NOVEL 2-SP ROCYCLOPROPYL CEPHALOSPORINSϋLFONE DERIVATIVES AND

PROCESSES FOR THE PREPARATION THEREOF

The present invention relates to novel 2-spirocyclopropyl cephalosporin sulfone derivatives and to processes for their preparatio .

BACKGROUND OF THE INVENTION

Emphysema is an abnormal- and irreversible enlargement of the air spaces around the bronchioles caused by chronic inflammation. It is also characterized by the destruction of the alveolar walls of the lungs. As the damage to the alveolar walls increases the lungs lose their elasticity. The progressive symptoms include shortness of breath upon minimal exertion, frequent respiratory infections and chronic cough. Emphysema is considered to be one of the chronic pulmonary diseases. The hydrolytic action of the enzyme human leukocyte elastase (HLE) on the connective tissue component elastin is believed to be the cause of pulmonary emphysema. Like other serine proteases, elastase may be inactivated by inhibitors which block the active site of the enzyme by binding tightly thereto. Under normal conditions, these enzymes are prevented from causing damage by the action of the natural inhibitor α^-antitrypsin, which is a glycoprotein present in human serum.

It would appear that the inflammation caused by cigarette smoke provokes the release of a large amount of leukocyte

elastase and hence an imbalance between the two enzymes results. The quantity of α^-antitrypsin present is thus insufficient to inhibit enough of the luekocyte elastase.

Consequently the excess elastase begins adhering to the surfaces of elastin fibers in the lungs. This eventually leads to the lung damage characteristic of emphysema.

Additionally, it is believed that the action of cigarette smoke functions to inactivate the α^-antitrypsin. Also an α- _j -antitrypsin deficiency may be caused by hereditary factors. Cephalosporin drugs are widely used for the treatment and prevention of various infectious diseases caused by pathogenic bacteria.

U.S. Patent 4,547,371, discloses that certain substituted cephalosporin sulfones demonstrate potent elastase inhibitory effects. U.S. 4,711,886, describes β-laσtam derivatives which are found to be potent elastase inhibitors. U.K. Patent Application GB 2,198,640A, relates to penicillin derivatives useful as anti-inflammatory and anti-degenerative agents. An article in Nature Vol. 322, 10 July 1886, by J.B. Doherty et al. illustrates that cephalosporin antibiotics can be modified to inhibit human leukocyte elastase. Additionally, a study of 1,3-dipolar cycloaddition reactions of cephalosporin derivatives is provided in a paper entitled, "Cycloaddition Reactions of Cephalosporin Compounds XI" by J. Pitlik et al, J. Heterocvcliσ Chem.. 26, 461 (1989).

DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided novel 2-spirocyclopropyl cephalosporin sulfones

SUBSTITUTE SHEET

having anti-elastase activity. Such derivatives, or elastas inhibitors, are useful in the prevention, control an treatment of inflammatory conditions, particularly rheumatoid arthritis, osteoarthritis, cystic fibrosis and emphysema. More specifically a 2-spirocyclopropyl cephalosporin sulfone derivative of the structural fσrmual (I) is provided.

wherein R ₁ in formula (I) represents 0R ₆

Where R ₆ is C _ ₆ alkyl; C,_ ₆ alkenyl; C,. ₆ alkynyl; C^ alkanoyl C^ alkyl; C,^ alkanoyl oxy C,_ ₆ alkyl; C^. ₆ alkoxy C^ alkyl; C ₃ . ₆ cycloalkyl; halo C^ alkyl; aryl; aralkyl; or a heterocyclic group. These groups can be unsubstituted or can be substituted by one or more groups such as chloro, bromo, fluoro, hydroxy, alkoxy, mercapto, amino, substituted amino, nitro, cyano, carboxylic acid and carboxylate, sulfinyl, sulfonyl, alkanoyloxy, carbamoyloxy, alkanoyl carboxamides and N-subsituted carboxamides.

SUBSTITUTE SHEET

R., in formula (I) also represents NR ₇ R ₈ , wherein R ₇ is the same as R ₆ , and R _β is the same as R ₆ or hydrogen.

I n l-h" formula NR R , R_ and R_ may together form part o a heteroaromatic ring selected from a group consisting of :

These ring systems can be further substituted by the groups as mentioned above.

In addition R ₇ and R may form part of a heterocyclic ring '& ) containi 3 \o 7 carbon atoms, which may in addition also contain at least one hete atom such as N, S, and 0.

Representative examples of such groups are:

-N N -j— COOII , -N

- ^" ,0 -N s— Ho)_ n = 0, 1 and 2

These rings can be further substituted at the carbon or at the nitrogen a by the groups mentioned above.

Furthermore, the moiety NR.-.R., may represent an amino acid, a dipeptide or a tripeptide moiety.

SUBSTITUTE SHEET

Preferably R ₆ and R ₇ are substituted or unsubstituted straight or branched loweralkyl, straight or branched loweralkenyl, cycloalkyl, haloalkyl, aryl> aralkyl, alkoxyloweralkyl, alkanoylloweralkyl, alkanoyloxyloweralkyl; and _g is the same as R ₆ or hydrogen.

Preferred examples of such groups are methyl, ethyl, t-butyl, allyl, methoxyethyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzy1, 2,2,2-trichloroethy1, pyrrolidine carboxamide, piperidine carboxamide, and the like. R ₂ is hydrogen, chloro, hydroxy, C_ _i _ _& alkyl, ,^ alkenyl, C^ _g alkynyl, cycloalkyl, C ₁ . ₆ alkoxy, trifluoromethyl, aldehyde, carboxylic acid; or

-CH ₂ X wherein X is hydroxy, chloro, bromo, fluoro, C,^ alkoxy, C ₂ . ₆ alkanoyloxy; arylcarbonyloxy; amino; -NHC, ₁ . ₆ alkyl; -H (C^_ ₆ alkyl) ₂ ; or a quaternary ammonium group (for example NH ₃ , NHZ ₂ , NZ ₃ where Z represents lower alkyl, aryl or aralkyl) ; -C0NH ₂ ; -C0NHC _M . ₆ alkyl; -CON C,^ alkyl) ₂ ; -OCONH ₂ or -OCONHC,_ ₆ alkyl; or -SCO where R _g is C,_ ₆ alkyl, phenyl, -CH ₂ phenyl, saturated or unsaturated monocyclic or fused polycyclic 3-8 membered heterocyclic ring.

When CH ₂ X is hydroxymethyl, the cephalosporin can also exist as the lactone which is formed by internal esterification with the adjacent carboxyl group.

In the formula CH ₂ X when X is amino, the cephalosporin compound can also exist in the lactam form by loss of water with the adjacent carboxyl group.

R ₂ can also be represented by the formula -CH ₂ YR _a where

SUBSTITUTE SHEET

Y is oxygen; sulfur; or nitrogen. R _a is an acyl group, a straight or branched loweralkyl; alkenyl; alkynyl; aryl; aralkyl; or a heterocyclic group such as heteroaryl, heterocycloalkyl. These groups can be substituted by one or more functional groups, such as alkyl, alkoxy, halo, cyano, carboxy, haloalkyl, amino, substituted amino, hydroxy, carboxyalkyl, carbamoylalkyl, sulfinyl, sulfonyl or the like.

In the formula -CH ₂ YR _a , when Y is nitrogen, R _a may represent the residue of amine. The term "the residue of an amine" for R _a includes aliphatic, aromatic and heterocyclic primary amino residues, suitable aliphatic amino primary residues include for example, C^ ₆ alkylamino; C_,_ ₆ cycloalkylamino. Suitable primary aromatic amino residues include for example, arylamino and aryl C.,_ ₆ alkylamino. Suitable secondary aliphatic amino residues include, for example, di C,^ alkylamino. Suitable secondary aromatic amino residues include for example, diarylamino and bis aryl C-,_ ₆ alkyl amino. In the formula -CH ₂ YR _a , Y may also be nitrogen which is part of the heterocyclic system, for example, morpholino, 4-methyl (or ethyl) piperazino, pyrrolidino, piperidino, pyridinium, etc.

Some representative examples of such groups are aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 1,2,3-triazol-l-yl-methyl, 1,2,4-triazol-l-yl-methyl, triazoles substituted with one or more functional groups consisting of chloro, fluoro, bromo, hydroxy, carboxy, carbomethoxy, carboethoxy, hydroxyalkyl, cyano, amino, substituted amino, and the like.

SUBSTITUTE SHEET

Some representative examples of quaternary ammoniu groups are:

In the formula -CH ₂ YR _a when Y is sulfur, R _a may b hydrogen or the residue of a thiol compound H _j ,. The term "residue of a thiol compound" means a residue obtained b omitting the hydrogen atom from a thiol compound HR _b . Suitable residues of thiol compounds include a cyclic o acyclic aliphatic thiol, aromatic thiol, or heterocyclic thiol compound. Suitable aliphatic thio groups include: straigh or branched chain alkylthio having from 1 to 20 carbon atoms, especially methyl, ethyl, isopropyl, t-butyl, pentyl, hexyl, etc.; cycloalkylthio having from 3 to 8 carbon atoms, especially cyclopropyl, cyclobutyl, cyclopentyl, etc.; alkenylthio having from 2 to 20 carbon atoms especially C ₂ . ₆ alkenyl, such as vinyl, allyl, etc.; and alkynylthio having from 2 to 20 carbon atoms, especially C ₂ . ₆ alkynyl, such as ethynyl, propynyl or hexynyl, etc.

Suitable aromatic thio groups include: arylthio having from 6 to 10 carbon atoms, especially phenyl, for example, phenylthio. Phenyl can be substituted, for example, tolylthio;

SUBSTITUTE SHEET

aralkylthio, for example, benzylthio. Suitable heterocyclic thio groups include onoheteroaryl, di- or polyheteroaryl, or fused heteroaryl containing from 1 to 3 of any one or more of the heteroatoms N, S, or 0, in each heteroaryl ring. Examples of such heteorcyclic groups that might be mentioned are: unsaturated 3 to 8 membered heteromonocyclic systems containing 1 to 4 nitrogen atoms, for example, pyrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its

N-oxide, pyrimidyl, pyrazinyl, triazolyl (e.g. 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc) and tetrazolyl (e.g. lH-tetrazolyl, 2H-tetrazolyl, etc) saturated 3 to 8-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms may include, for example, pyrrolidinyl, imidazolidinyl, piperidino, or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms may comprise, for example, indolyl, quinolyl, benzimidazolyl, or benzotriazolyl; saturated 3 to 8-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms may comprise, for example, morpholinyl; unsaturated 3 to 8-membered heteromonocyclic groups containing an oxygen atom would be furyl, for example; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms may include, for example, benzoxazolyl, benzoxadiazolyl; or unsaturated 3 to 8-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, could comprise thiazolyl, thiadiazolyl, e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl.

A typical saturated 3 to 8-membered heteromonocyclic

SUBSTITUTE SHEET

group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atom would be for example, thiazolidinyl. An example of a unsaturated 3 to 8-membered heteromonocyclic group containin a sulfur atom would be thienyl. Unsaturated condense heterocyclic groups containing 1 to 2 sulfur atoms and 1 t 3 nitrogen atoms may be selected from benzothiazolyl, benzothiadiazolyl or the like.

The above mentioned heterocyclic groups may be substituted with 1 to 6 appropriate substituents such as ,^ alkyl radical (e.g. methyl, ethyl) , or a C,.. ₆ alkoxy radical (e.g., methoxy, ethoxy) , or a halogen atom (e.g., fluorine, chlorine, bromine), or an aryl radical (e.g. phenyl, tolyl) , or a substituted aryl radical (e.g. chlorophenyl, nitrophenyl) , or a cyano group, or an amino group, or a hydroxy group, or the like.

In the formula CH ₂ YR _a when Y is sulfur, it is also to be understood that the -S- group may be present in the sulfoxide or the sulfone form, like:

O O

11 « -S- -S-

II

(α or β) O

The preferred groups representing R ₂ are: hydrogen, chloro, hydroxy, methoxy, methyl, trifluoromethyl, cyclopropyl, vinyl, acetoxymethyl , methoxymethyl , methyl thiomethyl , - loromethyl, bromomethyl, benzoyloxymethyl , carbamoyloxymethyl, (N-methylcarbamoyl) oxymethyl,

(N-ethylcarbamoyl) oxymethyl, hydroxymethyl , N,N-dimethyl- thiocarbamoylthiomethyl , N , N-diethylthiocarbamoyl thiomethyl ,

N-methylpiperazinium-1-thiocarbonylthiomethyl,

SUBSTITUTE SHEET

N,N-dimethylpiperaz in ium-1-thiocarbonyl thiomethyl , ( 5 -methyl -1, 3 , 4-thiadiazol-2-yl) thiomethyl,

1-methyl-l ,2,3, 4-tetrazolyl-5-thiomethyl .

More preferably R ₂ is: hydrogen, chloro, hydroxy, methoxy, methyl, trifluoromethyl, cyclopropyl, vinyl, methoxymethyl , ethoxymethyi , chloromethyl, bromomethyl, hydroxy methyl, acetoxymethyl , carbamoyloxymethyl ,

(N-methylcarbamoyl) oxymethyl , (N-ethylcarbamoyl) oxymethyl , acylthio,

SUBSTITUTE SHEET

The substituents R ₃ and R in formula (I) may be the sa or different and may comprise hydrogen; straight or branch loweralkyl; straight or branched loweralkenyl; cycloalky haloalkyl; hydroxyalkyl; alkoxyloweralkyl, alkanoyl1oweralky alkanoyloxyloweralkyl; aryl; aralkyl; -COOH; -CH ₂ COOH; -COOC, alkyl; alkyl; trifluoromethyl; unsubstituted substituted phenylthio C ₁ . ₆ alkyl; phenylsulfonyl ^_ ₆ alkyl; monocyclic (or fused polycyclic) saturated or unsaturat heterocyclic group containing from 1 to 3 of any one or mo of the heteroatoms N, S or 0 in each heterocyclic ring heteroarylalkyl such as 2-pyridylmethyl, 2-thienylmethyl o the like.

The above groups can be further substituted with one o more groups such as alkyl, alkoxy, hydroxy, halogen haloalkyl, hydroxyalkyl, nitro, amino, substituted amino cyano, arboxy, acyloxy, carboxamido, sulfinyl, sulfonyl, etc

More preferably R ₃ and R _A are: hydrogen; C,^ alky especially methyl, ethyl, isopropyl, t-butyl, n-pentyl; hal C^ alkyl especially chloromethyl, fluoromethyl; cyclopropyl phenol, p-chlorophenyl, p-fluorophenyl, benzyl p-carbomethoxybenzyl, p-carbomethoxyphenyl, trifluoromethyl -COOH, -CH ₂ COOH, -CH- _j COOC^ alkyl especially -CH ₂ COOCH ₃ -CH ₂ COOEt, pyridyl, thienyl, furyl, isoxazolyl, and the like

SUBSTITUTE SHEET

The substituent R _g in formula (I) can be hydrogen, or a halogen (e.g., chloro, bromo or fluoro) , or a hydroxy group or C^ alkoxy especially methoxy, ethoxy, propoxy; C,_ ₆ alkylthio especially methylthio, ethylthio; a lower alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl; a lower alkane sulfonyl group such as methane sulfonyl, ethane sulfonyl; an acyloxy group. The "acyl group" can lower alkanoyl group of 2 to 6 carbon atoms such as COCH ₃ , COC ₂ H ₅ or Further examples of "acyl" groups include halolower- alkanoyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl. Suitable examples of acyloxy may also include, for example, methane sulfonyloxy, trifluoromethane sulfonyloxy, benzenesulfonyloxy, toluene sulfonyloxy or the like. The substituent _g can be represented by the formula: R^NH, where R represents a substituted or unsubstituted aliphatic, aromatic or heterocyclic, araliphatic or heterocyclylaliphatic carboxylic acid radical known in the penicillin and cephalosporin art. In the formula R^NH, „ may represent hydrogen; or

l[substituted or unsubstituted]

and n is an integer of 0 to 2, preferably 2. Representative members of sulfonamido group are: phenyl- sulfonamide, trifluoromethane sulfonamide, methyl

SUBSTITUTE SHEET

sulfonamide, ethyl sulfonamide, and the like.

The carboxylic acid radicals can be represented by th general formula

O

II R ₁₂ -(CH ₂ ) _n -C wherein n is 0, 1 or 2 and R ₁₂ is:

(a) straight or branched chain alkyl having from 1 to 20 carbon atoms, especially methyl, ethyl, trifluoromethyl; (b) aryl having from 6 to 10 carbon atoms, especially phenyl, substituted phenyl;

(c) monoheteroaryl, di- or polyheteroaryl, or fused heteroaryl containing from 1 to 3 of any one or more of the heteroatoms N, S or 0 in each heteroaryl ring such as thienyl, furyl, pyridyl, isothiazolyl, imidazolyl, isoxazolyl and the like; or

(d) hydrogen.

The above groups can be substituted with one or more functional groups such as alkyl, alkoxy, halo such as fluoro, chloro, bromo, iodo, cyano, carboxy, carbamoyl, sulfonyl, amino, substituted amino such as monoalkylamino, dialkylamino, haloalkyl, carboxyalkyl, carbamoylalkyl, guanidino.

Representative examples of such acyl groups are: methyl, ethyl, cyanomethyl, trifluoromethyl, dichloromethyl, benzyl, p-hydroxybenzyl, 2-furylmethyl, 2-thienylmethyl.

The carboxylic acid radical can also be represented by the general formula:

SUBSTITUTE SHEET

R ₁₂ -X-(CH ₂ ) _n -CO wherein X is 0 or S and R ₁₂ and n are as previously defined.

Representative examples of such acyl groups are: phenoxymethyl, phenylthiomethyl, phenoxyethyl, 4-pyridylthiomethyl, p-(carboxy ethyl)phenoxymethyl, 2-thiazolylthiomethyl.

Preferably ₅ is: hydrogen, chloro, bromo, fluoro, hydroxy, methoxy, ethoxy, methylsulfonamido, ethylsulfonamido, trifluoromethyl sulfonamide,

R ₁₂ -(CH ₂ ) _n CO-

where R ₁₂ is hydrogen, methyl, trifluoromethyl, cyanomethyl, phenyl, thienyl, furyl; and n is 0 or 1; or R ₁₂ -X-(CH ₂ ) _n CO wherein X is oxygen or sulfur and R ₁₂ and n are as defined before.

More preferably, R ₅ is hydrogen, chloro, bromo, fluoro methoxy, ethoxy, methylsulfonamido, trifluoromethyl sulfonamide, methanesulfonyloxy, trifluoromethane sulfonyloxy. m is 0, 1 or 2, preferably 2.

The partial structure represented by the formula:

SUBSTITUTE SHEET

is to be understood to include both the regio isomers as represented by the formula

Furthermore, it should be noted that when R ₃ and R ₄ in formula (I) are different they may be present in the form of an optical isomer, for example, 1-, d- or dl- forms.

More specifically the most preferred embodiments of the present invention comprise the following compounds:

Benzhydryl 7α-chloro-2-spiro (2• ,2'-diphenyl) cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide;

Benzhydryl 7α-bromo-2-spiro (2• ,2'-diphenyl) cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide;

Benzhydryl 7,7-dihydro-2-spiro 2' ,2*-diphenyl) cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide; t-Butyl 7α-bromo-2-spiro (2',2'-diphenyl) cyclopropyl-3-methyl-3cephem-4- ^* -carboxylate-l,1-dioxide;

Benzhydryl 7α-bromo-2-spiro

[2• ,2'-(4' ,4 ^» -dichloro)diphenyl] cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide;

SUBSTITUTE SHEET

Benzhydryl 7α-bromo-2-spiro [2•,2*-(4' ,4'-difluoro) diphenyl] cyclopropyl-3-methyl-3-cephem-4- carboxylate-1,1-dioxide; t-Butyl 7α-chloro-2-spiro (2' ,2'-diphenyl) cyclopropyl-3 acetoxymethyl -3-cephem-4-carboxylate-l,1-dioxide; Benzhydryl

7α-bromo-2-spiro (2'-ethoxycarbonyl) cyclopropyl-3- methyl-3-cephem-4-carboxylate-l,1-dioxide; Benzhydryl 7α-bromo-2-spiro (2•-phenyl,2*-methyl) cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide; Benzhydryl 7α -bromo-2-spiro .(2'-phenyl) cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide; Benzhydryl-7α-methoxy-2-spiro (2• ,2'-diphenyl) cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide; 2,2,2-Trichloroethyl-7α-methoxy-2-spiro (2• ,2'-diphenyl) cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide;

7α-Methoxy-2-spiro (2• ,2'-diphenyl) cyclopropyl-3-methyl-3- cephem-4pyrrolidine carboxamide-1,1-dioxide; 7α-Methoxy-2-spiro (2' ,2•-diphenyl) cyclopropyl-3-methyl- 3-cephem-4-piperidine carboxamide-1,1-dioxide; 2,2,2-Trichloroethyl-7α-ethoxy-2-spiro (2' ,2'-diphenyl) cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide; 7α-Bromo-2-spiro (2• ,2•-diphenyl) cyclopropyl-3-methyl-3- cephem-4-pyrrolidine carboxamide-1,1-dioxide; p-Methoxybenzyl 7α-bromo-2-spiro (2',2'-diphenyl) cyclopropyl-3-chloromethyl-3-cephem-4-carboxylate-l, 1-dioxide; Benzhydryl 7α-bromo-2-spiro [2',2'- (4' ,4'-dichloro)diphenyl] cyclopropyl-3- [[(5-methyl-l,3,4-thiadiazol-2-yl) sulfonyl] methyl]-3- cephem-4-carboxylate-l,1-dioxide;

SUBSTITUTE SHEET

7α-methoxy-2-spiro(2' ,2•-diphenyl)cyclopropyl-3-methyl-3- cephem-4-[2-(s)-t-butoxycarbony1 pyrrolidine carboxamide]- 1,1-dioxide; and 7α-methoxy-2-spiro(2• ,2'-diphenyl) cyclopropyl-3-methyl-3-cephem-4-(N-methyl piperazine carboxamide)-1,1-dioxide.

In accordance with a second broad aspect of the invention, there is provided a process for preparing 2-spirocyclopropyl cephalosporin sulfone derivatives of thestructural formula I which comprises the following steps (Scheme I) .

^β

Co _j

₍ 1 _{) p} rovi _d ing a compound having the structural formula II

SUBSTITUTE SHEET

(2) esterifying the compound of formula II to thereby protect the carboxy group thereof and provide a compound having the structural formula III;

(3) halogenating the compound of formula III to provide a compound having the structural formula IV; „

co?*.

(4) oxidizing the compound of formula IV to provide a compound having the structural formula V;

(5) aninomethylating the compound of formula V to provide a compound having the structural formula VI; and

(6) carrying out a cycloaddition reaction ot th compound of the structural formula VI to provide a compoun having the structural formula I.

SUBSTITUTE SHEET

Altermatively steps (2) and (3) may be conducted in reverse order.

The following synthetic routs are useful in preparing the compound having the structural formula (I) :

SCHEME I

SUBSTITUTE SHEET

There is also provided a method for preparing 7- substituted cephalosporin derivatives which comprises the following steps: (Scheme II) (1) providing the compound having the formula VII;

(2) treating the compound VII with an appropriate alcohol (e.g., methanol, ethanol, etc.) to provide a compound having the formula VIII;

Co VIII

(3) oxidizing the compound VIII with a suitable oxidizing agent (e.g., m-chloro peroxy benzoic acid, peracetic acid, etc.) to provide a sulfoxide having the formula IX;

cop

SUBSTITUTE SHEET

(4) heating the compound IX with a suitable mercaptan (e.g. , 2-mercaptobenzothiazole) in a suitable organic solvent (e.g., benzene, toluene, etc.) to provide the compound having the formula X

Cθ ^* ? ₍ (5) treating the compound X with a suitable halogenating agent (e.g., chlorine, bromine, etc.) to provide a compound having the formula XI

(6) treating the compound XI with an organic base (e.g., pyridine, triethylamine, etc.) in a solvent like dimethyl sulfoxide to provide the 7- - substituted cephalosporin derivative having the formula XII

Alternatively cephalosporin derivative XII can also be obtained by heating the sulfoxide IX with acetic anhydride in dimethyl formamide

SHEET

The following synthetic routes are sueful in preparing the 7 -~ -substituted cephalosporin derivative XII

(Scheme II)

SCHEME ll

_^ -^E^^^ f .- ^•• • Ti

CoR,

-I

^■ I

R.

SUBSTITUTE SHEET

cog.

CO&

SUBSTITUTE SHEET

Esterification or Amidation

The carboxyl group of compound II can be protected according to the conventional methods described in the cephalosporin and penicillin literature, for example, a suitable salt of the compound II may be reacted with an alkyl halide, such as, benzyl bromide, 4-nitrobenzyl bromide, methyl iodide, allyl bromide or the like. The salts of compound II may be salts with an inorganic base such as alkali metal salts (e.g., sodium or potassium) or an alkaline earth metal salt (e.g., calcium or magnesium), the hydroxide, carbonate or bicarbonate thereof, a salt with an organic base such as trimethylamine, triethylamine, pyridine, N,N-dialkylamine, 1,5-diazabicyclo[4,3,0]non-5-ene,1,4-diazabicyclo[2,2,2]-oc tane, l,8-diazabicyclo[5,4,0]undec-7-ene etc.

The carboxyl group of compound II can also be converted into an ester by other alkylation methods, for example, by treatment with diazomethane or diphenyldiazomethane or the like.

The carboxyl group can be converted to an ester by treatment with a lower alkanol e.g., methanol, ethanol in the presence of a catalyst such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, trichloracetic acid, trifluoroacetic acid, or p-toluenesulfonic acid and a Lewis acid. Suitable Lewis acids for this reaction include, for example, boron halide (e.g., boron trichloride, boron trifluoride, titanium halide (e.g., titanium chloride, titanium bromide), stannic

SUBSTITUTE SHEET

halide, aluminium halide, zinc chloride, ferric chloride and the like.

Treatment with a lower alkene (e.g., isobutylene) , in the presence of a suitable acid catalyst (e.g., sulfuric acid) is also a preferable method of protecting the carboxyl group.

Esterification can also be carried out in the presence of a conventional condensing agent such as N,N-dicyclohexylcarbodiimide, N,N-diethylcarbodiimide, N,N-diisopropylcarbodiimide, or N,N-carbonyldiimidazole. Another method of esterification (also suitable for amidation) is by conversion of the carboxyl group to a suitable reactive derivative followed by reaction with an appropriate alcohol (or amine) . Suitable reactive derivatives of the carboxyl group may include an acid halide, a mixed or symmetrical anhydride, an activated amide or the like. A suitable example may be an acid chloride or bromide via treatment with a halogenating agent such as thionyl chloride, phosphorus pentachloride or phosphorus oxychloride.

The reactions are usually carried out in a conventional solvent such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N— dimethylformamide or any other organic solvent which does not adversely influence the reaction.

An interesting class of amides is that where the amine reactant is an amino acid or a peptide. The amino acid may be one of the naturally occurring amino acids, glycine.

SUBSTITUTE SHEET

alanine, valine, leucine, isoleucine, serine, threonine, cysteine, cystine, methionine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, phenylalanine, tyrosine, proline, hydroxyproline and tryptophan, or peptides containing or made from these amino acids. Of particular interest are amides made from amines which are dipeptides, such as proline-alanine, proline- valine, and proline-glycine.

The procedure used to prepare amides wherein the amine reactant is an amino acid or peptide is essentially the same as that used for the preparation of peptides. Such procedures are well known to those skilled in the art and involve the selective protection of end groups, a coupling step to form the peptide or amide bond, and a deprotection step. For example, dipeptides are prepared by activation of the carboxyl group in an N-protected amino acid (using Z or Boc as the blocking group) and adding an amino acid ester to the activated carboxyl group (the C-protecting group is an alkyl or benzyl ester) . Tri- and higher peptides are prepared in a similar manner. It is noted that the carboxylic acid corresponding to the compound of formula I (R^OH) may optionally contain an amino group, which, if present, would be protected as is customary in peptide synthesis.

Haloqenation It should be noted that when it is appropriate the compound II can be halogenated first and then subjected to esterification according to the procedures as described

SUBSTITUTE SHEET

before.

The compound IV, wherein R _j is a halogen, can be prepared by subjecting the amino group of compound II to the diazotization reaction in accordance with conventional methods in the presence of a hydrogen halide or a metal halide. Suitable hydrogen halides used in the present reaction include, for example, hydrogen chloride, hydrogen bromide, or hydrogen iodide and suitable metal halides include sodium bromide, potassium bromide, or cupric chloride. The present reaction is preferably carried out under mild conditions such as under cooling, at ambient or slightly elevated temperatures.

Oxidation The compound V in the present invention can be prepared by oxidizing the compound IV. The present oxidizing reaction is carried out under conditions wherein the -S- group can be converted to the sulfoxide or sulfone, most preferably to the sulfone. Typical oxidizing agents can be utilized such as for example, phenyliododichloride, ozone, isocyanuroyl chloride, periodic acid, perbenzoic acid, m-chloroperbenzoic acid, performic acid, peracetic acid, trifluoroperacetic acid, or hydrogen peroxide.

The present oxidizing reaction is usually carried out in the presence of a solvent such as chloroform, methylene chloride, dioxane, benzene, ethyl acetate, or other solvents which does not adversely affect the reaction. The reaction is usually carried out at room temperature or under cooling.

SUBSTITUTE SHEET

Aminomethylation (Mannich Reaction) The introduction of the exocyclic double bond at the 2position of compound V can be carried out according to the procedure detailed in the literature; [I.G. Wright et al., J. Med. Chem.. 14, 420 (1971)]. The reaction is usually carried out in a solvent such as alcohol (e.g. t-butanol) , methylene chloride, chloroform, carbon tetrachloride, mixed solvent thereof, or any other solvent not adversely affecting the reaction. There is no particular limitation to the reaction temperature and the present reaction is usually carried out from room temperature to about 150° C with or without reflux until the reaction is complete.

Cycloaddition For the introduction of the 2-spirocyclopropyl groups which may be substituted with suitable substituents, the reaction is carried out by reacting the compound VI with a compound of the formula R ₃ R ₄ CN ₂ where R ₃ and R ₄ may be the same or different and represent the groups as defined earlier herein. The reaction is usually carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, benzene, ether, ethyl acetate or any other solvent which does not adversely affect the reaction. The reaction is usually carried out under cooling to ambient temperature.

SUBSTITUTE SHEET

29

Biological Evidence

The in vitro test data on anti-elastase activity of exemplary derivatives having the structural formula I are shown in Table I herebelow.

TABLE

SUBSTITUTE SHEET

The compounds tested were as follows:

Benzhydryl-7α-chloro-2-spiro(2• ,2'-diphenyl)cyclopropyl-3- methyl-3-cephem-4-carboxylate-l,1-dioxide.

Benzhydryl-7α-bromo-2-spiro(2' ,2*-diphenyl)cyclopropyl-3-me thyl-3-cephem-4-carboxylate-l,1-dioxide.

Benzhydryl-7,7-dihydro-2-spiro(2• ,2-diphenyl)cyclopropyl-3- methyl-3-cephem-4-carboxylate-l,1-dioxide. t-Butyl 7α-bromo-2-spiro(2• ,2*-diphenyl)cyclopropyl

-3-methyl-3cephem-4-carboxylate-l,1-dioxide. Benzyhydryl-7α-bromo-2-spiro[2' ,2'-(4' ,4'-dichloro)diphenyl

]cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide.

Benzhydryl-7α-bromo-2-spiro[2' ,2'-(4 ^• ,4'-difluoro)diphenyl] cyclopropyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide. t-Butyl-7α-chloro-2-spiro(2' ,2'-diphenyl)cyclopropyl-3-acet oxymethyl-3-cephem-4-carboxylate-l,1-dioxide.

Benzhydryl-7α-bromo-2-spiro(2*-ethoxycarbonyl)cyclopropy l-3 methyl-3-cephem-4-carboxylate-l,1-dioxide.

Benzhydryl-7α-bromo-2-spiro(2'-phenyl-2'-methyl)cyclopro pyl

-3 methyl-3-cephem-4-carboxylate-l,1-dioxide. Benzhydryl-7α-bromo-2-spiro(2'-phenyl)cyclopropyl-3-methyl-

3cephem-4-carboxylate-l,1-dioxide.

7α-Bromo-2-spiro(2• ,2•-diphenyl)cyclopropyl-3-methyl-3- cephem-4pyrrolidine carboxamide-1,1-dioxide.

7α-methoxy-2-spiro(2• ,2'-diphenyl)cyclopropyl-3-methyl-3- cephem-4-pyrrolidine carboxamide-1,1-dioxide.

2,2,2-Trichloroethyl-7α-ethoxy-2-spiro(2' ,2'-diphenyl) cyclo-propyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide.

Benzhydryl-7α-methoxy-2-spiro(2' ,2'-diphenyl)cyclopropyl-3- methyl-3-cephem-4-carboxylate-l,1-dioxide.

SUBSTITUTE SHEET

2,2,2-Trichloroethyl-7α-methoxy-2-spiro(2' ,2'-diphenyl) cyclo-propyl-3-methyl-3-cephem-4-carboxylate-l,1-dioxide. 7α-Methoxy-2-spiro(2• ,2'-diphenyl)cyclopropyl-3-methyl-3- cephem-4piperidine carboxamide-1,1-dioxide. p-Methoxybenzyl 7α-bromo-2-spiro(2' ,2'-diphenyl) cyclopropyl-3 chloromethyl-3-cephem-4- carboxylate-1, 1-dioxide. Benzhydryl-7α-bromo-2-spiro[2• ,2'- (4* ,4'-dichloro)diphenyl]-cyclopropyl-3-[ (5-methyl-l,3,4- thiadiazol-2-yl)thiomethyl]-3cephem-4-carboxylate-l-oxide.

PROTOCOL

Enzvme Assay for Inhibition of HLE:

Enzyme: Purified elastase from human white blood cells.

Substrate:

MeO-succinyl-L-alanyl-L-alanyl-L-propyl-L-valine-p-nitro- anilide (NA) Reaction Mixture:

10 mM phosphate buffer (pH 7.6)

500 mM NaCl

10% dimethylsulfoxide (DMSO)

0.35 mM substrate The enzyme activity was determined by monitoring the increase in absorbance at 4•0 nm caused by the hydrolysis of chromogenic substrates. Inhibition of enzyme by the compounds described were determined after a 10 minute preincubation with the enzyme in reaction mixture minus

SUBSTITUTE SHEET

substrate. Reaction was initiated by the addition of substrate. The concentration of human leukocyte elastase used for assay was at 10 nM.

In order to demonstrate the specificity of the compounds of formula I against human leukocyte elastase, some of these compounds were further tested against various proteases and the IC50 values are shown in Table II herebelow.

SUBSTITUTE SHEET

TABLE II

SELECTIVITY OF 2-SPIRO<:YO!.OPROPYL CEΓIIΛLOSΓORIM SULFOHES AGAINST VARIOUS PROTEASES ιc, 5 _n 0 , - f,g m ,l- ^" ι ¹ )

) ^■ IRY HIP. PLM CTC APM IG CTD PPE

>lh.2 >26.2 2. 1 >26.2 >26.2 >10.6 >32.7 0.012

>36.6 >2-..t 2.2 >36.6 >36.6 12.2 >30.5 0.020

>21.8 >21.8 3.0 >21.8 >Z1.S 21.8 >27.2 0.051

0.333 >23 6.32 >23 >23 7. -.7 >28.7 0.018

ΛU >'.0 l .β >ftO >lιO 1ft.0 >33.4 0. 17

>27.6 J27.6 2.2 >27.6 >27.6 13.1 >34.5 0.0Λ4

0.089 >23. 7 3.26 >23. 7 >23.7 23.7 >29.6 0.033

>2 l. l >21.1 >21.1 >5.29 >5.29 >21.1 >5.I9 0.11

> 19.7 >19.7 >19.7 >Λ .92 >19.7 >15.2 >'..9Z <3.<3* _* 7

>5.85 >5.85 ^* >5.85 >5.85 >5.85 0.187 >5.85 0.009'.

> .06 >6.06 5.33 >6.06 >6.06 >6.06 >6.06 0.035

0.37 >5.70 0.7/.2 >5.70 >5.70 0.23 >5.70 0.013 >5.07 >20. Z >5.07 >5.07 >5.07 >5.07 >5.07 0.016

IILE, CIG, PPE and CTI) were tented at 30 C and the others were tested at 22 C.

TRY, trypsin; IIIR, thrombi!.; I'UI, plαsmin; CIC, catheps_.il C; AI t, aminopeptidase H;

CTG, catliepsiii G; CIl), cath»psln l); PE, porcine pnjtcrentic elastase.

SUBSTITUTE SHEET

PROTOCOL

Porcine Pancreatic Elastase (PPE)

Enzyme: Purified elastase from porcine pancreas

Substrate: MeO-succinyl-L-alanyl-L-alanyl-L-prolyl-L-valine-pNA

Reaction mixture:

50mM Tris[Tris(hydroxymethyl) aminomethane] . HC1 buffer

(pH 8.9)

500mM NaCl

10% DMSO 1.4mM Substrate

Cathepsin G (CTG)

Enzyme: Purified Cathepsin G from human white blood cells

Substrate:

N-succinyl-L-alanyl-L-alanyl-L-phenylalanyl-L-phenylalani ne

-p-NA

Reaction mixture: lOmM Phosphate buffer (pH 7.5)

500mM NaCl

10% DMSO

2.0mM Substrate

SUBSTITUTE SHEET

Trypsin (TRY)

Enzyme: Purified trypsin from bovine pancreas

Substrate: Bz-L-arginine-p-NA

Reaction mixture:

50mM Tricine[N-Tris(hydroxymethyl)methylglycine]-NaOH buffer (pH 8.8) 150mM NaCl 10% DMSO l.OmM Substrate

Thrombin (THR)

Enzyme: Purified thrombin from human plasma Substrate: Tosyl-glycyl-L-prolyl-L-arginine-p-NA acetate Reaction mixture: 50mM Tricine-NaOH buffer (PH 8.6) 500mM NaCl

0.1% Polyethyleneglycol 8000

10% DMSO

0.5mM Substrate

Plasmin (PLM)

Enzyme: Purified plasmin from human plasma

Substrate: Tosyl-glyclyl-L-prolyl-L-lysine-pNA acetate

SUBSTITUTE SHEET

Reaction mixture:

50mM Tris-HCl buffer (pH 8.9)

500mM NaCl

5% DMSO 0.5mM Substrate

Cathepsin C (CTC)

Enzyme: Purified cathepsin C from bovine spleen Substrate: Glycyl-L-phenylalanine-pNA

Reaction mixture:

50mM Citrate buffer (pH 5.4)

5mM B-Mercaptoethanol

150mM NaCl 10% DMSO

20mM Substrate

Aminopeptidase M (APM

Enzyme: Purified aminopeptidase M from porcine kidney

Substrate: L-Leucine-pNA

Reaction Mixture:

50mM Tricine buffer (pH 7.5)

500mM NaCl 10% DMSO

2.0mM Substrate

SUBSTITUTE SHEET

Cathepsin D (CTD)

Enzyme: Purified cathepsin D from bovine spleen Substrate: Hemoglobin (bovine) Reaction mixture: 250mM Glycine buffer (pH 3.2) 10% DMSO

Except for Cathepsin D, the enzyme activities were determined by monitoring the increase in absorbance at 410 nm caused by the hydrolysis of chromogenic substrates. The activity of Cathepsin D was determined by monitoring the absorbance of 5% trichloroacetic acid-soluble material at 280 nm.

Inhibition of enzymes by the compounds described were determined after a 10 minute preincubation with enzymes in reaction mixtures minus substrate. Reactions were initiated by the addition of substrates. The concentration used for assays were porcine pancreatic elastase at 240nM and human Cathepsin G at 50nM. Cathepsin D was used at the concentration that produced approximately 0.15 O.D. increase per 20 min at 280 nm under the standard conditions. All other proteases were assayed at the concentrations that produced approximately 0.1 O.D. change per minute at 410 nm under the standard conditions.

The compounds which had an IC ₅₀ value of less than 0.104M for HLE were tested against serine proteases (pancreatic elastase, leukocyte cathepsin G, trypsin, thrombin and plasmin) , a cysteine protease (cathepsin C) , metalloprotease (aminopeptidase M) and an aspartyl protease (cathepsin D) . The results clearly demonstrate the highly

SUBSTITUTE SHEET

selective nature of the inhibition of human leukocyte elastase by these compounds. The specificity of the compounds indicate that they should have little side effects caused by non-specific inhibition of proteases other than HLE when used in the treatment of various ailments in which HLE is the major causative agent.

For therapeutic administration, the compound having the structural formula I is used in the form of conventional pharmaceutical preparation which contains said compounds as an active ingredient in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparations may be in solid form such as capsule, tablet, ointment etc. or in liquid form such as solution, suspension or emulsion. There may be included in the above preparation auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffer and the other commonly used additives. In general, a daily dose of between 0.2 mg and 150 mg or even more per kilogram of body weight per day may be administered to a patient. However, the dose level may vary and will depend upon a variety of factors such as the activity of the specific compound employed, the age, body weight, sex, diet, time of administration, route of administration etc.

The following examples are provided to demonstrate the operability of the present invention. The structures of the compounds were established by the modes of synthesis, by

SUBSTITUTE SHEET

infrared spectroscopy, and by extensive high field nuclear magentic resonance spectral techniques and x-ray analysis.

EXAMPLE I

Benzhydryl

7α-chloro-2-spiro(2' .2'-diphenyl)cyclopropyl-3-methyl-3- cephem-4-carboxylate-l.1-dioxide

STEP A: Preparation of 7ot-chloro-3-methyl-3-cephem-4-carboxylic acid

A mixture of 7-ADCA (25 g, 0.117 mol) , ethanol (700 ml) , water (163 ml) and concentrated hydrochloric acid (163 ml) was cooled to 5 ^β C. Sodium nitrite (11.5 g, 0.167 mol) was added in small portions over 25 minutes and the mixture was stirred for 3.5 hours at 0-5 ^β C; 300 ml of brine was added and the reaction mixture was extracted with methylene chloride. The organic extract was washed with water, brine, dried over sodium sulfate and concentrated (16.1 g, 58.9%). This crude acid was directly used for the next step without further purification.

STEP B: Preparation of benzhydryl 7a-chloro-3-methyl-3-cephem-4 carboxylate

The 7α-chloro-3-methyl-3-cephem-4-carboxylic acid (10.0 g, 0.0428 mol) was dissolved in methylene chloride (200 ml), and diphenyldiazomethane (10.8 g, 0.0557 mol) dissolved in methylene chloride (50 ml) was added dropwise

SUBSTITUTE SHEET

over 30 minutes. The mixture was stirred at room temperature for two hours. Solvent was removed under reduced pressure and the product was purified over silica column using hexane-ethyl acetate mixture to yield benzhydryl 7α-chloro-3-methyl-3-cephem-4-carboxylate (7.8 g, 45.6%).

NMR (CDC1 ₃ ) δ 2.1 (s, 3H, CH ₃ ) , 3.25 (bs, 2H, H-2), 4.70 (bs, 1H), 4.75 (bs, 1H) , 7.0 (s, 1H, CHPh ₂ ) , 7.3-7.7 (m, 10H, aromatic) .

STEP C: Preparation of benzhvdryl

7ce-chloro-3-methγl-3-cephem-4 carboxylate 1.1-dioxide Benzhydryl 7α-chloro-3-methyl-3-cephem-4-carboxylate (7.6 g, 0.019 mol) was dissolved in methylene chloride (50 ml) and peracetic acid (13.0 g, 0.171 mol) ,was added dropwise over 15-20 minutes with ice-cooling. The mixture was stirred for 72 hours at room temperature and was then washed successively with portions of water, saturated sodium bicarbonate solution, and water. Drying over sodium sulfate, filtration, removal of the solvent under reduced pressure and filtration of the residue through a small column of silica gel using methylene chloride as eluant gave 9.3 g of benzhydryl 7α-chloro-3-methyl-3-cephem-4- carboxylate 1,1-dioxide as a white foam. NMR (CDCI ₃ ) δ 2.1 (s, 3H, CH ₃ ) , 3.8 (bs, 2H, H-2), 4.75 (bs, 1H) , 5.3 (bs, 1H) , 7.0 (s, 1H, CHPh ₂ ) , 7.4 (bs, 10H, aromatic) .

SUBSTITUTE SHEET

STEP D: Preparation of benzhvdryl

7a-chloro-2-methylene-3-methyl-3-cephem-4-carboxylate 1.l-dioxide

Benzhydryl 7α-chloro-3-methyl-3-cephem-4-carboxylate l,ldioxide (9.3 g, 0.0215 mol) was dissolved in methylene chloride (35 ml), dimethylamine hydrochloride (4.9 g, 0.0645 mol), formaldehyde solution (2.25 g, 0.075 mol) and t-butyl alcohol (300 ml) were added and the mixture was heated to reflux at 95 ^β C for 4 hours. After removing the solvent under reduced pressure the residue was redissolved in methylene chloride, washed successively with water, dried over sodium sulfate and concentrated. The product wa purified over a silica column using hexane-ethyl acetate mixture as the eluant to yield benzhydryl 7α-chloro-2-methylene-3-methyl-3-cephem-4carboxylate

1,1-dioxide (3.6 g, 40%) as a white foam. IR (Nujol) v max 1723, 1800 cm-1.

NMR (CDC1 ₃ ) δ 2.01 (s, 3H, CH,) , 4.82 (d, IH, J=1.5 Hz), 5. (d, IH, J=1.5 Hz), 6.12 (d, IH, exomethylene, J=2.0 Hz), 6.62 (d, IH, exomethylene, J=2.0 Hz), 6.93 (s, IH, CHPh ₂ ) , 7.25-7.39 (m, 10H, aromatic).

STEP E: Preparation of benzhydryl 7o:-chloro-2-spiro (2' .2'-diphenyl)cyclopr"r>yl-3-methyl-3-cephem-4-carboxylate 1.1-dioxide

Benzhydryl 7α-chloro-2-methylene-3-methyl-3-cephem-4- carboxylate 1,1-dioxide (1.0 g, 0.00225 mol) was dissolved in methylene chloride (70 ml) and cooled to -15°C. To this

SUBSTITUTE SHEET

solution diphenyldiazomethane (0.44 g, 0.00225 mol) was added and the mixture was stirred at room temperature for 2 hours, after removing the solvent under reduced pressure the crude product was purified over silica column using gradient elution with hexane-ethyl acetate mixture. IR

(Nujol) V max 1726, 1791 cm-1; NMR (CDCl _j ) δ 1.02 (s,3H,

CH ₃ ) , 2.37 (d, IH, cyclopropyl, J=7 Hz), 2.97 (d, IH, cyclopropyl, J=7 Hz), 5.01 (d, IH, J=1.8 Hz), 5.22 (d, IH,

J=1.8 HZ) ,7.0 (S, IH, CHPh ₂ ) , 7.28-8-7.48 (m, 20H, aromatic) .

EXAMPLE 2

STEP A: Preparation of 7-α;-bromo-3-methγl-3-cephem-4- carboxylic acid

To an ice-cooled mixture of 7-ADCA (10.0 g, 0.4667 mol) , ethanol (270 ml) , water (83 ml) and hydrobromic acid (48%, 56.7 ml), sodium nitrite (4.67 g, 0.6769 mol) was added in small portions over 25 minutes and the mixture was stirred for 2.5 hours at ice-temperature. Ethanol was removed under reduced pressure and the residual mass was diluted with methylene chloride, washed with water. The aqueous washings were saturated with brine and re-extracted with methylene chloride. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 9.8g (75.5%) of 7α-bromo-3-methyl -3-cephem-4-carboxylic acid. This crude acid was directly used for the next step without further purification.

SUBSTITUTE SHEET

STEP B: Preparation of benzhvdryl 7a-bromo-3-methyl-3- cephem-4carobxylate

To a stirred solution of 7α-bromo-3-methyl-3-cephem-4 carboxylic acid (9.8 g, 0.0353 mol) in 50 ml of dry methylene chloride was added dropwise a solution of diphenyldiazomethane (8.21 g, 0.04228 mol) dissolved in 50 ml of methylene chloride. The mixture was sitered at room temperature for 3 hours, washed with sodium bicarbonate solution, water, brine and concentrated to give 11.91 g (76%) of the crude product as. a brown foam.

The above crude product was purified over a silica colum with a mixture of hexane-ethyl acetate (85:15) to give 8.02 ( 5 1 . 2 % ) o f p u r e b e n z h y d r y 7α-bromo-3-methyl-3-cephem-4-carboxylate. NMR(CDC1 ₃ ) 2.15(S, 3H, CH ₃ ) , 3.29 (bs, 2H, H-2), 4.72(d, IH) , 4.87α(d) IH) , 6.99 (s, IH, CHPh ₂ ) , 7.25-7.55(m, 10H, aromatic).

STEP C: Preparation of benzhydryl 7α.-bromo-3-methγl-3 cephem-4carboxylate-1.1-dioxide

Benzhydryl 7α-bromo-3-methyl-3-cephem-4-carboxylate (16.0 g, 0.036 mol) was dissolved in methylene chloride (75 ml), peracetic acid (24.6 g, 0.324 mol) was added slowly and the mixture was stirred for 72 hours at room temperature, the mixture was washed successively with water, sodium bicarbonate solution and water. Drying over sodium sulfate, filtration, removal of solvent under reduced pressure and purification of the residue over a silica column using methylene chloride as eluant gave

SUBSTITUTE SHEET

benzhydryl α-bromo-3-methyl-3-cephem-4-carboxylate 1,1-dioxide (6.7 g, 40%) as a pale yellow foam. NMR (CDC1 ₃ ) δ 2.1(s, 3H, CH ₃ ) , 3.8(bs, 2H, H-2), 4.8(bs, IH), 5.25(bs, IH) , 6.95(s, IH, CHPh ₂ ) , 7.2-7.6(m, 10H, aromatic).

STEP D: Preparation of benzhydryl 7o;-bromo-2-methylene-3- methyl-3-cephem-4-carboxylate-l.1-dioxide To a stirred solution of benzhydryl 7α-bromo-3-methyl-3cephem-4-carboxylate-l,1-dioxide (2.8 g, 0.0059 mol) in methylene chloride (12 ml) were added dimethylamine hydrochloride (1.44 g, 0.0176 mol), formaldehyde (0.61 g, 0.020 mol) and t-butyl alcohol (100 ml), the mixture was heated to reflux at 95"C for 3 hours. Solvent was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography with a solvent gradient of 10 to 25% ethyl acetate/hexane to afford benzhydryl 7α-bromo-2-methylene-3-methyl- 3-cephem-4-carboxylate-1,

1-dioxide (2.0 g, 69.5%) as a white foam. IR (Nujol) v max 1720, 1800 cm-1. NMR (CDC1 ₃ ) δ 2.10(s, 3H, CH ₃ ) , 4.93(d, IH, J=1.5 Hz), 5.33(d, IH, J=1.5 Hz) , 6.20(d, IH, exomethylene, J=2 Hz), 6.70 (d, IH, exomethylene, J=2 Hz) , 6.98(s, IH, CHPh ₂ ) , 7.30-7.45(m, 10H,aromatic) .

SUBSTITUTE SHEET

STEP E: Preparation of benzhydryl 7a-bromo-2-spiro(2' .

2'-diphenyl) cvclopropyl-3-methyl-3-cephem-4-carboxylate-l.

1-dioxide

Benzhydryl 7a-bromo-2-methylene-3-methyl-3-cephem-4- carboxylate-1,1-dioxide (0.6 g, 0.00123 mol) was dissolved in methylene chloride (50 ml) and cooled to -15 ^β C, diphenyl diazomethane (0.263 g, 0.00135 mol) was added to the solution and the mixture was stirred at room temperature for 3 hours. Evaporation of the solvent under reduced pressure gave a light pink foam which was purified by column chromatography with a solvent gradient of 10 to 30% ethyl acetate/hexane to afford benzhydryl 7a-bromo-2-spiro- (2' ,2'-diphenyl)cyclopropyl-3-methyl-3-cephen-4-carboxylate -1,1-dioxide. IR (Nujol) v max 1728, 1790 cm-1; NMR (CDC1 ₃ ) δ 1.03 (s, 3H, CH ₃ ) , 2.38 (d, IH, cyclopropyl, J=7 Hz), 2.96 (d, IH, cyclopropyl, J=7 Hz), 5.04 (d, IH, J=1.8 Hz), 5.20 (d, IH, J=1.8 Hz), 7.0 (s, IH, CHPh ₂ ) , 7.22-7.47 (m, 20H, aromatic) .

EXAMPLE 3 t-Butyl 7a-bromo-2-spiro(2' .2'-diphenyl) cyclopropyl-3- methyl-3-cephem 4-carboxylate-l.1-dioxide

STEP A: Preparation of t-butyl 7a-amino-3-methyl -3-cephem-4-carboxylate

A mixture of 7-ADCA (10.0 g, 0.0467 mol), ethylene glycol dimethyl ether (80 ml) , concentrated sulfuric acid (6.0 ml) and isobutylene (36.0 g, 0.6416 mol) in a pressure bottle was stirred at room temperature for 32 hours.

SUBSTITUTE SHEET

Solvent was removed under reduced pressure. The residue was diluted with methylene chloride, washed with water, sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to give 4.18 g of t-butyl 7β-amino-3-methyl-3- cephem-4-carboxylate.

NMR (CDC1 ₃ ) δ 1.55 (s, 9H, t-butyl) , 2.07 (s, 3H) , 2.25 (bs, 2H, exchanged with D ₂ 0) , 3.12 (d, IH, J=18.0 Hz), 3.59 (d, IH, J=18.0 Hz), 4.70 (d, IH, J=4.0 Hz), 4.95 (d, IH, J=4.0 Hz).

STEP B: Preparation of t-butyl 7a-bromo-3-methyl-3- cephem-4-carboxylate

To an ice-cooled mixture of t-butyl 7α-amino-3-methyl-3cephem-4-carboxylate (1.3 g, 0.0048 mol), ethanol (30 ml), water (8.5 ml), hydrobromic acid (48%, 5.83 ml), sodium nitrite (0.48 g, 0.00696 mol) was added portionwise over 15 minutes and the mixture was stirred at ice-temperature (-5'C) for 3 hours, saturated with sodium chloride, extracted with ethyl acetate (3 times) . The combined ethyl acetate extract was washed with water, brine, dried and concentrated to give 800 mg (50%) of pure t-butyl 7a-bromo-3-methyl-3-cephem-4carboxylate. NMR (CDC1 ₃ ) 1.54 (s, 9H, t-butyl) , 2.10 (s, 3H) , 3.20 (d, IH, J=18.0 HZ), 3.60 (d, IH, J=18.0 Hz) , 4.71 (d, IH) , 4.85 (d, IH).

SUBSTITUTE SHEET

STEP C: Preparation of t-butyl 7a-bromo-3-methyl-3- cephem-4-carboxylate-l.1-dioxide

To a solution of t-butyl 7a-bromo-3-methyl-3-cephem-4- carboxylate (800 mg, 2.39 mmol) in methylene chloride (3 ml) was added peracetic acid (32%, 5.12 ml) and the mixture was stirred at room temperature for 48 hours, diluted with methylene chloride, washed with water, brine, dried and concentrated to give 700 mg (80%) of t-butyl 7a-bromo-3-methyl-3-cephem-4-carboxylate 1,1-dioxide. This product was directly used for. the next step.

NMR (CDC1 ₃ ) δ 1.55 (s, 9H, t-butyl) , 2.10 (s, 3H) , 3.63 (d, IH, J=18.0 Hz), 3.98 (d, IH, J=18.0 Hz) , 4.83 (d, IH) , 5.33 (d, IH).

STEP D: Preparation of t-butyl 7a-broroo-2-methylene-3- methyl-3cephem-4-carboxylate 1.1-dioxide

A mixture of t-butyl 7a-bromo-3-methyl-3-cephem -4-carboxylate 1,1-dioxide (700 mg, 1.9 mmol), dimethylamine hydrochloride (460 mg, 5.7 mmol), methylene chloride (3 ml) and t-butyl alcohol (50 ml) , formaldehyde (0.57 g, 37% w/v) was heated to reflux at 80-90 ^β C for 20 hours. t-Butyl alcohol was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, brine, dried and concentrated to give 200 mg of crude product which was purified over silica column using methylene chloride as eluant to give 40 mg of pure t-butyl 7-a-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate 1,1-dioxide.

NMR (CDC1 ₃ ) δ 1.55 (s, 9H, t-butyl) , 2.15 (s, 3H) , 4.95 (d, IH) , 5.32 (d, IH) , 6.21 (d, IH) , 6.70 (d, IH) .

SUBSTITUTE SHEET

STEP E: Preparation of t-butyl 7a-bromo-2-spiro(2' .2'

-diphenyl)-cvclopropyl-3-methyl-3-cephem-4-carboxγlate-l ,

1-dioxide

To a solution of t-butyl

7a-bromo-2-methylene-3-methyl-3cephem-4-carboxylate 1,1-dioxide(40 mg) in 7 ml of methylene chloride was added diphenyldiazomethane (23 mg) and the mixture was stirred at ice-temperature for 3 hours, after removal of the solvent the crude product was purified by preparative tic to give 30 mg of pure t-butyl

7a-bromo-2-spiro(2' ,2'-diphenyl)cyclopropyl-3-methyl-3- cephem-4-carboxylate-l,1-dioxide. NMR (CDC1 ₃ ) δ 1.10 (s, 3H, CH ₃ ) , 1.55 (s, 9H, t-butyl) , 2.37 (d, IH, J=7 Hz), 2.96 (d, IH, J=7 Hz), 5.03 (d, IH, J=2 Hz), 5.18 (d, IH, J=2 HZ), 7.23-7.48(m, 10H, aromatic).

EXAMPLE 4 t-Butγl 7a-chloro-2-spiro(2' .2'-diphenyl)cyclopropyl-3- acetoxymethyl-3-cephem-4-carboxylate-l.1-dioxide STEP A: Preparation of t-butyl 7a-amino-3- acetoxymethyl-3-cephem-4-carboxylate

Dry dioxane was freed from peroxide by passage through a column of neutral activated alumina. To 100 ml of this solvent was added, in turn, with ice-cooling 10 ml of concentrated H ₂ S0 ₄ , 10.9 g of 7-ACA and 50 ml of liquid isobutylene. The mixture was sealed in a pressure bottle, stirred at 30'C for 2 hours, poured into excess of ice-cold

SUBSTITUTE SHEET

aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate. The combined ethyl acetate extract was washed with brine and dried over sodium sulfate. Evaporation of the filtrate under reduced pressure gave a light brown foam, 8.3 g (63%) of t-butyl 7B-amino-3-acetoxymethyl-3-cephem-4-carboxylate. NMR (CDC1 ₃ ) 6 1.5(s, 9H, t-butyl), 1.8(bs, 2H, NH ₂ ) 2.1(s, 3H, OCOCH ₃ ) , 3.45(ABq, 2H, H-2, J=18 Hz) , 4.7-5.2(m, 4H, H-6+H-7+CH ₂ 0COCH ₃ ) .

STEP B: Preparation of t-butyl 7a-chloro-3-acetoxymethyl- 3-cephem-4-carboxylate

To an ice-cooled solution of t-butyl 7a-amino-3- acetoxymethyl-3-cephem-4-carboxylate (4.0 g, 0.0122 mol) in 75 ml of ethanol, 16.7 ml of water and 16.7 ml of concentrated hydrochloric acid was added portionwise over 15-20 minutes sodium nitrite (1.18 g, 0.017 mol). The reaction mixture was stirred at 0-5*C for 2.5 hours, saturated with sodium chloride, extracted with methylene chloride, washed with water, brine, dried Na ₂ S0 ₄ and concentrated to give 3.1g (73%) of t-butyl 7a-chloro-3- aσetoxymethyl-3-cephem-4carboxylate.

NMR (CDC1 ₃ ) δ 1. 55 (s , 9H, t-butyl) , 2 . 1 (S , 3H, OCOCH ₃ ) ,

3 . 5 (ABq, 2H, H-2 , J=18 Hz ) , 4 . 6-5. 1 (m, 4H, H-6+H-7+CH ₂ 0COCH ₃ .

SUBSTITUTE SHEET

STEP C: Preparation of t-butyl 7a-chloro-3-acetoxymethyl-3- cephem-4-carboxylate-l.1-dioxide

To a solution of t-butyl 7a-chloro-3-acetoxymethyl-3- cephem-4-carboxylate (3.1 g) in 50 ml of methylene chloride was added peracetic acid (22 ml) dropwise and the mixture was sitered at room temperature overnight. The reaction mixture was washed with water, sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, concentrated and the crude product was purified over silica column using hexane-ethyl acetate (3:1) to. give 1.9 g (48%) of pure t-butyl 7a-chloro-3-acetoxymethyl-3-cephem-4- carboxylate-1,1-dioxide.

NMR (CDC1 ₃ ) δ 1.55 (s, 9H, t-butyl) , 2.1 (s, 3H, OCOCH ₃ ) , 3.9 (ABq, 2H, H-2, J=18 Hz), 4.8 (bs, IH) , 4.95 (ABq, 2H, CH ₂ 0COCH ₃ , J=14 Hz) , 5.3 (bs, IH) .

STEP D: Preparation of t-butyl 7a-chloro-2-methylene -3-acetoxymethyl-3-cephem-4-carboxylate-l.1-dioxide

A mixture of t-butyl 7a-chloro-3-acetoxymethyl-3- cephem-4-carboxylate-1,1-dioxide (1.9 g) , methylene chloride (3 ml), dimethylamine hydrochloride (0.817 g) , t-butanol (80 ml) and formaldehyde solution (1.10 ml, 37% w/v in water) was heated to reflux at 90°C for 3 hours. Solvent was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, brine, dried and concentrated to give 1.6 g (81.6%) of t-butyl 7a-chloro-2methylene-3-acetoxymethyl-3-cephem -4-carboxylate-1,1-dioxide, m.p. 148 ^β -149 ^β C. This product without further purification was used in the next step.

SUBSTITUTE SHEET

STEP E: Preparation of t-butyl 7a-chloro-2-spiro

(2' .2'-diphenyl)-cyclopropyl-3-acetoxymethyl-3-cephem-4- carboxylate-1.1-dioxide

To an ice-cooled solution of t-butyl 7a-chioro-2-methylene-3-acetoxymethyl-3-cephem-4- carboxylate-1,1-dioxide (200 mg, 0.51 mmol) in 15 ml of methylene chloride was added a solution of diphenyl diazomethane (109 mg) in 5 ml of methylene chloride and the mixture was stirred at room temperature for 2 hours. After removal of the solvent the crude product was purified by preparative tic to afford pure t-butyl 7a-chloro-2-spiro- (2' ,2*-diphenyl)cyclopropyl-3-acetoxy methyl-3-cephem-4- carboxylate-1,1-dioxide (113 mg, 40%), mp. 163-165 ^β C. NMR (CDC1 ₃ ) δ 1.55 (s, 9H, t-butyl) , 2.01 (s, 3H, OCOCH ₃ ) , 2.37 (d, IH, J=7 Hz), 3.03 (d, IH, J=7 Hz), 3.12 and 4.08 (dd, 2H, CH ₂ 0COCH ₃ , J=13 Hz), 5.01 (d, IH, J=2 Hz) , 5.26 (d, IH, J=2 Hz) ,7.22-7.48 (m, 10H, aromatic).

EXAMPLE 5

Benzhydryl 7.7-dihvdro-2-spiro(2' .2'-diphenyl)cyclopropyl -3-methyl-3-cephem-4-carboxylate-l.1-dioxide

Following substantially the same procedure as described in Example 1, step E, 0.6 g of benzhydryl 7,7-dihydro-2-methylene-3-methyl-3-cephem-4-carboxylate-l, 1-dioxide in 50 ml of methylene chloride was treated with diphenyldiazomethane to give 0.340 g (39.4%) of benzhydryl 7,7-dihydro-2-spiro(2 ^• ,2'-diphenyl)cyclopropyl-3-methyl -3-cephem-4-carboxylate-1,1-dioxide. IR (Nujol) v max

SUBSTITUTE SHEET

1735 , 1786 cm-1.

NMR (CDC1 ₃ ) δ 1.02 (s, 3H, CH ₃ ) , 2.34 (d, IH, cyclopropyl,

J=7 Hz), 2.94 (d, IH,cyclopropyl, J=7 Hz), 3.48 (ABX, 2H,

H-7, J=2.5, 5.0,16.0 Hz5.03 (dd, IH, H-6, J=2.5, 5.0 Hz) , 7.0 (s, IH, CHPh2) ,7.2-7.48 (m, 20H, aromatic).

EXAMPLE 6 7a Bromo-2-spiro(2' .2'-diphenyl)cyclopropyl-3-methyl -3-cephem-4-pyrrolidine carboxamide-1 ,1-dioxide STEP A: Preparation of 7a-bromo-2-methylene-3-methyl-3- cephem-4-carboxylic acid-1.1-dioxide

To an ice-cooled stirred solution of benzhydryl 7a-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate-l, 1-dioxide (from step D, Example 2, 1.0 g, 2.047 mmol) in dry anisole (10 ml) was added trifluoroacetic acid (4.0 ml) and the mixture was stirred at ice-temperature for 1 hour; solvent was removed under reduced pressure to leave a yellow oil. Hexane was added directly to the yellow oil while a white solid was precipitated out which was collected by filtration (0.549 g, 83%).

NMR (CDC1 ₃ + DMSO-d6) δ 2.19 (s, 3H, CH ₃ ) , 5.13 (d, IH) , 5.4' (d,lH), 6.27 (d, IH) , 6.69 (d, IH) .

STEP B: Preparation of 7a-bromo-2-methylene-3-methyl -3-cephem-4 pyrrolidine carboxamide-1.1-dioxide

7α-Bromo-2-methylene-3-methyl-3-cephem-4-carboxylic acid 1,1-dioxide (440 mg, 1.366 mmol) was dissolved in 5 ml of methylene chloride and cooled to -20*C; to this solution

SUBSTITUTE SHEET

phosphorus oxychloride (0.133 ml, 1.434 mmol) was added over 10 minutes and the mixture was stirred at -20*C for 3 minutes. Pyrrolidine (0.456 ml, 5.464 mmol) was added and the mixture was stirred at -20*C for 2 hours. To the mixture ice-water was added and was stirred for 15 minutes, methylene chloride layer was separated out and the aqueous layer was reextracted with methylene chloride, the combine methylene chloride layer was washed with water, citric acid, brine, dried over anhydrous sodium sulfate and concentrated to give 400 mg (78%) of brown solid which was purified over silica column using ethyl acetate-acetonitrile (9:1) as eluant; Pure product (89 mg, 17.4%) was isolated as white solid. NMR (CDC1 ₃ ) δ 1.92 (s, 3H, CH ₃ ) , 1.85-2.1 (m, 4H, pyrrolidine), 3.42-3.73 (m, 4H, pyrrolidine), 4.98 (d, IH, J=1.6 Hz), 5.37 (d, 1H,J=1.6 Hz) , 6.0 (d, IH, J=1.8 Hz) , 6.54 (d, IH, J=1.8 Hz).

STEP C: Preparation of 7a-bromo-2-spiro(2' .2'-diphenyl cyclopropyl-3-methyl-3-cephem-4-pyrrolidine carboxamide-1. 1-dioxide

To an ice-cooled solution of 7α-bromo-2-methylene-3- methyl-3-cephem-4-pyrrolidine carboxamide-1,1-dioxide (60 mg, 0.1599 mmol) in 3 ml of methylene chloride was added diphenyl diazomethane (31 mg, 0.1599 mmol). The reaction mixture was stirred at ice-temperature for 1.5 hours and then concentrated to give 80 mg of the crude product which was purified by preparative tic (30 mg, 35%) . NMR (CDC1 ₃ ) δ 0.93 (s, 3H, CH ₃ ) , 1.86-2.0 (m, 4H,

SUBSTITUTE SHEET

pyrrolidine) ,

2.275 (d, IH, J=7.0 Hz, cyclopropyl), 2.94 (d, IH, J=7.0 Hz, cyclopropyl), 3.42-3.68 (m, 4H, pyrrolidine), 5.03 (d, IH, J=1.6 Hz), 5.20(d, IH, J=1.6 Hz) , 7.18-7.49 (m, 10H, aromatic) .

EXAMPLE 7

2.2.2-Trichloroethyl-7a-ethoxy-2-spiro (2 ^■ .2'-diphenyl)cyclo -propyl-3-methyl-3-cephem-4-carboxylate-l.1-dioxide STEP A: Preparation of 2.2.2-trichloroethyl-6a-ethoxy-2. 2-dimethyl penicillanate

To an ice-cooled solution of 6-diazopenicillanate (5.0 g, 0.01395 mol) in a mixture of ethanol (10 ml) and methylene chloride (20 ml) was added boron trifluoroetherate (4 drops) . The mixture was stirred at ice-temperature for 3 hours, washed with water, brine, dried and concentrated to give 4.56 g (87%) of crude product which was purified over silica column using hexane-ethyl acetate (4:1) as eluant. The yield of pure product was 3.4 g (54.1%).

NMR (CDC1 ₃ ) δ 1.25 (t, 3H) , 1.55 (s, 3H) , 1.6 (s, 3H) , 3.75 (q, 2H),4.65 (s, 2H) , 4.8 (s, 2H) , 5.30 (s, IH) .

STEP B: Preparation of 2.2.2-trichloroethyl-6a-ethoxy-2. 2-dimethyl penicillanate 1-oxide

To an ice-cooled solution of 2,2,2-trichloroethyl-6a- ethoxy-2, 2-dimethyl penicillanate (3.4 g, 9.026 mmol) in 40 ml of methylene chloride was added m-chloroperbenzoic

SUBSTITUTE SHEET

acid (80%, 1.95 g, 9.026 mmol) portionwise over 30 minutes. The mixture was stirred at ice-temperature until tic indicates that all starting material has been consumed. Th reaction mixture was washed with sodium bicarbonate solution, water, brine, dried and concentrated to give 4.0 g of crude product which was purified over silica column using methylene chloride as eluant (3.0 g, 84%). NMR (CDC1 ₃ ) δ 1. 3 (t, 3H) , 1. 34 (S, 3H) , 1. 80 (s, 3H) , 2. 85 (q, 2H)4.65 (s, IH) , 4.80 (s, IH) , 5.02 (s, 3H) .

STEP C: Preparation of 2.2.2-trichloroethyl-7a-ethoxy-3- methyl-3cephem-4-carboxylate

A solution of 2,2,2-trichloroethyl-6a-ethoxy-2, 2-dimethylpenicillanate 1-oxide (1.0 g, 2.546 mmol) in a mixture of DMF (10 ml) and acetic anhydride (0.659 ml) was heated to reflux at 125-1300C for 1.5 hours. Solvent was removed under reduced pressure and the residual dark oil was diluted with methylene chloride and was washed successively with water, sodium bicarbonate solution, brine, dried and concentrated to give 910 mg of the crude product which was purified on a silica column using methylene chloride as eluant, yield (400 mg, 42%). NMR (CDC1 ₃ ) δ 1.28 (t, 3H) , 2.165 (s, 3H) , 3.2'5 (d, IH, J=17.3 Hz), 3.51 (d, IH, J=17.3 Hz) , 3.62-3.88 (m, 2H) , 4.57 (d, IH, J-1.4 HZ), 4.72 (d, IH, J=1.4 Hz) , 4.80 (d, IH, J=12 Hz), 5.06 (d, IH, J=12 HZ).

SUBSTITUTE SHEET

STEP D: Preparation of 2.2.2-trichloroethyl-7α- ethoxy-3-methyl-3cephem-4-carboxylate-1.1-dioxide To an ice-cooled solution of 2,2,2-trichloroethyl-7a-ethoxy 3-methyl-3-cephem-4-carboxylate (340 mg, 0.9075 mmol) in methylene chloride (14 ml), peracetic acid (32%, 1.94 ml) was added dropwise and the mixture was stirred at room temperature for 24 hours; ice-cold water was added to the reaction mixture and the organic layer was separated out; the aqueous solution was saturated with solid sodium chloride and re-extracted with methylene chloride. The combined organic layer was washed with sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate and concentrated to give 370 mg of the crude product which was purified over silica column using hexane-ethyl acetate (4:1) mixture, yield (300 mg, 81%). NMR (CDC1 ₃ ) δ 1.29 (t, 3H) , 2.16 (s, 3H) , 3.68 (d, IH, J=18.0 Hz) , 3.92 (d, IH, J=18 Hz), 3.67-3.96 (m, 2H) , 4.67 (bs, IH) , 4.83 (d, IH, J=11.7 Hz), 5.035 (d, IH, J=11.7 Hz) , 5.22 (d, IH, J=1.4 HZ) .

STEP E: Preparation of 2.2.2-trichloroethyl-7a-ethoxy -2-methylene-3-methyl-3-cephem-4-carboxylate-l.1-dioxide 2,2,2-Trichloroethyl 7a-ethoxy-3-methyl-3-cephem-4- carboxylate 1,1-dioxide (290 mg, 0.7131 mmol) was dissolve in methylene chloride (5 ml) , dimethylamine hydrochloride

(168 mg, 2.066 mmol), formaldehyde solution (0.19 ml, 2.37 mmol, 37% w/v) and t-butyl alcohol (3.3 ml) was heated to reflux at 70-75 ^β C for 1.5 hours; solvent was removed under reduced pressure, the residue was diluted with methylene

SUBSTITUTE SHEET

chloride and washed with water, brine, dried and concentrated to give 300 mg of white solid which was directly used for the next step without further purification. NMR (CDC1 ₃ ) δ 1.30 (t, 3H) , 2.19 (s, 3H) , 3.67-3.89 (m, 2H) , 4.805 (d, IH, J=11.8 Hz), 5.12 (d, IH, J=11.8 Hz), 4.86 (d, IH) , 5.32 (d, IH) , 6.17 (d, IH, J=2.0 Hz), 6.68 (d, IH, J=2.0 Hz) .

STEP F: Preparation of 2.2.2-Trichloroethyl-7a- ethoxγ-2-spiro(2' .2'-diphenyl)cyclopropyl-3-methyl-3- cephem-4-carboxylate-1.1-dioxide

To an ice-cooled solution of 2,2,2-trichloroethyl

-7a-ethoxy-2-methylene-3-methyl-3-cephem-4-carboxylate 1,1-dioxide (100 mg, 0.2388 mmol) in methylene chloride (5 ml) was added diphenyldiazomethane (56 mg, 0.2866 mmol) and the mixture was stirred at ice-temperature for 2 hours; solvent was removed under reduced pressure and the crude product was purified over silica column using methylene chloride as eluant to give 68 mg of pure

2,2,2-trichloroethyl-7a-ethoxy-2-spiro (2' ,2'-diphenyl) cyclopropyl-3-methyl-3-cephem-4-carboxylate

-1,1-dioxide.

NMR (CDCl _j ) δ 1.16 (s, 3H, CH ₃ ) , 1-22 (t, 3H) , 2.38 (d, IH, J=7,0 Hz, cyclopropyl), 2.98 (d, IH, J=7.0 Hz, cyclopropyl), 3.46-3.82 (m, 2H) , 4.67 (d, IH, J-11.7 Hz),

5.02 (d, IH) , 5.11 (d, IH) , 5.24 (d, IH, J=11.7 Hz) ,

7.17-7.50 (m, 10H, aromatic).

SUBSTITUTE SHEET

EXAMPLE 8

2.2.2-Trichloroethyl-7a-methoxy-2-spiro(2' _r 2'-diphenyl) cyclo-propyl-3-methγl-3-cephem-4-carboxylate-l.1-dioxide

STEP A: Preparation of 2.2.2-trichloroethyl-6a-methoxy-2, 2-dimethyl penicillanate

To an ice-cooled solution of 6-diazopenicillanate (5.0 g, 0.01395 mol) in a mixture of methanol (25 ml) and methylene chloride (25 ml) was added boron trifluoroetherate (4-5 drops) and the mixture was stirred at ice-temperature for 2 hours, washed with water, brine dried and concentrated to give 3.4g of crude product which was purified over silica column using hexane-ethyl acetate

(3:2) as eluant to give 2.3g of pure

2,2,2-trichloroethyl-6a-methoxy-2,2-dimethyl penicillanate. NMR (CDC1 ₃ ) δ 1.55 (s, 3H) , 1,61 (s, 3H) , 3-55 (s, 3H,

OCH ₃ ) ,

4-625 (doublet overlapped with a singlet, 2H) , 4-79 (d,

2H) , 5-35 (d, IH) .

STEP B: Preparation of 2.2.2-trichloroethyl-6a-methoxy-2.2- dimethyl penicillanate-1-oxide

To an ice-cooled solution of 2,2,2-trichloroethyl-6a- methoxy-2,2-dimethyl penicillanate (35.6g, 0.09816 mol) in methylene chloride (350 ml) was added dropwise peracetic acid (15-4 ml, 32%) . The mixture was stirred at ice-temperature for one hour, washed with water, sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated to give 26.0 g of 2,2,2-trichloro- ethyl-6-a-methoxy-2,2-dimethyl penicillanate-1-oxide.

SUBSTITUTE SHEET

NMR (CDC1 ₃ ) δ 1. 34 (s , 3H) , 1. 75 (s , 3H) , 3 . 58 (s , 3H, OCH ₃ ) , 4-60 (s , IH) , 4 . 96 (s , 2H) , 4 . 63 (d, IH, J=12 . 0 Hz ) , 5. 03 (d, IH, J=12 . 0 Hz ) .

STEP C: Preparation of 2.2.2-trichloroethyl-2- (benzothiazol-2'-yldithio)-a-isopropenyl-4- oxo-3α-methoxy azetidine-1-acetate

A mixture of 2,2,2-trichloroethyl-6α-methoxy-2, 2-dimethyl penicillanate-1-oxide (15.Og, 0.0396 mol) and 2-mercaptobenzothiazole (7.44g, 0.04357 mol) in 250 ml of dry toluene was heated to reflux for 2 hours using a Dean-Stark trap; solvent was removed under reduced pressure. The residual brown oil was dissolved in methylene chloride and precipitated with hexane under ice-cooling. The precipitated solid (18.4g, 86%) was collected by filtration and used for the next step.

STEP D: Preparation of 2.2.2-trichloroethyl-6a-methoxy-2β- bromomethyl-2 -methyl penicillanate 2,2,2-Trichloroethyl-2-(benzothiazol-2•-yldithio)-α-isopr op enyl-4-oxo-3α-methoxy azetidine-1-acetate (7.4g, 0.01408 mol) was dissolved in methylene chloride (100 ml) and cooled to -30 ^* C; bromine (0.431 ml, 0.0084 mol) dissolved in methylene chloride was added dropwise to the above solution and the mixture was stirred at -30*C for 40 minutes, the precipitated solid was filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The residual mass was redissolved in ether and cooled, the precipitated solid was filtered off. The

SUBSTITUTE SHEET

filtrate was concentrated to give a foam (6.0 gm) . This product was used in the next step.

NMR (CDC1 ₃ ) δ 1.67 (s, 3H) , 3.55 (S, 5H, OCH ₃ + CH ₂ Br) , 4.67

(s, IH) , 4.80 (s, 2H) , 5.30 (s, IH) , 5.45 (s, IH) .

STEP E: Preparation of 2.2.2-trichloroethyl-7a-methoxy

-3-methyl-3-cephem-4-carboxylate

The crude mass (6.0 gm) from Step D was dissolved in a mixture of dimethyl sulfoxide (100 ml) and pyridine (9.0 ml) and the reaction mixture was stirred at room temperature for 20 hours; solvent was removed under reduced pressure. The sticky mass was dissolved in methylene chloride, washed successively with water, dilute hydrochloric acid, brine, dried and concentrated to give a semi solid (5.0 g) . NMR (CDC1 ₃ ) δ 2.15 (s, 3H) , 3.37 (d, 2H) , 3.55 (s, 3H) , 4.58 (s, IH) , 4.77 (s, 2H) , 4.90 (s, IH) .

STEP F: Preparation of 2.2.2-trichloroethyl-7a-methoxy-3- methyl-3-cephem-4-carboxylate-l.1-dioxide

2,2,2-Trichlorcethyl-7a-methoxy-3-methyl-3-cephem-4- carboxylate (8.7 g, 24.12 mmol) was dissolved in 100 ml of methylene chloride, peracetic acid (51.6 ml) was added dropwise and the mixture was stirred at room temperature for 18 hours. After the reaction, the reaction mixture was washed with water, sodium bicarbonate solution, brine, dried and concentrated to give a sticky solid. To the sticky mass a mixture of ether: hexane (1:1) was added with ice-cooling. The precipitated solid was collected by

SUBSTITUTE SHEET

filtration (9 . 33g, 98.5%) . NMR (CDC1 ₃ ) δ 2 . 17 (S , 3H) , 3-57

(s , 3H) , 4-13 (d , 2H) , 4 . 93 (s , IH) 5. 15 (d, IH) , 5. 20 (s ,

IH) , 5 , 96 (d , IH) .

STEP G: Preparation of 2.2.2-trichloroethyl-7a-methoxy -2-methylene-3-methyl-3-cephem-4-carboxylate-l.1-dioxide

A mixture of 2,2,2-trichloroethyl-7α-methoxy-3-methyl -3-cephem-4carboxylate-1,1-dioxide (2.0 g, 5.094 mmol), dimethylamine hydrochloride (1.24g, 15.28 mmol), t-BuOH (24 ml), methylene chloride ( 5 ml) and formaldehyde (1.4?. ml, 37% w/v in water) was heated to reflux at 800 C for 1.5 hours. The solvent was removed under reduced pressure and the residual mass was dissolved in methylene chloride, washed successively with water, dried and concentrated to give 1.78 gm (86.4%) of pure

2,2,2-trichloroethyl-7a-methoxy-2-methylene3-methyl -3-cephem-4-carboxylate-l,1-dioxide as a white solid. NMR (CDC1 ₃ ) δ 2.20 (s, 3H) , 3.60 (s, 3H) , 4.80 (d, IH, J=14 Hz), 4.90 (bs, IH) , 5.20 (d, IH, J=14 Hz), 5.30 (bs, IH) , 6.23 (d, IH) , 6.75 (d, IH) .

STEP H: Preparation of 2.2.2-trichloroethyl-7a- methoxy-2-spiro (2' .2'-diphenyl) cyclopropyl-3- methyl-3-cephem-4-carboxylate 1.1-dioxide 2,2,2-Trichloroethyl-7α-methoxy-2-methylene-3-methyl- 3-cephem-4-carboxylate-1,1-dioxide (1.78 g, 4.399 mmol) was dissolved in methylene chloride (70 ml) . To this solution diphenyl diazomethane (0.940g, 4.839 mmol) was added and the mixture was stirred at room temperature for 3 hours.

SUBSTITUTE SHEET

After removal of the solvent the pink foam was purified over silica column using methylene chloride as eluant; 900 mg (35-8%) .

NMR (CDC1 ₃ ) δ 2.16 (s, 3H) , 2.40 (d, IH, J=7-0 Hz) , 3,0 (d, IH, J=7.0 HZ), 3.47 (s, 3H) , 4.68 (d, IH, J=12 Hz), 5.02

(d, IH) , 5.07 (d, IH) , 5.23 (d, IH, J=12 Hz).

EXAMPLE 9 Benzhydryl 7a-methoxy-2-spiro (2' .2'-diphenyl) σyclopropyl-3-methyl-3-cepehm-4- carboxylate-1.1-dioxide STEP A: Preparation of 7α-methoxy-2-spiro (2' .2'-diphenyl) cyclopropyl-3-methyl-3-cephem-4-carboxylic aσid-1.ldioxide

2,2,2-Trichloroethyl 7α-methoxy-2-spiro (2' ,2'-diphenyl) cyclopropyl-3-methyl-3-cephem-4- carboxylate-1,1-dioxide (from Step H, Example 8, 2.39g,

4.187 mmol) was dissolved in 50 ml of glacial acetic acid, zinc powder(7.0 g) was added and the mixture was stirred at room temperature for 1 hour, excess zinc was removed by filtration through a bed of Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, brine, dried and concentrated to give 1.5 g (83%) of pure acid. NMR (CDC1 ₃ ) δ 1.23 (s, 3H) , 2.38 (d, IH, J=6.8 Hz) , 2.94 (d, IH, J=6.8 HZ), 3.47 (s, 3H) , 5.026 (bs, IH) , 5.054 (bs, IH) , 7.24-7.49 (m, 10 H, aromatic).

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STEP B: Preparation of benzhydryl 7a-methoxy-2-spiro (2' .2'-diphenyl)cyclopropyl-3-methγl-3-cephem-4- carboxylate-1.1-dioxide

To a stirred solution of 7a-methoxy-2-spiro (2* ,2'-diphenyl)cyclopropyl-3-methyl-3-cephem-4-carboxylic acid-1,1-dioxide (830 mg, 1.889 mmol) in 20 ml of methylene chloride was added diphenyl diazomethane (367 mg, 1.889 mmol) and the mixture was stirred at room temperature for 3 hours, washed with dilute sodium bicarbonate solution, brine, dried and concentrated to give 1.3 g of the crude product which was purified over silica column using methylene chloride as eluant to give 362 mg of pure benzhydryl 7α-methoxy-2-spiro(2' ,2•-diphenyl)cyclopropyl-3- methyl-3-cephem-4-carboxylatel,1-dioxide. NMR (CDC1 ₃ ) δ 0.96 (s, 3H) , 2.31 (d, IH, J=6.9 Hz) , 2.92 (d, IH, J=6.9 Hz), 3.44 (s, 3H) , 4.95 (d, IH, J=1.5 Hz), 5.05 (d, IH, J=1.5 Hz), 7.01 (s, IH) , 7.2-7.47 (m, 20 H, aromatic) .

EXAMPLE 10

7-a-Methoxy-2-spiro (2' .2'-diohenyl)cvclopropyl-3-methyl- 3-cephem-4-pyrrolidine carboxamide-1.1-dioxide

7α-Methoxy-2-spiro (2' ,2'-diphenyl)cyclopropyl-3- methyl-3-cephem-4-carboxylic acid-1,1-dioxide (1.84g, 4.187 mmol, from Step A, Example 9) was dissolved in 45 ml of methylene chloride, oxalyl chloride (797 mg, 6.280 mmol) was added followed by a drop of N,N-dimethyl formamide. The mixture was stirred at room temperature for one hour. Solvent was removed under reduced pressure and the light

SUBSTITUTE SHEET

brown solid was dried under high vacuum.

The solid was redissolved in dry methylene chloride (15 ml) , cooled in an ice-bath, and a solution of pyrrolidine (596 mg, 8.374 mmol) in dry methylene chloride (8 ml) was added dropwise. The mixture was stirred at ice-temperature for 1 hour, washed with cold water, dilute hydrochloric acid, water, brine, dried and concentrated to give 1.57 g of the crude product which was purified over a silica column using hexane-ethyl acetate (1:1) as eluant to give pure, 1.04 (50.5%), 7α-methoxy-2-spiro(2' ,2'-diphenyl) cyclopropyl-3-methyl-3-cephem-4- pyrrolidinecarboxamide-1, 1-dioxide; crystallization from ether gave a pale yellow solid, p. 222 'C (decomposed).

NMR (CDC1 ₃ ) δ 0.92 (s, 3H) , 1.71-2.04 (m, 4H, pyrrolidine), 2.23 (d, IH, J=6.7 Hz), 2.91 (d, IH, J=6.7 Hz) , 3.09-3.68 (m, 4H, pyrrolidine), 3.46 (s, 3H) , 4.94 (d, IH, J=1.5 Hz), 5.05 (d, IH, J=1.5 Hz), 7.17-7.50 (m, 10H, aromatic).

EXAMPLE 11

7a-Methoxy-2-spiro (2' ,2'-diphenyl)cvclopropyl-3-methyl-3- cephem-4-piperidine carboxamide-1,1-dioxide 7α-Methoxy-2-spiro (2' ,2'-diphenyl)cyclopropyl-3-methyl-3— cephem-4-carboxylic acid-1,1-dioxide (1-0 g, 2.275 mmol, from Step A, Example 9) was dissolved in 5 ml of methylene chloride, oxalyl chloride (0.3 ml, 3.413 mmol) was added followed by a drop of N,Ndimethyl formamide. The mixture was stirred at room temperature for one hour. Solvent was

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removed under reduced pressure.

The light brown solid was redissolved in dry methylene chloride (5 ml) , cooled in an ice-bath, piperidine (388 mg, 4.551 mmol) dissolved in 5 ml of dry methylene chloride was added dropwise and the reaction mixture was stirred at ice-temperature for 2 hours, washed with water, brine, dried and concentrated to give 980 mg of crude product which was purified on a silica column using hexane ethyl acetate (2:1) as eluant to give 491 mg (42-6%) of pure 7α-methoxy-2-spiro (2',2'-diphenyl)cyclopropyl-3-methyl -3-cephem-4-piperidine carboxamide-1,1-dioxide. NMR (CDC1 ₃ ) δ 0.903 (s, 3H) , 1.46-1.68 (m, 6H, piperidyl) , 2.23 (d, IH, J=6.8 Hz), 2.91 (d, IH, J=6.8 Hz) , 3.34-3.64 (m, 4H, piperidyl), 3.459 (s, 3H, OCH ₃ ) , 4.95 (d, IH, J=l-5 Hz) ,5.04 (d, IH, J=1.5 Hz) , 7.20-7.50 (m, 10H, aromatic).

EXAMPLE 12

Benzhydryl 7a-bromo-2-spiro [2 ^■ .2'-(4' .4'-dichloro) diphenyl1cvclopropγl-3-methyl-3-cephem-4-carboxγlate- 1.1-dioxide STEP A: Preparation of di(4-chlorophenyl)diazomethane

To a stirred ice-cold solution of 4,4'- dichlorobenzophenone hydrazone (1.303 g) in dry methylene chloride (20 ml) was added magnesium sulfate (590 mg) , silver oxide (1.196 g) was added in one portion followed by potassium carbonate (30 mg) . The mixture was stirred at ice-temperature for 1 hour, then at room temperature for an additional hour, filtered through Celite to give a dark

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purple solution which was directly used for the cycloaddition reaction.

STEP B: Preparation of benzhydryl 7.α-bromo-2-spiro f2' .2'-(4' .4'-dichloro)diphenyllcyclopropyl-3-methγl-3- cephem-4-carboxylate-1.1-dioxide

Benzhydryl 7α-bromo-2-methylene-3-methyl-3-cephem-4- carboxylate-1,1-dioxide (2.0 g, from Step D, Example 2) was dissolved in dry methylene chloride (30 ml) and cooled in an ice-bath. To this solution di(4-chlorophenyl) diazomethane (from Step A) was added and the mixture was stirred at ice-temperature for 1 hour. Evaporation of the solvent and purification over a silica column using hexane ethyl acetate mixture as eluant pure benzhydryl 7a-bromo-2-spiro [2•,2'-(4' ,4'-dichloro)diphenyl] cyclopropyl-3-methyl-3-cephem-4carboxylate-l,1-dioxide (1.2 g) was obtained, m.p. 202 ^* C (decomp.).

NMR (CDC1 ₃ ) δ 1.03 (s, 3H) , 2.32 (d, IH, J=7 Hz) , 2-90 (d, IH, J=7 Hz), 4.94 (d, 1 H, J=l,5 Hz), 5.23 (d, IH, J-1.5 Hz), 7.03 (s, IH, CHPh ₂ ) , 7.18-7.42 (m, 18H, aromatic).

EXAMPLE 13

Benzhydryl 7a-bromo-2-spiror2' .2'-(4' .4'- difluoro)diphenyl1 cyclopropyl-3-methyl-3-cephem-4- carboxylate-1.1-dioxide

STEP A: Preparation of di(4-fluorophenyl)diazomethane

4,4•-Difluorobenzophenone (1.0 g, 4.306 mmol) was dissolved in methylene chloride (9 ml) containing iodine (0.2 ml; 1% w/v) and 1,1,3,3-tetramethyl quanidine (2.1

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ml) . To this solution was added peracetic acid solution (1.23 ml, 6.459 mmol) at O' C over 20 minutes. The mixture was stirred at O'C for 1 hour, then washed with water until the washings were at pH 6. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated to give a deep purple oil (850 mg, 83.7%) which was directly utilized for the next reaction.

STEP B: Preparation of benzhydryl 7a-bromo-2-spiro f2'.2'-(4'.4'difluoro)diphenyl1cyclopropyl-3-methyl -3-cephem-4-carboxylatel.l-dioxide

Benzhydryl 7a-bromo-2-methylene-3-methyl-3-cephem-4- carboxyate-1,1-dioxide (1.6 g, from step D, Example 2) was dissolved in dry methylene chloride (20 ml) and cooled in an ice-bath. To this solution di (4-fluorophenyl) diazomethane (from step A) was added and the mixture was stirred at ice-temperature for 1 hour. Evaporation of the solvent and purification over a silica column using hexane- ethyl acetate mixture as eluant, pure benzhydryl 7α-bromo-2-spiro[2•,2'-(4',4'-difluoro) diphenyl]cyclopropyl-3-methyl-3-cephem-4-carboxylate-l, 1-dioxide (0.8 g) was obtained. NMR (CDC1 ₃ ) δ 1.04 (s, 3H) , 2.33 (d, IH, J=7.2 Hz), 2.92 (d, IH, J=7.2 Hz) , 4.92 (d, IH, J=1.5 HZ), 5.22 (d, IH, J=l-5 Hz) , 6.88-7.44 (m, 18H, aromatic) .

Following the procedure described in Example 13, Step B but starting with an appropriate diazo compound the following cyclopropyl derivatives were prepared:

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(1) Benzhydryl

7α-bromo-2-spiro(2'-ethoxycarbony1)cyclo propyl-3-methyl-3- cephem-4-carboxylate-l,1-dioxide, NMR (CDC1 ₃ ) δ 1.23 (t, 3H, COOCH ₂ CH ₃ ) , 1.80 (s, 3H, CH ₃ ) , 2.18 (d, 2H, cyclopropyl, J=8.5 Hz), 2.75 (t, IH, CHCOOCH ₂ CH ₃ , J=8.5 Hz), 4.17 (q, 2H, COOCH ₂ CH ₃ ) , 5.08 (d, IH, J=1.5 Hz), 3.26 (d, IH, J=1.5 Hz), 6.98 (s, IH, CHPh ₂ ) , 7.26-7.37 (m, 10 H, aromatic).

(2) Benzhydryl 7α-bromo-2-spiro(2'-phenyl-2'-methyl) cyclopropyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide.

NMR (CDC1 ₃ ) δ 0.92 (s, 3H, CH ₃ ) , 1.78 (s, 3H, CH ₃ ) , 2.23 (ABq, 2H, cyclopropyl, J=7 Hz), 5.03 (d, IH, J=1.7 Hz), 5.34 (d, IH, J=1.7 Hz), 6.9 (s, IH, CHPh ₂ ) , 7.18-7.48 (m, 15H, aromatic) .

(3) Benzhydryl 7α-bromo-2-spiro(2'-phenyl)cyclopropyl-3- methyl-3-cephem-4-carboxylate-1,1-dioxide.

NMR (CDC1 ₃ ) δ 1.07 (s, 3H, CH ₃ ) , 2.09 (dd, IH, cyclopropyl, J=6.8 Hz and 8.0 Hz), 2.39 (dd, IH, cyclopropyl, J=6.8 Hz and 8.0 Hz), 3.29 (dd, IH, cyclopropyl, J=8.0 Hz and 10.0 Hz), 5.16 (d, IH, J=1.4 HZ), 5.45 (d, IH, J=1.4 Hz), 6.90 (s, IH, CHPh ₂ ) , 7.22-7.36 (m, 15H, aromatic).

SUBSTITUTE SHEET