution, and extracted with dichloromethane. The extract is washed with water, dried, and evaporated. The residue is crystallized from ethyl acetate to give 90 mg of the title compound 5 in 46.34% yield.

mp. 138.degree.-146.degree. C.

EXAMPLES 3 TO 8-A

The following compounds may be prepared in the same manner as Example 1-A.

__________________________________________________________________________ ##STR33##Ex. Yield mpNo. R.sup.1 R.sup.2 Hal (%) (.degree.C.) IR: .nu. .sub.max.sup.CHCl.sbsp.3 cm.sup.-1 NMR: .delta..sup.CDCl.sbsp.3__________________________________________________________________________ ##STR34## Cl 41.5 -- -- 4.50(d,J = 3Hz,2H),4.82(s,1H), 5.05(s,1H),6.47(t,J = 3Hz,1H), 6.95(s,1H),7.2-7.6(m,10H), 8.07(s,1H)4 ##STR35## " 53 -- -- 2.00(s,3H),4.50(s,2H),4.82 (m,1H),4.88 + 5.18(ABq,2H), 5.10(s,1H),6.92(s,1H),7.2- 7.7(m,10H),8.09(d,1H)5 ##STR36## " -- -- -- 4.30(s,2H),4.76(s),4.80(s, 1H),5.20(s,1H),5.28(s,1H), 5.36(s,1H),5.41(s,1H),6.91 (s,1H),7.2-7.6(m,10H),8.00 (s),8.07(s,1H)6 ##STR37## ##STR38## " -- -- -- 2.07(s,3H),2.28(s,4H),3.98 (brs,1H),4.10(d,J = 3Hz,2H), 5.51(brs,1H),7.08(s,1H),7.2- 7.7(m,10H),8.16(d,J = 2Hz,1H)7 ##STR39## SCH.sub.3 " 46 -- -- 1.93(s,3H),2.06(s,3H),2.28 (s,3H),5.05-5.55(m,2H),7.00 (s,1H),7.2-7.5(m,10H),8.1 (d,J = 2Hz,1H)8 ##STR40## " 68 140-142 1783, 1731 1660 2.16(s,3H),4.17(s,1H),4.40 (s,2H),4.83(d,J = 2Hz,1H), 5.15(s,1H),7-7.8(m,10H), 8.13(d,J = 2Hz,1H)__________________________________________________________________________

EXAMPLES 3 TO 8-B

The following compounds may be prepared in the same manner as Example 1-B.

__________________________________________________________________________ ##STR41##Ex. Yield mpNo. R.sup.1 R.sup.2 Hal (%) (.degree.C.) IR: .nu. .sub.max.sup.CHCl.sbsp.3 NMR: .delta..sup.CDCl.sbsp.3__________________________________________________________________________ ##STR42## Cl -- -- -- --4 ##STR43## " -- -- -- 2.00(s,3H),4.50(s,2H),4.33 + 5.23(ABq,2H),5.37(s,1H),6.90 (s,1H),7.2-7.7(m,10H),7.97 (s,1H)5 ##STR44## " -- -- -- 4.31(s,2H),5.30(s,2H),5.40(s, 1H),5.71(s,1H),5.76(s,1H), 6.87(s,1H),7.1-7.5(m,10H), 7.86(s,1H)6 ##STR45## ##STR46## " -- -- 3300, 1780 1725. 2.03(s,3H),2.31(s,3H),4.18(d, 2H),5.83(s,1H),7.00(s,1H),7.1- 7.6(m,10H),8.03(s,1H)7 ##STR47## SCH.sub.3 " -- -- -- 1.92(s,3H),2.0(s,3H),2.28(s, 3H),5.55(s,1H),6.97(s,1H),7.2- 7.6(m,10H),8.03(s,1H)8 ##STR48## " -- -- 1780, 1725 (CHCl.sub.3) 1.93(s,3H),4.20(s,2H),5.27(s, 1H),6.97(s,1H),7.1-7.7(m, 10H),8.03 (s,1H)__________________________________________________________________________

EXAMPLES 3 TO 8-C TO D

The following compounds may be prepared in the same manner as Examples 1-C and D.

__________________________________________________________________________ ##STR49##Ex. Yield mpNo. R.sup.1 R.sup.2 (%) (.degree.C.) IR: .nu. .sub.max.sup.Nujol cm.sup.-1 NMR: .delta..sup.CDCl.sbsp.3__________________________________________________________________________ ##STR50## 50 -- 3530,3400,1785, 1725,1640 --4 ##STR51## -- -- 3400,1795,1730 2.01(s,3H),3.92(brs,3H),4.60 (brs,2H),4 .90(d,J=4Hz,1H), 5.10(d,J=4Hz,1H),5.20( d,J= 4Hz,1H),6.90(s,1H),7.2-7.6(m, 10H)5 ##STR52## -- -- 3350,1775,1745 1.9(br,2H),4.30(s,2H),5.1- 5.3(m,2H),5. 10(s,1H),5.25(s, 1H),5.30(s,1H),6.83(s, 1H), 7.1-7.6(m,10H)6 ##STR53## ##STR54## -- -- 3410,3320,2115, 1767,1720(CHCl.sub.3) 1.25(brs,3H),2.03(s,3H),2.26 (s,3H),4.1 6(brd,J=3Hz,3H), 5.33(d,J=3Hz,1H),6.97( s,1H), 7.15-7.5(m,10H)7 ##STR55## SCH.sub.3 -- -- -- 1.8(brs,2H),1.9(s,3H),2.01(s, 3H),2.25( s,3H),4.45(d,J=5Hz, 2H),4.96(d,J=5Hz,2H ),7.0(s, 1H),7.2-7.5(m,10H)8 ##STR56## -- -- -- 1.77(brs,2H),2.0(s,3H),4.3(s, 2H),4.46( d,J=4Hz,1H),4.97(d, J=4Hz,1H),6.9(s,1H) ,7.2-7.6 (m,10H)__________________________________________________________________________

EXAMPLES 9 TO 10

The following compounds may be prepared in the same manner as Example 2.

__________________________________________________________________________ ##STR57##Ex. Yield mpNo. R.sup.1 R.sup.2 (%) (.degree.C.) IR: .nu. .sub.max.sup.Nujol cm.sup.-1 NMR: .delta..sup.CDCl.sbsp.3__________________________________________________________________________ 9 ##STR58## 55.3 -- 1785,1720, 1710 2.07(brs,2H),4.40(s,2H), 4.45(d,J=4Hz,1H),4.98 (d, J=4Hz,1H),6.97(s,1H),7.2 -7.6(m,10H)10 ##STR59## 34 -- 3520,3400, 1785,1725, 1630 1.75(brs,2H),3.77(s,3H), 4.48(d,J=4Hz,1H),4.52 (s, 2H),4.98(d,J=4Hz,1H),6.98 (s,1H),7.2-7.6(m ,10H)__________________________________________________________________________

EXAMPLE 11

Diphenylmethyl 7.beta.-(.alpha.-chloroacetamido)-3-chloromethyl-1-oxadethia-3-cephem-4-carboxylate ##STR60##

(1) To a solution of 450 mg (0.9 mmole) of diphenylmethyl 7.alpha.-benzoylamino-3-chloromethyl-1-oxadethia-3-cephem-4-carboxylate 6 in 9 ml of methylene chloride are added 375 mg (1.8 mmoles) of phosphorus pentachloride, 146 .mu.l (1.8 mmoles) of pyridine and 1 .mu.l of dimethylformamide in turn, and the mixture is stirred for 2.5 hours under ice-cooling. Isobutanol (9 ml) is added thereto, and the mixture is allowed to stand at 3.degree. C. overnight and evaporated under reduced pressure. The residue is treated with ether to give diphenylmethyl 7.alpha.-amino-3-chloromethyl-1-oxadethia-3-cephem-4-carboxylate hydrochloride as crude product.

(2) To a solution of the above crude product in 6 ml of dichloromethane is added 97.5 .mu.l (0.99 mmole) of trichloroacetaldehyde. The mixture is refluxed for 4.5 hours, while the additional 97.5 .mu.l of trichloroacetaldehyde is added thereto over 1 hour period. The reaction mixture is concentrated under reduced pressure and the residue is chromatographed on a column of silica gel and eluted with benzene to give 281 mg of diphenylmethyl 7.alpha.-(2,2,2-trichloroethylidene)amino-3-chloromethyl-1-oxadethia-3-cephem-4-carboxylate as yellow foamy materials. (yield from Compound 6:63%).

IR: .nu..sub.max.sup.CHCl.sbsp.3 1787, 1726 cm.sup.-1.

NMR: .delta..sub.ppm.sup.CHCl.sbsp.3 4.53(s,2H), 4.62(s,2H), 4.83-4.97(m,1H), 5.20(s,1H), 6.98(s,1H), 7.17-7.77(m,10H), 8.13(d,J=2 Hz,1H).

(3) To a solution of 105 mg (0.2 mmole) of diphenylmethyl 7.alpha.-(2,2,2-trichloroethylidene)amino-3-chloromethyl-1-oxadethia-3-cephem-4-carboxylate 8 in 2 ml of tetrahydrofuran is added 37.4 .mu.l (0.21 mmole) of ethyl diisopropylamine at -40.degree. C., and the mixture is stirred at the same temperature for 20 minutes. A solution of 12 mg (0.222 mmole) of potassium borohydride in 0.5 ml of tetrahydrofuran and 0.5 ml of water is added thereto, and the mixture is reacted for 5 minutes under ice-cooling and mixed with 2 ml of 2 N hydrochloric acid, 1 ml of acetonitrile and 1 ml of tetrahydrofuran. After 1.5 hours, the reaction mixture is concentrated under reduced pressure and extracted with dichloromethane. The extract is washed with brine, dried and evaporated to give 60 mg of diphenylmethyl 7.beta.-amino-3-chloromethyl-1-oxadethia-3-cephem-4-carboxylate hydrochloride 9 as crude product.

(4) To a solution of 60 mg of diphenylmethyl 7.beta.-amino-3-chloromethyl-1-oxadethia-3-cephem-4-carboxylate hydrochloride 9 in 2 ml of methylene chloride are added 20.6 .mu.l (0.276 mmole) and 41.8 .mu.l of pyridine. After 30 minutes, the reaction mixture is poured into 2 N hydrochloric acid and extracted with methylene chloride. The extract is dried and concentrated. The residue is chromatographed on a prepacked silica gel column size A (Merck) and eluted with benzene and ethyl acetate (2:1) to give 44 mg of diphenylmethyl 7.beta.-(.alpha.-chloroacetamido)-3-chloromethyl-1-oxadethia-3-cephem-4-carboxylate 10.

IR: .nu..sub.max.sup.CHCl.sbsp.3 3405, 1796, 1724, 1683 cm.sup.-1.

NMR: .delta..sup.CDCl.sbsp.3 4.13(s,2H), 4.58(s,4H), 5.10(d,J=4 Hz,1H), 5.70(dd,J=10.4 Hz,1H), 6.98(s,1H), 7.07-7.70(m,10H).

Claims

1. A compound of the formula ##STR61## wherein R.sup.1 is a group of the formula ##STR62## in which R.sup.3 and R.sup.4 are the same or different C.sub.1 to C.sub.3 alkyl and COB.sup.1 is carboxy or a conventional carboxylic ester group, and R.sup.2 is C.sub.2 to C.sub.4 alkenyloxy, C.sub.2 to C.sub.4 alkynyloxy, C.sub.1 to C.sub.4 alkanoyloxy or C.sub.1 to C.sub.4 alkylthio, or R.sup.1 and R.sup.2 taken together represent a group of the formula ##STR63## wherein Y.sup.1 is hydrogen, halogen, C.sub.1 to C.sub.7 alkoxy or C.sub.1 to C.sub.7 alkyl which is unsubstituted or monosubstituted by halogen, acetoxy or 1-methyl-tetrazol-5-yl-thio, Y.sup.2 is C.sub.1 to C.sub.2 alkylidene, COB.sup.2 is carboxy or a conventional carboxylic ester group, and Hal is chloro, bromo or iodo, and wherein the conventional carboxylic ester group is diphenyl methyl ester, 2,2,2-trichloroethyl ester, p-nitrobenzyl ester, p-methoxybenzyl ester, phthalidyl ester, acetoxymethyl ester, pivaloyloxymethyl ester, t-butyl ester, phenyl ester, or indanyl ester.

2. A compound as claimed in claim 1, wherein R.sup.1 and R.sup.2 are taken together and represent a group of the formula: ##STR64## wherein Y.sup.1, Y.sup.2 and COB.sup.2 are as defined in claim 1.

3. A compound as claimed in claim 1 wherein Hal is chloro, R.sup.1 is ##STR65## wherein Ph is phenyl and R.sup.2 is ##STR66##

4. A compound as claimed in claim 1 wherein Hal is chloro, R.sup.1 is ##STR67## wherein Ph is phenyl and R.sup.2 is --SCH.sub.3.

5. A compound as claimed in claim 1 wherein Hal is chloro, R.sup.1 is ##STR68## wherein Ph is phenyl and R.sup.2 is --SCH.sub.3.

6. A compound as claimed in claim 1 wherein Hal is chloro, R.sup.1 and R.sup.2 are taken together and represent ##STR69## and wherein Tetr is 1-methyltetrazol-5-yl and Ph is phenyl.

7. A compound as claimed in claim 1 wherein Hal is chloro, R.sup.1 and R.sup.2 are taken together and represent ##STR70## and wherein Ph is phenyl.

8. A compound as claimed in claim 1 wherein Hal is chloro, R.sup.1 and R.sup.2 are taken together and represent ##STR71## and wherein Ph is phenyl.

9. A compound as claimed in claim 1 wherein Hal is chloro, R.sup.1 and R.sup.2 are taken together and represent ##STR72## and wherein Ph is phenyl.

10. A compound as claimed in claim 1 wherein Hal is chloro, R.sup.1 and R.sup.2 are taken together and represent ##STR73## and wherein Ph is phenyl.

11. A compound as claimed in claim 1 wherein Hal is chloro, R.sup.1 and R.sup.2 are taken together and represent ##STR74## and wherein Ph is phenyl.

12. A compound as claimed in claim 1 wherein Hal is chloro, R.sup.1 and R.sup.2 are taken together and represent ##STR75## and wherein Ph is phenyl.