IL37118A - Azetidin-2-one derivatives and their preparation - Google Patents

Description

Azetidin-2-one derivativea and their preparation YEDA RESEARCH AND DEVELOPMENT COMPANY LIMITED 37118/2 F This invention relates to novel azetldin-2-ones which carry a thio-substituent in the 4-^posi ion of the ring and which are useful as intermediates in the synthesis of fused ring bicyclic structures such as penams, cephams. and Δ -cephems.

According to the present invention there are provided azetldin-2-ones of formula I BR / \ 0 « c z wherein X is halogen, an azido group or an imido group derived from a dicarboxylic acid; R is an a^cyl, alkoxy-rcarbonylalkyl, aralkyl or nitroaralkyl group; ^ is an alkoxy or aralkoxy 2 3 group R and R are the same or different and each is hydrogen, alkyl, aralkoxy, or alkylthioalkyl; 7 and Z are each hydrogen or when taken together represent a bond joining the carbon atoms to which they are attached* For example R may be methyl, benzyl, 2-carbomethoxyethyl or j-nitrobenzyl; R may be -OCH^, Λ may be methyl# benzyloxy or methylthiomethyl and 3 R may be methyl.

The present invention also provides amethod far the preparation of ;.'-azetidin-2 )neB which method comprises reacting a thi imidate derivative of an a-amino acid ester of formula III hereinbelow, with a monosubstltuted acetyl halide of the formula 37118/2 wherein X is halogen, an azido group or an imido group derived from a dicarboxylic acid and the symbol "Hal** represents halogen, under anhydrous conditions in the presence of a tertiar base# One of the starting materials in the process of this{! invention is a thioimidate derivative of an a-amino acid- ester. ' Such compounds are amino acids wherein the a-amino group is replaced by a group of formula II wherein R has the same meaning as above . Thus, the thloimidate starting materials are defined by the general wherein R, B^, R2, R', Y and Z are as defined in formula (I).

The other starting material in the process of this invention is the monosubstituted acetyl halide of formula IV· Preferably the monosubstituted acetyl chloride or bromide is employed . The group X of formula IV may be inter alia an imido group derived froa a dicarboxylic acid, for example, a phthalimido or succinimido group* The tertiary base used in the method of this invention may conveniently be triethylamine.

The reaction may be carried out in an anhydrous organi 357118/2 solvent whic is inert under the reaction conditions, such as toluene, benzene or methylene chloride, and the reaction may if desired be carried out under an inert atmosphere such as nitrogen.

The products of the method of this invention are ea- azetidin-2-ones of formula (I) carrying a thio-substit- uent in the 4-position of the ring. These praiacts may be recovered from the reaction mixture by standard methods such as by evaporation of solvent, followed by purification by distillation and/or chromatography and recrystallisa- tion.

The azetidln-2-ones (I) are capable of existing in various stereoisomers forms and the present invention includes all such isomers and mixtures of such isomers. The substituents X and SR in the β-lactam ring may have either the cis configuration o the trans configuration. In some cases it is possible to invert the configuration of the less pre* erred isomer, and in most oases this will involve the conversion of the trans isomer to the cis. the latter being the configuration of the antibacterial penicillins and cephalosporins* The formation of certain 0-lactam structures by the reaction of acid chlorides with compounds containing a carbon nitrogen double bond has been described previously, see for example Sheehan et.al. Organic Reactions, 1958, £, 388 and Bose et.al, J.Amer. Chem.Soc. 1968 , 20, ^506, but the process has not heretofore been applied to the preparation of azetidin-2-ones carrying a thio-substituent in the 4- position of the ring.

The following Examples illustrate the invention: - EXAMPLE I (a) Preparation of N-Thloformylvaline Methyl Ester CH-, ^ CH-, ^CH^ y C7H,,N0 S S I ' d II /0Η^ΡΛΛ Η Calod.M.W.175.18.

HC-NH ^ C00CH3 Ethylthioformate (11.25 g. , 0.125 mol.), prepared according to Mayer and Berthold, Z.Chem.,^, 310 ( 1963 ) , in chloroform ( 30 ml.) was added, under a nitrogen atmosphere and with magnetic stirring, during 15 minutes, to a cold (ice-bath) solution of L-valine methyl ester hydrochloride ( 16.75 g.» 0.1 mol.) and triethylamine ( 10.12 g., 0.1 mol.) in chloroform ( 250 ml.). After the addition the ice-bath was removed and the reaction mixture was left to stand overnight at room temperature. It was then washed with IN hydrochloric acid (x 3 ) followed by saturated sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The pale yellow oil which remained was quickly distilled and the fraction boiling at 95-105°/0.07 mm was collected (13-30 g., 16%).

Analysis Calcd. for Ο-,Η^ΝΟ^: C, Vf.99; H, 7 8; Nf 8.00; S, 18.27; M.W. 175-18. Pound: C, 48.05; H, 7-62; N, 7. 1; 3, 18.21.

Spectral Data NMR: δ^1} 0.99 (d., J=7Hz, JH.CH^) 1.05 (d., J=7Hz, 3H, CH^); 2Λ (m. 1H, isopropylic methine); 3.78 (s., 3H, OCH^) 5-28 (dd., J=5 and 9Hz,lHz hydrogen); 8.53 (broad, 1H, NH); 9.53 (d., J=6HZ,1H, HCS) observed changes after treatment with DgO: .28 (d, J=5Hz, 1H); signal at 8.53 absent; 9.53 (s. , 1H).

IR (5-5-6.5 region): ,CHC13 5-75 y max Mass spectrum: m/e M+, 175· (b) Preparation of S-Methylthioformlmidate derivative of valine methyl ester, f S-Methyl-N-(l-carbo- methoxy-2-methylpropyl jthioformlmidatel CH, CH ,CH- CH I C8H15N02S CH Calcd. MW I89.2 HC = N C00.CH5 Thioformylvaline methyl ester (0.875 g., 0.005 mol) in dry toluene (25 ml.) was added, under a nitrogen atmosphere to a cold (ice-bath) stirred suspension of sodium hydride ( 0$ in paraffin, 0.26 g., 0.0055 mol) " in dry toluene (10 ml.)- The internal temperature was kept below 2°C throughout the addition (ca. 30 minutes). After standing for additional 45 minutes, methyl iodide (1.0 g., 0.007 mol.) in toluene (10 ml.) was added, dropwise, with stirring, during 40 minutes maintaining the internal temperature below 2°C.

After 1 hour the solution was filtered through celite, under nitrogen and the solvent evaporated in vacuo.

The oily residue was distilled at 45-6o°/0.02 nun, (0.720 g., 76%) .

NMR: CC14: 0.88 (d., J=7Hz, 6H, isopropylic methyl groups); °TMS 2.16 (m. , 1H, isopropylic methine). 2.35 (s., 3H, 1H, « hydrogen); 3.6 (s., 3H, OCH^); 8.20 (s., 1H, HCS).

IR: ^chloroform (5· -β.5 μ region) 5.77 μ. 6.27 μ.

Notes 1. Similar results were obtained when the toluene was substituted by tetrahydrofuran or benzene as solvents. 2. The title compound is unstable and was used immediately for subsequent reactions. ( c ) Preparation of 4-Methylthlo-3-chloro-2-azetidinone derived from valine methyl ester. f 4-Methylthlo- 3-chloro-l- (1 ' -carbomethoxy-2' -methylpropyl )-2- azetldlnonei " ~ Freshly distilled S-methylthioformimidate derivative of valine methyl ester ( 0. 73 g., 0.0025 mol.) and triethylamine (0.506 g. , 0.005 mol.) were dissolved in dry benzene (20 ml.). To this was added, at room temperature, under a nitrogen atmosphere, with stirring, over a period of 5 minutes, a solution of chloroacetyl chloride (O.565 g., O.OO5 mol.) in dry benzene (20 ml.). The precipitated triethylamine hydrochloride was filtered off, the solvent removed in vacuo and the oily residue was chromatographed on a Florisil column (75 g.), Elution with methylene chloride-hexane (1:1 v/v) first gave a compound which was shown by its spectral data to be one of the four possible isomers of 4-Methylthio-3-chloro-l-( 1 ' -carpomethoxy-2' -methylpropyl )-2-azetidinone , denoted as A, then, after a middle fraction containing two isomers ( A + B ), another fraction shown by its spectral data to be the second isomer B was collected.

The estimated conversion yield is about 0 .

NMR Spectrum of A 8C6D6 Ο.85 (d., J«=7Hz) and 0.94 (d., J=7Hz) - 6H, TMS isopropylic methyl groups. 1.5 (s.) - 3H, SCH^.2.55 (m. ) - 1H, isopropylic methine. 3-30 (s.) - 3H, OCH^. 3.71 (d,m Hz) and 4.41 (d., J=1.8 Hz) - 2H, β-lactam ring hydrogens.

IR Spectrum of region): -64 μ, 5.74 μ/ NMR Spectrum of B. 5C6D6 O.7 (d., J=7Hz) and Ο.96 (d., J=7Hz) - 6H . (Ο.855 g-» O.OO5 mol.) in absolute tetrahydrofuran (2° ml.) was added dropwise during one hour. The Internal temperature was maintained below 2°C throughout the reaction. After 1 hour, the solution was filtered through celite, under nitrogen, the solvent removed under reduced pressure, and the oily residue was distilled at 95-U0°/0.02 mm. (1.13 g. , 85#). The product was shown by Its NMR and IR spectra to be the title compound.

NMR 6C6D6 0.84 (d., J»7Hz) and 0.86 (d., J«=?Hz) - 6H, TMS isopropylic methyl groups. 2. 3 (m. ) - 1H, isopropylic methine. 3 - 35 (s.) - 3H, OCH^. 3-47 (d.) - 1H, a ' hydrogen. 4. 13 (s.) - 2H, benzylic. 7. 1 (tn. ), aromatic. 7.83 (s. ) - 1H, HCS.

IR: ^chloroform^5,5"6-5 μ re8ion): 5- 75 μ and 6.25 μ.

Notes 1 . The title compound is unstable and was used immediately for subsequent reactions. 2. Similar results were obtained when the tetrahydro- furan was substituted by toluene as solvent.

Freshly prepared 3-benzylthioformimidate derivative of valine methyl ester (1.327 g., 0. 005 mol.) and tri- ethylamine ( 0. 506 g. , 0. 005 mol.) were dissolved in dry methylene chloride ( 50 ml.). To this was added, under a nitrogen atmosphere, with stirring, at room temperature, during 5 hours, a solution of phthaloylglycylchloride CASE;-"0-Lactam Synthesis" YEDA RESEARCH AND DEVELOPMENT COMPANY LIMITED, a Research Institute, of The Welzmann Institute of Science, Rehovot, Israel.

TRUE AND FIRST INVENTOR :- MARIO DAVID BACHI, of 14, Hadar Street, Rehovot, Israel, an Israeli Subject TITLE:- "HETEROCYCLIC COMPOUNDS" CONVENTION: Based on British Patent Application No. 37057/70 filed on 51st July, 1970.

This invention relates to a method of preparing certain azetidin-2-ones which are useful as intermediates in the synthesis of fused ring bicyclic structures such as penaras, cephams. and ^-cephems.

According to the present invention there is provided a method for the preparation of azetidin-2-ones which carry a fchio-substituent in the 4- position of the ring, which method comprises reacting a thioimidate derivative of an a-amino acid ester with a monosubstituted acetyl halide of formula I:- X.CH.CO.Hal (I) wherein X is halogen, an azido group or an imido group derived from a dicarboxylic acid and the symbol ''Hal" represents halogen, under anhydrous conditions in the presence of a tertiary base.

One of the starting materials in the process of this invention is a thioimidate derivative of an a-amino acid ester. Such compounds are amino acids wherein the a-amino group is replaced by a group of formula II [RS - CH ■ N (II) wherein R is an organic radical, preferably one containing from 1 to 8 carbon atoms.

A particular sub class of thioimidate starting materials is defined by the general formula III wherein R is an alkyl or aralkyl group; R Is an 2 7» alkoxy or aralkoxy group; R and R^ are the same or different and each is hydrogen, alkyl, aralkoxy or alkylthioalkyl; Y and Z are each hydrogen or when taken together represent a bond Joining the carbon atoms to which they are attached. For example R may be methyl, benzyl, 2-carbomethoxyethyl or £-nitrobenzyl; R1 may be -OCH^, -OCHgCCl^ or -OCH^CgH^OCH^E.) ; R may t>e methyl, benzyloxy or methylthiomethyl and R^ may be methyl.

The other starting material in the process of this invention is the monosubstltuted acetyl halide of formula (I). Preferably the monosubstltuted acetyl chloride or bromide is employed. The group X if formula (I) may be inter alia an imido group derived from a dicarboxylic acid, for example a phthalimldo or succinimido group.

The tertiary base used in the method of this invention may conveniently be triethylamine.

The reaction may be carried out in an anhydrous organic solvent which is inert under the reaction conditions, such as toluene, benzene or methylene chloride, and the reaction may if desired be carried out under an inert atmosphere such as nitrogen.

The product of the method of this invention is an azetidin-2-one carrying a thio-substituent in the 4- position of the ring. Certain of these compounds are novel and this invention therefore includes an azetidin-2-one of wherein X is as defined in formula (I) and R,R ,R^,R^, Y and Z are as defined in formula (III).

The products of the method of this invention may be recovered from the reaction mixture by standard methods such as by evaporation of solvent, followed by purification by distillation and/or chromatography and recrystallisation.

The azetidin-2-ones (IV) are capable of existing in various stereoisomers forms and the present invention includes all such isomers and mixtures of such isomers. The substituents X and SR in the β-lactam ring may have either the cis configuration of the trans configuration. In some cases it is possible to invert the configuration o the less preferred isomer, and in most cases this will involve the conversion of the trans isomer to the cis, the latter being the configuration of the antibacterial penicillins and cephalosporins.

The formation of certain 0-lactam structures by the reaction of acid chlorides with compounds containing a carbon nitrogen double bond has been described previously, see for example Sheehan et.al. Organic Reactions, 1958, 2,, 588 and Bose et.al, J.Amer. Chem.Soc. 1968 , 20, ^506, but the process has not heretofore been applied to the preparation of azetidin-2-ones carrying a thio-substituent in the - position of the ring.

The following Examples illustrate the invention: - EXAMPLE I (a) Preparation of N-Thloformylvaline Methyl Ester CH-, ^ CH-, y ^CH^ > C„H,,N0 S S I 7 13 2 II /CH\^nrH Calod. M.W.175.18. ■ HC- H^ °υϋ0Η3 Ethylthioformate ( 11.25 g-» 0.125 mol.), prepared according to Mayer and Berthold, Z.Chem. , _, 310 ( 1963) , in chloroform ( 30 ml.) was added, under a nitrogen atmosphere and with magnetic stirring, during 15 minutes, to a cold (ice-bath) solution of L-valine methyl ester hydrochloride ( 16.75 g-# 0.1 mol.) and triethylamine ( 10.12 g., 0.1 mol.) in chloroform (250 ml.). After. the addition the ice-bath was removed and the reaction mixture was left to stand overnight at room temperature. It was then washed with IN hydrochloric acid (x 3) followed by saturated sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The pale yellow oil which remained was quickly distilled and the fraction boiling at 95-105°/0.07 mm was collected (13-30 g., 76*).

Analysis Calcd. for O^H^NC^S: C, 47-99; H, 7- 8 N, 8.00; S, 18.27; M.W. 175-18. Pound: C, 48.05; H, 7-62; N, 7-91; 3, 18.21.

Spectral Data N R: δ^1 0.99 (d., J=7Hz, 3H,CH5) 1.03 (3-. J=«7Hz, 3H, CHj); 2.4 (m. 1H, isopropylic methine); 3-78 (s., 3H, OCH^) 5-28 (dd., J=5 and 9Ηζ,1Ηζ a hydrogen); 8.53 (broad, 1H, NH); 9.53 (d., J=6Hz,lH, HCS) observed changes after treatment with D^O: -28 (d, J=5Hz 1H); signal at 8.53 absent; 9-53 (s. , 1H).

IR (5-5-6.5 region): CHC13 5-75 v max Mass spectrum: m/e M+, 17.5·.' Thioformylvaline methyl ester (0.875 -» 0.005 mol) in dry toluene (25 ml.) was added, under a nitrogen atmosphere to a cold (ice-bath) stirred suspension of sodium hydride (50* in paraffin, 0.26 g., 0.0055 mol) in dry toluene (10 ml.). The internal temperature was kept below 2°C throughout the addition (ca. 30 minutes). After standing for additional 5 minutes, methyl iodide (1.0 g., 0.007 mol.) in toluene (10 ml.) was added, dropwise, with stirring, during 40 minutes maintaining the internal temperature below 2°C.

After 1 hour the solution as filtered through celite, under nitrogen and the solvent evaporated in vacuo.

The oily residue was distilled at 45-6o°/0.02 mm, (0.720 g. , 76%).

NMR: CC1 : 0.88 (d., J*7Hz, 6H, isopropylic methyl groups); °TMS 2.16 (m. , 1H, isopropylic methine). 2.35 (s., 3H, SCH^); 3.56 (d., J=7Hz, 1H, a hydrogen); .6 (s., 3H, OCH^); 8.20 (s., 1H, HCS).

IR: Chloroform (5.5-6·.5 μ region) 5-77 μ. 6.27 μ.

Notes 1. Similar results were obtained when the toluene was substituted by tetrahydrofuran or benzene as solvents. 2. The title compound is unstable and was used immediately for subsequent reactions. (c ) Preparation of 4-Methylthio-3-chloro-2-azetldinone derived from valine methyl ester. [ 4-Methylthio- 3-chloro-l- ( 11 -carbomethoxy-2' -methylpropyl )-2- azetidlnone Freshly distilled S-methylthioformimidate derivative of valine methyl ester ( 0.473 g., 0.0025 mol.) and triethylamine (O.506 g., 0.005 mol.) were dissolved in dry benzene (20 ml.). To this was added, at room temperature, under a nitrogen atmosphere, with stirring, over a period of 45 minutes, a solution o chloroaoetyl chloride (Ο.565 g., 0.005 mol.) in dry benzene (20 ml.). The precipitated triethylamine hydrochloride was filtered off, the solvent removed in vacuo and the oily residue was chromatographed on a Florisil column (75 g.). Elution with methylene chloride-hexane (1:1 v/v) first gave a compound which was shown by its spectral data to be one o the four possible isomers of 4-Methylthio-3-chlbro-l-(l ' -carbomethoxy-2' -methylpropyl )-2-azetidinone , denoted as A, then, after a middle fraction containing two isomers ( A + B ), another fraction shown by its spectral data to be the second isomer B was collected.

The estimated conversion yield is about 30 · NMR Spectrum of A 6C6D6 Ο.85 (d., J«7Hz) and 0.94 (d., J=7Hz) - 6H, T S isopropylic methyl groups. 1.5 (s. ) - 3H, SCH^.2.55 (m. ) - 1H, isopropylic methine. 5.50 (s.) - 3H, OCH^. 3.71 (d,m J=8Hz) - 1H, hydrogen. .3 (d.,J=1.8 Hz) and 4.41 (d., J=1.8 Hz) - 2H, 0-lactam ring hydrogens.

IR Spectrum of A region): -6 μ, 5-74 μ.

NMR Spectrum of B_ 6C6D6 0.74 (d., J=7Hz) and Ο.96 (d., J=7Hz) - 6H . isopropylic methyl groups. I.63 (s.) - 3H, SCH^. 2.4 (m. ) - 1H, isopropylic methine. 3-25 (s.) - 3H, OCH-^. 3.73 (d., J=9Hz) - 1H, a hydrogen. 4.3 (d., J=1.8 Hz) and 4.57 (d.Y J»1.8 Hz) - 2H, β-lactam ring hydrogens. IR Spectrum of B ^chloroform^5*5"6'5 μ region): 5- 3 μ, 5.74μ.

EXAMPLE II (a) Preparation of S-Benzylthloformimldate derivative of valine meth l ester. [3-Benzyl N-(l-carbomethoxy -2-methylpropyl )thioformlmldate Ί .

PhCH2 Cl4H19N02S Calcd.MW. 265.30 H^ Thloformylvaline methyl ester (0.875 g., 0.005 mol.) prepared as in Example I in absolute tetrahydrofuran (20 ml.), was added during 30 minutes, under a nitrogen atmosphere, to a cold (ice-bath) stirred suspension of sodium hydride ( 0$ in paraffin, 0.26 g., 0.0055 mol.) in absolute tetrahydrofuran (10 ml.). After standing for an additional 1 hour, a solution of benzyl bromide (Ο.855 g-# O.OO5 mol.) in absolute tetrahydrofuran (20 ml.) was added dropwise during one hour. The internal temperature was maintained below 2°C throughout the reaction. After 1 hour, the solution was filtered through celite, under nitrogen, the solvent removed under reduced pressure, and the oily residue was distilled at 95-110°/0.02 mm. (1.13 ., 85#). The product was shown by Its NMR and IR spectra to be the title compound.

NMR 5C6D6 0.84 (d., J=7Hz) and 0.86 (d., J«=7Hz) - 6H, TMS Isopropylic methyl groups. 2.3 (m. ) - 1H, isopropylic methine. 2.35 (s.) - 3H, OCH^. 3- 7 (d. ) - 1H, hydrogen. 4.13 (s.) - 2H, benzylic. 7.1 (m. ), aromatic, 7.83 (s.) - 1H, HCS.

IR: chloroform(5.5-6.5 μ region): 5..75 and 6.25 .

Notes 1. The title compound is unstable and was used immediately for subsequent reactions. 2. Similar results were obtained when the tetrahydro- furan was substituted by toluene as solvent.

Freshly prepared S-benzylthioformimidate derivative of valine methyl ester (1.327 g., 0. 005 mol.) and tri- ethylamine ( 0. 506 g. , 0. 005 mol.) were dissolved in dry methylene chloride (50 ml.). To this was added, under a nitrogen atmosphere, with stirring, at room temperature, during 5 hours, a solution of phthaloylglycylchloride (1.12 g., 0.005 mol.) In dry methylene chloride (50 ml.). The reaction mixture was stirred overnight, and then washed in water (x 3) and dried over magnesium sulphate. The oily residue obtained after evaporation of the solvent under reduced pressure was chromatographed on a silica gel column (200 g.,), using methylene chloride-hexane-chloroform (85:10:5 v/v) as eluent .

The second collected fraction^, was shown by its NMR and IR spectra to be 4-benzylthio-3-phthalimido-l-(l' - carbomethoxy-2' -methyl propyl )-2-azetidlnone (Ο.883 g. » 39#* two isomers)., it was recrystallised from hexane-ethylacetate, m.p. 88-89°C.

Analysis Calcd. for C^H^N^S: C, 63.71; H, 5.35; N,6.19; S, 7.09; MW = 452.45. Found: C, 63.83; H, 5-48; N, 6.32; S, 7.19.

NMR 6 C6D6 0.9 d.; J*7Hz), 1.03 (d., J«=7Hz), I.15 TMS (d., J=7Hz), 1.22 (d.,J=7Hz) - 6H, isopropylic methyl groups of two isomers. 2.80 (m. ) - 1H, isopropylic methine. 3-50 (s.), 3-59 (s. ) - 3H, OCH^ of two isomers. 3·55 (s., pattern), 3-70 and 3-73 (inner lines of AB pattern) - 2H, benzylic hydrogens of two isomers. 3-93 (d., J=10 ± lHz), 4.08 (d., J=8.5 - lHz) - 1H, a hydrogen of two isomers. Two partially superimposable doublets centered at 5· 20, IH and two partially superimposable doublets centered at 5.41, IH, - β-lactam ring hydrogens. 7-1 (m. ) - 9H, aromatic hydrogens.

IR V - at 5.6l , 5 · 8ΐ with shoulder at 5 · 75 · Mass Spectrum; M/e : M+ 4 2 Notes 1. Similar results were obtained when the methylene chloride was substituted by toluene as solvent. 2. Purification of the crude product was alternatively performed on silica gel (OF 254 , Merck) preparative thick-plates by multldevelopment in hexane-acetone ( 3 : 1 v/v).

. The first fraction collected consisted o benzylmercaptan and dibenzyldisulphide . The third fraction, eluted after the title compound was shown by its NMR and IR spectra to be phthaloyl-glycyl-valine methyl ester (O.318 g. , 20#) mp. 192°C. [lit: m.p. 19β°, E. Taschner, Ann., 6 0, 136 ( 1961 ) ] .

EXAMPLE III Freshly prepared S-methylthioformimidate derivative of valine methyl ester ( 0.473 g., 0.0025 mol.) prepared as in Example I and triethylamine ( 0.253 g., 0. 0025 mol.) were dissolved in dry toluene (25 ml.). To this wis added under a nitrogen atmosphere, with stirring at room temperature, during 2 hours, a solution of phthaloylglycylchloride (Ο.56 g., 0. 0025 mol.) in dry toluene (25 ml.). The reaction mixture was stirred overnight, the precipitated triethylammonium chloride was filtered o , and the solvent removed under reduced pressure. The residue as chromatographed on silica gel (GF 2 ^ , Merck) preparative thickplates by multidevelopment in hexane-acetone (5 '· 2 v/v). Two .fractions were eluted. The less polar fraction was shown by its MR and IR spectra to be -methylthio-3"<-phthalimido-l-(l 1 -carbomethoxy-2' -methylpropyl )-2-azetidinone (IX, 0.376 g., 0#, two isomers). It was recx-ystallised from hexane-ethylacetate, m.p. 135-1^ °C Analysis Calcd. for Cl8H20N205S; C, 57. '+4; H, 5.35; N, 7.44; S, 8. 0; MW 36.36. Found: C, 57-39; H, 5-13; N. 7. 0 S, 8.5Ο.

NMR: 6 C6D6 Ο.99 (d., J«7Hz), 1.02 (d., J=7Hz), l.l6 (d. , TMS J=7Hz), I.27 (d., J=7Hz) - 6H, isopropyl methyl groups of two isomers. 2.70 (m. ) - 1H, isopropyl methine.

I.76 (s.), 1.88 (s.) - 3H, SCH5 of two isomers, 3.48 (s.), 3- 59 (s.) - 3H, OCH^ of two isomers. 3-92 (d., Jo9Hz), 3-99 (d., J=8Hz) - 1H, a hydrogen of two isomers. Two partially superlmposable doublets centered at 5.13, IK and two partially superlmposable doublets centered at 5. 5, lH - 0-lactam ring hydrogens of two isomers. 7·18 (m. ) - 4H, aromatic hydrogens. IR: ■ΥκΒΓ(5-5-'6·5 μ region) microns: 5.60, 5-66, 5-73, 5.81 br. with shoulder at 5-78.

Mass Spectrum: m/e M+ 376 Notes: 1. The more polar compound (0.073 g. , 9-2%) was shown by its NMR and IR spectra to be N-phthalimid glycyl-valine methyl ester, m.p. 191°C [lit: m.p. 196°C, E. Taschner, Ann., 640, I36 (1962) j .

EXAMPLE IV (a) Preparation of O-Ethylimldate derived from valine methyl ester [ 0-Ethyl-N-(l-carbomethoxy-2- methylpropyl )formlmldate * CH CH, CH N0 CH C9H17N03 HC 1= ^ N COgCH^ Calcd. M 187.23 Freshly prepared O-ethylformimidate (2.19 g., O.03O mol.j was dissolved in ether (60 ml.) and the solution was divided into three equal portions: (a), (b) and (c). A solution of valine methyl ester hydrochloride (I.67 g., 0.010 mol.) in water (3 ml.) was vigorously shaken with (a) during 4 minutes.

The aqueous layer was then transferred to (b), the remaining ethereal solution was washed with water ( 0.5 ml.) and the aqueous extract was also added to (b). This mixture was then shaken during minutes and the procedure repeated, transferring the aqueous layer from (b) to (o) etc. Magnesium sulphate was added to each ethereal portion immediately after washing. The ethereal solutions were combined, the ether and excess ethylformimidate were removed at the water pump (50-60° ) , and the residue was fractionated. 0-Ethyl-N-(l-carbomethoxy-2-methyl propyl ) -formimidate (1.53 g- , 82#) was collected at 45-6o°/0.1 mmHg.

NMR: 6 MSl5: 0,88 ^d ' J=6-5 Hz, 6H, two CHCH^): 1.28 (t., J=7Hz, 5H, CHgCH^); 2.18 (ra. , 1H, isopropylic methine); 3- 52 (d., J=7Hz, 1H, at hydrogen); 3.73 (s., 3H, OCH^); 4.23 (q., J=7Hz, 2H, CH^H^); 7 - 5 (s. , 1H, HCO). ^liquid film (5.- 5-6.5 μ region) microns: 5 - 73, 6. 05 - (b) Preparation of S- ( 2-Carbomethoxyethyl)thioformlm- idate derivative of valine methyl ester, f S- ( 2- Carbomethoxyeth l )-N-(l-carbomethoxy-2-methylpropyl thloformimldate ] .

CHC CHH19N04S I CH0 Calcd. MW 261.27 Method A : A mixture of S-methyl-N-(l-carbomethoxy-2-methylpropyl) thio-formimidate ( 9.46 g., 0.050 mol.) and methyl 3-mercaptopropionate (12 g., 0.10 mol.) was warmed under nitrogen at 115-120°C for 3 hrs. Methylmercaptan was evolved and the residue was distilled. S-(2-carbo-methoxyethyl )-N-(l-carbomethoxy-2-methylpropyl )thioform-iraidate ( 6.8 g., 52#) was collected at 96O-104°/0,l mmHg, IR: ^liquid film (5-5-6.5 μ region) microns: 5.75 (ε· ), 6. 25 (w. ).

Method B: A mixture of O-ethyl-N- (l-carbomethoxy-2-methyl propyl )formimidate prepared as in Example IV(a) (Ο.374 g., 0. 002 mol.) and methyl 3-mercaptopropionate ( 0.48 g., 0.004 mol.) was warmed at 120° during 3 hrs., occasionally a slo stream of nitrogen was passed through the reaction flask. Excess methyl 3-mercapto propionate was removed at the water pump ( 100° ) and the residue was fractionated.

S- ( 2-carbornethoxyet y 1 ) -N- ( 1-carbornethox - -methylpropyl)thloformimidate ( 0.275 g., 53#) was collected at 95-105°/0.1 mmHg.

IR: ^liquid film ( 5 - - . μ region) microns: 5 - 75 (s. ), 6. 25 (w. ). (c) Preparation of 4- ( 2 ' -carbomethoxyethyl) -3-Phthalimido -2-azetldinone derived from valine methyl ester. Γ - ( 2 ' -carbomethoxyethyl ) -3-phthallmido-l- ( 1 ' - ~ carbomethoxy-^' -methylpropyl )-2-azetidlnoneT To a solution of S-(2-carboxyethyl)-N-(l-carbo methoxy-2-methylpropyl )thioformimidate (0.522 g. , 0.002 mol.) and triethylamine ( 0.303 g. , 0.003 mol.) in dry toluene (20 ml. ) was added with stirring under nitrogen, during 4 hrs. a solution of phthaloylglycyl-chloride (0.447 g., 0.002 mol.) in dry toluene (25 ml.). The reaction mixture was stirred for an additional 1 hr . and then filtered. The filtrate was washed with water and dried over magnesium sulphate. Chromatography of the residue obtained after evaporation of the solvent, over silica gel (GF 254, Merck) preparative thick-plates by multidevelopment in hexane-acetone (5:2 v/v), afforded 4-(2' -carbomethoxyethyl )-3-phthalimido-1- (1 ' -carbomethoxy-2' -methylpropyl )-2-azetidinone (0.340 g. , 38£).

NMR: 6CDC13 : 1.00-1.21 (ra., 6H, CH,); 2.57-3.00 (m. , TMS ? S-CH2-CH2-C0); . 5 (s., 3H, OCH^); 3-88 (s., 3H, OCH^); 5-15-5-33 (m. , 2H, 0-lactam ring hydrogens); 7-9 (4H, aromatic).

IR: liquid film (5-5-6.5 - region) microns: ·6 » 5·8θ.

Mass spectrum: m/e: + 448 (MW calcd. for ^ 1^2^2^'' 4 8 · )· EXAMPLE V Freshly distilled S-benzylthioformimidate derivative of valine methyl ester, prepared as in Example 11(a), ( 2.65 g. , 0. 010 mol.) and triethylamine ( 2.10 g. , 0. 021 mol.) were dissolved in dry toluene (50 ml.).

To this was added at room temperature, under a nitrogen atmosphere, with stirring, over a period of 2.5 hours, a solution of chloroacetyl chloride (2.27 g., 0. 020 mol.) in dry toluene ( 100 ml.). The reaction mixture was filtered through celite and the filtrate was washed with # sodium bicarbonate solution (x 2 ) and then with water (x 2 ) , dried over magnesium sulphate and evaporated under reduced pressure.

Chromatography of the oily residue ( 3· 8 g. ) over 38 g. acid washed alumina (Merck) using benzene-ethyl acetate ( 10: 1 v/v) as eluent, gave a fraction which consisted of the crude chlorolactam ( 2. 18 g.). A second chromatography on an acid washed alumina column ( 22 g. ) using hexane-ethyl acetate (15 : 1 v/v) as eluent afforded 4-benzylthio-3-chloro-l-(l ' -carbomethoxy-2 ' -methylpropyl ) -2-azetidinone (1.537 g., ) . This product exhibited one spot on several t.l.c. systems but was shown by its N R spectrum to consist of a mixture of two diasteroisomeric β-lactams denoted as A and B.

The ring hydrogen atoms in both 0-lactarns are of the trans configuration. The mixture was separated to its components by repeated chromatographies on Florisil using hexane-methylene chloride (1:1 v/v) as eluent. A, which was eluted first solidified on standing m.p. 52-55° (hexane-ethylacetate) . B was isolated as a pure oil.

Analysis of A: Calcd. for Cl6H20ClN05S: C, 56.21; H, 5-90; N, 4.09; S, 9-58; CI, IO.37. MW 3 1.85. Found: C, 56.I8; H, 5. 3 N, 4.02; . S, 10.14; CI, -10.60.

NMR of A: 6C6D6 : O.87 (d., J-7H2) and 0.93 (d., J=7Hz) - 6H, TMS isopropylic methyl groups; 2.47 (m., 1H, isopropylic methine); 3-35 (s., 3H, CH^); 3- 7 (s., 2H, benzylic methylene). 3. 5 (d.„ J=8Hz, lH, IK spectrum of A: chloroform (5»5-6-5^region) : 5·62μ, β-lactam carbonyl. 5.74μ, ester oarbonyl.

NMR spectrum of B: 6C6D6 : O.74 (d., J«6.6Hz) and Ο.96 (d.,J=6.6Hz) - 6H, TMS isopropylic methyl groups; 2.50 (m. , isopropylic methine); 3.26 (s. 3H, CH^); 3-53 and 3.5 (inner lines of AB pattern, 2H, benzylic hydrogens); 3·74 (d., J=9Hz, IH, T hydrogen); 4.33 (d., J=1.75 Hz, 1H), and 4.68 (d., J=1.75 Hz, 1H), 0-lactam ring hydrogens. 7-15 (m. , aromatic ) .

IR spectrum of B; ^chloroform ( 5.5-6.5 region): 5. 62μ, β-lactam carbonyl. 5.7^M.» ester carbonyl.

Mass spectrum of [4-Benzylthio-3-chloro-l-(l ' -carbomethoxy -2'-p½thylpropyl)-2-azetldlnonej"; . .. · ' m/e: M+ 34l.

EXAMPLE VI -Benzylthio-3-chloro-l-( 1 ' -carbomethoxy-2' -methylpropyl )-2-azetidinone ( 0.342 g.; 0.001 mol., a mixture of two trans isomers prepared as in Example V) and sodium azide (O. I30 g., 0.002 mol.) were dissolved in dimethyl sulfoxide (3 ml.) and stirred in the dark at 85-95° for a period of 24 hours. It was then cooled and treated with a mixture of water and ether, the aqueous layer was extracted (x 3) with ether and the combined ethereal extracts were washed with water and dried over magnesium sulphate. The residue obtained after evaporation of the ether (0.286 g. ) was chromatographed on silica gel (GF 254 , Merck) preparative thick-plates by development in benzene-ethyl - 20 acetate (15:1 v/v). Two fractions were eluted. The less polar fraction consisted of the starting material (Ο.Ο92 g., 2 ) and the more polar fraction was shown by its NMR and IR spectra to be 4-benzylthio-3-azido- 1(1 ' -carbometh0xy-2' -methylpropyl )-2-azetidinone (88 mg., 25$, two cls isomers). It was recrystallised from benzene-hexane, m. p. 76-77°.

Analysis: Calcd. for C, 55-16; H. 5.T9 N, I6.O8; S, 9.19. W 348.35- Found: C, 55-07; H, 5.65 N, 16.16; S, 9-17-NMR spectrum: 6C6D6 : Ο.76 (d., J=6.5Hz), Ο.87 (d., J=6.5Hz), TMS Ο.94 (d., J=7Hz), and .1.00 (d., J«7Hz) - 6H, isopropylic methyl groups of two isomers; 2.4 (m. 1H, isopropylic methine); 3.56 (s., 3H, OCH^); 3. 3 (d., J=8.5Hz), and 4.00 (d., J=9-5Hz) - 1H, a hydrogens of two isomers; 3.57 (s., Ag pattern) and 3.73 and 3.77 (inner lines of AB pattern) - 2H, benzylic hydrogens of two isomers; 4.06 (d. , J=4.75Hz), 4.18 (d., J=5Hz), 4.53 (d., J=5Hz) and 4.87 (d. , J=4.75Hz), - 2H, 0-lactarn ring hydrogens of two isomers; 7.2 (irii, aromatic ) .

IR spectrum: ^chloroform^-5"6'^ reSlon) ^·72 , azido group. .63μ, β-lactam carbonyl. 5·74μ, ester carbonyl. 21 EXAMPLE VII (a) Preparation of N- hioformyl-O-benzylserine methyl ester Ethylthioformate (3-62 g., 0.θ4θ mol.) was added at room temperature, to a stirred solution of O-benzylserine methyl ester (4.21 g., 0.020 mol.) in chloroform (5 ml.). After standing overnight the reaction mixture was washed with 1 N hydrochloric acid followed by saturated sodium chloride solution, dried over magnesium sulphate, and the solvent was removed under reduced pressure. Recrystallisatlon of the residue from methylene chloride-hexane afforded N-thioformyl-O-behzylserine methyl ester (3.· 5 g.,68#) m.p. 74-75°· Analysis; Calcd. for C^H^NO^S: C, 56.91; H, 5-97: N, 5.53; S, 12.64; M.W. 2 .2 . Pound: C, 57-10; H, 5-92; N, 5-73; S, 12.46.

NMR: 6CDC13 :3.80 (s., 3H, OCH,); 3-96 (d., J=>3.0Hz, 2H, TMS CH-CHgO); 4.55 (s., 2H, OCHgPh); 5. 0 (m. , 1H, a hydrogen); 7-35 (s., 5H, aromatic); 8.42 (broad, 1H, NH); 9.5Ο (d., J=3-0Hz, 1H, HCS). Changes after treatment with D20: 5.50 (t., J=3Hz, 1H); 8.42 absent; 9. 0 (s., IK). ^chloroform <5·5-6.5μ region) microns: 5-73.

Notes: o 1. Ethylthioformace was prepared according to R.Mayers and H.Berthold, Z, Chem. , , 3510 (1963). 2. O-Benzylserine inethyl ester was prepared according to K.Inouye and H.Otsuka. Bull. Chem. Soc. Japan, 34, 1, (1961). (b) Preparation of S-Methylthl ormlmldate derivative of 0-benzylserine methyl ester. iS-Methyl-N- (l-carbomethoxy-2-benzyloxyethyl jthioformimidateT 0 CH2Ph CH, CH, S • c C. ,Η.7N0,S I CH HC=N C02CH? Calcd. MW 267.27 N-Thioformyl-O-benzylserine methyl ester (2.53 g-> 0.010 mol.) in dry toluene (75 ml-) was added during minutes, under a nitrogen atmosphere, at -15° to a stirred suspension of sodium hydride (0.288g., 0.012 mol.) in dry toluene (5 ml.). The reaction mixture was stirred for an additional 60 minutes at 0° and a solution of methyl iodide (4.26 g. , 0.020 mol.) in dry toluene (5 ml.) was added dropwise during 5 minutes while the temperature was kept at 0°. After 60 minutes at room temperature the reaction mixture was filtered through celite under nitrogen, the solvent was removed under reduced pressure, and the oily residue was distilled (Kiiger.rohr technique). S-Methyl-N-(1-carboBiethoxy-2-ben -yloxyethyl )thioformimidate (2.43 g., M IR: ^liquid film ( 5 - 5-6. 5 region) micron: 5 - 73, 6. 25.

Note : The title compound is unstable and was used immediately after distillation. (c) Preparation of S-(2-Carbomethoxyeth l )thio- formlmldate derivative of O-benzylserlne methyl ester. 13-(2-carbomethoxyethyl)-N- Tl^carbomethoxy-2-ben2yloxyethyl jthloformlmldate .339 - 3 A mixture of S-methyl-N- (1-carbornethoxy-2-benzyloxyethyl )thioformimidate (2. 6† g,, 0.010 mol.) and methyl 3-mercaptopropionate (2.40 g., 0. 020 mol.) was warmed, under nitrogen for 6 hours. Methyl-mercaptan was evolved and the residue was distilled (Kiigelrohr technique). S- ( 2-carbomethoxyethyl)-N-(l-carbomethoxy-2-benzyloxyethyl )thioformimidate (2.92 g., Q6%) was. collected at 90-105°/0.02 mmHg.

IR: ^liquid film ( . 5-6. μ region) micron: 5-74 (s.), 6.24 (m. ).

Note : The title compound is unstable and was used immediately after distillation.

Freshly prepared S-(2-carbomethoxyethyl)-N- (l-carbomethoxy-2-benzyloxyethylthioformimidate (1.70 g., 0.005 mol.) and triethylamine (0.758 g. , 0.0075 mol.) were dissolved in dry toluene (30 ml.) and a solution of phthaloylglycylchloride (I.676 g. , O.OO75 raol.) in dry toluene (100 ml.) was added, with stirring, under a nitrogen atmosphere, over a period of 9 hours. The reaction mixture was stirred overnight, washed with water, dried over magnesium sulphate and the solvent was removed under reduoed pressure.

Chromatography of the residue on a silica gel (400 g. ) column, using methylene chloride-hexane-chloroform (17:2:1 v/v) as eluent afforded -(2! -carbomethoxyethyl thio)-3-phthalimido-l-(l'-carbomethoxy-2,-benzyloxy- ethyl)-2razetidinone (1.15 g-, W) .

MR: 6C6D6: 2.2-2.9 (m. , H, SCH9CH5C0): 3-29 (s.,3H, OCH,); TMS ? 3.52 (s., 3H, OCH-j) 5-35-5-50 (m. , 2H, 0-lactam ring hydrogens of two isomers). a nitrogen atmosphere with stirring, dur ng 1 m nu es to a solution of methionine methyl ester hydrochloride (20.0 g. , 0.1 mol. ) and triethylamine (10.1 g. , 0.1 mol.) in methanol (120 ml. ). After standing overnight it was evaporated to dryness under reduced pressure and the residue was dissolved in chloroform and filtered through a silica gel column. The oil obtained after evaporation of the chloroform was distilled (Kugelrohr technique) and the fraction boiling at l 0.150°/0.05 mm. was collected (l6.1 g. , 78#).

Analysis: Calcd. for C7H15 02S2: C, 40.58; H, 6.32; N, 6.76; S, 3 .89>; M.W. 207.18. Pound: C, 40.75; H> 6.43; N, 6.73; 3, 30.68.

NMR: CDC1 protons); 3-85 (s., JH, OCHj); 5·*3 (m., 1H, a hydrogen); 8.93 (broad, lH, NH); 9-58 (d., J=6Hz, lH, HCS).

BR: ^liquid film (5·5- .5μ region): 5.75μ.

Mass spectrum; m/e M+ 207.

Notes; 1. R.Mayer and H.Berthold, Z.Chem., £ , 1963, 310. 2. The methanol can be replaced by chloroform as solvent. 3. The spectra were recorded on: Varian A-60 (N.M.R.); Perkin Elmer; Infracord (i.r. ); Atlas MAT CH (ra.s. ). (b) Preparation of S-Methylthloformlmldate derivative of methionine methyl ester. 1" S-Methyl-N- (1- carbomethoxy-3-methylthlopropy ) niorormimHate ] .

^ CH2SCH3 CHjS ¾ Calcd. MW: 221.21 I ^ CH. C H^NO^S- HC=N^ C02CH5 0 15 d d Thioformylmethionine methyl ester (2.07 g.« 0.010 mol. ) in dry toluene (50 ml. ) was added during 1 hr. , under a nitrogen atmosphere to a stirred suspension of sodium, hydride (0.29 g., 0.012 mol. ) in dry toluene (10 ml.). After an additional 1 hou at room temperature the reaction mixture was cooled to 0°C and methyl iodide (1.51 g. , 0.011 mol.) was added dropwise with stirring during 10 minutes. The cooling bath was then removed and stirring continued for 1 hour at room temperature. Filtration through cellte and removal of the solvent yielded an oil which was distilled at 95-120°/0.1 mm. (1.44 g., 6 #) .

IR: ' ^liquid film (5- 5-6.5 region) microns: 5-75, 6.25.

Notes; 1. The toluene can be replaced by tetrahydrofuran and the reaction is then performed at ice-bath temperature. (c Preparation of -Methylthio-3-phthalimido-2- To a solution of freshly distilled S-methylthio-imidate derivative of methionine methyl ester (1.10 g., O.OO5 mol.) and triethylamine (0.8l g., 0.008 mol.) in dry toluene (5 ml.) was added, over a period of 6 hours, under a nitrogen atmosphere, with stirring at room temperature a solution of phthaloylglycylchlorlde (1.79 g.* O.OO8 raol. ) in dry toluene (40 ml.). The reaction mixture was stirred overnight and then filtered through cellte. The toluene was removed under reduced pressure and the residue was taken up with chloroform, washed with ether (x 3) and dried over magnesium sulphate. The oily residue obtained after evaporation of the chloroform was chromatographed on silica gel (GP 254, Merck) preparative thickplates by multi-development in hexane-ethylacetate (2:1 v/v). The fraction containiag the 4-methylthio-3-phthalimido -1-(1 ' -carbomethoxy-5' -methylthiopropyl)-2-azetidinone was eluted and recrystalllsed from hexane-ethylacetate (Ο. 5Ο g., 22% ) , ra.p. I56-70.

Analysis: Calcd. for GlQH20 205S2: C, 52.9^ H, .9 ; N, 6.86; S, 15.67; M. . 408.56. Pound: C, 52.99 H, 4.94; N, 6.90; S, 1 .59.

MR: 6CDC13 2.17 (s) and 2.21 (s) (6H, two SCH,) TMS ^ 2.3-3.O (4H, methylene protons); 3.86 (s., 3H, OCH^); 4.6I (t. , J=7Hz, 1H, a hydrogen), 5.18 (d., J=2.5Hz, 1H, β-lactam proton); 5.40 (d. , J=>2.5Hz, 1H, 0-lactam proton); 7-86 (4H, aromatic).

IR: ^chloroform^5'5"6*^ re8lon) microns: 5.63. 5-79· Mass spectrum:. m/e : M+ 408. (a ) N-Thioformylmethionine methyl ester (0.414 g., 0.002 mol.) in dry toluene (10 ml.) was added within two minutes, under nitrogen, to a stirred suspension of sodium hydride (50# in paraffin, Ο.38 g., 0.008 mol.) in dry toluene (20 ml.). After JO minutes a solution of p-nltrobenzyl chloride (1.8 g., 0.01 mol.) in dry toluene (10 ml. ) was adderd at once. The reaction mixture was vigorously stirred for 75 minutes and then filtered under nitrogen through celite, the solvent was removed under reduced pressure and the oily residue was fractionated (Kiigelrohr technique).

The S-(4-nitrobenzyl)-N-(l-carbomethoxy-3-methyl-thiopropyl)-thioformimidate (0.470 g. , 69$) was collected at 150-l60°/0.1 mmHg. (b) Preparation of 4- (4 ' -Nitrobenzylthlo)-3-Phthalimido ^2-azetidlnone derived from methionine methyl ester. "Ρ 4 ' -Nltrobenzylthlo)-3-Phthalimido-l- ( 1 ' -carbo- methoxy-3' -methylthiopropyl )-2-azetidinone ] ♦ -carbo- methoxy-3-methylthiopropyl )thioformimldate (0.542 g., 0.001 mol.) and triethylamine (O.60 g., 0.006 mol.) were dissolved In dry toluene (40 ml.) under a nitrogen atmosphere. A solution of phthaloylglycylchloride (Ο.895 g., 0.004 mol.) in dry toluene (60 ml.) was added with stirrin during 8 hr. The resulting yellow suspension was stirred overnight, filtered through celite, and the toluene was removed under reduced pressure. Chromatography of the residue on silica gel (GF 254 , Merck) preparative thlckplates by multidevelopment in hexane-acetone (5 : 2 v/v) afforded 4- ( 4 ' -nitrobenzylthio) -3-phthalimido-l- (1V-carbomethoxy-3 ' -methy thiopropyl ) -2-azetidinone (O. I85 g«, 35#) .

The n.m.r. spectrum of the product indicated the presence of two isomers A and B, in approximately equal amounts.

Recrystallisation from carbon tetrachloride afforded A in a crystalline form m.p. 139-140° while B was isolated as an oil.

Analysis of A; Calcd. for C2 H2^N;507S2: C, 54.43 H, .58; N, 7-94; S, 12.2; MW 529.57. Pound: C, 54.47; H, 4.34; N, 8.09; S, 12.3.

NMR of A: * 5C6D6 : I.98 (a., 3H, SCH,); 2.1-2.85 (m.,4H, TMS SCHg'WgC); 3-55 (s.,2H, be zylic); 3-62 (s., 3H, OCH^); 4.52 (t'., -J»7Hz, 1H, a hydrogen); 5-20 (d., J*2.8HZ, lH, β lactam ring hydrogen); , 6.65-7.9 (m., 8H, aromatic).

IR of A: ^-^,( . -6.5u region) micron: 5·6θ, 5·62, 5-70 and 5.80.

Mass spectrum of A: m/e: M+ 529-NMR of B: 6C6D6: I.87 (s., 3H, SCH,): 2.0-3.0 (m.,4H, TMS ' SCH2CH2C); 3.40 (s., 3H, 0CH-); 3-47 (s.,2H, benzylic); 4.6 (1H, ot-hydrogen); 5.Ο8 (d.,J=2.5Hz, 1H, β-lactarn ring hydrogen); 6.7-7.8 (m. , ell, aromatic ) .

IR of B: ^chloroform (5·5-6.5μ region) micron: 5.63 with a shoulder at 5.6Ο, 5.79 with a shoulder at 5.75.

* Containing a few drops of CDCl^ for increasing the solubility. 32 EXAMPLE X Preparation of N-Thloformyl-3-methylthiovaline . methyl ester. ■■ s -CH, SII CH,-C -CH, C0H,i-N0 So 3 I 3 o 15 ? 2 HC -HN -CHCO^CH, • Calcd. M.W.221.21 To a solution of 3-methylthiovaline methyl ester hydrochloride (2.14 g., 0.01 raol.) in methanol (25 ml.) o was added at 0 under a nitrogen atmosphere, with stirring, during 10 minutes, a solution of triethylamine (1.11 g., 0.011 mol.) in methanol (10 ml.). To this mixture was added during 15 minutes a solution of ethylthioformate (1.8 g. , 0.02 mol.) in methanol (15 ml.). After standing overnight at room temperature, it was evaporated, chloroform was added to the residue and the solution was washed with cold 0.1 hydrochloric acid (x 3) followed by saturated sodium chloride solution (x 4), dried over magnesium sulphate and evaporated. Chromatography of the remaining oil (2.25 £5·) over silica gel (100 g. ) using benzene-ethyl acetate (10:1 v/v) as eluent, gave the thioformyl compound '(.1.085 g. , ^9 ).

NMR: BCDC13 : I.4 (s., 6H, CH,); 2.08 (s., 3H, SCH,); TMS 3-83 (s. , 3H, 0CH?); 5.2 (d., J=8Hz., lH, a hydrogen); 8.33 (broad, 1H, NH). .64 (d., J=6Hz, lH, HCS).

IR: ^chloroform ^·5-6.5μ region) microns: 5.75. (b) N-Thioformyl-3-methylthiovaline methyl ester (0.221 g., 0.001 mol.) in dry benzene (10 ml.) was added under a nitrogen atmosphere and with stirring to sodium hydride (50/6 in paraffin, 0.053 g., 0.0011 mol.) After 30 minutes, methyl iodide (0. ^0 g. , 0.003 mol.) was added, stirring was continued for an additional 1 hour, and the reaction mixture was filtered under nitroge through celite, the solvent was removed in vacuo and the oily residue was distilled (Kugelrohr technique). S-Methyl-N- [ l-carbomethoxy-2-methyl-2-methylthiopropyl)thioformimidate (0.214 g., 91#) was collected at 80-95°/0.03 mmHg.

NMR: 6 CDC13 : 1.37 (s. ), 1.41 (s.), (6H, CH,); 2.07 (s., TMS ? 3H, SCH5); 2.42 (s., 3H, ^C-SCH^); 3-75 (s., 3H, OCH^); 4.00 (s., 1H, a-hydrogen); 8.35 (s., 1H,HCS).

IR: 'ΟΗ1ΟΓΟΊ.ΟΓΗΙ(5.5-6.5μ region) microns: 5-73, 6.27. (c ) Preparation of S-Methylthioformimidate derivative of dehydrovallne methyl ester. fS-Methyl-N- ( l-carbomethoxy-2-methylpropen-l-yl )thlo ormimidate 1 CH, CH, 3 CH,S C CgH13N02S H-C « N - C-COOCH- Calcd. M.W. I87.I9 S-Methyl-N-(l-carbomethoxy-2-methyl-2-methylthio-propyl)thloformimidate (2.35 g., 0.010 mol.) in dry dimethylforraamlde (10 ml.) was added under a nitrogen atmosphere and with vigorous stirring to sodium hydride (50# in paraffin, 0.53 g-, 0.011 mol.). After 30 minutes methyl iodide (1.48 g., 0.010 mol.) was added. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. The residue was taken up in benzene and the insoluble material was filtered off. The oil obtained after evaporation of the benzene was fractionated (Kiigelrohr technique). S-Methyl-N- (l-carbomethoxy-2-methylpropen -1-yl) thloformimidate (0.670 g., 36#) was collected at 50°/0.03 mmHg.

NMR: 6CDC13 : I.97 (s., 6H, =C-CH,); 2.45 (s., 3H, TMS ? «=C-SCH5); 3.82 (s., 3H, OCH^); 8.30 (s., 1H, HCS).

IR: ^chloroform (5' 5-6·5μ region) microns: 5-84, 6.35· S-Methyl-N-(l-carbomethoxy-2-methylpropen-l-yl) thioformimidate (O.I87 g., 0.001 mol.) and triethyl-amine (0.357 β· , 0.0035 mol.) were dissolved in dry toluene (10 ml.). To this was added, under a nitrogen atmosphere, with stirring, during nr., a solution of phthaloylglycylohloride (O.67I g., 0.003 mol.) in dru toluene (50 ml.). The reaction mixture was filtered and evaporated under reduced pressure. The oily residue was chromatographed on silica gel (GP 254, Merck) preparative thick-plates by raultidevelopment in hexane-acetone (5:2 v/v). The fraction which was shown by its n.m.r. and i.r. spectra to be the crude lactam was rechromatographed on silica gel preparative thick-plates by miltidevelopment in methylenechloride-acetone (200:1 v/v) to give pure 4-methylthio-3-phthal imido-1- ( 1 ' -carbomethoxy-2 ' -methylpropen-1 ' -yl)-2-azetidinone (Ο.263 g., 70#). m.p. 194-196° (from ethyl acetate).

Analysis: Calcd. for C^H^NgO^: C, 57-75; H, 4.85; N, 7-48; S, 8.55- M.W. 37 .3 . Found: C, 57-82; H, 4.75; N, 7.47; S, 8.5Ο.

NMR: ι» χ5 . 2.10 (s., 3H) 2.18 (s., JH); 2.28 (s., 3H) TMS ■ isopropylldene methyl groups and SCH^. 383 (s., 3H, OCH^); 5-35 (d., J=3Hz, 1H, β-lactam ring hydrogen) ; 5.48 (d. , J=3Hz, 1H, β-lactam ring hydrogen); 7.82 (m. , H, aromatic).

IR: ^chloroform ^ 5- 5-6.5 region) microns: 5.65 with a shoulder at 5.60, 5-79· Mass spectrum: m/e: M+. yh. 37 -

Claims (1)

1. CLAIMS 1. Azetidln^^ones of the general formula wherein X is halogen, an azldo group or an imido group derived from a dicarboxylic acid; R is an alkyl, alkoxy- 1 carbonylalkyl, aralkyl or nitroaralkyl group'j R is an 2 3 alkoxy or aralkoxy group; R and R are the same or different and each is hydrogen, alkyl, aralkoxy, or alkyl-thioalky j Y and Z are each hydrogen or when taken together represent a bond joining the carbon atoms to which they are attached* · 4-Methylthlo-3-chloro-l-(1Lcarbomethoxy-2 '-methyl-propyl)-2-azetidinone· 3» 4-Benzylthio-3-phthaJ.imido^l-(1'-carbomethoxy-2·-methylpropyl)-2-azetidinone· 4· 4«¾ethylthio^3-phthalimldo-l-(l·-carbomethoxy-2 ·-methylpropyl)<-2-azetidlnone· ¾ 4^(2-Carbomethoxyethyl)-3-phthalimido-l-(1*-carbomethoxy-2•-methylpropyl)-2-azetidinone· 6· 4-Benzylthio-3-chloro-l-(1·-carbomethoxy-2 '-methylpropyl)¾-2-azetidinone# , ,,. 7* 4-Benzylthio-3-azido-l-(l ♦«*carbomethoxy-2 methylpropyl)^2-azetidinone» 37118/2 I 1-(11 -carbomethoxy-2 ' -ben?,yloxyethyl )-2-azetidinone. 9. 4-Methylthio-3-phthalimido-l- ( 1 · -carbomethoxy-3 ' -methyl hiopropyl ) -2-azetidinone . 10. 4-(4'-Nitrobenaylthio)-3-phthalimido-l-(l'-caitomethoxy-^'-methylthiopropyl -azetidinone* 11. 4-Methylthio-3-phthalimido-l-(l,-carbomethoxy--2 '-methylpropen-l 1 -yl )-2-azetidinoneP 12. A method for the preparation of azetidin-2-onea of formula I in claim 1 which comprises reacting a thioimidate derivative of an a-amino acid ester of the formula o - ■ 1 2 3 wherein R, R , R , R t Y and Z have the same meaning as in Claim 1, with a monosubstituted acetyl halide of the formula , X. CH.CO.Hal (IV) wherein X is halogen, an azido group or. an imido group derived from a dicarboxylin acid and the symbol ".Hal" represents halogen, under anhydrous conditions in the pr sence of a tertiary base. - - 37118/2 13. A method as claimed in claim 12, wherein the monosubstituted acetyl halifle is a chloride or a bromide. 14» A method as claimed in claim 12 or claim 13 · wherein the tertiary base is triethylamine. For the Appl ND/DD