GB1566262A - 3 - amino - 4 - oxoazetidine derivatives - Google Patents

Description

PATENT SPECIFICATION ( 11) 1 566 262

( 21) Application No 17327/79 ( 22) Filed 3 Sept 1976 ( 62) Divided out of No1566261 ( ( 31) Convention Application No 610517 ( 32) Filed 3 Sept1975 i ( 31) Convention Application No 687805 ( 32) Filed 19 May 1976 in ( 33) United States of America (US) ( 44) Complete Specification published 30 April 1980 ( 51) INT CL 3 C 07 D 205/08 ( 52) Index at acceptance C 2 C 1200 1310 1371 215 220 225 226 227 22 Y 247 250 251 255 Y 280 281 282 28 X 305 30 Y 311 313 314 316 31 Y 321 324 328 32 Y 338 339 340 342 34 Y 351 352 360 361 362 364 365 366 367 368 36 Y 387 388 395 39 Y 43 X 440 503 Y 603 60 X 620 623 624 625 627 628 62 X 634 635 650 652 658 65 X 662 670 678 682 694 697 699 700 702 71 Y 722 72 Y 761 762 768 AA KA KB KH KM KN KR KS LY LZ MA MG RA RD RJ RX TT TX ( 54) 3-AMINO-4-OXOAZETIDINE DERIVATIVES ( 71) We, SMITHKLINE CORPORATION, of 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, United States of America, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly 5

described in and by the following statement:-

This invention concerns cis-2-azidomethyl and cis-2-aminomethyl-3-amino-4oxoazetidines and derivatives thereof which can be used as intermediates in preparing 1,3-diazabicyclol 3 2 O lheptan-7-one penicillin analogues as described and claimed in our copending Application 35505/76 (Serial No1,566,261) 10 According to the present invention there is provided a compound of the formula H H N_ i CH Y N O HI where R is hydrogen, 0 R 2 15 or R 5; R 2 is phenyl; phenoxymethyl; benzyl; a-aminobenzyl; a-hydroxybenzyl; acarboxybenzyl; phenyl substituted with lower alkyl of from one to four carbon atoms, lower alkoxy of from one to four carbon atoms, trifluoromethyl, halo or hydroxy; or benzyl substituted on the phenyl ring with lower alkyl 20 of from one to four carbon atoms, lower alkoxy of from one to four carbon atoms, trifluoromethyl, halo or hydroxy; R 5 is an easily removable amine protecting group; and Y is azido, or amino when R is.

0 11 25 R 2 C -.

2 1,566,262 2 R 5 may be trityl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, isobenzyloxycarbonyl or 1-methoxycarbonyl-2propenyl.

Scheme 1 hereinafter shows the preparation of compounds of formula I (a-d) according to the invention, the compounds of formula Id being of particular use in in the series of steps described in Scheme 1 of our copending Application 35505/76 5 in preparing 1,3-diazabicyclol 3 2 O lheptan-7-one penicillin analogues described and claimed therein.

According to Scheme 1, when the imine resulting from the condensation of methyl glyoxalate and 2,4-dimethoxy-benzylamine is allowed to react with a mixed anhydride of azidoacetic acid, azetidinone II is obtained Hydrogenation of this com 10 pound gives the corresponding amino derivative which can be protected with an amine protecting group by standard methods to give compound III In formula III, R 5 can be a phthaloyl or imine-forming group The hydrogen atom shown attached to the adjacent nitrogen atom being absent Treatment of III with potassium persulfate results in removal of the dimethoxybenzyl group to give compound IV which upon 15 reduction, for example with sodium borohydride, gives V Reaction of the tosylate derivative of V with an azide such as sodium azide gives the corresponding azidomethyl compound Ia in accordance with the invention The amine protective group is removed, for example by treatment of Ia with trifluoroacetic acid, and the resulting amino compound Ib can be acylated according to standard procedures to give Ic 20 Reduction of Ic gives the aminomethyl compound Id.

When the amine protective group R 5 is itself a group desired as a 6substituent in a 1,3-diazabicyclol 3 2 O lheptan-7-one penicillin analogue described and claimed in copending Application 35505/76 (Serial No 1,566,261), viz one of the formula R 2 CO where R 2 is defined as above, the steps of deblocking of the amine function 25 and subsequent acylation can be eliminated from the reaction sequence depicted in Scheme 1 (X being halogen).

The 3-azido-azetidinone II can alternatively be converted into a 3-amino2-tosyloxymethyl derivative by cleavage of the 2,4-dimethoxybenzyl group, followed by reduction of the ester function, conversion of the product hydroxymethyl compound 30 into the tosylate, and reduction of the azide moiety, all as described above.

Examples of compounds of the present invention are cis-2-azidomethyl-4oxo-3phenoxyacetyl-aminoazetidine, cis-2-azidomethyl-3-mandeloylamino-4oxoazetidine, cis-2-aminomethyl-3-mandeloylamino-4-oxoazetidine and cis-3-amino-2azidomethyl4-oxoazetidine 35 The starting materials for the compounds of this invention are commercially available, can be prepared by known methods, or are prepared as described herein.

L 2 1566262 3 HV -, c I C O 2 z C-'43 11 W -t >MB -D M is &t k o is b 5 e-^z | 3 O O 0 3 ZI 4 l R NH H " Hi jii: W 4 H H H 14 9 R s H A Cm X 1 Hu n W 3 RÂ H:' /"CH i 0 O e IS,RTW W 1 $ clzo W O NH W Co CI 43 K Rco NH g I Rlc N I # I W caIts 2 _ H H l-c Tdc O O ' tf N' C.-X O O N'"; O It is recognized that, due to asymmetric carbon atoms both in the bicyclic P 3lactam ring system and in some acyl side chains, stereoisomers will exist All of these isomers, including separated isomers and mixtures thereof, are included within the scope of this invention.

The following Preparations and Examples illustrate the invention, but are not to be construed as limiting the scope thereof All temperatures are in degrees Centigrade ( C) unless otherwise indicated.

PREPARATION 1 Methyl cis-3-azido-1-( 2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate To a mixture containing 16 82 g ( 0 101 mole) of 2,4-dimethoxybenzylamine and anhydrous magnesium sulfate in 150 ml of methylene chloride at 25 was added a solution of 10 05 g ( 0 114 mole) of methyl glyoxalate in 20 ml of methylene chloride.

The reaction mixture was stirred at room temperature overnight ( 15 hours) and then was filtered and the solvents were removed in vacuo to afford the imine of Scheme 1 as a dark orange gum.

To a solution of 15 1 g ( 0 149 mole) of azidoacetic acid in 130 mnil of anhydrous methylene chloride at 0 (ice bath) was added dropwise 21 0 ml ( 0 15 mole) of trifluoroacetic anhydride This mixture was stirred at 0 for 15 min and then 20 8 ml ( 0.15 mole) of triethylamine was added dropwise Stirring was continued for an additional 45 min and then the entire reaction mixture was transferred under argon 1.566,262 into an addition funnel which was cooled externally by dry ice The addition funnel was attached to a flask containing the imine from above, 200 ml of anhydrous methylene chloride and 20 8 ml ( O 15 mole) of triethylamrnine The solution of the mixed anhydride obtained was added dropwise from the addition funnel to the solution of the imine at 0 Stirring was continued at 00 for 1 hour and then the dark reaction 5 mixture was transferred to a separatory funnel and washed with water, aqueous sodium bicarbonate and brine and dried over anhydrous magnesium sulfate The solvents were removed in vacuo and the residue was chromatographed on 300 g of silica gel ( 70-230 mesh), affording an off-white solid which was further purified by trituration with ether to give the title compound as a white solid; tic:benzene:ethyl 10 acetate ( 1: 1), silica gel GF, Rf= O 64; mp 82-840 (ethyl acetate-hexane) .

PREPARATION 2 Methyl cis-4-oxo-3-phenoxyacetylaminoazetidine-2-carboxylate A mixture containing 10 0 g ( 0 0312 mole) of methyl cis-3-azido-l-( 2,4dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, 1 0 g of 10 % palladium on carbon 15 and 200 ml of ethanol was hydrogenated at 60 psi of hydrogen at 40-450 for 2 hours The reaction mixture was allowed to cool to 250 and was filtered through Celite (registered Trade Mark) After removing the solvents in vacuo, there remained a clear, yellow gum The crude amine was taken up in 100 ml of anhydrous methylene dichloride and was cooled to 00 in an ice bath To this solution was added 4 32 ml 20 ( 0.0312 mole) of triethylamine followed by the slow addition of a solution of 5 32 g ( 0.0312 mole) of phenoxyacetyl chloride in 40 ml of methylene dichloride The mixture was stirred at O for 1 hour, then extracted successively with water, aqueous hydrochloric acid, aqueous sodium bicarbonate and brine and was dried over anhydrous magnesium sulfate Fltration, followed by removal of the solvent in vacuao 25 afforded a yellow solid This material was partially dissolved in ether, cooled to -250 and filtered to give methyl cis-1-( 2,4-dimethoxybenzyl)-4-oxo-3phenoxyacetylaminoazetidine-2-carboxylate as a white solid; tic: benzene:ethyl acetate ( 1:1), silica gel, Rf= O 38; mp 115 5-116 00 (ethyl acetate-hexane).

To 900 ml of acetonitrile, which had been thoroughly degassed with argon, was 30 added 30 0 g ( 0 070 mole) of methyl cis-1-( 2,4-dimethoxybenzyl)-4-oxo-3phenoxyacetylaminoazetidine-2-carboxylate and the solid was rinsed into the reaction vessel with an additional 50 ml of degassed acetonitrile This solution was heated to 780 under argon and to its was added a degassed solution of 75 6 g ( O 28 mole) of potassium persulfate and 37 5 g ( 0 14 mole) of sodium monohydrogen phosphate in 35 1400 ml of water Addition of the aqueous solution was made in six portions of 250 ml over a period of 1 hour while maintaining the external temperature between 78 and 820 After cooling the reaction mixture, the acetonitrile was removed by evaporation Sodium chloride was added to the concentrated reaction mixture and it was extracted four times with ethyl acetate The combined ethyl acetate extracts 40 were dried (Mg SO 4), filtered and concentrated in vacuo to approximately 100-200 ml Addition of ether (ca 300 ml), followed by low temperature (-25 C) crystallization, afforded the title compound; tic: silica gel GF, ethyl acetate, Rf0 44; ethyl acetate: benzene ( 1: 1), RF 1 = 0 21; mp 140 1410 (ethyl acetate-hexane).

PREPARATION 3 45 cs-2-Hydroxymethyl-4-oxo-3-phenoxyacetylaminoazetidine To a solution of 13 5 g ( 0 049 mole) of methyl cis-4-oxo-3phenoxyacetylaminoazetidine-2-carboxylate in 975 ml of tetrahydrofuran and 100 ml of water at 00 (ice bath) was added a cold solution of 3 75 g ( 0 099 mole) of sodium borohydride in 250 ml of water over a period of 10 min The solution was stirred at O for 40 50 min and then glacial acetic acid was added dropwise until hydrogen evolution ceased.

Solid sodium bicarbonate and sodium chloride were added and this mixture was extracted five times with 250 ml portions of ethyl acetate After drying the combined extracts (Mg SO,), the solvent was removed in vacao The resulting residue was dissolved in ethyl acetate, clarified with Norit (registered Trade Mark) and 55 allowed to crystallize to give the title compound; tic: ethyl acetate, silica gel GF, Rf= O 10; mp 153-154 C (ethyl acetate).

PREPARATION 4 cis-3-Amino-4-oxo-2-p-toluenesulfonyloxymethyazetidine A degassed solution of 3 8 g ( O 012 mole) of ethyl cis-3-azido-l-( 2,4dimethoxy 60 benzyl)-4-oxoazetidine-2-carboxylate was treated with potassium persulfate and sodium monohydrogen phosphate as described in Preparation 2 to give methyl cis-31,566,262 t i azido-4-oxoazetidine-2-carboxylate which was purified by chromatography on silica gel with benzene-ethyl acetate as eluant.

Methyl cis-3-azido-4-oxoazetidine-2-carboxylate was reduced with sodium borohydride as described in Preparation 3 and the product was chromatographed on silica gel with ethyl acetate as eluant to give cis-3-azido-2-hydroxymethyl-4oxoazetidine 5 cis-3-Azido-4-oxo-2-p-toluenesulfonyloxymethyl-azetidine was prepared from cis3-azido-2-hydroxymethyl-4-oxoazetidine according to the procedure of Example 1.

Zinc dust ( 2 0 g, 0 03 mole) was slowly added with cooling to a solution of 5 0 g ( 0.011 mole) of cis-3-azido-4-oxo-2-p-toluenesulfonyloxymethylazetidine in 50 ml of 50 % aqueous acetic acid The reaction mixture was stirred for 30 minutes and 10 filtered The solids were washed with water and the filtrate was saturated with hydrogen sulfide, filtered and concentrated to near dryness The residue was dissolved in ehyl acetate-water and the p H was adjusted to 8 0 by addition of sodium carbonate and sodium hydroxide solutions The layers were separated and the aqueous phase was extracted twice with ethyl acetate The extracts were combined, dried (Mg 504) and 15 evaporated to dryness to give the title compound.

EXAMPLE 1 cis-2-Azidomethyl-4-oxo-3-phenoxyacetylaminoazetidine To a solution of 4 30 g ( 0 022 mole) of 98 % p-toluenesulfonyl chloride in 24 ml of anhydrous pyridine at O (ice bath) were added 2 64 g ( 0 011 mole) of cis-2 20 hydroxymethyl-4-oxo-3-phenoxyacetylaminoazetidine, prepared in Preparation 3, in one portion The solution was stirred at 0 for 3 hours, then was stored at -25 overnight After warming to 00, 1 0 ml of 85 % lactic acid was added and stirring was continued for 1 hour The reaction mixture was poured into ethyl acetate and extracted successively with water, dilute aqueous hydrochloric acid, aqueous sodium 25 bicarbonate and brine, and was dried (Mg SO 4) Filtration, followed by removal of the solvent in vacuo, resulted in a yellow solid Clarification of a hot solution of this material in ethyl acetate ( 375 ml), followed by the addition of hexane ( 200 ml) and recrystallization afforded cis-4-oxo-3-phenoxyacetylamino-2-ptoluenesulfonyloxymethyl-azetidine; tic: ethyl acetate, silica gel GF, Rf= 0 47; m 136 (dec) 30 A mixture containing 1 131 g ( 2 8 mmole) of cis-4-oxo-3phenoxyacetylamino-2p-toluenesulfonyloxymethyl-azetidine, 0 961 g ( 14 8 rmmole) of sodium azide and 25 ml of anhydrous N,N-dimethylformamide was heated under argon at 40 for 6 hours, then at ambient temperature for 24 hours The reaction mixture was poured into ethyl acetate and was washed with water The combined aqueous washes were extracted 35 once with ethyl acetate and the ethyl acetate fractions were combined and extracted with brine After drying the ethyl acetate solution (Mg SO 4) and filtering, the solvent was removed in vacua to afford a yellow semi-crystalline residue This residue was slurried in methylene dichloride and chromatographed on 25 g of silica gel ( 70-230 mesh) The 1:1 ethyl acetate:methylene dichloride fractions afforded the title com 40 pound; tic: ethyl acetate, ethyl acetate, silica gel GF, Rf= 0 38; mp 142143 (dec) (ethyl acetate-hexane).

EXAMPLE 2 cis-2-Azidomethyl-3-t-butoxycarbonylamino-4-oxoazetidine A mixture containing 10 0 g ( 0 0312 mole) of methyl cis-3-azido-1-( 2,4di 45 methoxybenzyl)-4-oxoazetidine-2-carboxylate, prepared as in Preparation 1, 1 0 g of % palladium on carbon and 200 ml of ethanol was hydrogenated for 2 hours at 40-50 and 60 psi of hydrogen The reaction mixture was allowed to cool to 25 and was filtered through a filter-aid After removing solvents in vacuo there remained methyl cis-3-amino-l-( 12,4-dimethoxybenzyl)-4-oxoazetidine -2carboxylate 50 A solution of 5 5 g ( 18 8 mmole) of methyl cis-3-amino-1-2,4dimethoxybenzyl)4-oxoazetidine-2-carboxylate in 100 ml of dry toluene were cooled to -78 and 2 5 ml ( 18 8 mmole) of triethylamine was added, followed by rapid addition of 35 ml ( 42 mmole) of a 12 % solution of phosgene in benzene The mixture was stirred for 15 rmin at-780, and 3 hours at 45 (acetonitrile-dry ice), then warmed to room tem 55 perature and concentrated to half volume in vacua To the resulting solution were added 50 ml of t-butanol and the mixture was stirred at room temperature overnight The solvents were removed in vacua and the residue diluted with ethyl acetate and filtered The filtrate was transferred to a separatory funnel and washed with 5 % aqueous sodium bicarbonate, 5 % hydrochloric acid and brine, dried (Mg SOI 4), and 60 evaporated to dryness Recrystallization of the crude, crystalline product from ether gave methyl cis-3-t-butoxycarbonylanmino-l-( 2,4-dimethoxybenzyl)-4oxoazetidine-2carboxylate, mp 134-135 .

A solution of 10 5 g ( 26 7 mmole) of methyl 3-t-butoxycarbonylamino-1-( 2,41,566262 dimethoxybenzyl)-4-oxoazetidine-2-carboxylate in 500 ml of acetonitrile was degassed with argon and warmed to 80 A degassed solution of 15 g ( 55 5 mmole) of potassium persulfate and 7 5 g ( 28 mmole) of sodium monohydrogen phosphate in 150 ml of water was added in five portions over 1 hour The reaction mixture was stirred at 80-85 under argon for 2-3 hours until all starting material had disappeared (tic) 5 The reaction mixture was cooled, concentrated in vacuo and shaken with ethylacetate water The organic phase was washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and brine; dried (Mg SO 4); and evaporated to dryness.

The residue was chromatographed on silica gel with 1: 1 benzene: ethyl acetate to afford pure product which crystallized from ethyl acetate-hexane to give methyl cis-3 10 t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate, mp 140-144 .

Sodium borohydride reduction of methyl cis-3-t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate as described in Preparation 3, followed by conversion of the 2-hydroxymethylazetidine product to the p-toluene-sulfonate derivative, mp 160162 (d), and reaction of the derivative with sodium azide as described in Example 15 1 gives the title compound.

EXAMPLE 3 cis-3-Amino-2-azidomethyl-4-oxoazetidine cis-2-Azidomethyl-3-t-butoxycarbonylamino-4-oxoazetidine prepared as in Example 1 (ca 1 g) is dissolved in 2 ml of methylene chloride and the solution is 20 cooled to O and treated with 0 5 ml of trifluoroacetic acid for 30 minutes at 0 The solution is washed with 5 % aqueous sodium bicarbonate and extracted with dilute hydrochloric acid The aqueous phase is neutralized and extracted with ethyl acetate.

Evaporation of the solvent gives the title compound.

EXAMPLE 4 25 cis-2-Aminomethyl-4-oxo-3-mandeloylaminoazetidine When cis-3-amino-4-oxo-2-p-toluenesulfonyloxymethylazetidine is reacted with Obenzylmandeloyl chloride according to the procedure described in Preparation 2 and the product is subsequently converted to the corresponding 2-azidomethyl compound which is subsequently reduced with zinc and acetic acid as described in Example 2, 30 cis-2-aminomethyl-3-(a-benzyloxyphenylacetylamino)-4-oxoazetidine is obtained.

A suspension of 14 mg of 10 % palladium on carbon and 0 06 mole of cis-2aminomethyl-3-(a-benzyloxyphenylacetylamino)-4-oxoazetidine in ca 2 ml of anhydrous ethylacetate is hydrogenated at room temperature at atmospheric pressure.

The reaction mixture is filtered and the filtrate is evaporated to dryness to give the 35 title compound.

EXAMPLE 5

Reaction of cis-3-amino-4-oxo-2-p-toluenesulfonyloxymethylazetidine with a halide of an acid listed below, suitably protected as necessary:

benzoic acid 40 p-toluic acid 4-ethylbenzoic acid 4-t-butylbenzoic acid r anisic acid 4-n-butoxybenzoic acid 45 2-chlorobenzoic acid 4-bromobenzoic acid 4-hydroxybenzoic acid 3-trifluoromethylbenzoic acid phenylacetic acid 50 a-aminophenylacetic acid a-carboxyphenylacetic acid 4-fluorophenylacetic acid 3-hydroxyphenylacetic acid 4-trifluoromethylphenylacetic acid 55 according to the procedure described in Preparation 2, followed by conversion of the products thus formed to the corresponding 2-azidomethyl compounds as described in Example 1 gives the following azetidines after removal of any protective groups:

cis-2-azidomethyl-3-benzoylamino-4-oxoazetidine cis-2-azidomethyl-4-oxo-3-(p-toluoylamino)azetidine 60 1,566 x 262 c s-2-azidomethyl-3-( 4-ethylbenzoylamino)-4-oxoazetidine cis-2-azidomethyl-3-( 4-eth-butylbenzoylamino)-4-oxoazetidine cis-2-azidomethyl-3 -( 4-t-butylbenzoylamino)-4-oxoazetidine cis-3-(m-anisoylamino)-2-azidomethyl-4-oxoazetidine cis-2-azidomethyl-3-( 4-n-butoxybenzoylamino)-4-oxoazetidine cis-2-azidomethyl-3-( 2-chlorobenzoylamino)-4-oxoazetidine 5 cis-2-azidomethyl-3-( 4-bromobenzoylamino)-4-oxoazetidine cis-2-azidomethyl-3-( 4-hydroxybenzoylamino)-4-oxoazetidine cis-2-azidomethyl-4-oxo-3-( 3-trifluoromethylbenzoylamino)azetidine cis-2-azidomethyl-4-oxo-3-phenylacetylaminoazetidine cis-3-(Q-aminophenylacetylamino)-2-azidomethyl-4-oxoazetidine 10 cis-2-azidomethyl-3-(x-carboxyphenylacetylamino)-4-oxoazetidine cis-2-azidomethyl-3-( 4-fiuorophenylacetylamino)-4-oxoazetidine cis-2-azidomethyl-3-( 3-hydroxyphenylacetylamino)-4-oxoazetidine cis-2-azidomethyl-4-oxo-3-( 4-trifluoromethylphenylacetylamino)azetidine.

EXAMPLE 6 15 cis-2-Aminomethyl-4-oxo-3-phenoxyacetylaminoazetidine A suspension of 0 499 g ( 1 81 mmole) of cis-2-azidomethyl-4-oxo-3phenoxyacetylaminoazetidine and 0 189 g of 10 % palladium on carbon in 25 ml of absolute ethanol was hydrogenated at atmospheric pressure and at 40 for 1 hour The solution was filtered through Celite and the solvent was removed in vacuo to afford the title 20 compound as a colorless gum.

EXAMPLE 7

Reduction of a 2-azidomethyl-3-substituted-4-oxoazetidine listed in Example 5 according to the procedures described in Example 4 or Example 6 gives the following 2-aminomethyl compounds: 25 cis-2-aminomethyl-3-benzoylamino-4-oxoazetidine cis-2-aminomethyl-4-oxo-3-(p-toluoylamino)azetidine cis-2-aminomethyl-3-( 4-ethylbenzoylamino)-4-oxoazetidine cis-2-aminomethyl-3-( 4-t-butylbenzoylamino)-4-oxoazetidine cis-2-aminomethyl-3-(m-anisoylamino)-4-oxoazetidine 30 cis-2-aminomethyl-3-( 4-n-butoxybenzoylamino)-4-oxoazetidine cis-2-aminomethyl-3-( 2-chlorobenzoylamino)-4-oxoazetidine cis-2-aminomethyl-3-( 4-bromobenzoylamino)-4-oxoazetidine cis-2-aminomethyl-3-( 4-hydroxybenzoylamino)-4-oxoazetidine cis-2-aminomethyl-4-oxo-3-( 3-trifluoromethylbenzoylamino)azetidine 35 cis-2-aminomethyl-4-oxo-3-phenylacetylaminoazetidine cis-2-aminomethyl-3-(a-aminophenylacetylamino-4-oxoazetidine cis-2-aminomethyl-3-(a-carboxyphenylacetylamino)-4-oxoazetidine cis-2-aminomethyl-3-( 4-fluorophenylacetylamino)-4-oxoazetidine cis-2-aminomethyl-3-( 3-hydroxyphenylacetylamino)-4-oxoazetidine 40 cis-2-aminomethyl-4-oxo-3-( 4-trifluoromethylphenylacetylamino)azetidine.

EXAMPLE 8 cis-2-Azidomethyl-3-( 4,5-diphenyl-2-oxo-4-oxa 2 olin-3-yl)-4oxoazetidine To a mixture containing 16 82 g ( 0 101 mole) of 2,4-dimethoxybenzylamine and anhydrous magnesium sulfate in 150 ml of methylene chloride at 25 is added a 45 solution of 10 05 g ( 0 114 mole) of methyl glyoxalate in 20 ml of methylene chloride.

The reaction mixture is stirred at room temperature overnight ( 15 hours) and then is filtered The solvents are removed in vacuo to afford methyl N-( 2,4dimethoxybenzyl)iminoacetate as a dark orange gum.

A mixture of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid ( 2 1 g, 7 1 mmole) 50 l 1 Org Chem, 38, 3034 ( 1973)l, 5 ml of thionyl chloride and 20 ml of methylene chloride is refluxed for 2 5 hours After cooling to room temperature the solvent is removed in vacuo and the resulting oil crystallizes on standing The product is triturated with ether-hexane to give 4,5-diphenyl-2-oxo-4-oxazolin-3ylacetic acid chloride, mp 104-112 55 Methyl N-( 2,4-dimethoxybenzyl)iminoacetate ( 1 43 g) is dissolved in 13 ml of dry methylene chloride and 1 ml of triethylamine and cooled in an ice bath A solution of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid chloride ( 2 0 g, 6 4 mmole) in 10 ml of methylene chloride is added over a 10 minute period After one hour, the mixture is washed with water and 5 % aqueous sodium bicarbonate, then dried and 60 evaporated to give a red oil which is chromatographed on silica gel to give methyl 1,566,262 cis 1 ( 2,4 dimethoxybenzyl) 3 ( 4,5 diphenyl 2 oxo 4 oxazolin 3 yl) 4 oxoazetidine 2 carboxylate.

Methyl cis-1-( 2,4-dimethoxybenzyl)-3-( 4,5-diphenyl-2-oxo-4-oxazolin-3yl)-4-oxoazetidine-2-carboxylate is treated with potassium persulfate and sodium monohydrogen phosphate as described in Example 2 to give methyl cis-3-( 4,5-diphenyl-2oxo-4 5 oxazolin -3-yl)-4-oxoazetidine-2-carboxylate.

Sodium borohydride reduction of methyl cis-3-( 4,5-diphenyl-2-oxo-4oxazolin-3yl)-4-oxoazetidine-2-carboxylate as described in Preparation 3, followed by conversion of the 2-hydroxymethylazetidine product to the p-toluenesulfonate derivative and reaction of this derivative with sodium azide as described in Example 1 gives the title corn 10 pound.

EXAMPLE 9

When p-methoxybenzyl alcohol, isoborneol, benzyl alcohol or 2,2,2trichloroethanol is substituted for t-butanol in Example 2 in the reaction with methyl cis 3 amino 1 ( 2,4 dimethoxybenzyl) 4 oxoazetidine 2 carboxylate, methyl Cds 15 1 ( 2,4 dimethoxybenzyl) 3 (p methoxybenzyloxycarbonylamino) 4 oxoazetidine 2 carboxylate, methyl cis 1 ( 2,4 dimethoxybenzyl) 3 isobornyloxycarbonylamino 4 oxoazetidine 2 carboxylate, methyl cis 3 benzyloxycarbonylamino 1 ( 2,4 dimethoxybenzyl) 4 oxo azetidine 2 carboxylate or methyl cis 1 ( 2,4 dimethoxybenzyl) 4 oxo 3 ( 2,2,2 trichloroethoxycarbonyl 20 amino) azetidine 2 carboxylate is obtained respectively.

Methyl 3-isobornyloxycarbonylamino-1-( 2,4-dimethoxybenzyl)-4oxoazetidine-2carboxylate can also be prepared by treating the 3-amino compound with isobomrnyloxycarbonyl chloride in the presence of base according to standard procedures; Chemn Pharm Bull, 20, 1017 ( 1972) 25 Treatment of the methyl cis-1-( 2,4-dimethoxybenzyl)-3-(substituted oxycarbonylamino)4-oxoazetidine-2-carboxylates mentioned above with potassium persulfate and sodium monohydrogen phosphate as described in Example 2 gives the following compounds, respectively:

methyl ds-3-(p-methoxybenzyloxycarbonylamino)-4-oxoazetidine-2carboxylate 30 methyl cis-3-isobornyloxycarbonylamino-4-oxoazetidine-2-carboxylate methyl cis-3-benzyloxycarbonylamnino-4-oxoazetidine-2-carboxylate methyl cis-4-oxo-3-( 2,2,2-trichloroethoxycarbonylamino)azetidine-2carboxylate.

Sodium borohydride reduction of a methyl cis-3-(substituted oxycarbonylamino)4-oxoazetidine-2-carboxylate listed above as described in Preparation 3, followed by 35 conversion of the 2-hydroxymethylazetidine product thus formed to the ptoluenesulfonate derivative and reaction of this derivative with sodium azide as described in Example 1 gives the following compounds, respectively:

cis-2-azidomethyl-3-(p-methoxybenzyloxycarbonylamino)-4-oxoazetidine cis-2-azidomethyl-3-isobornyloxycarbonylamino-4-oxoazetidine 40 cis-2-azidomethyl-3-benzyloxycarbonylamniino-4-oxoazetidine cis-2-azidomethyl-4-oxo-3-( 2,2,2-trichloroethoxycarbonylamino)azetidine.

Claims (1)

1. WHAT WE CLAIM IS:-

   1 A compound of the formula:

   I H H R -N / CH -Y 45 _ > 45 N 0 H in which:

   R is hydrogen, R Rfi or RW; 1,566,262 9 1,566,262 9 RX is phenyl; phenoxymethyl; benzyl; a-aminobenzyl; a-hydroxybenzyl; carboxybenzyl; phenyl substituted with lower alkyl of from one to four carbon atoms, lower alkoxy of from one to four carbon atoms, trifluoromethyl, halo or hydroxy; or benzyl substituted on the phenyl ring with lower alkyl of from one to four carbon atoms, lower alkoxy of from one to four carbon atoms, trifluoromethyl, halo or hydroxy; R 5 is an easily removable amine protecting group; and Y is azido or amino when R is 0 II R 2-C-.

   2 A compound as claimed in claim 1, in which Y is azido 10 3 A compound as claimed in claim 2, in which R is RI.

   4 A compound as claimed in claim 2, in which R is 0 II R'-C A compound as claimed in claim 2, in which R is hydrogen.

   6 A compound as claimed in claim 1, in which R is 15 0 R 2-Cand Y is amino.

   7 A compound as claimed in claim 3, in which RI is trityl, tbutoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, isobornyloxycarbonyl, 1-methoxycarbonyl-2-propenyl, phthaloyl or an imine-forming group 20 8 cis-2-Azidomethyl-4-oxo-3-phenoxyacetylaminoazetidine.

   9 cis-2-Azidomethyl-3-mandeloylamino-4-oxoazetidine.

   cis-2-Aminomethyl-4-oxo-3-phenoxyacetylaminoazetidine.

   11 cis-2-Aminomethyl-3-mandeloylamino-4-oxoazetidine.

   12 cis-2-Azidomethyl-3-t-butoxycarbonylamrnino-4-oxoazetidine.

   13 A process for preparing a compound according to claim 1 which comprises 25 (a) (where R represents R 5 and Y represents azido) reacting a compound of the formula N == c Hz O S Oa_-(-CH 0 H vn (where R is as defined in claim 1) with an azide; 30 (b) (where R represents H and Y represents azido) replacing the protecting group R 5 by H; (c) (where R represents RICO and Y represents azido) reacting the compound according to claim 1 (where R represents H and Y represents azido) with a compound of formula R 2 COX (where X is halogen); or 35 (d) (where R represents R'CO and Y represents amino) reducing a compound according to claim 1 (where R represents R 2 CO and Y represents azido).

   14 A process for preparing a compound according to claim 1, the process being substantially as herein described.

   1,566,262 1,566,262 10 A process for preparing a compound according to claim 1, the process being substantially as herein described in any of the Examples.

   16 A compound according to claim 1, when prepared by a process according to any one of claims 13 to 15.

   G H HARGREAVES Chartered Patent Agent Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa 1980 Published by The Patent Office 25 Southampton Buildings, London WC 2 A IAY from which copies may be obtained.