CA1211118A

CA1211118A - 7-oxo-4-thia-1-azabicyclo[3,2,0]heptane derivatives

Info

Publication number: CA1211118A
Application number: CA000487761A
Authority: CA
Inventors: Barry C. Ross; Graham Johnson
Original assignee: Hoechst UK Ltd
Current assignee: Sanofi Aventis UK Holdings Ltd
Priority date: 1982-03-26
Filing date: 1985-07-30
Publication date: 1986-09-09
Also published as: CA1210772A

Abstract

Abstract of the Disclosure Compounds of the formula IIa, IIb and IIc

Description

2 - JOE 82/S 001 The present invention relates to certain intermediates for the preparation of 7-oxo-4-thia-1-azabicyclo[3,2,0]-Hutton and Hutton derivatives, and to a process for their preparation.
7-Oxo 4-thia-1-a~abicyclo[3,2,0]heptane and 7-oxo 4-thia-1-azabicyclo[3,2,0~hept-2-ene penes have the following structures:

I owe Hutton Hutton Certain derivatives of these basic structures have antibiotic properties, see, for example, British Patent Applications Nos. 2 074 563, 2 042 520 and 2 013 674. There are, however, disadvantages in the methods proposed for synthesizing such compounds, for example, the low yields generally achieved, which are exacerbated by the isometric composition of the product: it is well known that certain stereochemistry in penes compounds is desirable as isomers having this stereochemistry are more biologically active than other isomers. Many of the processes proposed for the production of penes derivatives and their precursors do not give predominantly the desired isomers, and the search continues for more effective methods of synthesizing these structures.
The present invention provides a compound of the general formula It and its tautomer It H OH

COO COO
(It) (It) ~211~

- 3 - HOE 82/S 001 in which formulae R represents a carboxyl esterifying group removable by hydrolysis, photolysis, reduction, or en eye Ashley to give the free acid.
The term "a compound of the general formula I" and "a compound of formula I" are both used herein to denote a compound of the general formula Ian a compound of the general formula IBM or any mixture thereof. "A compound of formula II" is used to denote collectively compounds of formulae Ida, Jib and Tic. The terms "a compound of formula III" and "a compound of formula IV" are used analogously.
The present invention also provides a process for the production of a compound of the general formula I, which comprises treating a compound of the general formula Ida, Jib, or Tic 1 X Scorn X S

ROOT Sorb ROOT
(IIaj (Jib) DO
3 , p ROOT
(Tic) in which R is as defined above, R represents a chlorine or bromide atom, the radicals Ray and Rub, which may be the same or different, each represents an alkyd group having from 1 to 4 carbon atoms, I,,, Lo

- 4 - HOE 82/S 001 especially a methyl or t~butyl group, an aureole group, especially a phenol group, or an aralkyl group, especially a bouncily group, and A represents a direct bond or the residue of a dicarboxylic acid, with a base.
The base used in the above reaction must be capable of splitting a sulphur-carbonyl bond in the compound of formula II and of bringing about ring closure. The base may be inorganic or organic, for example, ammonia, or an alkali metal (especially a sodium or potassium) carbonate bicarbonate, or hydroxide; a primary amine, for example, methyl amine, ethyl amine, aniline or benzylamine; an alkali metal alkoxide, for example, sodium methoxide; or a heterocyclic base, for example, having a Pea within the range of from 5 to 9, for example, imidazole or pardon or a substituted pardon, for example, an alkyd-, amino-, or alkylamino-substituted pardon, for example, 4-methyl- or 4-dime~lylamino-pyridine. Imidazole is particularly preferred.
The reaction is generally carried out in a solvent or delineate, the choice of which is wide, provided that it is inert under the reaction conditions. Examples of solvents and delineates are oxygenated hydrocarbons, for example, alcohols, for example, having up to 4 carbon atoms, for example, methanol and ethanol; ethers, for example, having up to 4 carbon atoms, for example, deathly ether, also twitter-hydrofuran and Dixon; kittens, for example, having up to 4 carbon atoms, for example acetone and methyl ethyl kitten; esters for example, methyl acetate and ethyl acetate; and asides, for example, dimethylformamide and dimethylacetamide; also chlorinated hydrocarbons, for example, chloroform, ethylene chloride and carton twitter-chloride; aromatic hydrocarbons, for example, Bunsen and Tulane; and other solvents, for example, asset-nitrite and nitromethane. A mixture of any two or more solvents may be used, and solvents are preferably used I

- 5 - HOE US 001 in admixture with water, preferably a water-miscible solvent in admixture with 5 to 20 % (v/v) water, especially a mixture of Dixon and water, preferably 5 to 10 % (v/v) water.
The reaction is generally carried out at a temperature within the range of from 0 to 40C, preferably from 0 to 20C .
An esterified carboxyl group -COO is, for example, an ester formed with an unsubstituted or substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aureole, araliphatic, heterocyclic or heterocyclic-ali-phatic alcohol having up to 20 carbon atoms, or is, for example, s sill or Stanley ester.
R may represent, for example a straight or branched chain substituted or unsubstituted alkyd, alkenyl or alkynyl group having up to 18 carbon atoms preferably, up to 8 carbon atoms, and especially up to 4 carbon atoms, for example, a methyl, ethyl, n-propyl, isopropyl n-bottle, sec-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, ally, or vinyl group.
An aliphatic group R, especially a methyl group, may be substituted by a cycloalkyl, aureole or heterocyclic group, or R may itself represent a cycloalkyl, aureole or heterocyclic group.
A cycloaliphatic group R may have up to 18 carbon atoms and is, for example, a cyclopentyl, cyclohexyl or adamantly group. An aureole group may have up to 12 carbon atoms and may have two or more fused rings. An aureole group R is, for example, an unsubstituted or substituted phenol group, and an unsubstituted or substituted aralkyl group is, for example, a bouncily, ~-nitrobenzyl or bent-hydryl group.
A heterocyclic group may have one or more hotter-atoms, selected from oxygen, nitrogen and Selfware, and up to 14 atoms in total. A heterocyclic group is, for example, an oxygen-containing heterocyclic group, for example, a tetrahydropyranyl or phthalidyl group.

'I

I

- 6 - HOE 82/S 001 A Stanley group R may have up to 24 carbon atoms, for example, R may represent a Stanley group having three substituents, which may be the same or different, selected from alkyd, alkenyl, cycloalkyl, aureole, aralkyl, alkoxy and aralkoxy groups, for example, alkyd groups having up to 4 carbon atoms, for example, n-butyl groups, phenol and bouncily groups, especially three n- bottle groups.
A sill group R may also have up to 24 carbon atoms and three substituents, which may be the same or different, selected from alkyd, alkenyl, cycloalkyl, aureole and aralkyl groups, for example alkyd groups having up to 4 carbon atoms, for example, methyl and t-butyl groups.
Any group R that is capable of substitution may be substituted, for example, with a halogen atom, especially a chlorine or bromide atom, or a vitro group.
The group R may be removable by hydrolysis, by photolysis, by reduction or by enzyme action to give the free acid, or two or more methods may be used, for example, reduction followed by hydrolysis. A group R that may be removed readily without substantial degradation of the rest of the molecule is particularly useful as a carboxyl protecting group. Examples of esters that are readily split by reduction are arylmethyl esters, for example, bouncily, ~-nitrobenzyl, benzhydryl and tritely esters.
A Stanley ester, for example, a tri-n-butyl Stanley ester, may be split readily by hydrolysis, for example, by solvolysis, for example, using water, an alcohol, a phenol or a carboxylic acid, for example, acetic acid.
Certain ester groups may be split off by base hydrolysis, for example, acetylmethyl and acetoxymethyl ester groups.
There may be used an esterifying group that is removable under physiological conditions, that is to say, the esterifying group is split off in viva to give the free acid or the carboxylate, for example, an acyloxy-methyl ester, e.g. an acetoxymethyl or pivaloyloxymethyl ., .
)'"' ,,~ I

I

- 7 -- HOE 82/S 001 ester, an aminoalkanyloxymethyl ester, for example, an L-glycyloxymethyl, L-valyloxymethyl or L-leucyloxymethyl ester, or a phthalidyl ester, or an optionally substituted 2-aminoethyl ester, for example, a 2-diethylamino-ethyl or 2-(1-morpholino)-ethyl ester.
Preferred esters are the p-nitrobenzyl, phthalid~yl, pivaloyloxymethyl, acetylmethyl and acetoxy-methyl esters.
A compound of the general formula Ida, Jib, or Tic is preferably produced by halogenating a compound of the general formula IIIa, IIIb or Icky, respectively, OH / OH
SHEA c~3 ROOT Sorb ROOT

(IIIa) (IIIb) OH

SO O

CLUE )~. So O

ROOT
Icky in which R, Ray Rub and A are defined as above, and R3 represents an alkyd group having from 1 to

8, preferably from 1 to 6, and especially from 1 to 4 carbon atoms, for example, an ethyl group, or an alkenyl group having up to 6 carbon atoms, especially an ally group.

r r I.

I

The halogenation of a compound of formula IIIa, IIIb or Icky is carried out with an agent capable of splitting a carbon-sulphur bond and introducing a halogen atom. Such agents are well known in the art and include, for example, molecular chlorine, molecular bromide, sulphuryl chloride, sulphuryl bromide, t-butyl hype-chlorite and cyanogen chloride.
The halogenating agent is generally used in an amount of from 1 to 2 mole equivalents, calculated on the compound I of formula III. The reaction is generally carried out at a temperature within the range of from -40 to +20C. The reaction is generally carried out in a solvent or delineate that is aprotic and is inert under the reaction conditions, for example, an ether, a hydrocarbon or a halogenated hydra-carbon, for example, Dixon, Bunsen, chloroform ormethylene chloride. A mixture of two or more solvents may be used. Examples of halogenating systems are: chlorine in chloroform and, especially, chlorine in Bunsen and t-bottle hypochlorite in Bunsen. In the latter two cases, the temperature is preferably from 5 to 20C, and especially from 5 to 10C.
A compound of formula IIIa, IIIb, or Icky is prefer-ably produced by removing the protective group from a compound of formula Ivan Ivy or Ivy, respectively, o'er or SHEA I sR3 SHEA - C, SR3 N Scorn N

ROOT Sorb ROW S
(Ivy) (Ivy) I lull

- 9 - HOE 82/S 001 OR
SHEA - C

Oslo ROOT
(Ivy) in which R, R2, , R3 and A are defined as above, and R4 denotes a hydroxy protecting group.
Preferred groups R4 are those which are compatible with the synthesis of the compound of formula IV and which may be removed under reaction conditions in which the resulting compound III is stable. Compound III has been found to be stable in the presence of a proton source, for example, hydrogen chloride, aqueous hydrochloric acid or aqueous hydrofluoric acid. Accordingly, one type of preferred hydroxy protecting groups R4 are those which may be removed under acidic conditions. Such groups are well known in the art and are for example, tetrahydropyranyl and tetrahydrofuranyl groups; acutely and petal groups, for example, of formula o'er ~R5 in which R6 and Rut which may be the same or different, each represents a hydrogen atom or a lower alkyd group, preferably a methyl group, or R6 and R7 together with the carbon atom to which they are attached represent a cycloalkyl ring having from 4 to 7 carbon atoms, for example, a tetrahydropyranyl or tetrahydrofuranyl ring;
and R5 represents a lower alkyd group, preferably a methyl or ethyl group.

- 10 - HOE 82/S 001 R4 may also represent a sill group, for example, as described above in relation to R, for example, -SiR8R9R10 groups, in which R8, R9 and Rl0, which may be the same or different, each represents a lower alkyd group or an aureole group, for example, triethylsilyl, t-butyldimethyl-sill and methyldiphenylsilyl groups; and Stanley groups, for example, as described above in relation to R, for example, Sir R R groups, in which R , R and R
which may be the same or different, each represents a lower alkyd group, for example, a tri-n-butylstannyl group.
Preferred I groups are tetrahydropyranyl, 2-metho~yprop-yule and t-butyldimethylsilyl groups.
A t-butyldimethylsilyl group may be removed in a known manner by acid hydrolysis, for example, using moderately concentrated hydrochloric acid, for example EM
Hal, e.g., in tetrahydrofuran (of Belgian Patent Specie ligation No. 881 o'er hydrogen chloride in twitter-hydrofuran, dimethylformamide, Dixon, a lower alkanol, or acetonitrile; Tetra(n-butyl)ammonium fluoride in an acidic medium, e.g., in acetic acid (of Belgian Patent Specification No. 882 764); or aqueous hydrogen fluoride e.g., in the presence of acetonitrile (of J. Chum. Sock Perking 1, 1981, 2055). (The term 'known' is used herein to mean in actual use in the art or described in the literal lure of the art).
A compound of the general formula IV may be prepared according to the following reaction scheme:

o'er o'er OH - C Octal 9 SO

H
O I
VI I I

OR ~,~

I
ROOT

1;

I I 2 pi SR3 SHEA C, sR3 Scorn I

ROOT Sorb ROOT ROOT

Ivy Ivy Ivy in which R, Ray Rub, R3, R4 and A are as defined above.
A compound of formula VOW may be prepared as described in Belgian Patent Specification No. 882 764.
A compound of formula VOW may be converted into a compound of formula VI by reaction with a compound of formula VIII

R3 - S - R14 (VIII) in which R3 is as defined above and R14 represents a hydrogen atom or an alkali metal atom, especially a sodium or potassium atom. R3 preferably represents a straight chain lower alkyd group, especially an ethyl group, or a straight chain lower alkenyl group, especially an ally group.
The reaction is generally carried out in a solvent, preferably a erotic solvent, for example, water or an alcohol, or an aprotic, water-miscible solvent which is preferably polar, for example, dimethylformamide, dim ethyl sulphoxide, tetrahydrofuran or dioxin. The reaction temperature is, for example, from -20 to ~50, preferably from -10 to +20C.
To obtain a compound of formula V a compound of formula VI may be reacted, in the presence of a base, with a compound of formula IX

y1CH2C2R (IX) in which R is as defined above and ye represents a group that is capable of being replaced by a nucleophilic group and is, for example, a halogen atom, preferably a bromide or iodine atom, or a modified hydroxy group, preferably a sulphonyloxy group of the formula SYRIA in which R16 represents a lower alkyd or -CF3 group, or a phenol group which is us-substituted or is substituted by a nutria, Brigham or p-methyl group.

I Lo Y preferably represents a bromide or iodine atom or a methylsulphonate, trifluoromethylsulphonate~ toll-sulphonate or benzenesulphonate group.
The base may be inorganic, organic or organometallic, for example an alkali metal or alkaline earth metal hydroxide, oxide, carbonate, bicarbonate or hydride,for example, sodium hydroxide, magnesium oxide, potassium carbonate, potassium bicarbonate or sodium hydrides a tertiary amine, for example, a trialkylamine, for example, triethylamine, DABCO (diazabicyclo[2,2,2]octane), pardon, or an alkyl-substituted or amino-substituted or dialkylamino-substituted pardon, for example, NUN-dimethylaminopyridine, or colliding; a guanidine, for example, tetramethylguanidine; DUN (diazabicyclo[4,3,0]non-15 ennui) or DUB (diazabicyclo[5,4,0]undec-7-ene~, a polymeric base i.e., a base attached to an inert polymeric support e.g., Hunks base (diisopropylethylamine attached to e.g., polystyrene); a mutilated amine, for example, a mutilated alkyd- or arylamine, for example, lithium diisopropylamide (LEA), lithium hexamethyldisilazide, lithium piperidide, lithium 2,2,6,6-tetramethylpiperidide, or a Grignard reagent, for example, methyl magnesium bromide. Preferred bases are, for example, potassium carbonate, sodium hydrides lithium diisopropylamide and triethylamine.
The reaction is generally carried out in an aprotic solvent or delineate, for example, a tertiary aside, for example, dimethylformamide, dimethylacetamide or hexamethyl-phosphoramide; a hydrocarbon, for example, Bunsen or lot-gene; or an ether, for example, deathly ether, tetrahydro-Furman or Dixon; or acetonitrile, dim ethyl sulphoxide, or sulpholane. Dimethylformamide and dimethylacetamide are preferred. A mixture of two or more solvents and/or delineates may be used.
The reaction may be carried out at a temperature generally within the range of from -80C to +30C
preferably from -40 to +30C, and especially from -20 to ~2~C.
I
Jo ., I

From 1 to 1.5 moles of compound It are preferably used per mole of compound VI especially from 1 to 1.1 moles of IX per mole of VI. The base is used in an amount, for example, from 1 to 4 moles of base per mole of compound VI.
The reaction is preferably carried out by dissolving compound VI in a solvent, advantageously in dimethylform-aside with stirring, adding the base, adding the compound of formula IX and reacting at the desired temperature. The resulting compound of formula V may be worked up and is-fated in the usual manner, for example, using cremate-graphic and/or crystallization techniques, or the subset quint reaction may be carried out directly on the resulting reaction mixture after removal of any solvent that is not compatible with the subsequent reaction.
If R in formula V represents a carboxyl esterifying group, this group may be converted into another ester-lying group R, for example, to introduce a group R that is more easily removable under desired conditions. This transesterification is generally carried out as follows:
the ester for formula V is hydrolyzed in a known manner using, for example, acid or alkaline hydrolysis, prefer-ably using an alkali metal hydroxide, especially sodium or potassium hydroxide. The ester of formula V, for example, a methyl ester, is preferably hydrolyzed using an alkali metal hydroxide, especially one mole thereof per mole of the ester of formula V in a solvent, for example ethanol, methanol or water, or an aqueous-organic solvent, for example, tetrahydrofuran/water, ethanol/
water, or acetonitrile/water.
The reaction mixture may then be acidified to give a solution of pi 1 to 5, preferably 2 to I, and the free acid may then be isolated and, if desired, the free acid is then esterified with an esterifying agent capable of introducing a different esterifying group R, for example with an alcohol ROW in the presence of an acid or another . . , ~21~

activating agent, for example, dicyclohexylcarbodiimide, or with an alkylating agent RYE in which ye is as defined above. Preferably a salt may be isolated and esterified directly.
A compound of formula V may be converted into a compound of formula IV by treatment with a base in the presence of carbon disulphide followed by reaction with an assaulting agent, or by treatment with a base, then with carbon disulphide, and finally reaction with an assaulting agent. An assaulting agent is generally an activated carboxylic acid.
The activated carboxylic acid may be any activated acid derivative comprising the group R2. Such derivatives are well known in the art, and include acid halides, acid androids, and activated esters. An android may be symmetrical or asymmetrical. SCORN
For the introduction of a group a to give a compound of formula Ivan the assaulting Sorb agent preferably has one of the formulae Pa to Xb R2COZ (Pa) RbCOZ ( Xb) O O O O
Ray C - O - C - Rare _ C - O - C - Rub (Xc) (Ed) O O
q ,- " q Rub - C - O - C - I;

(X e) in which Ray and Rub are as defined above, and Z represents a halogen atom, especially a chlorine or bromide atom or represents an activated ester or aside, or a radical derived from an acid aside. Such coupling reagents are well known in the art of peptize chemistry.

I

In the case of formula Ivy/ the group S

I
S

may be introduced by means of an assaulting agent of formula XI o Hal - C - Hal in which Hal represents a halogen atom especially a chlorine atom.
For the introduction of a group to give a S
Jo to compound of formula Ivy, a dicarboxylic acid derivative of formula XII is used Casey A

CASEY
in which A and Z are as defined above, and Z preferably represents a halogen atom, especially z chlorine atom. As mentioned above, A represents the residue of a dicarboxylic acid or represents a direct bond. A is derived, for example, from Masonic, dimethylmalonic, succinic, glutaric, adipic, pimelic or phthalic acid.
The compound of formula V is preferably reacted first with a base, then with carbon disulphide, and then finally with the assaulting agent.
The base preferably has a pi 20, and is preferably a mutilated amine. Examples of preferred bases are lithium diisopropylamide, lithium 2,2,6,6-tetramethyl-piperidide, lithium cyclohexyl isopropylamide, lithium hexamethyl dieselized, and sodamide.
The reaction is generally carried out in an inert solvent, for example, an oxygenated hydrocarbon, preferably an ether, for example, deathly ether, tetrahydrofuran, , .

~211~1~8 Dixon, glum or diglyme. The reaction temperature is, for example, from -120 to +30C, preferably from -100 to -20C.
The amount of base used is for example, from 1 to 4 moles, calculated per mole of compound V, preferably from 2.0 to 3.0 moles of base. Carbon disulphide is preferably used in amount of from 1 to 5 moles, especially from 2 to 3 moles, per mole of compound V.
The reaction is preferably carried out as follows:
to a stirred solution of compound V under an inert atmosphere is added the base then carbon disulphide~ if desired in solution in the same solvent as compound V or in a different solvent, and finally the assaulting agent to complete the reaction.
There may then be admixed a erotic source having a pi less than 10, and especially from 5 to pharaoh example, acetic, citric, oxalic or formic acid.
The compound of the general formula I has R stereo chemistry at position 5. This is the stereochemistry found in naturally occurring penicillins and is, in general, preferable to US stereochemistry, more OR compounds being antibiotically active than are US compounds.
We have found a process that gives predominantly the desired OR compound of formula I. It has been proposed previously (British Patent Application AYE) to halogen ate a compound of formula IV i.e., a compound having a protected hydroxy group in the side chain attached to the 3-position, but we have found that this process gives only a OR halogenated compound, which in its turn, gives a compound analogous to that of formula I but having the undesired US stereochemistry. We have found that, very surprisingly, if the protective group is removed from compound IV prior to halogenation, the resulting halogenated compound of formula II is predominantly US. The isomer ratio 4S:4R in compound II resulting from the halogenation varies according to the reaction conditions but is, for example, in the range of from 3:1 to as high as 9:1. More-over, the OR and US isomers of formula II can be separated easily, for example, by chromatography.
The US halogenated intermediates of formula II give virtually exclusively a compound of formula I with the OR
stereochemistry as shown. The presumed participation of the free hydroxyl group of the side chain of formula II in giving the more starkly hindered compound of formula I
is also unexpected and constitutes a valuable advance in the preparation Go the penes compounds of formula I.
The compound of formula I is itself a very useful starting material for the preparation of various don-natives substituted at position 3, especially by -SR3, wherein R represents alkyd having 1-10 carbon atoms or substituted alkyd; particularly alkyd having 1-4 C-atoms, i.e., in the synthesis of 3-substituted 7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene 2-carboxylate derivatives, that possess antibacterial properties and which are useful for the treatment of bacterial infections in humans and animals.
The following Examples illustrate the invention. In them, temperatures are given in degrees Celsius.

....

I

Example 1 4-(R)-Allylthio-3lS)-[11(R)-~dimethyl-~2-methylproopal -silyloxy~ eth~l]azetidin-2-one To a stirred solution of 1.14 ml ox ally mercaptan and 0.4 g of sodium hydroxide in 25 ml of water under an argon atmosphere was added a solution of 2.87 g of 4-Aztecs'-- dimethyl-~2-methylprop yule silyloxy~ ethyl]azetid-in-2-one in 10 ml of methanol.
After 30 minutes, the mixture was partitioned between dichloromethane and water. The separated organic layer was washed with water, was dried over magnesium sulfite, evaporated to dryness and then chromatographed on silica gel. Elusion with ethyl acetate / hexane mixtures afforded 1.8 g of the title compound as white crystals.

)cDcl3 3420, 1767 cm (CDCl3) 0.05 ohs 0.88 (OH, s) 1.20 (OH, d, J6Hz) 2.9 - 3.2 (OH, m) 3.9 - 4.3 (OH, m, H-1') 3.84 (OH, d Jo 4 2Hz, H-4) 4.95 - 6.3 (OH, m) 7.28 (OH, broad s) Example 2 Methyl 2-(4(R)-allylthio-3-(S)-[1'(R)- methyl 2-methylprop-2-yl~ silyloxy~ ethyl]azetidin-2-on-1-yl) acetate To a stirred solution of 1.76 g of 4(R)-allylthio-3-(S~-[1'(R)- dim ethyl ~2-methylprop-2-yl~ silyloxy~
ethyl]azetidin-2-one in 60 ml of dry dimethylformamide was added 3.52 g of finely ground potassium carbonate and 0.6 ml of methyl bromoacetate. After 18 hours, the mixture was filtered and then partitioned between ethyl acetate and water. The separated organic layer was washed with I Lo water and dried over magnesium sulfite. Evaporation in vacua afforded a crude product which was cremate-graphed on silica gel. Elusion with ethyl acetate/hexane mixtures afforded 1.56 g of the title compound as a pale yellow oil.

CDCl3 1753, 1768 cm 1 (CDC13) 0006 (OH, s) 0.86 (OH, s) 1.23 (OH, d 6J.5Hz) 3.2 (OH, Al) 3.70 (OH, s) 3.6 - 4.3 (OH, m) 4.87 (lo, d J 2Hz, Ho 4.9 - 6.3 (OH, m) Example 3 4-Nitrobenzyl 2-(4(R)-allylthio-3(S)-[1'-(R) dimethYl 2-meth~lprop~2-yl~silyloxy~ ethyl]azetidin-~-on-1-yl)acetate To a stirred solution of 3.04 g of potassium hydroxide in 80 ml of 95 % ethanol was added a solution of 16 g of methyl2-(4(R)-allylthio-3tS)-[1'(R)-dimethyl~2-methvlprfop-2-yl~silyloxy~ethyl]azetidin-2-on-1-yl)acetate. After 10 minutes, the mixture was evaporated to about 1/5 of its original volume; 2 ml of dim ethyl acetamide were added, followed by a solution of 3.25 g of 4-nitrobenzyl bromide in 50 ml of dimethylacetamide. After 1 hour, the mixture assay partitioned between 0.01M Hal and ethyl acetate. The separated organic layers were washed with 0.01M Hal, with water, with cold, saturated sodium bit carbonate, and with brine, and were then dried and evaporated. The resulting crude product was cremate-graphed over silica gel; elusion with ethyl acetate/
hexane mixtures afford 19.5 g of the title compound as an oil.

I
- 21 - HOE 82/S 001 _ Max (CDC13) 1755, 1769 cm 1 ~(CDC13) 0.07 and 0~09 (OH, two singlets) 0.88 (OH, s) 1.25 (OH, d J6Hz) 3.2 (OH, m) 3.7 - 4.5 (OH, m) 4.95 (OH, d J2Hz, H-4 4.9 - 6.3 (OH, m) I - 8.35 (OH, m) Example 4 4-Nitrobenzyl 3, 3-di(acetylthlo)-[(3S,4R)-4-allylthlo 3~[1'(R) dimethyl-~2-methylprop-2-yl~ silyloxy~ ethyl]
2-azetidinon-1-yl)propenoate A solution of lithium hexamethyldisilazide was pro pared by the addition of n-butyllithium in hexane (2. 79 ml of a 1.6 M solution) to 0. 982 ml of hexamethyldisilazane in 8 ml of dry tetrahydrofuran at -10C, while stirring under argon. The solution was cooled to -78C and added by Connally to a solution of 0.98 g of 4-nitrobenzyl 2-(4(R)-allylthio-3(S)-[1'(R)-dimethyl-~2-methylproopal silyloxy~ ethyl]azetidin-2-on-1-yl) acetate in 8 ml of dry tetrahydrofuran at -78C, with stirring under argon.
After 5 minutes, 0.357 ml of carbon disulphide was added by syringe, followed by 0.748 ml of acetic android. The mixture was allowed to warm to room temperature, and 30 ml of dichloromethane was added, followed by 30 ml of water.
The organic layer was separated, and the aqueous layer was extracted with further dichloromethane. The combined organic extracts were washed with lo Hal, with water, and with a 12 % sodium chloride solution, and were then dried over magnesium sulfite and evaporated to give 1.38 g of an orange oil. 1.21 g of this crude product was chromatographed on silica gel using ethyl acetate/hexane mixtures as fluent to give 0.800 g of the title compound in purified form.

(cDcl3) 1778, 1745 cm 1 ~(CDCl3) 0.06 (OH, s) 0.85 (OH, s) 1.26 (OH, d J6Hz~
2.25 (OH, s) 2.35 (OH, 5) 3.11 - 3.52 (OH, m, 3-H) OWE (OH, d, J 6Hz) 4.14 4.39 (IT, m) 4.95 - 6.30 (OH, m) 5.35 (OH, s) 5.56 (IT, d J3Hz, 4-H) 7.44 - 8.38 (OH, m) Example pa 4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4R)-4-allylthio-3-~1'(R)-hydroxyethyl~-2-azetidinon-1-yl]propenoatlo To a solution of 0.601 g of 4-nitrobenzyl Dow-(acetylthio~-2-[(3S,4R)-4~allylthio-3-(1'(R)-dimeethyl-2-methylprop-2-yl~silyloxy~ethyl)-2 azetidinon-1-yl]-preappoint in 12 ml tetrahydrofuran was added a solution of 1 ml of concentrated hydrochloric acid and 1 ml of tetrahydrofuran. The solution was set aside for 24 hours and then evaporated in vacua. Bunsen was added and the mixture was evaporated to remove residual water to give 0.424 g of crude title product. A portion (0.197 g) of this crude material was chromatographed on silica gel eluding with ethyl acetate - hexane mixtures to give 0.142 g of pure title compound.
Max 1774, 1738 cm 1 (CDCl3) 1.26 (OH, d, J6Hz) ? 24 (OH, s) 2.38 (OH, so 3.35 (OH, d, J7Hz) 3.22 - 3.48 (OH, m) 3.98 - 4.45 (OH, m) ,. . .
I so ,...

.

5.30 (OH, s) 4.95 - 6.1 (OH, m) 7.42 - 8.23 (OH, m) Example 5b 4-Nitrobenzyl 3,3-di~acetylthio)-2 [issuer thio-3-~1'(R)-hydroxyethyl~-2-azetidlnon-1 yl1propenoate To a stirred solution of 0.088 g of 4-nitrobenzyl 3,3-di-(acetylthio)-2-[(3S,4R) 4-allylthio-3-(1'(R)-dimethyl-~2-methylprop-2-yl~silyloxy3ethyl~ 2-azetidinon-1-yl]propenoate in 5 ml of acetonitrile was added 2.35 ml of concentrated (40 %) hydrofluoric acid. A further volume of acetonitrile (5 ml) was added after 5 minutes, and the solution was quenched with a saturated aqueous sodium bicarbonate solution. The resulting solution was extracted with dichloromethane. The resulting organic phase was washed with water, with sodium bicarbonate, and then with brine. It was then dried over McCoy and chromatographed on silica gel, eluding with ethyl acetate -hexane mixtures to give 0.03 g of recovered starting material and then 0.0296 g of the title compound.
For spectral details see Example pa.
Example_5c 4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4R)-4-allylthio-3-1'(R)-hydroxyethyl~-2-azetidinon-1-yll]
preappoint To a solution of 5.58 g of 4-nitrobenzyl Dow-(acetylthio)-2-[(3S, 4R)-4-allylthio-3-(1'(R~-dimethyl-~2-methylprop-2-yl~silyloxy~ethyl~ 2-azetidinon-1-yl]-preappoint in 6.5 ml of tetrahydrofuran was added a freshly prepared solution of 3.72 g of hydrogen chloride in 32 ml of tetrahydrofuran.
The solution was set aside at room temperature until the reaction was complete, and was then evaporated in vacua. Chromatography on silica gel, eluding with ethyl acetate -hexane mixtures gave 3.10 g of the title compound.
For spectral details see Example pa.

I

Example pa 4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4S)-4-chloro 3-~1'(R)-~ydroxyeth~l~-2-azetidinon-1-yl]pro~enoatlo To a solution of 0.246 g of 4-nitrobenzyl Dow-(acetylthio)-2-[(3S,4R)-4~allylthio-3-(1'(R)-hydrooxyethyl)-2-azetidinon-1-yl]propenoate in 13 ml of Bunsen was added under an inert atmosphere 0.095 ml of t-butylhypochlorite.
When the starting material had been consumed the reaction mixture was chromatographed on silica gel to give as the minor product 0.045 g of 4-nitrobenzyl Dow-(acetyl-thio)-2-[(3S,4R)-4-chloro-3~ (R)-hydroxyethyl)-2-azetidinon-1-yl]propenoate (20 I) and as the major product 0.121 g of the title compound.
For spectral details see Example aye.
Example 6b 4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4S)-4-chloro-3-~1'(R)-hydroxyethy~ -2-azetidinon-1-Yl]propenoate To a solution of 3.10 g of 4-nitrobenzyl Dow-(acetylthio)-2-[(3S,4R)-4-allylthio-3-(1'(R)-hydrooxyethyl)-2-azetidinon-1-yl]propenoate in 70 ml of dry Bunsen cooled to 6 was added drops a solution of 1.5 mow equivalent of chlorine in 9.5 ml of carbon tetrachloride.
When the starting material had been consumed, the solution was reduced in volume in vacua and chromatographed on silica gel, eluding with ethyl acetate - hexane mixtures to give as the minor product 0.695 g of 4-nitrobenzyl 3,3-di-(acetylthio)-2-[(3S,4R)-4-chloro-3-(1(R)-hyydroxy-ethyl)-2-azetidinon-1-yl]propenoate, and as the major product 1.808 g of the title compound.
For spectral details see Example aye.
Example 7 4-Nitrobenzyl (5R,6S) 6-~8'(R)-h~droxyethyl~-7-oxo-4-thia-3-thioxo-1-azabicyclo[3,2,o]hept-2-ane 2-carboxylate To a solution of 0.525 g of 4-nitrobenzyl Dow-35(acetylthio)-2-[~3S,4S)-4-chloro-3-(1'(R)-hydroxyeethyl)-I, 2-azetidinon-1-yl]propenoate in 15 ml of dioxin and 1.5 ml of water was added OWE g of imidazole. When the react lion was complete the solution was diluted with ethyl acetate and water, acidified with dilute hydrochloric acid and extracted. The aqueous phase was extracted with a second volume of ethyl acetate. The combined ethyl acetate solution was washed with water and then with brine, dried over McCoy and evaporated in vacua to give the title compound as an orange solid in quantitative yield.
Max (liquid film) 1791, 1751 cm 1 (CDCl3) 1.39 (OH, d, J6Hz) 3.00 (OH, s) C H
3.76 (OH, Ed, JOB c~c~ 4Hz~ Joy 4.05 - 4.53 (OH, m) 5.35 (OH, s) 5.45 us 5.95 (OH, d, 5-H) 7.36 - 8.45 (OH, m).
Example 8 3(S)-~1'(R)-Dimethyl(2-methylprop-2-yl)silyloxyethHoyle (R)-ethylthioazetidin-2-one To a stirred solution of 2.03 g of sodium hydroxide in 70 ml of water at 0C under an argon atmosphere was added 3.94 g of ethanol they'll. After 30 minutes stirring, a solution of 12.6 g of 3(S~-{1'(R)-dimethyl(2-methylprop-2-yl)silyloxy-ethyl~-4-acetoxyazetidin-2-one in 200 ml of methanol was added. The mixture was warmed to room temperature and, after 90 minutes, was partitioned between ethyl acetate and water. The aqueous layer was further washed with ethyl acetate. The combined organic layers were back-washed with brine, dried over sodium sulfite, and evaporated to dryness. 6.9 g of the title product were obtained. Yield: 54 %

'I

I

Max lCDCl3) 1765 cm J (CDCl3) 0.10 ohs 0 90 (OH, s) 1026 (OH, d, J = 6 Ho) 1.33 (OH, t, J = 7 Ho 2.68 12H, q, J = 7Hz) 3.16 (OH, m) 4.1 - 4.3 (OH, m) 4.85 (OH, d, J = 2 Ho) 6.78 (OH, broad s).
Example 9 Methyl 2-[3(S)-~ (R)-~dimeth~l(2-methylprop-2-yl)s lye-_ oxyethyl}~4(R)-ethylthio-azetidin-2-on-1-yl]acetatlo To a stirred solution of 6.9 g of Dow-methyl(2-methylprop-2-yl)silyloxyethyl3-4(R)-ethyllthio -azetidin-2-one in 150 ml of dry dimethylformamide was added 13.15 g of finely ground an hydrous potassium carbonate and 2.82 ml of methyl bromoacetate. After 24 hours, the mixture was filtered and then partitioned between ethyl acetate and water. The aqueous layer was adjusted to pi 2 by drops addition of dilute hydrochloric acid, and then back-extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfite, and evaporated n vacua to give an orange oil, which was chromatographed over silica gel.
Elusion with ethyl acetate/hexane mixtures afforded 6.37 g of the title compound as a pale yellow oil.
Yield: 72 %.
Max (CDCl3) 1749 jester) and 1760 (B-lactam) cm (CDCl3) 0.06 (OH, s) 0.36 (OH, s) 1.3 (OH, m) 2.58 (OH, q) J = 6Hz) 3.12 OH dud, J = 2Hz and 4 Ho) 3.70 (OH, s) 3.93 (OH, dud, J gem = 17 Ho) 4.3 (lo, my 4.92 (OH, d, J = 2Hz)~

I

Example 10 4-Nitrobenzyl 2-[3-(S)-~1~(R)-dimethyl-(2-methylprop-2-yl)-silyloxyethyl3-4(R)-e~ylthio-azetidin-2-on-1yule]-acetate To a solution of 6 .37 g of methyl 2-[3(S)-1'(R)-dimethyl(2-methylprop-2-yl)silyloxyethyl~-4(R)-ethhealth-azetidin-2-on-1-yl]acetate in 25 ml of 95 % ethanol was added a solution of 1.16 g of potassium hydroxide in 25 ml of 95 ethanol. After 15 minutes, the mixture was evaporated in vacua to dryness. The product was dissolved immediately in Z5 ml of dimethylacetamide, and 4.24 g of solid 4-nitrobenzyl bromide were added with vigorous stirring. After 60 minutes, the mixture was partitioned between ethyl acetate and water. The separated aqueous layer was washed with further ethyl acetate; the combined organic layers were backwashes with water, then with brine, and were then dried over sodium sulfite and evaporated in vacua to afford an orange oil. Cremate-graph over silica gel, eluding with ethyl acetate/hexane mixtures afforded the title compound as a pale yellow, viscous oil. Yield: 6.18 g, 80 %.
Max (CDCl3) 1765 (B-lactam) and 1755 (ester)cm 1 (CDC13) 0.05 (OH, s) 0.08 (OH, s) 0.88 (OH, s) 1.25 (OH, t, J = 7Hz) 1.28 13H, d, J = 6 Ho) 2.58 (OH, q, J = 7Hz) 3.18 I dud, J = 2 Ho and 4 Ho) 4.05 (OH, dud, Gem = 18 Ho) 4.1 - 4.3 (OH, m) 4.93 (OH, d, J = 2Hz) , ~29~L18 - 28 - HOE 82lS 001 Example 11 4-Nitrobenzyl 3,3-di(acetylthio)-2 [(3S,4R) 4-ethylthio-3-(1l(R)-(dimethyl-~2-meth~lprop-2-yl~siilyloxy~
ethyl)-2-azetidinon-1-yl]propenoate A solution of 2.0 g of 4-nitrobenzyl 2-[3S,4R)-4-ethylthio-3-l1'(R)-~dimethyl-2 -methylprop-2-yl~ silylox~ -ethyl)-2-azetidinon-1-yl]acetate in 30 ml of dry twitter-hydrofuran was held under an inert atmosphere and cooled to -78. To the well-stirred solution was added a cooled (-78C) preformed solution of lithium hexamethyldisilazide (prepared by addition of bottle lithium (1.55 molar, 6.01 ml, 9.31 Molly) to a tetrahydrofuran solution (20 ml) of hexamethyldisilazane (2.05 ml) cooled to -10). After 5 minutes, 0.747 ml of carbon disulphide was added, followed after a further 5 minutes stirring by 1.56 ml of acetic android, and the solution was warmed to -20.
80 ml of ethyl acetate was added to the solution, followed by 150 ml of dilute hydrochloric acid (0.4 molar). The aqueous layer was extracted with a further volume of ethyl acetate. The combined ethyl acetate phase was washed with brine, then dried over magnesium sulfite and evaporated in vacua to yield 3.03 g of the title -compound, which was used subsequently without further purification.
Max (CDCl3) 1776, 1739, 1715 cm 1 d (CDC13) 0.06 (OH, s) 0.85 (OH, s) 1.06 - 1.64 OH m) 2.10 - 3.16 (OH, m) 2.23 (OH, s) 2.35 (OH, s) 3.25 - 3.50 (OH, m, 3-H) 4.05 - 4.67 (OH, m) 5.34 (OH, s) 5.56 (OH, Ahab 7.37 - 3.44 (OH, m).

IT
'I

I

Example 12 4-Nitrobenzyl 3,3-di(acetylthi_ -2-[(3S,4R)-4-ethylthio-3~ (R)-h~droxyethyl,3-2-azetidinon-1~y~
preappoint 0.303 g of 4-nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4R)-4-ethylthio-3-(1'(R)-~dimethyl-~2-methylpprop-2-yl~-silylox~ ethyl)~2-azetidinon 1-yl]propenoate was dissolved in a solution of 12 mow equivalent of hydrogen chloride in S ml of tetrahydrofuran. The solution was stirred for 6 hours then evaporated in vacua to 1/3 of its volume. Ethanol free chloroform was added and the solution evaporated. The residue was chromatographed on silica gel eluding with ethyl acetate - hexane mixtures to give 0.066 g of recovered starting material and 0.12g of the title compound.
(Max) 1770, 1738 cm 1 (CDCl3) 1.03 - 1.63 (OH, m) 2.00 - 3 18 (OH, m) 3.19 - 3.48 (OH, m, 3-H) 3.95 - 4.46 (OH, m) 5.30 (OH, s) 5. 3 OH 4~.,3B' 7.33 - 8.37 (OH, m).
Example aye 4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4S)-4-chloro-3-~1'(R)-h~droxyethyl~-2-azetidinon-1-yl]prrepent A solution of 0.10 g of 4-nitrobenzyl dustily-thio)-2-[(3S,4R)-4-ethylthio-3-~11(R)-hydroxyethyllo azetidinon-1-yl]propenoate in 1.3 ml of ethanol-free chloroform was cooled to -60 under an inert atmosphere.
To this solution was added a solution of chlorine in carbon tetrachloride until the starting material had been consumed. The reaction was evaporated in awoke and chromatographed on silica gel to give 0.032 g of the title compound.

or I, ~21~L~8 Max (liquid film) 1790, 1739 cm 1 d (CDC13) 1.37 (OH, d, J7Hz) 2.24 (OH, s) 2.39 (OH, s) 3.58 (OH, Ed, JOB, O-CH-CH3 10Hz, JOB
5 Ho, 3-H) 4.00 - 4.56 (OH, m) 5~30 (OH, s) 6.27 (OH, I, 4-H) 7.38 - 8.25 (OH, m).
Example lob _Nitrobenzyl 3,3-di~acetylthio)-2-~3S,4S) 4-chloro-3-~1'(R)-hvdroxyethyl-2-azetidinon~1-yl]proopenoate To a solution of 0.10 g of 4-nitrobenzyl Dow-15 (acetylthio)-2-[(3S,4R) 4-ethylthio-3-~1'(R)-hydroxyethyl-2-azetidinon-1-yl]propenoate in 2 ml of dry Bunsen cooled to 6 was added slowly a solution of 1.5 mole equivalent of chlorine in carbon tetrachloride until the starting material had been consumed. The solution was then chromatographed on silica gel, eluding with ethyl acetate -hexane mixtures to give as a minor product 0.011 g of 4-nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4R) sheller-3-(1'(R)-hydroxyethyl)-2-azetidinon-1-yl]propenoatlo, thetas the major product, 0.065 g of the title compound.
For spectral details see Example aye.
Example 14 4-Nitrobenzyl 3,3-di(ace~y~_hio)-2-[(3S,4R)-4-chloro-3-(1'(R)-dimethyl-~2-methylprop-2-yl~silyllucks ethyl)-2-azetidinon-1-yl]propenoate A stirred solution of 3.S19 g of 4-nitrobenzyl-3,3-di(acetylthio)-2-[(3S,4R)-4-allylthio-3-(1'1R)Dow-methyl methylprop-2-yl}silyloxy~ethyl)-2-azetidinon-1-yl]-propenoate in 20 ml of ethanol-free chloroform was cooled to -60. To it was added a solution of 0.48 g of chlorine in 5.6 ml of carbon tetrachloride. The resulting solution was maintained at -60 for 20 minutes, _, I

Lo and was then warmed to room temperature, evaporated in vacua and chromatographed on silica gel to yield 2.32 g of the title compound. my 145--146 (from ethyl acetate/
hexane) Max (CDCl3) 1795, 1743 cm 1 (CDCl3) 0.06 (OH, s) 0.85 (OH, s) 1.31 (OH, d, J6Hz) 2.25 (OH, s) 2.40 (OH, s) 3.53 (OH, Ed, J3B,4~ 2Hz~ J3B/SiOCH
3Hz, 3-H) 4.08 - 4.50 (OH, m) 5.37 ohs 6.28 (OH, d, 4-H) 7.45 - 8.42 (OH, m) Example 15 4-Nitrobenzyl ! 5S,6S) 6-(~(R)-dimethyl-2-methyl-prop-2-yl}silyloxy~ethyl)-7-oxo-4-thia-3-thioxo-1--azabicyclor3,2,0]hept-2-ane-2-carboxylate To a stirred solution of 0.741 g of 4-nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4R)4-chloro-3-(1(R)-~dimmethyl-~2-methylprop-2-yl~ silyloxy3 ethyl-2-azetidinon-1-yl]-preappoint in 20 ml of dioxin and 2 ml of water was added 0.247 g of imidazole. After 20 minutes the solution was diluted with 120 ml of ethyl acetate and extracted with dilute hydrochloric acid, followed by brine. The organic phase was dried over McCoy and evaporated in vacua to give the title compound in quantitative yield.
Max (liquid film) 1793, 1755 cm 1 tCDC13) 0.11 (OH, s) 0.89 (OH, s) 1.41 (OH, d, J6Hz) 3.96 (OH, Ed, JOB Seiko OH 6B,5B
9Hz, 6-H) 4.13 - 4.63 (OH, m) 5.25 - 5.48 (OH, m) 5.36 (OH, s) 6.05 (lo, d, 5-H) 7 37 - 8.45 (OH, m) Example 16 4-Nitrobenzyl 5(R),3-ethylthio-6-(S)-~8(R)-hydroxy-ethyl oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene 2-carboxylate To a stirred solution of 0.1~ g of 4-nitrobenzyl (5R,6S)-~1'(R)-hydroxyethyl3-7-oxo-~-thia-3-thioxoo-1-azabicyclo [eighteen 2-carboxylate in 10 ml of dry twitter-hydrofuran was added 0.094 ml of ethyl disopropylamine followed by 0.119 ml of iodoethane. When the reaction was shown to be complete (by means of thin layer chrome-tography) the solvent was removed in vacua and the residue chromatographed on 10 g of silica gel (eluding with ethyl acetate-hexane) to give 0.14 g of the title compound.
Example 17 Potassium 5(R), 3-ethylthio-6(S)-~8(R)-hydroxyethyl-~
7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene 2-carboxylate To a solution of 0.139 g of 4-nitrobenzyl 5(R), 3-ethylthio-6(S~-~1(R)-hydroxyethyl~-7-oxo-~-thia ~-azabicyclo [eighteen 2-carboxylate 15 ml of ethyl acetate was added 15 ml of an aqueous solution of 0.034 g of potassium bicarbonate followed by 0.28 g of palladium on charcoal. The mixture was hydrogenated at 50 psi for one hour then filtered through '~YFI,O' which is a trade mark for a filtration aid. The aqueous phase was extracted once with 10 ml of fresh ethyl acetate and then hydra-lucid to give 0.06 g of the title compound.

lZl~ 8 Example 18 4-Nitrobenzyl 2-(4(R)~ethylthio-3(S)-[1'(R)-dimethyl [2-methylprop-2-yl]silyloxyethyl]-2-azetidinon-1-yyule-(4-oxo-1,3-dithietan -2-ylidene)acetate A solution of lithium hexamethyldisilazide was prepared by the addition of n-butyllithium in hexane (4.21 ml of a 1.6M solution) to 2.13 ml of hexamethyl-disilazane in 10 ml of dry tetrahydrofuran at 0C while stirring under nitrogen. The solution was added via a Connally to a solution of 1.08 g of 4-nitrobenzyl 2-~4(R)-ethylthio-3(S)-[1'(R)-dimethyl-~2-methylprRipley silyloxyethyl]-2-azetidinon-1-yl)acetate in 10 ml of dry tetrahydrofuran at -78C, with stirring under nitrogen.
After 5 minutes, 0.35 ml of carbon disulphide was added by syringe and after a further 90 minutes phosgene in Tulane (3.56 ml of a 12.5 % solution) was added by syringe. The mixture was stirred for 90 minutes and poured into 50 ml of deathly ether and 10 ml of EM acetic acid. The organic layer was separated, washed with water, 12 sodium chloride solution, dried over magnesium sulfite and evaporated to give an orange oil. Chromatography over silica gel using deathly ether/
hexane mixtures as fluent gave 0.485 g of the title compound in purified form.
of ax (CDC13) 1770, 1760 cm 6(CDCl3) 0.04 (OH, s) 0.81 (OH, s) 1.18 (OH, t, J = 7 Ho) 1.22 (OH, d, J = 7 Ho) 2.51 (OH, q, J = 7 Ho) 3.18 (OH, dud, J = 2.7 and 3.7 Ho) 4.24 (OH, do, J = 2.7 and 7 Ho) 5.31 (OH, d, J = 2.7 Ho) 5.23, 5.45 (OH, ABE J = 13 Ho) 7.55, 8.23 (OH, AHAB, J = 9 Ho) . . .

I

Example 19 4-Nitrobenzyl-2-(4(R)-ethyl-thio-3(S)-[1'(R)-hydroox-ethyl]-2-azetidinon-1-yl)-2-(4-oxo-1,3~dithietan-22-ylidene) acetate 0.30 g of 4-Nitrobenzyl 2-(4(R)-ethylthio-3(S)-[1(R)-dimethyl~2-methylprop-2-yl}silyloxyethyl]-2--azetidinon-1-yl)-2-(4-oxo-1,3-dithietan-2-ylidene)) acetate was dissolved in 4 ml of dry DMF containing a trace of -queenly under a nitrogen atmosphere protected from light. The solution was treated with 5 mow equivalent of hydrogen chloride in 2.2 ml of DMF. The solution was stirred for 4 hours and diluted with 5 ml of water, poured into 20 ml of deathly ether and the organic layer separated. The aqueous portion was no-extracted with a further volume of deathly ether and the organic fractions combined washed with water, dried over magnesium sulfite and evaporated to give a yellow oil. Chromatography over silica gel using deathly ether/
hexane mixtures as eluant gave 0.21 g of the title compound in purified form.

Max (CDC13) 34 50, 1785, 1760 cm 1, o (CDCl3; 1.13 OH t, J = 7 Ho 1.18 (OH, d, J = 7 Ho) 2.39 (OH, by s) 2.51 (OH, q, J = 7 Ho) 3.17 (OH, dud, J = 2.7 and 3.3 Ho) 4.22 (OH, m) 5.24 (OH, d, J = 2.7 Ho) 5.29 (OH, s) 7.52, 8.17 (OH, AHAB, J = 9 Ho) Example 20 4-Nitrobenzyl 2-(4(S)-chloro-3(S)-[1'(R)-hydroxyethyl]-2-azetidinon-1~ 2-(4-oxo-1,3-dithietan-2-ylidene)_ acetate X

~2~118 A solution of 0.208 g of 4-nitrobenzyl 2-(4~R)-ethylthio-3(S~-[1'(R)-hydroxyethyl]-2-azetidinon-1yule-(4-oxo-1,3-dithietan-2-ylidene)acetate in 1 ml of ethanol-free chloroform was cooled to -30C under a nitrogen atmosphere and treated with 1.1 mow equivalent of chlorine in 0.82 ml of carbon tetrachloride. The reaction mixture was permitted to warm to room tempera-lure and the solvent evaporated in vacua. Chromatography on silica gel using deathly ether/hexane mixtures as 10 eluant gave 0.015 g of 4-nitrobenzyl 2-(4(R)-chloro-3(S)-[1(R)-hydxoxyethyl]-2-azetidinon-1-yl-2-(4-oxo-1,33-dithietan-2-ylidene)acetate and 0.03 g of the title compound.

Mecca (CDCL3) 1775 cm 1.

(CDC13) 1.45 (OH, d, J = 6.3 Ho) 3.59 (OH, dud, J = 4.4 and 9.3 Ho) 4.37 (OH, m) 5.33, 5.40 (OH, ABE J = 13 I
6.08 t1H, d, J = 4.4 Ho) 7.53 , 8.27 I AHAB, J = 8.6 Ho) Example 21 4-Nitrobenzyl (OR, US) 6-(8(R)-hydroxyethyl)-7=
oxo-~-thia-3-thioxo-1-azabicyclo[3,2,0]hept-2-ane--2-carboxylate To a solution of 0.028 g 4-nitrobenzyl 2-(4(S)-chloro-3(S)-[1'(R)-hydroxyethyl]-2-azetidinon-1-yll-2-30 (4-oxo-1,3-dithietan-2-ylidene)acetate in 1 ml of 10 %
aqueous Dixon at 5C was added a trace of imidazole.
When the reaction was complete the solution was diluted with deathly ether and water, acidified with dilute hydrochloric acid and extracted. The aqueous phase was extracted with a second volume of deathly ether and the organic portions combined, washed with water, 12 %

r Jo sodium chloride solution, dried over magnesium sulfite and evaporated to give 0.01 g of crude product. Comparison of its NOR spectrum with that of the product of example 7 proved the existence of the title compound in the product mixture.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula IIa, lIb or IIc IIa IIb IIc wherein R represents a carboxyl esterifying group removable by hydrolysis, photolysis, reduction or enzyme action to give the free acid, R1 represents a chlorine or bromine atom R2a and R2b, which may be the same or different, each represents an alkyl group having from 1 to 4 carbon atoms, an aryl group, and A represents a direct bond or the residue of a dicarboxylic acid, in which a compound of the general formula IIIa, IIIb or IIIc IIIa IIIb IIIc wherein R; R?,R? and A are as defined above, and R3 represents an alkyl group having from 1 to 8 carbon atoms, or an alkenyl group having up to 6 carbon atoms, is halogenated to give a compound of the formula IIa, IIb or IIc.

2. The process as claimed in claim 1, wherein R3 is an ethyl group or an allyl group.

3. A compound of the general formula IIa, IIb or IIc IIa IIb IIc wherein R represents a carboxyl esterifying group removable by hydrolysis, photolysis, reduction, or enzyme action to give the free acid R1 represents a chlorine or bromine atom, R? and R?, which may be the same or different, each represents an alkyl group having from 1 to 4 carbon atoms, an aryl group, and A represents a direct bond or the residue of a dicarboxylic acid, whenever obtained according to the process as claimed in claim 1 or claim 2 or by an obvious chemical equivalent thereof.