IE43846B1 - Azetidine compounds - Google Patents

Description

This invention relates to azetidine compounds which are chemical intermediates for cephalosporin-1 ike compounds having antibacterial activity, and to processes for preparing them.

Cephalosporins obtained by fermentation processes or ring expansion of penicillins all contain the 8-oxo-5-thia-l-azabicyc1o/4.2.07oct-2-ene nucleus having the structure lompounds with this ring system have been the object of intense research and lumerous scientific articles and patents, and are the basis of a considerable lumber of commercial products available as antibacterial agents.

Analogous ring systems in which the sulfur atom is in another position n the six-membered ring cannot be obtained by the same methods as those which have - 2 been described for the above nucleus and a totally synthetic approach must be employed. One system which has been attempted with varied success is the 8-oxo4-thia-l-azabicyclo/—4.2.0_7octane to which the trivial name isocephalosporin can be given, that is The synthesis of 7 g -phenylacetamido-7 a -methyl-6 a Η-δ-οχο-4-thia1- azabicyclo/”4.2.07oct-2-ene-2-carboxylic acid and the 2,3-dihydro derivative has been reported in J. Chem, Soc., 1321 (1973). These compounds, which Tack the 2,3 double bond believed necessary for biological activity and/or have a 7 a 10 methyl group which is not present in naturally-occurring cephalosporins, were reported to have no antibacterial activity when tested at high levels against three bacteria. Also reported in the same publication was a derivative with transconfiguration, 7 a -phenyl-acetamido-6 a H-8-oxo-4-thia-l-azabicyclo-/74.2.07octane2- carboxylic acid: this compound also showed no activity, and attempts to prepare the nucleus without the methyl substituent and with the 2,3 double bond were unsuccessful. Further attempts were reported in J, Chem. Soc. Perkin I, 2092 (1974) and were also unsuccessful.

Compounds have now been prepared having the 6,7 a H-8-oxo-4-thia-lazabicyclo/“4.2.07oct-2-ene ring system, in particular, 7 6 -acy1amino-6 “ H-820 oxo-4-thia-l-azabicyclo-/~4.2.07oct-2-ene-2-carboxylic acids and their derivatives of the structural formula: - 3 43846 (here R is an acyl group and E is hydrogen, methyl, bromomethyl, dr lower alkanoyl ixymethyl, and many of these are described and claimed in Patent Specification No. '72/76. The compounds of the present invention are intermediates useful for the reparation of compounds of Formula I.

The azetidine compounds of this invention are those of the structural ormula: Formula II lere A is azido N3, amino, aeylamino, or protected amino; B is COOH, lower Ikoxycarbonyl, iodomethyl, £-methoxybenzylthiomethy1, triphenylmethylthiomethyl, ircaptomethyl; or CHgOM, where M is hydrogen, lower alkanesulfonyl, or phenylilfonyl, such phenyl being unsubstituted or substituted with methyl or halogen; id fi is hydrogen or 2,4-dimethoxybenzyl.

By aeylamino group is meant a carboxylic aeylamino group and by ower alkoxycarbonyl and lower alkanesulfonyl are meant radicals whose alkyl irtion is an alkyl group containing from 1 to 6 carbon atoms. By halogen is ant fluorine, chlorine or bromine. - 4 «3810 Preferably the acylamino is ;; r· - /acetamido, a -t-butoxycarbonylaminophenylacetamido, 2-thienyIacetamido or 3-0-formylmandelamido group, but the acyl portion of the acylamino group can also, for example, be any one of the acyl groups R disclosed in Patent Specification No. 972/75 which is inert to the 6 -bromo- a -keto esters used to form the bicyclic system as described below.

A protected amino group is an amino group which has been masked by another group so as to protect it during subsequent chemical reactions following which the masking group can be removed to regenerate the amino group. Hany groups are known and used for this purpose within the penicillin, cephalosporin, and peptide synthetic arts. Preferably the protected amino group is a t-butoxycarbonylamino, 4,5-diphenyl-2-oxo-4-oxazo1in-3-y1, phthalimido, isobornyloxycarbonylamino, £-methoxybenzyloxycarbonylamino, benzyloxycarbonylamino, or 2,2,2-trichloroethoxycarbonylamino group. Treatment of a phthalimido groupwith hydrazine by published procedures cleaves the phthaloyl group to regenerate the amino group. Formation of the 2-oxo-4-oxazolin-3-yl group and regeneration of an amino group from it are taught in J, Org. Chem., 38, 3034 (1973).

A route for the preparation of compounds of the Invention of Formula II and their conversion to compounds of Formula I is outlined in Scheme I. In Scheme I, DMB means a 2,4-dimethoxybenzyl group, R is an acyl group, R^NH is a protected amino 2 group, R is an ester-forming group, and E is hydrogen or methyl.

A cyclo-addition reaction between the imine (1) obtained from the condensation of 2,4-dimethoxybenzylamine with methyl glyoxylate, and the mixed anhydride (2) or an acid halide of azidoacetic acid gives methyl cis-I-(2,4-dimethoxybenzyl)-3-azido-4-oxoazetidine-2-carboxylate (3). The azido group of this intermediate is reduced by catalytic hydrogenation or by chemical reduction such as with zinc and acetic acid to give a 3-aminoazetidine derivative, - 5 438 46 SCHEME I - 6 4384G which is then protected by a removable amino protect...g group such as t-butoxycarbonyl to give the protected derivative (4). A protected 3-aminoazetidine derivative can also be prepared directly by substitution of a glycine derivative in which the amino group has been protected. For example, 4,5-diphenyl-2-oxo-4oxazolin-3-ylacetyl chloride or phthalimidoacetyl chloride can be used in the cyclization reaction in the same manner as azidoacetyl compound (2) to give the corresponding protected 3-amino-azetidine derivative. The derivative (4) is converted by oxidation with potassium persulphate to the secondary amine (5), and this is reduced with sodium borohydride to the alcohol (6), which is converted in a series of steps to the mercaptomethyl derivative (7).

The intermediate (3) or the protected 3-aminoazetidine (4) can be converted by a series of reactions into the 2-tosyloxymethyl derivative as illustrated by compound (11) in Scheme II, where Ts is a tosyl (toluene-j>sulfonyl) group. Various reaction sequences can be used in the preparation of compounds such as (11). Scheme II sets forth two alternative pathways which can be used to convert compound (3) to compound (11). It is apparent to persons skilled in the art that conversion of the azido group to the protected amino group is not limited to the two illustrated places along the reaction sequence but can also be effected at other places. Reduction of the azido moiety is advantageously effected on compound (3) in Scheme II or on the 3-azido-2-tosy1oxymethyl derivative (12).

The tosyl derivative (11) is then converted stepwise to the mercaptomethyl derivative (7a), equivalent to (7) in Scheme I. Using sodium iodide the tosyl group is displaced by iodide, which is in turn displaced with a mercaptan R SH such as ja-methoxybenzyl mercaptan or tri phenylmethyl mercaptan. Cleavage of these derivatives by standard synthetic methods gives the mercaptomethyl compound (7a). The £-methoxybenzyl group is cleaved by treatment with mercuric salts.

The triphenylmethyl group is cleaved by treatment with silver salts including silver nitrate and silver tetrafluoroborate and therefore is advantageous where other groups within the compound are sensitive to mercuric ion. - 7 43846 - 8 4 3 8 4 C Returning to Scheme I, the mercaptoraet·'., v-jiipound (7) is reacted with a β -bromo- a -keto ester to give the bicyclic compound (8). When a bromopyruvate ester is used, compound (3) where E is hydrogen is obtained. When a 3bromo-2-oxobutyrate ester is used, compound (8) where E is methyl is obtained.

These compounds are dehydrated to give the 8-oxo-4-thia-l-azabicyclo/~4.2.07-oct2-ene compound (9). Standard dehydration reagents such as thionyl chloride, trifluoroacetic anhydride, and methanesulfonic anhydride can be used.

Compounds of structure (9) where E is bromomethyl are prepared by radical bromination of the 3-methyl compounds using the procedures known in the cephalosporin art. Bromination reagents include N-bromosuccinimide used in the presence of radical initiators such as benzoyl peroxide or azobisisobutyronitrile.

The bromomethyl derivatives can be reacted with various acetate salts to give compounds of structure (9) where E is acetoxymethyl. Examples of salts useful for this purpose include sodium, potassium, or silver acetate.

Compounds of structure (10) are prepared from compounds of structure (9) by removal of the amino-protecting group followed by acylation with the desired acyl group using standard acylation methods. Following the acylation any additional protecting groups are removed. During the acylation reaction any sensitive groups such as amino or hydroxyl are protected. Standard acylation methods include activation of the carboxyl group by use of mixed anhydrides, activated esters, and acid halides or by use of coupling reagents such as dicyclohexylcarbodiimide.

Some compounds of Formula I can alternatively be prepared by acylation with the desired acyl group earlier in the reaction sequence. For example, the 3aminoazetidinone derivative can be prepared from the azide (13) and acylated and conversion effected at the same places as those disclosed in Scheme II. When this acylated monocyclic e -lactam is carried along the reaction sequence herein disclosed the desired final products are obtained. Examples of acyl groups for which this alternative method can be used include phenoxyacetyl, « -aminophenylacetyl, « -amino-£-hydroxyphenylacetyl, and 2-thienylacetyl. - 9 4 3 8 46 More specifically, when 2,4-dimethoxybenzylamine /Chem. Ber., 101, 3623 (1968)7 is condensed with methyl glyoxylate /“(Synthesis, 544 (1972))7, the imine (1) is obtained. Reaction of this imine with the mixed anhydride (2) of trifluoroacetic acid and azidoacetic acid /“Tetrahedron Lett., 2319 (1973)7 gives i. ethy. c__ HmeUia.-ybenzyl ,· 3-azido-4-oxo-2-azetidinecarboxylate (3). x This reaction can be run as a two-step process by first generating the mixed anhydride and then adding this to a solution of the imine. Alternatively, a onestep procedure can be used in which the azidoacetic acid is added to a solution of the imine followed by the addition of the trifluoroacetic anhydride. In addition, other glyoxylate esters such as the ethyl or propyl ester can be used in the same manner.

The 2,4-dimethoxybenzyl group is removed by oxidative methods. For example, treatment of the N-(2,4-dimethoxybenzyl)- 0-lactam with potassium persulfate effects the deblocking reaction to generate the free β -lactam. This reaction is carried out in the presence of sodium monohydrogen phosphate. With some derivatives, pH control during the reaction within a range of 5-6 may be advantageous to the reaction yield. Under these conditions we have found that the benzyl group is not removed like the dimethoxybenzyl group. However, one skilled in the art could try other substituted benzyl moieties and determine if ;hey are removable and therefore are also able to perform the same function as the Jimethoxybenzyl group.

Reduction of the 2-alkoxycarbonyl group with suitable reducing agents ;uch as sodium borohydride gives the 2-hydroxymethyl derivative. In particular, .he methoxycarbonyl group is readily reduced with sodium borohydride to give the Icohol derivative.

The alcohol derivative can also bp prepared by reduction of the 2arboxylic acid by standard reduction methods known in the art. The acid is repared from the ester derivative by base hydrolysis. For example, the methyl ster hydrolyzes to the carboxylic acid by treatment with sodium carbonate, potassium arbonate or a similar base. The carboxylic acid can be converted to its acid - 10 4 2 8 Ί e chloride and reduced with sodium borohydride to giv.> uie desired alcohol. The 1-(2,4-dimethoxybenzyl)-2-carboxylic acid derivative can be reduced to the 2hydroxymethyl derivative which can be converted to the corresponding tosylate.

The dimethoxybenzyl group can be removed at this point to give the 8 -lactam methyl tosylate precursor which can be carried further as has been described.

The alcohol is treated with toluene-£-su1fonyl chloride, benzenesulfonyl chloride, £-bromobenzenesulfony1 chloride, mesyl chloride or similar reagents which convert the hydroxy group into a group which is readily displaced by iodide ion by nucleophilic displacement. Standard nucleophilic displacement of the sulfonate moiety with iodide followed by another nucleophilic displacement with sulfur derivatives gives the mercaptomethyl group or a group which can be converted to the desired mercaptomethyl group. Triphenylmethylmercapto and £methoxybenzylmercapto are typical groups which are readily cleaved to the free mercapto group as set out above.

The compounds of Formula I can then be generated by a cyclization reaction of the mercaptomethyl compound and a bromopyruvate derivative. The product formed contains a hydroxy group alpha to the carboxyl group. Dehydration of this hydroxy group places the double bond in the nucleus at the 2,3-position analogous to the cephalosporin series. Dehydration is best carried out with thionyl chloride and pyridine or trifluoroacetic anhydride.

The starting materials for the compounds of this invention are commercially available, prepared by known methods or described herein.

The following Examples illustrate the invention and are accompanied by Preparations of intermediates. All temperatures are in °C.

PREPARATION 1.

Methyl N-(2,4-dimethoxybenzyl)iminoacetate 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 solution of 10.05 g (0.114 mole) of methyl glyoxylate in 20 ml of methylene chloride. The reaction mixture is stirred at room temperature overnight (15 hours) - 11 4384θ and then is filtered and the solvents are removed in vacuo to afford the imine as a dark orange gum.

PREPARATION 2. 4,5-Diphenyl-2-oxo-4-oxazolin-3-ylacetic acid chloride A mixture of 4,5-d-ip;.fc.nyt-2-oxo-4-oxazolih-3-ylacetic acid (2.1 g, 7.1 mmol) /~~J· Org. Chem., 38, 3034 (1973J7, thionyl chloride (5 ml) and methylene chloride (20 ml) is refluxed for 2.5 hours. After cooling to room temperature the solvent is removed in vacuo and resulting oil crystallizes on standing. The product is triturated with ether-hexane to give the title compound; 2.0 g mp 104-112°.

PREPARATION 3.

Bromopyruvate Esters To a solution of 3.3 g (37.5 mmole) of pyruvic acid and 7.9 g (37.5 mmole) of 2,2,2-trichloroethyl chloroformate in 20 ml of dry tetrahydrofuran at 0° is added dropwise 0.6 ml of pyridine. After stirring fdr 2 hrs. at room temperature, the mixture is concentrated in vacuo, diluted with water and extracted with ethyl acetate. The extract is washed with 58 HC1, dried over HgSO^, evaporated ind distilled in vacuo to give 4.0 g (508) 2,2,2-trichloroethyl pyruvate, bp '5-82° (17 mm). 2,2,2-Trichloroethyl pyruvate (3.7 g, 17 mmole) is heated to 65° and .1 ml (17 mmole) of bromine is added dropwise over 1 hr. A stream of carbon lioxide is passed through the reaction mixture during the addition to remove the HBr 'ormed in the reaction. The mixture is cooled to room temperature, diluted with 'ater and extracted with ethyl acetate. The extract is dried over MgSO^, evaporated nd distilled in vacuo to give 1.8 g of 2,2,2-trichloroethyl bromopyruvate, bp 74-77° 0.01 mm).

Bromopyruvic acid is treated with diphenyl diazomethane by standard ethods to give benzhydryl bromopyruvate.

The t^butyl ester is also prepared by standard methods, by reacting 0-t- 12 4 3 8 ί. δ butyl-Ν,Ν'-di isopropyl pseudourea / Ann, Chem., 597, 235 (1955/7 and bromopyruvic acid.

PREPARATION 4. 3-Bromo-2-oxobutyrate esters At room temperature under argon 1.85 g (9.6 mmol) of diphenyldiazomethane in 15 ml of dry benzene is added dropwise to a solution of 1.30 g (7.35 mmol) of 3-bromo-2-oxobutyric acid in 15 ml of dry benzene with vigorous stirring. Addition of the diazo compound is continued until a faint red colour persisted (0.5 hr). The solvent is removed in vacuo and the yellow oil is dissolved in ether, filtered and concentrated to give 3.12 g crude benzhydryl ester. Chromatography on silica gel, eluting with benzene affords 2.43 g (95%) pure benzhydryl 3-bromo-2-oxobutyrate as a yellow oil A solution of 1.6 g (8.85 mmol) of 3-bromo-2-oxobutyric acid and 7 g (4 equivalents) of O-t-butyl-N,Ν'-di isopropyl pseudourea in 15 ml methylene chloride is stirred overnight at room temperature. After filtration, the solution is washed with NaHCOg and brine, dried and evaporated to an oil which is chromatographed on silica gel with benzene as eluant to give 1 g (45%) of t-butyl-3-bromo2-oxobutyrate.

EXAMPLE 1.

Methyl cis-3-azido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate Method A: To a solution of 15.1 g (0.149 mole) of azidoacetic acid in 130 ml of anhydrous methylene chloride at 0° (ice bath) is added dropwise 21.0 ml (0.15 mole) of trifluoroacetic anhydride. This mixture is stirred at 0° for 15 min. and then 20.8 ml (0.15 mole) of triethylamine is added dropwise. . Stirring is continued for an additional 45 m1n. and then the entire reaction mixture is transferred under argon into an addition funnel which is cooled externally by dry ice. The addition funnel is attached to a flask containing the imine from Preparation 1, 200 ml of anhydrous methylene chloride, and 20.8 ml (0.15 mole) of triethylamine, The solution of the mixed anhydride is added dropwise from the addition funnel to the solution of imine - 13 4 3 8 4 6 at 0°. Stirring is continued at 0° for 1 hr and then the dark reaction mixture is transferred to a separatory funnel and washed with HgO, aqueous NaHCOg and brine and then dried over anhydrous magnesium sulfate. The solvents are removed in vacuo and the residue is chromatographed on 300 g of silica gel (70-230 mesh), affording an cff-irHV· 'did ddc.h is further purified by trituration with ether to give 14.45 g (45S) of the title product as a white solid; tic: benzene: ethyl acetate (1:1), silica gel GF, Rf = 0.54. Recrystallization from ethyl acetate-hexane affords an analytical sample, mp 82-84°, Method B: A solution of 1.6 g (9.55 nmol) 2,4-dimethoxybenzylantine in 5 ml of CHgClj is rapidly addeo at 0° to a solution ot 1.06 g (10 mmol) freshly distilled methyl glyoxylate in 15 ml CHgClg. A slight exotherm occurred and water droplets appeared. Magnesium sulfate (5 g) is added and the mixture stirred at 0° for 2 hr. Fresh magnesium sulfate (1.0 g) is added, the magnesium sulfate removed by filtration under argon and washed with a minimum of CHgCTg.

To a solution of 3.8 (36 mmol) of azidoacetic acid (pumped in high vacuum over 3 hr) in 125 ml of CHgClg is added 10.6 ml (76 mmol) of triethylamine vith cooling. Magnesium sulfate (3 gm) is added, the mixture stirred 10 min. at -oom temperature, filtered under argon and washed with a 25 ml CHgClg.

The azidoacetic acid solution is added at 0° to the imine, sufficient lethylene chloride is added to bring the total volume to 200 ml, the solution cooled :o 0° under argon and 5.3 ml (38 mol) trifluoroacetic anhydride added slowly over /2 hr with vigorous stirring and cooling. The mixture is stirred for 1 hr at 0°, llowed to warm to room temperature, transferred to a separatory funnel ,·washed with >ater, 5% NaHCOj, 2% phosphoric acid and 5# NaHCOg, dried over magnesium sulfateharcoal; filtered and the filtrate is retreated twice with charcoal and evaporated o dryness. The residue is dissolved in a minimum of ether and stored at -20° to How crystallization. The crystalline mass was isolated and washed with cold ether o give 1.9 gm (64X) product, mp 79-80.5°. - 14 43846 EXAMPLE 2.

Methyl eis-3-amino-1-(2,4-dimethoxybenzyl)-4-oxoazeti di ne-2-carboxyla te A mixture containing 10.0 g (0.0312 mole) of methyl cis-l-(2,4dimethoxybenzyl)-3-azido-4-oxoazetidine-2-carboxylate, 1.0 g of 10% palladium on carbon, and 200 ml of ethanol is hydrogenated for 2 hrs at 40-45° and 60 psi of hydrogen. The reaction mixture is allowed to cool to 25° and is filtered through a filter-aid. After removing the solvents in vacuo a clear, yellow gum of the title product is obtained.

EXAMPLE 3.

Methyl ci£-3-j>butoxycarbonylamino-l-(2,4-dimethoxybenzy1)-4-oxoazetidine-2-carboxylate A solution of 5.5 g (18.8 mmole) of methyl cis-3-amino-1-(2,4-dimethoxybenzy1)-4-oxoazetidine-2-carboxylate in 100 ml of dry toluene is cooled to -78°C; 2.5 ml (18.8 mmole) of triethylamine is added, followed by rapid addition of 35 ml (42 mmole) of a 12% solution of phosgene in benzene. The mixture is stirred for 15 min. at 178° and 3 hr at -45° (acetonitrile-dry ice), then warmed to room temperature and concentrated to half volume in vacuum. To the resulting solution is added 50 ml of t-butanol and the mixture is stirred at room temperature overnight. The solvents are removed in vacuo, the residue is diluted with ethyl acetate and filtered. The filtrate is transferred to a separatory funnel and washed with 5% NaHCOg, 5% HCI and brine; dried over magnesium sulfate and evaporated to dryness. Recrystallization of the crude, crystalline product affords 3.8 g (52%) of the title compound. Recrystallization from ether gives an analytical sample.

EXAMPLE 4.

Methyl cis-1-(2,4-dimethoxybenzyl)-3-phthalimido-4-oxoazetidine-2-carboxylate 2,4-Dimethoxybenzylamine (5.01 g, 0.03 mol) and methyl glyoxylate (3.17 g, 0.036 mol) are condensed as in Preparation 1 but at 0-5° for 2 hours. The resulting imine is dissolved in methylene chloride (800 ml) and cooled in an ice bath. Triethylamine (5.4 ml) is added, followed by the dropwise addition of a solution of phthalimidoacetyl chloride (7.54 g, 0.0338 mol) /~J. Amer. Chem. Soc., 71., 1856 (1949)7 in methylene chloride (80 ml). After the reaction mixture is - 15 438 46 stirred for 2 hours, the solution is concentrated and then is washed with water, dilute HCl, and dilute NaHCOg. The dried organic phase is evaporated to give the title product which is triturated with ether; 6.4 g (50%).

EXAMPLE 5.

Rethy! £j>-'!-(2,4-dimetriOX/benz,yl )-3-(4,5-diphenyl-2-oxo-4-oxazo1in-3-yl )-4oxoazetidine-2-carboxylate The imine from Preparation 1 (1.43 g) is dissolved in '-y methylene chloride (13 ml) and triethylamine (1 ml) and cooled in an ice bath. The acid chloride from Preparation 2 (2.0 g, 6.4 mmoT) in methylene chloride (10 ml) is added over a 10-minute period. After one hour, the mixture is washed with water and 5% NaHCOg, the dried solution is evaporated to a red oil which is chromatographed on 60 g of silica gel with 5% ethyl acetate in chloroform as eluant to give the title product, 2.37 g.

EXAMPLE 6.

Methyl cis-l-(2,4-dimethoxybenzyl)-3-phenoxyacetamido-4-oxo-azetidine-2-carboxylate The crude amine prepared in Example 2 from 10 g of the azido precursor is taken up in 100 ml of anhydrous methylene dichloride and is cooled to 0° in an ice bath. To this solution is added 4.32 ml (0.0312 mol) of triethylamine,followed by the slow addition of a solution of 5.32 g (0.0312 mol) of phenoxyacetyl chloride in 40 ml of methylene dichloride. The mixture is stirred at 0°for 1 hr, then poured into a separatory funnel and extracted successively with water,aqueous HCl, aqueous NaHCOg and brine and is dried over anhydrous magnesium sulfate.- After filtration the solvent is removed in vacuo to give a yellow solid. This material 1s partially lissolved in ether, cooled to -25°, and filtered to afford 11,2 g (84%) of the titTe iroduct as a white solid which is one spot on tic: benzene-ethyl acetate (1:1), iilica gel, Rf 0.38. An analytical sample, mp 115.5-116°, is obtained by ^crystallization from ethyl acetate-hexane.

EXAMPLE 7.

When jj-methoxybenzyl alcohol, isoborneol, benzyl alcohol, or 2,2,2:richloroethanol is substituted for t-butanol in Example 3, methyl 3-{]j-methoxy- 16 4 3 8 4 6 benzyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxodzetidine-2-carboxylate, methyl-3-(i sobornyloxycarbonylami no )-1-(2,4-dimethoxybenzyl)-4-oxoazeti dine-2carboxylate, methyl-3-(benzyloxycarbonylami no)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, or methyl-3-(2,2,2-trichloroethoxycarbonyl amino)-!-(2,4dimethoxybenzyl)-4-oxoazetidine-2-carboxylate is obtained.

Methyl-3-(isobornyloxycarbonylamino)-l-(2,4-dimethoxybenzyl)-4oxoazetidine-2-carboxylate can also be prepared by treating the 3-amino compound with isobornyloxycarbonyl chloride in the presence of base according to standard procedures; Chem. Pharm. Bull,, 20, 1017 (1972).

EXAMPLE 8.

Methyl ci£-3-t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate A solution of 10.5 g (26.7 mmole) of methyl cis-3-t-butoxycarbonylamino-1-(2,4-dimethoxybenzyl)»4-oxoazetidine-2-carboxylate in 500 ml of acetonitrile is 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 is added in five portions over 1 hr. The reaction mixture is stirred at 80-85° under argon for 2-3 hrs until all starting material is consumed (tic), The reaction is cooled, concentrated in vacuo and shaken with ethyl acetatewater. The organic phase is washed with dilute HC1, NaHCOg solution and brine; dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed over silica gel with 1:1 benzene-ethyl acetate to afford pure product which is crystallized from ethyl acetate-hexane to yield 2.0 g (31%) of the title compound. A less pure fraction from the column, is crystallized from ethyl acetate-hexane to give an additional 0.5 g of product, overall yield, 38%.

EXAMPLE 9.

When the products of Examples 1, 4, 5, 6 and 7 are treated with potassium persulfate and sodium monohydrogen phosphate according to the procedure of Example 8 the following products are obtained: methyl cis-3-azido-4-oxoazetidine-2-carboxylate; 72% yield mp 77-78° methyl cis-3-phthal1mido-4-oxoazet1dine-2-carboxylate; 40% yield - 17 43846 methyl ci£-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxoazetidine-2-carboxylate, 32« yield methyl cis-3-phenoxyacetamido-4-oxoazetidine-2-carboxylate; 695! yield, mp 140-41° methyl £is-3-isobornyloxycarbonylamino-4-oxoazetidine-2-carboxy1ate methy' eg-3-(jw^thoxybenzyl οχ> carbonyl amino) -4-oxoazeti dine-2-carboxyl ate methyl ci£-3-(benzyloxycarbonylamino)-4-oxoazetidine-2-carboxylate methyl cis-3-(2,2,2-trich1oroethoxycarbony1amino)-4-oxoazetidine-2-carboxylate.

EXAMPLE 10.

Methy! cis.-3-amino-4-oxoazetidine-2-carboxylate A solution of methyl cis-3-azido-4-oxoazetidine-2-carboxylate (8.5 g, mmol) and an equivalent of toluene-]3-sulfonic acid in 200 ml of ethanol is hydrogenated for 3 hours over 1 g of 10Ϊ Pd on carbon at 40 psi. The solution is filtered and the filtrate is evaporated to give the title product or the tosylate salt which can be converted to the free base by standard methods.

EXAMPLE 11.

A solutioftof anhydrous KgCOg m9» 1.8 mmol) in tetrahydrofuran (8 ml) and water (12 ml) is degassed with argon and then methyl cis-3-phenoxyacetamido-l-(2s4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate (150 mg, 0,35 mmol) is added. The reaction mixture is stirred for 1.5 hours at room temperature, the organic solvent is evaporated and the aqueous layer is acidified and extracted with methylene chloride. The dried extracts are evaporated to give a solid which is recrystallized from ethyl acetate-hexane to give pure cis-3-phenoxyacetamido-l(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylic acid, mp 169-170° (dec).

Methyl crs-3-phenoxyacetamido-4-oxoazetidine-2-carboxy1ate is treated with KgCOg 1n methanol-water as above to give cis-3-phenoxyacetam1do-4-oxoazetidine2-carboxylic acid, mp 150-51° from ethyl acetate.

EXAMPLE 12. cis-3-t-Butoxycarbonylamino-2-hydroxymethyl-4-oxoazetidine A solution of 2.0 g (8.2 nmole) of methyl cis-3-t-butoxycarbonylaminol-oxoazetidine-2-carboxylate in 20.ml of tetrahydrofuran is cooled in ice and a - 18 43846 solution of 0.75 g (20 mmole) of sodium borohydride in 10 ml of water is added.

The mixture is stirred for 20 min. at 0° and then 1.5 hr at room temperature.

Acetic acid is added dropwise to decompose the excess borohydride and the mixture is concentrated in vacuo. The residue is diluted with brine and extracted with ethyl acetate. The organic phase is washed with brine and 5% NaHCOgj dried over magnesium sulfate and evaporated to dryness to give 0.9 g (50%) of the title product as white crystals, mp 128-131°.

EXAMPLE 13.

When the 3-azido,3-oxazolinyl, 3-phenoxyacetamido, 3-isobornyloxy10 carbonylamino, 3-(£-methoxybenzyloxycarbonylamino, and 3 benzyloxycarbonylami no compounds from Example 9 are reduced with sodium borohydride by the procedure of Example 12 the following products are obtained: ci£-3-azido-2-hydroxymethyl-4-oxoazet1d1ne; 56» yield cis-2-hydroxymethyl-3-(4,5-di phenyl-2-oxo-4-oxazoli n-3-yl)-4-oxoazeti dine; ca. 100» yield cis.-2-hydroxymethyl-3-phenoxyacetamido-4-oxoazetidine; 68» yield, mp 153-4° (from ethyl acetate) cis-2-hydroxymethyl-3-isobornyloxycarbonylamino-4-oxoazetidine ci s-2-hydroxymethyl-3- (^-methoxybenzyloxycarbonylami no)-4-oxoazetidi ne e1s-3-benzyloxycarbonylamino-2-hydroxymethy1-4-oxoazet1dine.

EXAMPLE 14. cis_-3-t-Butoxycarbonylam1no-4Oxo-2-azet1dinylmethyl tosylate To a solution of 0.09 g (4.3 mmole) of 98» £-toluenesulfonyl chloride in 10 ml of dry pyridine at 0° is added 0.9 g (4.15 mmole) of cis-3-t-butoxy25 carbonylamino-2-hydroxymethyl-4-oxoazetidine. The mixture is stirred for 2 hr at 0° and then stored at 5° overnight. After addition of 0.5 ml of 85» lactic acid, the mixture is stirred for 1 hr, poured into ethyl acetate and washed with dilute HC1, 5» NaHCOj, and brine. The extract is dried over magnesium sulfate and evaporated to dryness to give 1.1 g (70») of crystalline title product. Recrystall ization from hexane-ethyl acetate gives an analytical sample; mp 160-162°(d). - 19 43846 EXAMPLE 15.

Treatment of the products obtained in Example 13 with toluene-£sulfonyl chloride according to the procedure of Example 14 gives the corresponding tosylates: cls-3^zi^-4OAU-2-azetidinylmGthy1 tosylate; 808 yield mp 87-89° cis-3-(415-di phenyl-2-oxo-4-oxazolin-3-yl)-4-oxo-2-azetidinylmethyltosylate £is-3-phenoxyacetamido'-4-oxo-2-azetidinylmethyl tosylate; 718 yield, mp 136° (dec) ci£-3-isobornyloxycarbonylamino-4-QXo-2-azetidinylmethyl tosylate cis-3-(j3-methoxybenzyloxycarbonylamino)-4-oxo-2-azetidinylmethyl tosylate ci£-3-benzyloxycarbonylamino-4-oxo-2-azetidinylmethyl tosylate When cis-2-hydroxymethyl -3-(4,5-di phenyl-2-oxo-4-oxazoIi n-3-y1)-4oxoazetidine is reacted according to Example 14 except that mesyl chloride is substituted for toluene-jj-sulfonyl chloride, cis-3-(4,5-diphenyl-2-oxo-4-oxazolin3-yl)-4-oxo-2-azetidinylmethyl mesylate is obtained; 738 yield, mp 185-8° from ethyl acetate-hexane.

EXAMPLE 16. cis-3-Amino-4-oxo-2-azetidi nylmethyl tosylate A solution of cis-3-azido-4-oxo-2-azetidin,ylmethy1 tosylate (5,0 g) in 308 aqueous acetic acid (50 ml) is cooled and then treated with zinc dust (2.0 g).

The reaction mixture is stirred for 30 minutes, filtered, and the solid washed with -LjO (50 ml). The filtrate is saturated with HgS over 1/2 hour, the zinc sulfide is emoved by filtration and the filtrate evaporated to near dryness. The residue is iissolved in ethyl acetate-water and adjusted to pH 10. Phases are separated and :he aqueous layer is extracted with ethyl acetate. The dried organic phases are svaporated to give the amino compound; 3.0 g (668).

EXAMPLE 17.

A mixture of the 3-amino tosylate compound from Example 16 (0.14 g), l-t-butoxycarbonylphenyl glycine (0,16 g) and di cyclohexyl carbamide (0,12 g) in ethylene chloride (5 ml) is stirred for one hour at 0°. The solid is removed by jltration and the filtrate is evaporated to dryness. The residue Is chromatographed - 20 4 3 8 46 on silica gel with 80:20 ethyl acetate-benzene as eluant to give cis-3-(alpha-tbutoxycarbonylaminophenylacetamido)-4-oxo-2-azetidinylmethyl tosylate; 0.19 g (70%). 2-Thienylacetic acid, the 3-amino derivative from Example 16, and dicyclohexylcarbodiimide (3.7 mmol of each) are reacted in methylene chloride as above. The mixture is diluted with ethyl acetate (150 ml) and filtered; the filtrate is washed with 5% (NaHCOg, dilute HCI, and brine, dried, evaporated and crystallized from acetoneether to give cis-3-(2-thienylacetamido)-4-oxo-2-azetidinylmethyl tosylate; 0.9 g (69%) mp 121-124°.

The 3-amino derivative is acylated with 0-forfliylmandelic acid chloride in the presence of triethylamine to give cis-3-0-fonnylmandelamido-4-oxo-2azetidinylmethyl tosylate, 98% mp 111-113 (dec).

EXAMPLE 18. cis-3-Phenoxyacetamido-4-oxo-2-azetidinylmethyl iodide A mixture containing 13.68 g (33.9 mmol) of cis-3-phenoxyacetamido-4oxo-2-azetidinylmethyl tosylate, 39.8 g (0.265 mol) of sodium iodide and 550 ml of acetone is heated at reflux for a period of 6 hr and then is allowed to cool to ambient temperature. The acetone is removed in vacuo and the residue is suspended in ethyl acetate and extracted with water, sodium thiosulfate and brine.

The dried ethyl acetate solution was evaporated in vacuo to give a yellow semicrystalline residue, Recrystallization from ethyl acetate resulted in 10.3 g (84%) of crystalline product; mp 150° (dec).

EXAMPLE 19.

When the appropriate tosylates or mesylate which are disclosed in Example 14, 15 and 17 are treated with sodium iodide by the procedure disclosed in Example 18 the following products are obtained: c1s-3-t-butoxycarbonylamino-4-oxo-2-azetidinylmethy1 iodide c1s-3-azido-4-oxo-2-azetidinylmethyl iodide cjs-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxo-2-azetidinylmethyl iodide - 21 cis-3-(alpha-t-butoxycarbonylaminophenylacetamido)-4-oxo-2-azetidinylmethyl iodide, 78« yield cis-3-(2-thienylacetamido)-4-oxo-2-azetidinylmethyl iodide, 98« yield cis-3-0-formylmandelamido-4-oxo-2-azetidinylmethyl iodide cisp3-isoborn.yloxycarbonylatnino-4-oxo-2-azetidinylniethyl iodide cis-3-(£-methoxybenzyloxycarbanylamino)-4-oxo-2-azetidinylmethyl iodide c£s-3-benzyloxycarbonylamino-4-oxo-2-azetid1nylmethy1 iodide.

EXAMPLE 20. 3-t-Butoxycai”bonylamino-4-oxo-2-(£-methoxybenzyl thiomethyl jazetidine To a solution of 1.1 g (2.97 mmole) of 3-t-butoxycarbonylamino-4oxo-Z-azetidinylm&thyl xosylate in 15 ml cf dry diiiiethylformamide under arflvn was added 4.0 g (26 mmole) of sodium iodide. The mixture was heated to 65° for 4 hours, then stirred'at room temperature overnight. The resulting suspension was diluted with 50 ml of ethyl acetate, filtered, concentrated in vacuo, flushed with argon and 3.0 ml of ja-methoxybenzyl mercaptan and 2.0 ml of triethylamine were added.

The mixture was stirred at room temperature for 18 hours and then poured into ice ) water-ethyl acetate. The organic phase was separated and washed with water, 5« NaHCOj and brine; dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed over silica gel with 1:1 benzene-ethyl acetone to afford after evaporation and crystallization from ethyl acetate-hexane, 335 mg (32%) of pure product, mp 120-123°.

EXAMPLE 21..

When an appropriate iodide derivative is reacted with £-methoxybenzyl nercaptan (2 equivalents) in the presence of triethylamine (2 equivalents) according to the procedure set forth in Example 20 the following compounds are obtained: c[s-3-phenoxyacetamido-4-oxo-2-(£-methoxybenzylthiomethyl)azetidine; mp 139-41° ^1s-3-0-formylmandelamido-4-oxo-2-(£-methoxybenzylthiomethyl)azet1d1ne :is-3-(alpha-t-butoxycarbonylaminophenylacetamido)-4-oxo-2-(p-methoxy benzylthionethyl)axetidine jis-3-i sobornyl oxycarbonylami no-4-oxo-2-(j5-methoxybenzyl thiomethyl )azeti di ne - 22 4 3 8:6 cls-3-(])-methoxybenzyloxycarbonylamino)-4-oxo-2- (^-methoxybenzyl thiomethyl)azetidine cis-3-benzyloxycarbonylamino-4-oxo-2-(^-methoxybenzyl thiomethyl )azetidine.

EXAMPLE 22. cis-3-(2-Thi enylacetami do)-4-oxo-2-(tri phenylmethylthiomethyl)azeti di ne To a solution of 0.8 g (2.3 mmole) of cis-3-(2-thlenylacetamido)-4oxo-2-azetidinemethyl iodide and 0.9 g (9 mmole) of triethylamine in 10 ml of dry dimethylformamide is added 1.27 g (4.6 mmole) of triphenylmethanethiol. The mixture is stirred under argon overnight, diluted with 100 ml of ethyl acetate and washed with dilute HCl and water. After drying with magnesium sulfate, the extract is evaporated to dryness and the residue triturated with ether. The crystalline product is filtered and dried to give the title compound.

EXAMPLE 23.

When the methyl iodide derivatives of Examples 18 and 19 are reacted with triphenylmethanethiol according to the procedure of Example 22 the following compounds are obtained. cis-3-phenoxyacetamido-4-oxo-2-(triphenylmethylthiomethy1)azetidine cis-3-t-butoxycarbony1am i no-4-oxo-2-(tri pheny1methylth1omethyl)azetidi ne cis-3-(4,5-diphenyl-2-oxo-4-oxazo1in-3-yl)-4-oxo-2-(triphenylmethylthiomethy1)azetidine cist-3-(alpha-t-butoxycarbonylaminophenylacetamido)-4-oxo-2-(tr1phenylmethylthiomethyl)azetidine ci£-3-0-formy1mandelamido-4-oxo-2-(triphenylmethylthiomethyl)azetidine cis-3-isobornyloxycarbonylami no-4-oxo-2-(tri phenylmethylthi omethyl)azeti dine cis -3-(£-methoxybenzyloxycarbonylamino)-4-oxo-2-(triphenylmethylthiomethylJazetidine cis-3-benzyloxycarbonylami no-4-oxo-2-(tri phenylmethyl thiomethyl)azeti di ne.

EXAMPLE 24.

Cis-3-t>-Butoxycarbony1amino-4-oxo-2-meicaptomethylazetid1ne To a solution of 335 mg (0.95 mmole) of ci s-3-t-bu toxycarbonylami no-4oxo-2-(£-methoxybenzylthiomethyl)azetidine in 5 ml of methanol and 20 ml of methylene chloride is added 1.7 g (5.3 mmole) of mercuric acetate. The mixture is stirred for „38 Αθ hours under argon, diluted with excess ether and the precipitated mercury adduct filtered off and washed well with ether. The mercury complex is suspended in water, layered with ethyl acetate and hydrogen sulfide gas is passed through the mixture for 1 hour. The mercuric sulfide is removed by filtration, the ethyl acetc.% layer is separated and washec, with brine, dried over magnesium sulfate and evaporated to dryness. Trituration of the residue with 1:1 ethyl acetate-hexane gives 122 mg (55%) of the crystalline title product.

EXAMPLE 25. cis-3-(2-Thienylacetamido)-4-oxo-2-mercaptomethylazetidine To a solution of 0 .1 g (0.2 mmole) of cis-3-(2-thi enylacetami do)-4oxo-2-(triphenylmethylthiomethy1)azetidine in 3 ml of methanol is added a solution containing 34 mg (0.2 mmole) of silver nitrate and 16 mg (0.2 mmole) of pyridine.

A precipitate of the silver mercaptide is formed Immediately. Hydrogen sulfide gas is passed through the mixture for 5 minutes, the silver sulfide removed by filtration and the filtrate diluted with ethyl acetate and washed with dilute HC1 and brine. The extract 1s dried and evaporated to dryness; trituration with ether gives the title compound as white crystals.

EXAMPLE 26.

When the jimethoxybenzyl thiomethyl derivatives prepared in Example 21 are deblocked according to the procedure of Example 24 the following compounds are obtained. cis.-3-phenoxyacetamido-4-oxo-2-mercaptomethyl azeti dine cis-3-Q-formylmandelami do-4-oxo-2-mercaptomethylazeti dine cis-3-(alpha-t-butoxycarbonylami nophenylacetami do)-4-0xo-2-mercaptomethylazeti di ne cis-3-isobornyloxycarbonylami no-4-oxo-2-mercaptomethylazeti dine cis-3- (jj-methoxybenzyl oxycarbonyl ami no) -4-oxo-2-mercaptomethyl azeti di ne cis-3-benzyloxycarbonylami no-4-oxo-2-mercaptomethylazeti d1ne.

Similarly when the triphenylmethylthiomethyl derivatives prepared in Example 23 are deblocked by the procedure set forth in Example 25 the corresponding mercaptomethyl compounds are obtained. - 24 43846 EXAMPLE 27.

A solution of methyl cis-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4oxoazetidine-2-carboxylate (2.0 g, 3.9 mmol) in 50 ml ethanol is added to 10% Pd on carbon (0.4 g) which is premoistened with 2 ml 2N HCl. The mixture is hydrogenated for 12 hours at 50 psi and 40°C. After filtration, the solvent is removed and the oil is dissolved in methylene chloride which is then washed with NaHCOg and brine and dried. The solution is evaporated to give cis-3-amino-4oxoazeti dine-2-carboxylate.

Claims (36)

1. TO 1. An azetidine compound of the formula where A is azido, amino, acylamino, or protected amino; B is COOH, lower alkoxycarbonyl, iodomethyl, £-methoxybenzylthiomethyl, tri phenylmethylthiomethyl, mercaptomethyl; or CHgOM, where M is hydrogen, lower alkane-sulfonyl, or phenyl]5 sulfonyl, such phenyl being unsubstituted or substituted with methyl or halogen, and G is hydrogen or 2,4-dimethoxybenzyl.

2. A compound as claimed in Claim 1, where G is hydrogen.

3. A compound as claimed in Claim 1 or Claim 2, where A is azido,

4. Methyl cis-3-azido-l-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxy1ate. 20 5. Methyl cis-3-azido-4-oxoazetidine-2-carboxylate. 6 · Ci s-3-azido-2-hydroxymethyl-4-oxoa2eti di ne.

5. 7. Cis-3-azido-4-oxo-2-azetidinylmethyl tosylate.

6. 8. A compound as claimed in Claim 1 or Claim 2, where A is NHg,

7. 9. Methyl c1s-3-amino-I-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxy1ate. - 25 43846

8. 10. Cis-3-anrino-4-oxo-2-azetidinylmethyl tosylate.

9. 11. A compound as claimed in Claim 1 or Claim 2, where A is acylamino.

10. 12. Methyl cis-1-(2,4-dimethoxybenzyl)-3-phenoxyacetamido-4-oxoazetidine2- carboxylate.

11. 13. M-ithy'l cls-3-phenoxyacetar ido-4-oxoazetidine-2-carboxylate.

12. 14. Cis-2-hydroxymethyl-3-phenoxyacetami do-4-oxoazeti dine,

13. 15. Cis-3-phenoxyacetamido-4-oxo-2-azetidinylmethyl tosylate.

14. 16. Cis-3-(aipha-t-butoxycarbonylaminophenylacetami do)-4-oxo-2-a2etidi nylmethyl tosylate.

15. 17. Cis.-3-(2-thienylacetamido)-4-oxo-2-azetidinylmethyl tosylate.

16. 18. Ci£-2-0-formylmande1anrido-4-oxo-2-azetidinylmethyl tosylate.

17. 19. Cis-3-phenoxyacetamido-4-oxo-2-azetidinylmethyl iodide.

18. 20. Cis-3-(2-thienylacetamido)-4-oxo-2-azetidinyl methyl iodide.

19. 21. Ci s-3-phenoxyacetami do-4-oxo-2-(p-methoxyben2ylthi omethyl)-azetid1ne.

20. 22. Cis-3-(2-thienylacetamido)-4-oxo-2-(triphenylmethylthiomethyl)-azetidine.

21. 23. Cis-3-phenoxyacetamido-4-oxo-2-mercaptomethylazetidine.

22. 24. Cis-3-(2-thienylacetamido)-4-oxo-2-mercaptomethylazetidine.

23. 25. A compound as claimed in Claim 1 or Claim 2, where A is protected amino.

24. 26. A compound as claimed in Claim 25, where A is t-butoxycarbonylamino, 4,5-diphenyl-2-oxo-4-oxazolin-3-yl, phthalimido, isobornyloxycarhonylamino,£methoxybenzyloxycarbonylamino, benzyloxycarbonylamino, or 2,2,2-trichloroethoxycarbonylamino,

25. 27. Methyl cis-3-t-butoxycarbonylamino-1-(2,4-dimethoxybenzyl)-4oxoazetidine-2-carboxylate.

26. 28. Methyl cis-l-(2,4-dimethoxybenzyl)-3-phthalimido-4-oxoazetidine-2carboxylate.

27. 29. Methyl cis-1-(2,4-dimethoxybenzyl)-3-(4,5-diphenyl-2-oxo-4-oxazolin3- yl)-4-oxoazetidine-2-carboxylate.

28. 30. Methyl cis-3-t-butoxycarbonylamino-4-oxoazet1dine-2-carboxylate. 3T. Methyl cis-3-phthalimido-4-oxoazetidine-2-carboxylate. - 26 10

29. 32. Methyl c/s-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl}-4-oxoazetidine-2carboxylate.

30. 33. Cis-3-t-butoxycarbonylami no-2-hydroxymethyl-4-oxoazeti di ne.

31. 34. Cis-2-hydroxymethy1-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4oxoazetidine.

32. 35. Cis-3-t-butoxycarbonylamino-4-oxo-2-azetidinylmethyl tosylate.

33. 36. Cis-3-t-butoxycarbonylam1no-4-oxo-2-azetidinylmethyl iodide.

34. 37. Cis-3-t-butoxycarbonylamino-4-oxo-2-(]3-methoxyben2ylthiomethy1)azetidine.

35. 38. Cis-3-t-butoxycarbonylami no-4-oxo-2-(tri phenylmethylthiomethyl)azeti dine. 39 · Cis-3-t-butoxycarbonylami no-4-oxo-2-mercaptomethy1azeti di ne.

36. 40. A process for preparing a compound according to Claim 1, substantially as described in any one of the Examples.