FI100327B - New 4-propargyl-2-oxo-1-azetidinacetic acid derivatives - Google Patents

Description

100327

Separate from 4-propargyl-2-oxo-1-azetidine acetic acid derivatives separated from FI patent application 911701 5

The invention relates to novel 4-propargyl-2-oxo-1-azetidine acetic acid derivatives of the formula 10 R1 wx / Ln \ r30

0 I

CO 3 R 3 wherein R 1 is 1-hydroxyethyl which may be substituted by benzyloxycarbonyl or t-butyldimethylsilyl, R 3 is p-methoxybenzyl, p-nitrobenzyl, 2-chloro-2-propenyl or sodium or potassium ion, R 30 is hydrogen, -CO 2 R 16, - (C = O) -R 17 or -CHOH-R 17, R 16 is a straight or branched lower alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, and R 17 is a phenyl ring optionally substituted with halogen.

The novel compounds of the invention are useful as intermediates in the preparation of the novel 2-substituted alkyl-3-carboxycarbapenems of formula II described in FI patent application 911701 (FI patent 95256), which are useful as antibiotics and 6-lactamase inhibitors. , III, IV and VI: 35 2 100327 5 CO? RJ 001x3 (II) (III) W 'r- <co, R> «o» * 1 (IV) (VI) where R1 and R3 have the same meaning as above and X is H, wherein Y is phenylsulfonyl, wherein the phenyl group may be substituted by one or two halogen, branched or linear C 1-4 alkyl or C 1-4 alkoxy or by one trifluoromethyl or acylamino group, thienylsulfonyl or quinolinylsulfonyl, or X is halogen, wherein Y is lower alkoxycarbonyl

via the 4-alkyl-2-oxo-1-azetidineacetic acid derivatives of formula XVII described in the co-pending FI patent application 943056

.25 B, x.

try, // N \ 'Y (XVII)

o 1 Q

COjR3 wherein R1, R3, X and Y are as defined above and Q is a suitable leaving group such as halogen using the Michael addition elimination reaction.

2-Substituted alkyl-3-carboxycarbapenems are known as effective antibiotics. For example, T. N. Salzmann et al. in "Recent Advances in the ti: Ari l nm i i t u 100327 3

Chemistry of β-Lactam Antibiotics ", P. H. Bentley and R. Southgate, eds. Royal Society of Chemistry, 1989, pp. 171-189, state that such carbapenems have antibacterial activity.

5 Sandoz reported in Tetrahedron Letters 25 (52) (1984) 5989-5992 that an intermolecular Wittig reaction between 2-oxocarbapenem-3-carboxylic acid esters and triphenylphosphorane ylides has been reported to give exo- and endo-product mixtures 10 R5 R5 »_R ^ \ = o / w 2o ° c Γ "τ VX.

X- + ArP = (- * v N // W

Ν-γ 3 ^ r7 molecule7 o *,

co r6 Iin space co-R

2 2 (dashed lines represent a mixture of endocyclic and exocyclic double bonds) wherein W is CN, CO 2 CH 3 or COCH 3 and R 7 is H, R 5 is ethyl or fluoroethyl and R 6 is either an ester group or a cationic group.

EP 0 265 117, published April 4, 1988, discusses the same process for the preparation of 2-alkyl-3-carboxycarbapenem using the Wittig method. In this publication, V is CN, COR8 or CO2R8; R 8 is C 1 -C 4 alkyl, ΰ 7 -ϋ 31-25 aralkyl; R 9 is H, C 1 -C 4 alkyl; R 10 is hydroxyethyl or protected hydroxyethyl; Rn is an ester protecting group.

R '/ v 30 0 COjR1'

Both publications found that the intermolecular Wittig reaction method gave much higher yields than the commonly used intramolecular reactions 4,100,327, as described below (wherein W, R 10 and R 11 are defined and thus selected as the method.

The choice of R7 and R9 in these publications is limited to the H or C substitution. Other substituents at this position, such as halogen, i.e. 5 '' vr '/ fin., Wlttlg C0, 1M C0j * n in these publications, are limited. .chlorine, is not accepted in either form of reaction (intramolecular or intermolecular Wittig reaction) A comprehensive literature review does not really reveal any publication on triarylphosphorane groups having the general structure w '.

Ph, p -

20 Z

wherein VI1 is as defined above for W and V and z is halogen (F, Cl, Br, I).

Thus, it is highly unlikely that 2-halo-25-alkyl-3-carboxylic carbapenems could be prepared

Wittig methodology. However, such compounds can be prepared by the intramolecular Michael addition-elimination reaction described in this application.

In Japanese Patent Application 58-103 388 30 (Sankyo), published June 20, 1983, carbapenems were prepared by an intramolecular Wittig reaction as follows: R10 .GH2-CCH2-BA-R12 35 Ί I __ '' I Ο ^ Η, -Β-Α-R 12

,, C0, R

co2R '1 5 100327 wherein B is thio, sulfinyl or sulfonyl; A is either a single bond or a linear or branched alkylene chain; R12 is a cyclic amine residue which forms a 3- to 8-membered ring and may contain in the ring oxygen, nitrogen, sulfur, sulfinyl, sulfonyl or carbonyl, of which nitrogen may be substituted by a lower aliphatic acyl which may have an amino group, a (lower alkyl) mo- nos-substituted amino- or (lower alkyl) -disubstituted aminoalkylene, or a group of formula 10 -C-HR14 wherein R13 is hydrogen, amino or lower alkyl; and R 14 is hydrogen or lower alkyl, and further a group of formula R 15

20 -HH

wherein R 15 is hydrogen or lower alkyl present in the acyl or alkyl substituent on said cyclic amine residue may be replaced by a group of the formula: -N C --- N R '4

R, s R, S

30 'wherein R13, R14 and R15 are as defined above.

Sankyo's publication does not contain any teaching or suggestion for the preparation of new endocyclic double bond isomers of the formulas 35 6 100327 12 p 10 R. B-A-RiZ R \ ___, ϊψ · 5 co2ru co2ru E-isomer Z-isomer

In the Sankyo ring closure method (intramolecular Wittig reaction), neither of the E- or Z-exo-to-10 isomers is possible, only the endocyclic double bond isomers. The two exoisomeric products can be prepared by a method comprising the Michael addition elimination series disclosed in this application. Sankyo's publication also does not provide any data on in vitro antibacterial activity.

In Heterocycles, 23 (8) (1985) 1915-1919, the Sandoz group disclosed the 2-alkyl-3-carboxycarbapenem of formula 20 HO obtained by the intramolecular Wittig reaction.

Va _ oj co2r11 25 No antibacterial data on this carbapenem have been published.

The 4-propargyl-2-oxo-1-azetidine acetic acid derivatives of the present invention are useful as intermediates in the preparation of the novel carbapenem antibiotics described in strain application 30 (F1 Patent 92656) via a new and general chemical method using Michael addition elimination. These novel 2-substituted alkyl-3-carboxycarbenenems having activity as antibiotics and β-35 lactamase inhibitors have one of the formulas II, III, IV and VI set forth and defined above, which compounds comprise all diastereomeric forms II-VIII.

100327 7: s co2R3 c o 2 r 3 λ 2 1

Δ - # ndo II Δ -indo I I I

10) = ςκ kx 15 o ', o \ C02R C02 R 3 (Z) - exo I V X - H (Z) - exo V | χ J h

(E) - exo V X ^ H (E) - exo VM X - H

20 R 1 trVcxr co2r3: · 25

exo YI I I

The exo isomers may be in the E and Z forms and this depends on the nature of X. If X is H, then formulas V and VII represent the E-isomer. On the other hand, if X is F, Cl, Br or I, then formulas IV and VI represent Z-isomeric forms. Formula VIII represents mixtures of E and Z isomers.

Removal of the ester protecting group from these compounds results in a compound of formula IX 35 8 100327

r1 X

wherein R20 is H or a water-soluble cation such as sodium or potassium, or a physiologically active ester group such as pivaloylmethoxymethyl and IX comprises both the delta1 and delta2 endo forms and the exo- forms X-XVI: CO2 R 26 CO2R20

2 g Δ2- · ηΊο X Δ1 - # ndo XI

! 25 CO 2 R 20 C 0 2 R 2 ° (2) -exo XII X-H _exo XIV x / h

30 (E) -exo XIM X / H "exo XV X'H

-

35 0 '7D

COjR 0 exo X Yl I. «« Il li * H I |; I4 100327 9

The novel carbapenems described above are prepared by treating the substituted allyl azetidinone of formula XVII as defined above with an appropriate base such as lithium bis (trime-5-silyl) amide under an inert atmosphere at an optimum temperature of -80 ° C to -20 ° C under an inert atmosphere. ° C.

In formula XVII, X is fluorine, chlorine, bromine, iodine or hydrogen and Q may be any suitable leaving group commonly used in this type of reaction.

Some representative examples are: F, Cl, Br, I, R21S, R21SO2, NR213, PR213, OR21, OCOR21, OOH, 00R21, -OP (0) (OPh) 2, -OP (0) (OCO3) 2, - OSO2Ph, -OSO2 (4-nitro-phenyl), -OSO2CH3 and CN, wherein R21 is an alkyl group which may be straight or branched and has 1 to 10 carbon atoms; preferably 1 to 6, most preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl; a phenyl-substituted alkyl group such as benzyl, benzhydryl CH (C 6 H 6) 2, 2-phenylethyl; phenyl optionally substituted with 1 to 3 substituents independently selected from, for example, fluorine, chlorine, bromine or C 1 -C 4 alkyl.

The novel intermediates of this invention are used in the preparation of novel carbapenems according to the reaction schemes set forth below.

10 100327

Scheme 1 W '”' / χ -. - Phase 1 silicon / \ _____ /) - NH + ^ 5

l * "'XII

R 1

I f ^ EmäS R \ / X

/ j — H \ H I ^

10 1 R1JCHjC0.H XXI ό XH

C 0 2 H 1 o '

Step 2 xxil xx R3 ö h xxiv 15 Step dcc, duap 3

T

R ', S0iR'7 Γ "\'. <K 1 - C 0, R 3, 1 CO2Rj

XXIII

XXV

ΑΓ S O j R17 SOR * 7 25 r 'I 2 R1 502r ^ Base N-f - "^ \ j s'-N I -► J_ / 0 N i Step 5 o ^ c o j R 3 C 0 j R 3 30

xxv Exo XXVI

s ° 2r’7 R ’1

35 VrV

C 02 R 3

End XXVII

k! »A.μ otu i> i ii · 11 100327

Diagram 1 - continued p.

VrV Base y-r \ J

-p * "-p

0 1 Step 6 0 I

C02R3 C0jRj 10 Exo XXVI · n d β XXVII -

n - B u 4 N F

Step 1 H F

Step 6

I 'V

15 H0 H0 J''rT'V / S0! "'' *». J "prV'S0!“ ”//“ - Ύ ^ rr * —f

COjR3 C0jRJ

20 Exo XXVIII _ · n d o XXX

Step ® Step 10

HO HO

: ”C0zR20 CO, R20

Exo XXIX Endo XXXI

30 12 100327

In Scheme 1, step 1, a propargyl-azetidinone compound of formula XX is formed by contacting acetoxyacetidinone XVIII and propargyl halide XIX with the elemental metal M in the presence of a Lewis acid LA, wherein R 1 is as defined above and R 22 is Cl, Br or I, M is Zn or Mg, of which Zn is preferred, LA is a suitable Lewis acid such as, but not limited to, diethylaluminum chloride; in the presence of a suitable solvent such as tetrahydrofuran, toluene, diethyl ether or dimethoxyethane, of which tetrahydrofuran is preferred. It is preferred to use the reactants XIX, M and LA in an excess relative to XVIII, usually in a ratio of 1.5: 1.5: 1.5: 1, respectively. Reaction concentrations are usually maintained at 0.2 to 0.5 molar for the limiting reactant (XVIII).

Acetoxyazetidinone XVIII and propargyl halide XIX can be contacted with metal M and Lewis acid LA at temperatures from about 0 ° C to about room temperature (25 ° C). The presence of Lewis acid LA is not absolute in the preparation of XX, however, optimum yields for XX are obtained when step 1 is carried out in the presence of Lewis acid. Reaction times are usually of the order of 2 to 12 hours and preferably 2 to 5 hours. Reaction product XX is isolated after a series of reactions initiated by the addition of a 2.5 molar excess of a weak aromatic base, such as pyridine, over one hour, followed by conventional methods in the art, including filtration, washing, crystallization, chromatography, and the like. The yields of product XX are 30-90%, and preferably 70%.

30 In Scheme 1, step 2, propargyl azetidinone XX

the nitrogen is alkylated with a functional acetic acid of formula XXI. Product XXII is formed by contacting XX and XXI with a suitable base such as, but not limited to, lithium, bis (trimethylsilyl) amide, lithium hydride, or sodium hydride in an appropriate mixed solvent system such as diethyl ether: N, N in dimethylformamide (DMF), toluene: DMF or tetrahydrofuran: DMF, preferably tetrahydrofuran: DMF. In the reactant XXI, R23 may include, but is not limited to, chlorine, bromine, iodine, toluenesulfonyl, but preferably bromine.

An excess of reactant XXI and base relative to compound XX is generally preferred in a ratio of 1.2: 3.2: 1, respectively. Reaction concentrations are generally considered to be 0.2 to 10 to 0.5 molar for limiting reagent XX. Compounds XX and XXI can be contacted with a base at a temperature in the range of 0 ° C to about room temperature under an inert atmosphere of nitrogen or argon (ambient pressure) for 2-18 hours, preferably 12 hours.

Reaction product XXII is isolated according to conventional methods in the art, including washing with dilute inorganic acid, filtration, washing with water and crystallization.

The yields of XXII are 30 to 80%, preferably 60 to 70%.

In Scheme 1, step 3, acid XXII is esterified to ester XXIII by contacting XXII with alcohol XXIV, dicyclohexylcarbodiimide (DCC), and 4-dimethylaminopyridine (DMAP) according to the general procedure described by A, Hassner in Tetrahedron Lett., ( 1978) page 4475, and wherein R 3 is as defined above. The yields of product XXIII are 30-95% and preferably 80-90%.

In Scheme 1, step 4, terminal acetylene XXIII is regioselectively and stereospecifically converted to iodovinyl sulfone XXV, wherein R 17 is, for example, substituted phenyl and R 20 is as defined above. The reaction method for preparing a compound of formula XXV follows the method described by W. Truce et al. in J. Org.

Chem. 36 (13) (1971) 1727-31 and also T. Kobayashi et al. in Chem. Lett. (1987) 1209-1212. The yields of product XX XXV are 20-88% and preferably 70-80%.

14 100327

In Scheme 1, step 5, compounds of formula XXV are contacted with the appropriate base in a suitable solvent at temperatures from -100 ° C to room temperature. Although any suitable temperatures may be used, it is preferable to use temperatures of -100 ° C to 70 ° C

to eliminate unwanted degradation. The Michael additlo elimination reaction thus induced forms carbapenems XXVI and XXVII.

Suitable bases which can be used in step 5, 10 are usually non-aqueous and comprise: lithium diisopropylamide - lithium bis (trimethylsilyl) amide - sodium bis (trimethylsilyl) amide - potassium bis (trimethylsilyl) amide 15 - potassium t-butoxide - diethylammonium magnesium - diisopropylaminomagnesium bromide - lithium diethylamide - Grignard reagents such as (primary, secondary and tertiary) alkyl-magnesium halides - lithium-N-methylanilide - methylanilinomagnesium bromide - lithium, sodium or potassium piperidide 25 - or potassium naphthalenide - lithium, sodium or potassium isopropoxide - lithium, sodium or potassium isopropoxide - alkali metal salts of dimethyl sulphoxide - 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) 30-1,5-diazabicyclo [4.3. O] non-5-ene (DBN) - alkyllithiums, such as primary, secondary and tertiary alkyllithiums, for example: n-butyllithium, sec-butyllithium and tertbutyllithium 35 - lithium, sodium or potassium hydride.

100327 15

Other strong bases that may be suitably used are listed in "Modern Synthetic Reactions" by H. House, W.A. Benjamin, Inc., Menlo Park, California, 1972.

Suitable solvents that can be used include, but are not limited to, non-aqueous aprotic solvents such as, but not limited to: tetrahydrofuran (THF) diethyl ether dimethoxyethane (DME) dimethylformamide (DMF) N, N-dimethylacetamide (DMA) N, N-dimethylpyrrolidinone (DMP) ) 1,4-dioxane acetonitrile 15 ethyl acetate hexanes, pentane, heptane, cyclohexane. The solvent can be used in amounts sufficient to dissolve allyl azetidinone XXV. Usually, solutions of XXV in 0.05 to 2.0 molar are used in the Michael addition-elimination cyclization reaction, preferably 0.15 to 0.5 molar.

The allyl azetidinone of Step 5 of Scheme 1 may be contacted with 1.1 to 3 equivalents of a suitable base, preferably 1.3 equivalents of lithium bis-25 (trimethylsilyl) amide at a suitable temperature for 0.1 to 3.0 hours, preferably 0.75 hours of argon or nitrogen. in an inert atmosphere.

Reaction products XXVI and XXVII are isolated after a series of reactions by the addition of 2-5 equivalents of weak acid having an acidity in the pH range of 4-5, such as acetic acid or an aqueous solution of potassium dihydrogen phosphate, followed by equilibration to 0 °. To C and then using conventional methods known in the art, including washing, crystallization or chromatography. The combined yields of products XXVI and XXVII range from 10 to 70%.

100327 16

Exo-carbapenem XXVI can be converted to endo-isomer XXVII. Contacting the exo-isomer XXVI with a suitable tertiary amine base in a suitable solvent at a temperature in the range of 0 ° C to 40 ° C gives the endo-isomer XXVII within 1-24 hours.

Suitable amines include triethylamine, diisobutylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, of which diisopropylethylamine is preferred.

Suitable solvents are those described above for the cyclization of XXVin, of which methylene chloride is preferred. Substrate XXVI is usually contacted with a 2 to 4 molar excess of amine in a sufficient amount of solvent to give a concentration of 0.1 to 1.0 mol / L, the optimum being 0.3 mol / L. After isolation of the product, conventional methods in the art follow, including washing with an aqueous acid solution such as potassium dihydrogen phosphate, chromatography, and the like. Yields of product XXVII range from 70 to 95%.

In formulas XXVI and XXVII, R1 is selected as the independent-20 ti. When R 1 is 1- (t-butyldimethyl) silyloxyethyl or 1- (benzyloxycarbonyloxy) ethyl, the removal of such protecting groups can be accomplished by a variety of conventional methods, such as acid hydrolysis of silyl-containing groups.

In Scheme 1, step 7, a preferred 1- (t-butyldimethyl) silyloxyethyl group of exo-carbapenem XXVI is hydrolyzed to 1-hydroxyethyloxocarbapenem XXVIII by standard methods in the art, wherein XXVI is contacted with hydrogen fluoride in an acetonitrile solvent according to the general procedure R. Newton et al. in Tetrahedron Lett., 41 (1979) 3981-3982. The product yields of this step are 40-80%, preferably 60-70%.

Accordingly, the preferred 35 1- (t-butyldimethyl) silyloxyethyl group of endo-carbapenem XXVII is hydrolyzed in step 1 of Scheme 1 to 1-hydroxyethylenecarbapenem XXX via tetra-n-butylammonium fluoride in a hydrolytic standard method described in the art. in J. Med. Chem. 30 5 (1987) 871-880. The product yields of this process range from 25 to 55%. It should be noted that only the latter hydrolytic process (tetra-n-butylammonium fluoride) produces endo-XXX from endo-XXVII. If the hydrogen fluoride method were used in step 8, it would only produce decomposition products. The tetra-n-butylammonium fluoride method is suitable for step 7 as well as step 8, but is not optimal for step 7, as is the hydrogen fluoride method.

In Scheme 1, step 9, endo-XXX is formed from endo-15 XXVIII by contacting an exo-carbapenem with a tertiary amine. The process and the isolated yields of product XXX are very similar to step 6 of Scheme 1 described previously.

Following the formation of the carbapenems of the desired general formulas of exo-XXVIII and endo-20XX, the carboxyl protecting group R3 of these intermediates may optionally be removed by conventional methods such as solvolysis, chemical reduction or hydrogenation.

When using a protecting group such as p-nitrobenzyl which can be removed by catalytic hydrogenation, intermediates XXVIII or XXX in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether buffer, tetrahydrofuran-aqueous dipotassium hydrogen phosphate or isopropylphosphate may be treated under a hydrogen pressure of 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium / carbon, palladium hydroxide, platinum oxide or the like at a temperature of 0 ° C to 40 ° C for about 0.2 to 4 hours. Protecting groups such as 2,2,2-trichloroethyl can be removed by weak zinc reduction. The allyl protecting group 35 can be removed using a catalyst-containing mixture of 18,100,327 of a palladium compound and triphenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride, or diethyl ether in ether. Similarly, other common carboxyl protecting groups can be removed by methods known to those skilled in the art.

Finally, compounds of formulas exo-XXVIII and endo-XXX, wherein R 3 is a physiologically hydrolyzable ester such as acetoxymethyl, pivaloyloxymethyl, methoxymethyl, etc., can be administered directly to the patient without deprotection because the esters are hydrolyzed in vivo under physiological conditions.

Thus, the carbapenems exo-XXIX and endo-XXXI can be prepared separately according to steps 9 and 10 of Scheme 1, respectively, wherein R 20 is as defined above.

Depending on the carboxyl protecting group, the deprotection method varies as described above. Isolation of the product from the deprotection step again varies due to the method used, but all methods used in this transformation follow standard methods in the art, including chromatography and freeze-drying. Product yields of exo-XXIX or endo-XXXI range from 10 to 80%, with a range of 50 to 60% being preferred.

Variations of Scheme 1 allow for the preparation of other carbapenems of formulas II, III, IV and VI, and these follow in Scheme 2, where R 16 may be, for example, lower alkyl.

».

• i ttfii astu M »** · 100327 19

Figure 2

rl

Phase 1 \-

0 I

C0jRJ

XXIII

TM / CO / R, OH

0 *

10 I

r '.

15 COjR

D o η

COjR J

XXXI I

CuX ·, /

Step 7 1 / / L I X · 20 »x *" 1 — f ^ c ° s? ~ H) - • 25 co2r *

XXXVI I I

In Scheme 2, step 1, propargyl azetidinone ester XXIII, the preparation of which is considered relevant above in Scheme 1, is converted to the acetylene ester XXXII wherein R 1, R 3 and R 16 are as defined above. The acetylene ester XXXII is formed by contacting the head with ethylene XXIII with a transition metal catalyst TM such as palladium dichloride, palladium diacetate, palladium dis (trifluoroacetate) or nickel dichloride, of which palladium dichloride is preferred. The amounts of catalyst used in Step 1 range from 1 mole% to 10 mole%, based on terminal acetylene XXIII. Oxidant Ox 5 is used to initiate the catalytic cycle. Common oxidizing agents include anhydrous copper salts such as copper (II) acetate, copper (II) chloride, etc., of which copper (II) chloride is preferred. The oxidant is usually used in amounts of 1.5 to 3.5 equivalents for Compound XXIII, with 2.0 equivalents being preferred. Step 1 of Scheme 2 is carried out in an alcoholic solvent, R160H, which also acts as a reactant. Substrate concentrations range from 0.05 to 5 mol / L, with 0.1 to 1 mol / L being preferred. If the alcohol R16OH is solid, an inert co-solvent can be used while maintaining the desired concentrations.

Suitable co-solvents include tetrahydrofuran, acetonitrile, diethyl ether, etc. The reaction is carried out in the presence of a suitable buffer such as sodium acetate in the range of 1.5 to 3.5 equivalents relative to the starting acetylene.

The reaction is best carried out in a solution saturated with carbon monoxide and at a single atmospheric pressure of carbon monoxide. Higher carbon monoxide pressures can be used, but there is no real benefit. Reaction times range from 0.5 to 10 hours, of which 1 to 3 hours is typical. Isolation of the product follows standard methods in the art, including washing, filtration, crystallization, or chromatography. Product yields vary depending on R160H and range from 20 to 85%, of which 50 to 70% is preferred. This method has been used in non-corresponding terminal acetylenes by J. Tsuji et al. Tetrahe dron Lett. 21 (1980) 849-51. Other methods for converting terminal acetylene to acetylene ester are common in the art. The method described above is preferred.

In Scheme 2, step 7, the acetylene diester XXXII is converted to the dihaloester XXXVIII by contacting XXXII. With a suitable halogenating agent in which X 'is chlorine, bromine or iodine. There are many acetylene halogenation methods in the art, many of which are useful in transforming step 7 and are found in S. Pa-5 or (published) "The Chemistry of the Carbon-Carbon Triple

Bond "Part 1, J. Wiley, 1978, pages 320-327. In the preferred process of Step 7, acetylene XXXII is contacted with an anhydrous copper (II) halide and a lithium halide such as a copper (II) chloride-lithium chloride pair or a copper (II) bromide-lithium bromide pair. , in a suitable solvent such as acetonitrile under an inert atmosphere such as argon at a temperature in the range of 25 ° C to 100 ° C, preferably at 80 ° C, for 1 to 16 hours, usually 6 to 8 hours, is a preferred period of time. the generation is the same as that used for non-corresponding acetylenes, as described by S. Uemura et al in J. Chem. Soc. Chem. Commun. (1975) pages 925-6. filtration, washing and chromatography, with product yields ranging from 50 to 90%.

The preparation of other 2-alkyl-substituted 3-carboxycarbenenems is based on modifications of the general preparations of Schemes 1 and 2. The preparation route of Scheme 3 uses propargyl azetidinone XXII prepared as shown in Scheme 1 as a starting point for the preparation of carbapenems of formulas II, III, IV and VI wherein Y is COR17.

In Scheme 3, step 1, propargyl alcohol XLV is formed from XXII after sequential treatment of XXII with two equivalents of a suitable strong base such as n-butyllithium in a suitable solvent such as terahydrofuran under an inert atmosphere such as argon at -80 to 0 ° C. preferably at -70 ° C. The amount of solvent 35 commonly used is sufficient to cause dissolution of acid XXII, with a final concentration range of 0.05 to 2 mol / L, with 0.1 to 0.3 mol / L being preferred. After vigorous base treatment, the appropriate aldehyde R17CHO is contacted with the recently base-treated compound XXli if R17 is as defined above. The amount of aldehyde ranges from about 1 to 5 equivalents, based on compound XXII, with 1.2 to 3 equivalents being preferred. Reaction times of the aldehyde with the base-treated compound XXII range from 0.5 to 5 hours, with 2-3 hours being preferred, while the reaction temperature is allowed to range from -80 to 20 ° C, with a range from -80 to 0 ° C being preferred. The reaction is terminated by adding 2 to 10 equivalents of a suitable weak acid, preferably 2 to 5 equivalents of acetic acid to the reaction mixture. The product is isolated using standard methods known in the art, including washing and chromatography. Yields of XLV range from 20 to 85%, depending on the nature of the aldehyde used, with a range of 50 to 85% being preferred.

In Scheme 3, step 2, acid XLV is esterified to compound XLVI according to one or more methods known in the art. Preferably, the general method described in Step 3 of Scheme 1 is used, wherein R 3 is as defined above.

In step 3 of Figure 3, the secondary alcohol XLVI! 25 is oxidized to the corresponding ketone XLVII. Oxidation of propargyl alcohols to propargyl ketones is common in the art and many methods are available. Many of these methods are acceptable for Step 3 transformation, such as pyridine chlorochromate in methylene chloride, barium permanganate in methylene chloride, and manganase oxide in chloroform. Preferred in step 3 is pyridine chlorochromate (PCC) in methylene chloride. A methylene chloride solution containing XLVI at a concentration of about 0.05 to 3 mol / L, preferably 0.2 to 1 mol / L, is contacted with about 1.2 to 5 molar equivalents of PCC, tl | preferably with 2-3 equivalents, in the temperature range of about 0 ° C to room temperature, preferably at room temperature, for 1-24 hours, preferably for 1-4 hours. The product is isolated using conventional methods in the art, including filtration, washing and chromatography. The product yields of XLVIrr range from 30 to 90%, with a range of 60 to 90% being preferred.

In Scheme 3, step 4, the unsaturated dichloroketone XLVIII is formed by contacting XLV1I with identical reactants and under the reaction conditions described in detail in Scheme 2, step 7. The product yields of XLVIII range from 30 to 70%.

Figure 3 24 100327 5 1

R I

\ Step 1 R

fC \ -12- = S-. Jut? Y-1 '

0 I 2) R, 7CH0 ^ S I

CO, H 1 ° H

C O, H

10 xni

- * · υ XLV

Step 2 Ri ° H

OCC / DUAP

v 15 .k'r '' ΚΥ "

.0 I HO

20 COjR C O j R1 XLV I |

X L V I

CuX · j L I X '

Step 4 ’25, x · WV”

J — H X- O

0 I

COjR1 30 XLVI "ii; jli.i Rilli I I I: || 100327 25

In step 1 of Scheme 4, the substituted allylazetidinone XLIX undergoes an intermolecular Michael addition-elimination reaction with nucleophile Q to form L, where Q, R 1, R 3, X 'and Y are as defined above. Compound 5 L is prepared by contacting the dihalogen compound XLIX with a suitable nucleophile Q in a suitable solvent such as, but not limited to, acetone, acetone triil, dimethoxyethane, dimethylformamide, methanol, ethanol, pyridine, at a temperature in the range of 10 ° C to 80 ° C. , preferably at 20 to 50 ° C for 1 to 24 hours depending on the nature of X 'and Q. The reaction described above is not critical to the next reaction, which is carbapenem-forming ring closure.

K>

Scheme 4 „100327 ΔΌ =" χχΎ <, V "\ X '

o I XL! X

COj R3 10 Phase, 0 V 0

0 1 L

C O j R 5

Step 2 Base 20 kv: kx kv: 25 oi oi oi COjR5 COjR5 CO2R3

Δ1 - «ndo LII (E) -exo L I I I (z) ~ eksoLIV

R 1 30 \ ------ .X ‘FT * COjR3 2

Δ - »ndo LV

35

Il: Ettt; E itu I "t it 27 100327

Step 1 of Scheme 4 is optional for replacing X 'with a group Q that is a better leaving group than X'. Those skilled in the art have found that addition-elimination reactions can be enhanced by selecting a sensibly leaving group Q.

This improvement is reflected, for example, in improved yields of carbapenems, less degradation of Compound L, or shortened or more accurate reaction times. This empirical finding is described in detail in simpler systems in J. March, 10 "Advanced Organic Chemistry", J, Wiley, 3rd Edition, 1985, pages 295-296. Thus, the purpose of Step 1 is to prepare a compound of formula L from XLIX which has optimal reactivity in the Michael addition elimination reaction to form 2-alkyl-substituted α-3-carboxycarbapenems.

In Scheme 4, step 2, compound L is contacted with the appropriate base in a suitable solvent at a temperature in the range of -100 ° C to room temperature. Although any suitable temperature can be used, it is preferable to use temperatures in the range of -100 ° C to -40 ° C.

to eliminate unwanted degradations. The resulting Michael addition-elimination reaction forms carbapenems LII-LV in varying amounts. Factors that control the relative ratio of carbapenem products LII-LV in ring closure in step 2 include, but are not limited to, structural factors such as Y and X ', reaction time, reaction temperature, base strength, and amount of excess base.

Suitable bases that can be used in step 2, 30 are usually non-aqueous and are described above in step 5 of Scheme 1. Accordingly, suitable solvents that can be used are usually anhydrous, aprotic solvents and are identified above in step 5 of Scheme 1.

35 100327 28

The solvent can be used in effective amounts to dissolve Compound L. Usually, a concentration range of 0.05 to 2.0 mol / L in L-solutions is used in Step 2 of Scheme 4. Preferably, the concentration is 0.15 to 0.5 mol / L.

Allylazetidinone may be contacted with 1.1 to 3 equivalents of a suitable base as defined above, preferably 1.3 equivalents of lithium bis (trimethylsilyl) amide at a suitable temperature for 0.1 to 3.0 hours, preferably 0.75 hours under argon or nitrogen inert. -10 weather atmosphere.

Reaction products III-LV are isolated following the following procedure in which 2-5 equivalents of a weak acid having an acidity in the pH range of 4-5, such as acetic acid or an aqueous solution of potassium dihydrogen phosphate, are added, followed by temperature equilibration. ° C and thereafter using conventional methods in the art, including washing, crystallization or chromatography. The combined yields of the products LII-LV range from 10 to 70%.

The conversion of the delta1-endo-LII, (E) -exo-LII and (Z) -exo-LIV isomers to the delta2-endo-isomer LV is shown in Scheme 5.

«29 100327

Figure 5 5 p i U * p '

tO <x tO <T

/} - * - / r </ ηύ 1 // ~ ηΎ * 'COjR3 C 0 j R 3 C 0 j R 3 10 Δ' - * ndo LII (E) _exoLM, (Z) _exo L | v

Base '1 15 CO j R 3. 2

Δ -endo LV

; Contact of the delta1-endo-isomer LII and / or the exo-isomers LIU and LIV with a suitable tertiary amine base in a suitable solvent at a temperature in the range of -70 to 40 ° C gives the endo-isomer LV over 0.25 to 24 hours at a temperature of -70 to -20 ° C is preferred over a period of 0.25 to 0.75 hours.

Suitable amines include triethylamine, diisobutylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), of which The DBU is preferred.

Suitable solvents include methylene chloride, tetrahydrofuran, acetonitrile, dimethoxyethane and acetone, of which methylene chloride is preferred.

The delta-endo-isomer LII and / or the exo-isomers LIU 15 and LIV are contacted with a 0.1 to 1.8 molar excess of amine, preferably a 0.9 molar excess in a sufficient amount of solvent so that the concentration is in the range of 0 , 1 to 1.0 mol / l, with 0.3 mol / l being optimal. After isolation of the product, conventional methods in the art follow, including washing with an aqueous acid solution such as potassium dihydrogen phosphate, chromatography, and the like. The yields of the product LV vary in the range of 10 -95%.

In Scheme 6, the compound of formula LVI represents! 25 (E) - and (Z) -exo-isomeric forms together with the LV of the endo-isomer, wherein R1 is as defined above. Removal of such protecting groups in steps 1 and 2 of Scheme 6 can be accomplished by one or more conventional methods, such as acid hydrolysis of silyl-containing groups. These commonly used deprotection methods are well known in the art and are discussed in T. Greene, "Protective Groups in Organic Synthesis" J. Wiley, 1981, pages 14-71.

100327 31

Scheme 6 5 tO- <x '/> Μ-γ /> - xr

0 3 o I

cojr co2r3

(E) exo (z) LVI Λ * - · ndo L V

10

Phase 1 Phase 2 t v

H0 HO

Vv -Vrv / '· ppcx'r iZp, C02r3 0 C 0 j R3

20 (E) and (Z) ekSO LVI 1 A2-.ndo LVI I I

Step 3 Step 4 ‘25

OH OH

0 1 o 30 co2r20 co2r1 °

Exo L I X Δ · n d o - L X

100327 32

To isolate the product in step 1 or 2 of Scheme 6, this deprotection method uses similar methods conventional in the art, such as washing, filtration, and chromatography. The product yields of exo-LVII from step 1 5 or the product yields of endo-LVIII from step 2 range from 20 to 85%.

After formation of the carbapenems of the desired general formulas of the exo-LVII and endo-LVIII, the carboxyl protecting group R 3 of these intermediates can optionally be removed by conventional methods such as solvolysis, chemical reduction or hydrogenation. If a protecting group such as p-nitrobenzyl or p-methoxybenzyl is used, it can be removed by catalytic hydrogenation. Intermediates LVII and LVIII in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether buffer, tetrahydrofuran-aqueous dipotassium hydrogen phosphate isopropanol or the like can be treated with hydrogen at a pressure of 1 to 4 atmospheres. such as 20 palladium / carbon, palladium hydroxide, platinum oxide or the like at a temperature of 0 to 40 ° C for about 0.2 to 4 hours. The allyl protecting group can be removed using a catalyst containing a mixture of a palladium compound and triphenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Similarly, other common carboxyl protecting groups can be removed by methods known to those skilled in the art.

Compounds of formulas exo-LVII and endo-LVIII wherein R3 is a physiologically hydrolyzable ester such as acetoxymethyl, pivaloyloxymethyl, methoxymethyl, etc. may be administered directly to a patient without deprotection because such esters are hydrolyzable in vitro upon addition. in the presence of esterase or in vivo under physiological conditions.

Thus, carbapenems exo-LIX and endo-LX in which R20 is as defined above can be separately prepared according to Steps 3 and 4, respectively. Depending on the carboxyl protecting group, the deprotection method as described above varies. Isolation of the product from the deprotection step again varies based on the method used, but all methods used in this transformation follow methods common in the art, including chromatography and freeze-drying. Yields of exo-LIX range from 20% to 70% and endo-LX yields from 10% to 60%.

It should be noted that certain products of formula LXI fall within 15 R 1

\ / X LXI

* 0 to N ^ // Y

CO, R3 can be formed as optical isomers as well as epimeric mixtures thereof. For example, when the 6-substituent in LXI is 1- (t-butyldimethyl) silyloxyethyl, such a substituent may be in either the R or S configuration, of which the R configuration is preferred. Accordingly, the configuration of the carbapenem core may be 5R or 5S and 6R or 6S, of which 5R, 6S is the preferred configuration.

In the parent application, i.e. samples of the carbapenene-30 compounds of formulas II, III, IV and VI prepared in FI patent 95 256, when dissolved in water and diluted with nutrient broth, the following minimum inhibitory concentrations (MIC) pg / ml were found to be organisms as determined by overnight incubation at 37 ° C by tube dilution (Table 35 1).

34 100327

table 1

Antibacterial activity of carbapenem derivatives in vivo 5 Carbapenem Organism

Ec (1) Ec (2) SA (1) SA (2) SW EntC MIC pg / ml? H / - \ 8 8 0.06 0.06 32 54 CO ”Ho *

Example 43 oh _.1 1 0.06 0.06 32 32 CO "Ha *

Example 10

OH

20 A — p- c 1 ^ h ^ = Nco ch 128 128 64 54 128 128 COjN ·

Example 44 '25

Ec (1) - E. coli ATCC 25822; 30 Ec (2) - E. coli ATCC 35218; SA (1) - Staph, aureus ATCC 29213; SA (2) - Staph, aureus ACCC 25823; SW - Ser. marcesiens: Ent C - Ent. cleacae 35 • f '* H: i MM I t l rt 100327 35 A sample of carbapenems prepared in FI patent 95256 was examined in combination with penicillin piperacillin. The increased, combined synergistic antibacterial activity describes the α-β-β-lactamase properties of these carbapenems (Table 2).

Table 2

In vitro antibacterial activity of a 1: 1 mixture of carbapenem, piperacillin and carbapenem: piperacillin

Carbapenem: piperacillin

^ —— V sillin 0 / I

0 ‘co, N · co, n. f *

Piperacillin 20 M.I.C. pg / ml

Organisms —--- E. Coli-OXA-2 32 16 0,5 E. Coli-OXA-4 32 8 2 E. Coli-OXA-7 16 128 0,5 25 E. Coli-OXA-5 32 2 0 , 25

Pseudomonas OXA-6 128 32 4 30 When used for the use described above, the compounds may be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered parenterally in the form of sterile injectable solutions or suspensions containing of.

36 100327 0.05 to 5% suspending agent in isotonic medium. Such pharmaceutical preparations may contain, for example, 0.05% and up to 90% of active ingredient together with a carrier, usually about 5 to 60% by weight.

The effective dose of the active ingredient may vary depending on the particular compound used, the mode of administration and the severity of the disease being treated. Usually, however, satisfactory results are obtained when the compounds are administered from about 2 to about 100 mg / kg of the live weight of the animal in a daily dose, preferably in divided doses 2 to 4 times a day. For the largest mammals, the total daily dose is about 100 to about 750 mg, preferably about 100 to 500 mg. Dosage forms suitable for internal use contain from about 100 to about 750 mg of active compound in good admixture with a liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to achieve the optimal therapeutic result. For example, many divided doses may be administered daily or the dose may be periodically reduced as indicated by the exigencies and the therapeutic situation. A practical advantage of these active compounds is that they can be administered intravenously, intramuscularly or subcutaneously. Liquid carriers include sterile water, polyethylene glycols, nonionic surfactants, and edible oils, such as corn, peanut, and sesame oils, which are appropriate to the nature of the active ingredient and the particular form of administration desired. Additives commonly used in the preparation of pharmaceutical compositions may advantageously be present, such as colorants, preservatives, antioxidants, for example vitamin E, ascorbic acid, BHT and BHA.

These active compounds can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds can be prepared in suitable admixture with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The invention is described in more detail in connection with the following specific examples, which should not be construed as limiting the scope of the invention.

Example 1 [3S- [3a (S *), 48]] - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -4- (2-propynyl) -2- ATSE-tidinoni

To a dry three-necked round bottom flask equipped with a mechanical stirrer, an additional 1000 mL funnel, and a thermometer were added 146.6 g of zinc and 1 L of tetrahydrofuran. The slurry was stirred at 0 ° C under argon while 800 mL of diethylaluminum chloride (1.8M in toluene) was added through the tube. A solution of 320 g of [3S- [3a (S *), 48]] -4- (acetyloxy) -3- [1 - [[1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] - 2-Azetidinone and 168 ml of propargyl bromide (in 80% toluene solution) in 800 ml of tetrachlorofuran were added via addition funnel over 90 minutes and the reaction mixture was stirred at 0 ° C for two hours, then at room temperature overnight. The reaction mixture was cooled to 0 ° C and 200 ml of pyridine was added dropwise over 50 minutes. The solution was filtered through diatomaceous earth, washing with dichloromethane. The filtrate was concentrated in vacuo to 1 L and the solid was dissolved in dichloromethane. The resulting solution was added to a stirred 3 L ice / water slurry over 45 minutes and stirring was continued for an additional 30 minutes. The solution was filtered through a second pad of magnesium silicate and the filtrate was evaporated to give 196.6 g (66.9%) of recrystallization from heptane.

1 H NMR (CDCl 3) δ 0.073 (s, 6H), 0.877 (s, 9H), 1.23 (d, 3H), 2.05 (t, H), 2.54 (m, 2H), 2, 90 (m, H), 3.86 (m, H), 4.21 (m, H), 5.98 (brs, OH).

IR (KBr) 1702, 1754 cm-1.

Example 2 [3S- [3 «(S *), 48]] - 3-Cl-C [1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2-oxo-4- (2-propynyl) 1-Azetidineacetic acid 4.48 g of a slurry of prewashed sodium hydride (50% dispersion in oil) in 200 ml of anhydrous tetrahydrofuran were cooled in an ice bath under argon pressure. To this slurry was added, over 30 minutes, a solution of 10 g of the acetidinone prepared in Example 1 and 6.22 g of bromoacetic acid in anhydrous tetrahydrofuran. The resulting reaction mixture was stirred for an additional 20 minutes and then 16 mL of dry dimethyl-30-formoform was added dropwise. The ice bath was then removed and the slurry was stirred overnight at room temperature. 100 ml of 1N hydrochloric acid was slowly added to the slurry, followed by 200 ml of water. The product was extracted three times with 300 ml of ethyl acetate. The organic phase was washed with 2 x 35 mL of water, 2 x 200 mL of brine, dried over magnesium sulfate and filtered. The filtrate was evaporated to give, after recrystallization from hot hexane, 10.9 g of product (90.2%). Sp. 86-88 ° C.

1 H NMR (CDCl 3) β 0.068 (d, 6H), 0.895 (s, 9H), 1.24 (d, 3H), 2.07 (m, H), 2.6 (m, 2H), 2.97 (m, H), 3.98 (m, H), 4.1 (q, 2H), 4.2 (m, H), 7.8 (brs, OH).

IR (KBr) 1702, 1755 cm-1.

Example 3 [3S- [3β (S *), 48]] - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2-oxo-4- (2-propynyl) -10 1-azetidineacetic acid, 2-chloro-2-propenyl ester

To a solution of 10 g of the acid prepared in Example 2 in 150 ml of anhydrous tetrahydrofuran were added, under argon, 3.2 ml of 2-chloro-2-propen-1-ol, 0.369 g of 4-dimethylaminopyridine and 7.57 g of 1.3 -dicyclohexylcarbodiimide. The resulting slurry was stirred overnight at room temperature, filtered and the filtrate was evaporated to dryness. The resulting oil was dissolved in 200 mL of ethyl acetate, the cloudy solution was filtered, and the filtrate was washed with 20 mL portions of 5% aqueous acetic acid, water, and brine. The organic phase was dried over magnesium sulfate and evaporated to dryness to give, after flame column chromatography (10-20% ethyl acetate / hexane), 6.56 g (82.2%) of product as a colorless oil.

NMR (CDCl 3) δ 0.07 (d, 6H), 0.867 (s, 9H), 1.25 (d, 3H), 2.05 (m, H), 2.61 (m, 2H), 2 .95 (m, H), 4.1 (q, 2H), 4.71 (d, 2H), 5.46 (d, 2H).

Example 3A

[3S- [3a (S *), 48]] -3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2-oxo-3- (2-propynyl) - 1-azetidineacetic acid, (4-nitrophenyl) methyl ester

The title compound was prepared by the method of Example 3 using 11 g of the product of Example 2, 150 ml of tetrahydrofuran, 7.04 g of 4-nitrobenzyl alcohol, 0.182 g of 4-dimethylaminopyridine and 7.04 g of 1,3-dicyclohexyl-10032740 carbodiimide. The reaction mixture was purified by flash chromatography to give 6.2 g (40%) of white crystalline product.

1 H NMR (CDCl 3) δ 0.055 (d, 6H), 0.855 (s, 9H), 1.24 (d, 3H), δ 1.99 (m, H), 2.58 (m, 2H), 2, 95 (m, H), 3.95 (m, H), 4.13 (d, 2H), 4.19 (m, H), 5.26 (d, 2H), 7.52 (d, 2H) ), 8.23 (d. 2H).

IR (KBr) 1193, 1350, 1526, 1735, 1761 cm-1.

Example 4 [2R- [2d (E), 3B (R *)]] - 2- [3 - [(2,4-difluorophenyl) sulfonyl] -3-iodo-2-propenyl] -3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -4-oxo-1-azetidineacetic acid, 2-chloro-2-propenyl ester A solution of 2 g of 2-chloro-2- propenyl ester prepared in Example 3, 2.05 g of 2,4-difluorophenyl-15-sulfinic acid, 1.27 g of iodine, 0.965 g of sodium bicarbonate and 0.942 g of sodium acetate in 50 ml of ethyl acetate and 25 ml of water were irradiated with 400 watt bulb for 45 minutes. The resulting colorless solution was cooled to room temperature, the aqueous phase was separated and extracted with 2 x 20 mL of ethyl acetate. The combined organic phase was washed with 50 mL of 5% aqueous sodium bisulfite solution, 2 x 50 mL of water, and 50 mL of brine. The organic layer was dried over magnesium sulfate and evaporated to dryness to give, after flash column chromatography, 2.36 g (67%) of product as a colorless oil which solidified on standing.

1 H NMR (CDCl 3) δ 0.09 (d, 6H), 0.879 (s, 9H), 1.24 (d, 3H), 3.2 (m, H), 3.39 (m, 2H), δ .70 (m, H), 4.04 (q, 2H), 4.21 (m, H), 4.7 (s, 2H), 5.45 (d, 2H), 7.04 (m, 2H), 7.97 (m, H).

30 Example 4A

[2R- [2d (E) 3 O (R *)]] - 2- [3 - [(3,4-dimethoxyphenyl-yl) sulfonyl] -2-iodo-2-propenyl] -3- [1- [ [(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -4-oxo-1-azetidineacetic acid, 2-chloro-2-propenyl ester

The title compound was prepared according to the method of Example 4, 100327 41, using 9.25 g of 3,4-dimethoxyphenylsulfinic acid, 6.1 g of the product of Example 3, 3.87 g of iodine, 3.84 g of sodium bicarbonate, 3.75 g of sodium acetate, 150 ml of ethyl acetate. and 75 ml of water. The reaction mixture was purified by flash chromatography to give 5.81 g (52%) of product.

1 H NMR (CDCl 3) δ 0.093 (d, 6H), 0.881 (s, 9H), 1.26 (d, 3H), 3.21 (m, H), 3.37 (m, H), 3, 73 (m, H), 3.96 (d, 6H), 3.99 (q, 2H), 4.22 (m, H), 4.71 (s, 9H), 5.46 (d, 2H) ), 7.00 (d, H), 7.12 (s, H), 7.31 (d, H), 7.52 (d, H).

CI-MS: m / z 745 (M + NH 3.

Example 4B

[2R- [2 «(E), 38 (R *)]] - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2- [3 - [[4- (1,1-Dimethylethyl) phenyl] sulfonyl] -2-iodo-2-propenyl-4-15 oxo-1-azetidineacetic acid, 2-chloro-2-propenyl ester

The title compound was prepared according to the method of Example 4 using 2.97 g of 4- (1,1-dimethylethyl) phenylsulfinic acid, 2.0 g of 2-chloro-2-propenyl ester from Example 3, 1.27 g of iodine, 1.26 g. g of sodium bicarbonate, 1.23 g of sodium acetate, 50 ml of ethyl acetate and 25 ml of water. The reaction mixture was purified by flash chromatography to give 1.95 g (54%) of a white crystalline product.

1 H NMR (CDCl 3) δ 0.091 (s, 6H), 0.88 (s, 6H), 1.25 (d, 3H), δ 1.36 (s, 9H), 3.20 (m, H), 3.31 (m, H), 3.91 (q, 2H), 4.21 (m, 2H), 4.71 (s, 2H), 5.46 (d, 2H), 7.12 (s , H), 7.59 (d, H), 7.81 (d, H).

Example 4C

[2R- [2a (E), 3B (R *)]] - 3- [1 - [[(1,1-dimethylethyl) di-methylsilyl] oxy] ethyl] -2- [2-iodo-3- (2-Thienyl-sulfonyl) -2-propenyl] -4-oxo-1-azetidineacetic acid, (4-nitrophenyl) methyl ester The title compound was prepared according to the method of Example 4 using 6.63 g of 2-thiophenesulfonic acid, 5.13 g ( 4-nitrophenyl) methyl ester from Example 3A, 2.81 g of iodine, 1.87 g of sodium bicarbonate, 3.19 g of sodium acetate, 200 ml of ethyl acetate and 50 ml of water The reaction mixture was purified by chromatography to give 4.21 g (57%) of the desired product. .

1 H NMR (CDCl 3) δ 0.07 (d, 6H), 0.87 (s, 9H), 1.24 (d, 3H), δ 3.21 (m, H), 3.29 (m, H ), 3.80 (m, H), 4.03 (q, 2H), 4.18 (m, 2H), 5.27 (s, 2H), 7.18 (m, 2H), 7.53 (d, 2H), 7.70 (m, H), 7.78 (m, H), 8.23 (d, 2H).

IR (KBr) 1755 cm-1.

Example 5 10 [5R- [5β, 6 # (R *)]] - 3 - [[(2,4-difluorophenyl) sulfonyl] methyl] -6- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -7-oxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, 2-chloro-2-propenyl ester and [5R- [5a, 6a (R *)] ] -3 - [[(2,4-difluoro-15-phenyl) sulfonyl] methyl] -6-11 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, 2-chloro-2-propenyl ester 4.23 g of the iodosulfone 20 prepared in Example 4 were dissolved in 45 ml of anhydrous tetrahydrofuran under argon and the solution was cooled to -80 ° C ( ether / carbon-lihappojäähaude). To this solution was added over 10 minutes 7.8 ml of a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran. The resulting yellow solution was stirred at -80 ° C for 1.5 h under argon and then quenched with 0.53 mL of acetic acid. After stirring for 5 minutes, 2.1 ml of 0.5 M potassium dihydrogen phosphate solution was added and the cooling bath was removed. The solution was warmed to -20 to 0 ° C and an additional 20 mL of 0.5 M potassium dihydrogen phosphate solution was added, followed by 75 mL of ethyl acetate. The aqueous phase was separated, washed with 3 x 75 mL of ethyl acetate and the washes were combined with the organic phase of the reaction mixture. The combined organic phase was washed with 75 mL of water and 75 mL of brine. The organic phase was dried over magnesium sulfate and evaporated to give, after flash column chromatography (20% ethyl acetate / hexane), 1.13 g (33%) of the endocyclic product and 1.8 g (52%) of the exocyclic product.

1 H NMR (endo) (CDCl 3) δ 0.071 (d, 6H), 0.879 (s, 9H), 1.24 (d, 3H), 3.23 (m, 2H), 4.25 (m, 2H), 4.56 (q, 2H), 4.62 δ (s, 2H), 5.36 (s, H), 5.57 (d, H), 6.94 (m, H), 7.03 ( m, H), 7.89 (m, H).

1 H NMR (exo) (CDCl 3) δ 0.061 (d, 6H), 0.87 (s, 9H), 1.22 (d, 3H), 2.99 (m, 2H), 3.10 (m, H), 3.77 (m, H), 4.39 (m, H), 4.79 (q, 2H), 5.22 (s, H), 5.43 (d, H), 5, 63 (d, H), 6.59 (s, H), 7.02 (m, 2H), 7.93 (m, H).

Example 5A

[5R- [3E, 5e, 6e (R *)]] - 3 - [[(3,4-dimethoxyphenyl) sulfonyl] methylene] -6- [1 - [[(1,1-dimethylethyl) di- methylsilyl] oxy] ethyl] -7-oxo-1-azabicyclo-15 [3.2.0] heptane-2-carboxylic acid, 2-chloro-2-propenyl ester

The title compound was prepared by the method of Example 5 using 5.7 g of iodosulfone from Example 4A, 60 ml of anhydrous tetrahydrofuran, 10.2 ml of a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran, 0.7 ml of acetic acid and 2.8 ml of + 26 ml of 0.5M potassium dihydrogen phosphate. The reaction mixture was purified by chromatography to give 3.02 g (64%) of pure exocyclic product as a white solid.

: 25 δ NMR (CDCl 3) δ 0.066 (S, 6H), 0.873 (s, 9H), 1.22 (d, 3H), 2.87 (m, H), 2.94 (d, H), 2 .96 (d, H), 3.76 (m, H), 3.95 (d, 6H), 4.17 (m, H), 4.70 (d, H), 4.89 (d, H), 5.30 (s, H), 5.42 (s, H), 5.73 (s, H), 6.36 (s, H), 6.98 (d, H), 7, 29 (d, H), 7.5 (d, 2H).

CI-MS: m / z 617 (M + NH 3)

Example 5B

[5R- [3E, 5β, 6d (R *)]] - 6- [1 - [[(1,1-dimethylethyl) di-methylsilyl] oxy] ethyl] -3 - [[[4- (1,1 -dimethylethyl) phenyl] sulfonyl] methylene] -7-oxo-1-aza-35 bicyclo [3.2.0] heptane-2-carboxylic acid, 2-chloro-2-propenyl ester

The title compound was prepared by the method of Example 5 using 6.18 g of iodosulfone from Example 4B, 64 ml of anhydrous tetrahydrofuran, 11.1 ml of a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran, 0.75 ml of acetic acid and 3 ml of + 28.5 ml of 0.5 M potassium di-5 hydrogen phosphate. The reaction mixture was purified by chromatography to give 1.5 g (15%) of pure exocyclic product as a white solid.

1 H NMR (CDCl 3). S 0, 0.62 (S, 6H), 0.871 (s, 9H), 1.22 (d, 3H), 1 (J ', 1.34 (s, 9H), 2.79 (m, H), 2r82 ( d, H), 2.86 (d, H), 2f95 (d, H), 3.75 (m, H), 4f17 (m, H), 4.79 (q, 2H), 5.29 ( s, H), δ r 4 3 (s, H), 5; 68 (s, H), 6.39 (s, H), 7.56 (d, 2H), 7.77 (d, 2H) .

Example 5C

[2R- [2e, 3Z, 5e, 6 «(R *)]] -6- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -7-oxo-3 - [ 2-Thienyl isophenyl] -1-azabicyclo [3.2.0] heptane-2-carboxylic acid, (4-nitrophenyl) methyl ester The title compound was prepared by the method of Example 5 using 4.1 g of iodosulfone from Example 4C, 50 ml of anhydrous tetrahydrofuran, 7.25 ml of a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran, 0.59 ml of acetic acid and 2 ml + 20 ml of 0.5M potassium dihydrogen phosphate. The reaction mixture was purified by chromatography to give 1.85 g of the desired product as a white solid, m.p. 157-159 ° C.

1 H NMR (CDCl 3) δ OrO71 (d, 6H), O r876 (s, 9H), 1.23 (d, 3H), 3Q 2; 84 (m, H), 2.91 (m # H) / 2; 98 (m, H), 5.25 (m, H), 5.38 (d, H), 6> 49 (m, H), 7-12 (m, H), 7.58 (m, H) ), 7.67 (m, 2H), 7.1 (m, H), 8.21 (m, 2H).

-1 IR (KBr) 1744, 1771 cm.

35 „100327 45

Example 6 [5R- [5a, 6 «(R *)]] - 3 - [[(2,4-difluorophenyl) sulfonyl] methyl] -6- (1-hydroxyethyl) -7-oxo-1-azab -Cyclo [3.2.0] hept-2-ene-2-carboxylic acid [2-chloro-5R-2-propenyl ester

To a solution of 1 g of the endocyclic product prepared in Example 5 in 33 ml of anhydrous tetrahydrofuran was added 8.7 ml of a molar solution of tetrabutylammonium fluoride in tetrahydrofuran and 1.5 ml of acetic acid. The reaction mixture was kept in the refrigerator overnight and then diluted with 20 ml of cold ethyl acetate. The organic phase was washed with 2 x 20 mL of cold water, 20 mL of cold 10% aqueous sodium bicarbonate solution and 20 mL of cold brine. The organic layer was dried over magnesium sulfate and evaporated without heating to give 0.80 g of crude product.

Example 7 [5R- [3E, 5β, 6e (R *)]] - 3 - [[(3,4-dimethoxyphenyl) sulfonyl] methylene] -6- (1-hydroxyethyl) -7-oxo-1- 20 azabicyclo [3.2.0] heptane-2-carboxylic acid, 2-chloro-2-propenyl ester 1.20 g of the exocyclic product prepared in Example 5A were dissolved in 11.6 ml of acetonitrile. The solution was added to a polyethylene flask containing 4.4 mL of 50% aqueous hydrogen fluoride and 39 mL of acetonitrile. After stirring for 2 hours at room temperature, 12-13 g of solid sodium bicarbonate was added until a pH of 7-8 was reached. The solids were then filtered off and the acetonitrile was removed under reduced pressure. The aqueous solution was extracted with 2 x 50 mL of ethyl acetate.

The combined organic phase was washed with 50 mL of water, 50 mL of brine and dried over magnesium sulfate. The solid was filtered and the filtrate was evaporated to dryness to give 0.568 g (60.4%) of product after flash column chromatography (ethyl acetate system).

100327 46 δ NMR (CDCl 3) δ 1; 33 (d, 3H), 1.77 (d, OH), 2.8 (m, H), 2.94 (d, H), 3 j 03 (d, H), 3.79 (m, H), 3.95 (d, 6H), 4; 21 (m, H), 4.80 (d, 2H), 5; 3 (S, H), 5, 43 (s, H), 5.73 (s, H), 6.38 (s, H), 6r 96 (d, H), 7 f 29 (s, H), 7.49 (d, H) .

5 Example 7A

[5R- [3E, 5α, 6α (R *)]] - 3 - [[[4- (1,1-dimethylethyl) phenyl] sulfonyl] methylene] -6- (1-hydroxyethyl) -7-oxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, 2-chloro-2-propenyl ester.

The title compound was prepared by the method of Example 7 using 1.5 g of the exocyclic product from Example 5B, 15 ml of acetonitrile, 5.5 ml of 50% aqueous hydrogen fluoride in 49 ml of acetonitrile and excess sodium bicarbonate (pH 7-8). . 0.994 g (83%) of product 15 was isolated without further purification. CI-MS: m / z 499 (M + NH 4) * and 482 (M + H) +.

Example 8 [5R- [5a, 6a (R *)]] - 3 - [[(3,4-dimethoxyphenyl) sulfonyl] methyl] -6- (1-hydroxyethyl) -7-oxo-1-aza- 20 Sabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, 2-chloro-2-propenyl ester

A solution of 0.568 g of the exocyclic product of Example 7 and 3.4 ml of diisopropylethylamine in methylene chloride was stirred for three hours at room temperature and then in the refrigerator for two days. The solution was then evaporated to dryness without heating to give 0.363 g (64%) of product, after flash column chromatography (cold ethyl acetate as eluent).

Example 8A

[5R- [5a, 6a (R *)]] - 3 - [[[4- (1,1-dimethylethyl) phenyl] sulfonyl] methyl] -6- (1-hydroxyethyl) -7-Oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, 2-chloro-2-propenyl ester

The title compound was prepared by the method of Example 8 using 0.97 g of the exocyclic product of Example 7A, 5.8 ml of diisopropylethylamine and 6.8 ml of methylene chloride. 0.66 g (68%) of product was isolated without further purification.

Example 9 [5R- [5H, 6e (R *)]] - 3 - [[(2,4-difluorophenyl) sulfonyl-5H] methyl] -6- (1-hydroxyethyl) -7-oxo-1-azab - cyclo [3.2.0] hept-2-ene-2-carboxylic acid, monopotassium salt

To a solution of 0.80 g of the product prepared in Example 6 in 10 ml of ethyl acetate and 10 ml of 10 methylene chloride were added under argon 0.040 g of triphenylphosphine, 13.3 ml of 0.13 molar potassium 2-ethylhexanoate in ethyl acetate and 0.066 g of tetrakis. - (triphenylphosphine) palladium catalyst. The reaction mixture was stirred at room temperature for two hours and evaporated to dryness without heating. It was purified by reverse phase thin layer chromatography (water / ethanol: 95/5) to give 0.0655 g (20.7%) of the product as the potassium salt.

1 H NMR (D 2 O) β 1.27 (d, 3H), 3.09 (m, 2H), 3.41 (m, H), 4.20 (m, 2H), 4.64 (d, H) , 4.95 (d, 2 H), 7.21 (m, 2 H), 7.90 (m, H).

2 0 Example 9A

[5R- [5β, 6a (R *)]] - 3 - [[(3,4-dimethoxyphenyl) sulfonyl] methyl] -6- (1-hydroxyethyl) -7-oxo-1-azabicyclo [ 3.2.0-] hept-2-ene-2-carboxylic acid, monopotassium salt The title compound was prepared by the method of Example 9 using 0.366 g of the endocyclic product of Example 8, 4.5 ml of ethyl acetate, 4.5 ml of methylene chloride, 0.027 g of triphenylphosphine, 0.237 g of potassium 2-ethylhexanoate and 0.045 g of tetrakis (triphenylphosphine) palladium-30 dium catalyst. 0.828 g (25%) of product was isolated after reverse phase thin layer chromatography (water / ethanol: 95/5).

Δ NMR (D., O) δ 1126 (d, 3H), 2.97 (ra, 2H), 3.33 (m, H), 3.95 (d, 6H), 4.1 (m, H ), 4.2 (m, H), 4.55 (d, H), 4.91 (d, H), 7.18 (d, H), 7.36 (d, H), 7.51 (d, H).

100327 48

Example 9B

[5R- [5a, 6 # (R *)]] - 3 - [[[4- (1,1-dimethylethyl) phenyl] sulfonyl] methyl] -6- (1-hydroxyethyl) -7-oxo -1-Azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, 5 monopotassium salt

The title compound was prepared by the method of Example 9 using 0.660 g of the endocyclic product of Example 8A, 8 ml of ethyl acetate, 8 ml of methylene chloride, 0.52 g of triphenylphosphine, 0.278 g of potassium 2-ethylhexanoate and 0.052 g of tetrakis (triphenylphosphine) palladium catalyst.

0.1194 g (20%) of product was isolated after reverse phase thin layer chromatography (water / ethanol 75/25).

1 H NMR (D 2 O) δ 1; 25 (d, 3H), 1.34 (s, 9H), 2.92 (m, 2H), 3.31 ("> Ή"), 4.1 (m, H) 4, 2 (m, H), 4.56 (d, H), 4.9 (d, H), 7.70 (d, 2H), 7.80 (d, 2H).

Example 10 [5R- [5H, 6 # (R *)]] - 6- (1-hydroxyethyl) -3 - [(2-thienylsulfonyl) methyl] -7-oxo-1-azabicyclo [3.2.0] -20 hept-2-ene-2-carboxylic acid, monosodium salt

Following the procedure of Example 7, 0.614 g of the exocyclic product of Example 5C, 10 ml of acetonitrile, 8 ml of 50% aqueous hydrogen fluoride in 42 ml of acetonitrile and excess sodium bicarbonate (pH 7-8) are reacted. 0.405 g (81%) of the desired product is obtained and used in the next reaction without purification.

To a solution of 15 ml of methylene chloride and 15 ml of diisopropylethylamine is added 0.400 g of the above alcohol. The reaction solution is stored at 4 ° C for 7 hours. The solution is concentrated to dryness, extracted with ethyl acetate and washed with 0.5N potassium hydrogen phosphate until the solution is neutral. The organic layer is dried over sodium sulfate, filtered and concentrated to give 0.370 g of the desired product.

100327 49

To a solution of 0.370 g of the preceding endocyclic alcohol in 3.15 ml of water and 17.68 ml of dioxane are added 0.0682 g of sodium bicarbonate and 0.130 g of palladium hydroxide. The solution is hydrogenated on a Parr apparatus for one 5 hour at 20 psi, filtered through diatomaceous earth and washed with water. The filtrate is concentrated, extracted with diethyl ether and the aqueous phase is lyophilized. The resulting solid is purified by reverse phase chromatography (5% ethanol: water, v / v) to give 0.045 g (26%) of the desired product.

1 H NMR (D 2 O) δ 1.28 (d, 3H), 3.04 (m, 2H), 3.42 (m, H), 4.20 (m, 2H), 4.7 (m, 2H) , 7.27 (t, H), 7.71 (d, H), 7.92 (m, H). Example 11 [2R- [2e (E), 3B (R *)]] - 3- [1 - [[(1,1-dimethylethyl) di-15-methylsilyl] oxy] ethyl] -2- [2-iodo- 3 - [(4-methylphenyl) sulfonyl] -2-propenyl] -4-oxo-1-azetidineacetic acid, (4-methoxyphenyl) methyl ester The title compound was prepared by the method of Example 4, 0.87 g of p-methoxybenzyl ester from Example 23, 0.63 g of sodium 4-toluenesulfinate dihydrate, 0.50 g of iodine, 0.25 g of sodium acetate in 12 ml of ethyl acetate and 6 ml of water were irradiated with a 300 watt incandescent lamp for 45 minutes. After purification, 1.04 g (73%) of product were obtained as an oil.

1 H NMR (CDCl 3) δ 0.1 (s, 6H, 2CH 3), 0.9 (s, 9H, 3CH 3), 1.25 (d, 3H, CH 3), 2.45 (s, 3H, CH3), 3.18 (dd, 1H, H3), 3.25 (dd, 1H, allyl H), 3.75 (dddd, 1H, allyl H), 3.8 (s, 3H, CH3 O) , 3.9 (dd, 2H, CH 2 CO 2), 4.15 (m, 2H, CHOSi, H 4), 5.1 (dd, 2H, CH 2 O), 6.87 (d, 2H, aromatic), 7.1 (s, 1H, vinyl H), 7.3 (d, 2H, aromatic), 7.38 (d, 2H, aromatic), 7.8 (d, 2H, aromatic).

IR (neat) 1738, 1753 cm-1.

100327 50

Example 12 [5R- [5 ', 6e (R *)]] - 3 - [[(4-methylphenyl) sulfonyl] methyl] -6- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -7-oxo-1-azabicyclo [3.2.0] hept-5 2-ene-2-carboxylic acid, (4-methoxyphenyl) methyl ester and [5R- [3E, 5β, 6 «(R *)]] - 3 - [[(4-methylphenyl) sulfonyl] methyl] -6- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -7-oxo-1-aza-bicyclo [ 3.2.0] heptane-2-carboxylic acid, (4-methoxy-10-phenyl) -methyl ester

The title compounds were prepared by the method of Example 5 using 2.3 g of iodovinyl sulfone from Example 11, 25 ml of anhydrous tetrahydrofuran and 4.7 ml of a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran. The product, as an oil, consisted of two isomers and weighed 1.0 g after purification by flash column chromatography.

Example 13 [2R- [2β, 3E, 5 «, 6« (R *)]] -6- (1-hydroxyethyl) -3 - [[(4-20 methylphenyl) sulfonyl] methylene] -7-oxo- 1-Azabicyclo [3.2.0] heptane-1-carboxylic acid, (4-methoxy-phenyl) -methyl ester 0.450 g of the isomeric mixture prepared in Example 12 was dissolved in a solution of 13 ml of tetrahydrofuran and 0.63 ml of acetic acid. To this was added 3.6 ml of a 1 M solution of tetra-n-butylammonium fluoride / tetrahydrofuran according to the method described in J. Med. Chem. (1987) 30,879. After the described treatment and purification, 0.244 g (67%) of product was obtained as an oil.

30 H NMR (CDCl 3) & 1.3 (d, 3H, CH 3), 2.42 (s, 3H, CH 3), 2.78 (m, 1H, allyl H), 2.9 (dd, 1H, allyl H), 3.02 (dd, 1H, H6), 3.75 (m, 1H, H5), 3.8 (s, 3H, CH3O), 4.2 (p, 1H, CHO), 21 (s, 2H, CH 2 CO 2), 5.23 (s, 1H, H 3), 6.35 (s, 1H, vinyl H), 6.9 (d, 2H, aromatic), 7.3 (d, 2H , aromatic), 7.4 35 (d, 2H, aromatic), 7.65 (d, 2H, aromatic).

IR (KBr) 3448, 3038, 2968, 1765, 1740 cm-1.

100327 51

Example 14 [2R- [2 «, 3E, 5«, 6B (R *)]] - 6- (1-hydroxyethyl) -3 - [[4-methylphenyl) sulfonyl] methylene] -7-oxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, mono-5 sodium salt

Applying the same experimental conditions as in Example 28 as well as in J Org. Chem. (1984), 49, 5271, 0.20 g of the carbapenene male blade prepared in Example 13 was dissolved in 2.6 ml of anisole and 1 ml of methylene chloride at -50 ° C under an inert atmosphere. To this was added 0.190 g of anhydrous aluminum chloride. The reaction product was isolated as its sodium salt and weighed 0.044 g (27%).

1 H NMR (D 2 O) δ 1.27 (d, 3H, CH 3), 2.45 (S, 3H, CH 3), 2.8 (m, 1H, allyl H), 3.0 (dd, 1H, allyl H) ), 3.78 (m, 1H, CH-15 N), 4.22 (p, 1H, CH-O), 6.62 (srlH, vinyl H), 7.5 (d, 2H, aromatic) , 7.82 (d, 2H, aromatic).

IR (KBr) 3427, 2970, 2923, 1742, 1623 cm-1.

Example 15 [5R- [5 ', 6e (R *)]] - 6- (1-hydroxyethyl) -3 - [[(4-methyl-2-phenyl) sulfonyl] methyl] -7-oxo-1-azabicyclo Lo [3.2.0] hept-2-ene-2-carboxylic acid, (4-methoxy-phenyl) -methyl ester

The title compound was prepared by the method of Example 8 to give 0.283 g of the title compound prepared in Example 13; 25 bapenem ester to react with 2.0 mL of diisopropylethylamine in 5 mL of methylene chloride for 16 hours at 45 ° C to give 0.110 g of product (39%) after purification.

1 H NMR (CDCl 3) δ 1.32 (d, 3H, CH 3), 1.8 (d, 1H, OH), δ 2.4 (s, 3H, CH 3), 3.05 (dd, 1H, allyl H ), 3.2 (dd, 1H, H6), 3.3 (dd, 1H, allyl H), 3.8 (s, 3H, CH3), 4.2 (m, 2H, CHN, CHO), 4 .27 (d, 1H, CHSO 2), 4.67 (d, 1H, CHSO 2), 4.96 (dd, 2H, CH 2 O), 6.8 (d, 2H, aromatic), 7.35 (m, 4H , aromatic), 7.7 (d, 2H, aromatic).

35 IR (KBr) 3440, 2967, 2839, 1779, 1715 cm-1.

52 100327

Example 16 [5R- [5Ct, 6 «(R *)]] - 6- (1-hydroxyethyl) -3 - [[(4-methylphenyl) sulfonyl] methyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, monosodium-5 rium salt

The title compound was prepared by the method of Example 14, 0.10 g of the carbapenemester blade prepared in Example 15 was hydrolyzed to give 0.030 g (38%) of the product as the sodium salt.

1 H NMR (D 2 O) & 1.12 (d, 3H, CH 3), 2.23 (s, 3H, CH 3), 2.93 (dd, 1H, allyl H), 3.04 (dd, 1H, allyl H), 3.35 (dd, 1H, H6), 4.12 (m, 1H, H5), 4.2 (p, 1H, CHO), 4.55 (d, 1H, CHSO 2), 4.88 (d, 1H, CHSO 2), 7.43 (d, 2H, aromatic), 7.75 (d, 2H, aromatic).

IR (KBr) 3420, 2960, 1760, 1660 cm-1.

Example 17 [2R- [2β (E), 3B (R *)]] - 2- [3 - [[4- (acetylamino) phenyl] sulfonyl] -2-iodo-2-propenyl] -3- [ 1 - [[1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -4-oxo-20 1-azetidineacetic acid, 2-chloro-2-propenyl ester

The title compound was prepared by the method of Example 4 using 1.4 g of the 2-chloroallyl ester from Example 3, 1.4 g of 4-acetamidobenzenesulfinic acid, 0.89 g of iodine, 0.30 g of sodium bicarbonate and 0.89 g of sodium acetate in 20 ml of ethyl acetate and 10 ml of in water. After purification, 1.85 g (73%) of product were obtained as an oil.

1 H NMR (CDCl 3) δ 0.09 (s, 6H, 2CH 3), 0.9 (s, 9H, C (CH 3) 3), 1.2 (d, 3H, CH 3), 2.2 (s, 3H , CH3), 3.2 (dd, 1H, H3), 3.35 (dd, 1H, allyl CH), 3.7 (dd, 1H, allyl CH), 3.95 (q, 2H, CH2CO2) , 4, 22 (m, 2H, CHOSi, H4), 4.7 (s, 2H, allyl CH2), 5.43 (d, 1H, vinyl H), 5.5 (d, 1H, vinyl H), 7.1 (s, 1H, vinyl H), 7.75 (d, 2H, aromatic), 7.8 (d, 2H, aromatic), 7.77 (bs, ΙΗ, ΝΗ).

35 K, HU I MM IMfl 100327 53

Example 18 [5R- [3E, 5cc, 6tt (R)]] - 3 - [[4-acetamidophenyl) sulfonyl] methylene] -6 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl ] -7-oxo-1-azabicyclo-5-holo [3.2.0] heptene-2-carboxylic acid, 2-chloro-2-propenyl ester

The title compound was prepared by the method of Example 5 using 1.78 g of iodovinyl sulfone from Example 17, 18 ml of anhydrous tetrahydrofuran and 5.7 ml of a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran. After purification, 0.25 g (17%) of product was obtained.

1 H NMR (CDCl 3) δ 0.1 (s, 6H, 2CH 3), 0.75 (s, 9H, C (CH 3) 3), 1.25 (d, 3H, H 3), 2.2 (s, 3H , CH3), 3.2 (m, 3H, allyl CH2 and H6), 4.2 (m, 1H, H5), 4.5 (q, 2H, allyl CH2), 5.35 (s, 1H, vinyl H), 5.65 (s, 1H, vinyl H), 7.48 (bs, 1H, NH), 7.65 (d, 2H, aromatic), 7.75 (d, 2H, aromatic).

Example 19 [5R- [3E, 5β, 6e (R *)]] - 3 - [[(4-acetamidophenyl) sulfo-20-yl] methylene] -6- [1-hydroxyethyl] -7-oxo-1- azabicyclo [3.2.0] heptene-2-carboxylic acid, 2-chloro-2-propenyl ester

The title compound was prepared by the method of Example 6 by reacting 0.251 g of the carban penenem of Example 18, 8 ml of anhydrous tetrahydrofuran, 0.37 ml of acetic acid, 2.1 ml of a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran for 7 hours. At 20 eC in an inert atmosphere; then the solution was stored overnight at 4 ° C. The reaction solution was purified to give 0.115 g (57%) of the desired product and 0.042 g of unreacted starting material.

1 H NMR (CDCl 3) δ 1.3 (d, 3H, CH 3), 2.2 (s, 3H, CH 3), 2.3 (bs, 1H, OH), 3.1 (dd, 1H, allyl H) , 3.25 (dd, 1H, H6), 3.35 (dddd, 1H, allyl H), 4.2 (m, 2H, CHO and H5), 4.4 (dd, 2H, CH2), 4 , 65 (t, 2H, CH 2), 5.4 (d, 1H, vinyl H), 5.6 (d, 1H, vinyl H), 7.8 (ra, 4H, aromatic), 100327 54 9.35 (S, ΙΗ, ΝΗ).

IR (KBr) 3492 (ΟΗ, ΝΗ), 1811, 1729, 1640 cm-1.

Example 20 [5R- [5β, 6e (R *)]] - 3 - [[(4-acetamidophenyl) sulfonyl-5H] methylene] -6- [1-hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, monopotassium salt

The title compound was prepared according to the method described in Example 9 and J. Med. Chem.

10 (1987) 30, 879, using 0.105 g of hydroxyethylcarbapenem from Example 19, 0.013 g of tetrakis (triphenylphosphine) palladium, 0.006 g of triphenylphosphine, 0.045 g of potassium 2-ethylhexanoate in 2 ml of ethyl acetate and 2 ml of water. After workup, the reaction mixture gave 0.040 g (41%) of the desired product.

1 H NMR (D 2 O) δ 1.25 (d, 3H, CH 3), 2.2 (s, 3H, CH 3), 3.0 (dddd, 2H, allylCH 2), 3.37 (dd, 1H, H 6) , 4.15 (m, 3H, CH-O, H 4 and CHSO 2), 4.52 (d, 1H, CHSO 2), 7.78 (dd, 4H, aromatic).

IR (KBr) 3418 (broad), 1760, 1687, 1591 cm -1.

Example 21 [2R- [2e, 3B (R *)]] -3- [1 - [[(1,2-dimethyl) dimethylsilyloxy] ethyl] -2- (4-methoxy- 4-Oxo-2-butynyl) -4-oxo-1-azetidineacetic acid, (4-nitrophenyl) methyl ester * To 50 ml of a methanolic solution of 2.5 g of the acetylene ester prepared in Example 3A was added 0.1 g. palladium chloride, 1.6 g of anhydrous copper (II) chloride and 1.1 g of sodium acetate. The reaction solution was degassed three times using carbon monoxide. The reaction flask was then connected to a sphere containing about 300 ml of gaseous carbon monoxide. The reaction solution was stirred under this atmosphere of carbon monoxide until the green reaction solution turned black. Thin layer chromatography showed that all of the starting material acetylene had been consumed. The reaction-35 mixture was poured into a mixture of ice water and diethyl ether. After water treatment and purification by flash column chromatography, a crystalline material isolated 2.0 g (71%) m.p. 55 ° C.

1 H NMR (CDCl 3) δ 0.01 (s, 3H, CH 3), 0.04 (s, 3H, CH 3), 0.84 (s, 9H, t-Bu), 1.24 (d, 3H, CH 3) ), 2.7 (m, 2H, propargyl CH 2), δ 2.9 (dd, 1H, H 3), 3.73 (s, 3H, OCH 3), 4.0 (m, 1H, H 4), 4, 13 (dd, 2H, CH 2), 4.3 (m, 1H, CH-O-Si), 5.25 (s, 2H, benzyl CH 2), 7.53 (d, 2H, aromatic), 8.25 (d, 2H, aromatic). Calculated for C25H34N2OeSi: C, 57.90; H, 6.61; N, 5.40.

Found: C, 57.57; H, 6.56; N, 5.35.

Example 22 [2R- [20 (E), 36 (R *)]] - 2- (2,3-dichloro-4-methoxy-4-oxo-2-butenyl) -3- [1 - [ [(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -4-oxo-1-azetidineacetic acid (4-nitrophenyl) methyl ester 45 A mixture of 0.11 g of acetylene methyl ester from Example 21, 0.54 g of copper (II) chloride, 0.16 g of lithium chloride and 6 ml of acetonitrile were heated at 80 ° C until the starting material acetylene was consumed (thin layer chromatography analysis). The reaction was cooled and then filtered through diatomaceous earth to remove any solids. Diethyl ether and water were added to the filtrate, followed by treatment with water. Purification by flash column chromatography gave 0.086 g (73%) of product as a colorless solid, m.p. 73-75 ° C.

• 25 * Η NMR (CDCl 3) δ 0.05 (s, 3H, CH 3), 0.07 (s, 3H, CH 3), 0.85 (s, 9H, C (CH 3) 3), 1.25 ( d, 3H, CH 3), 3.1 (m, 2H, allyl CH 2), 3.03 (dd, 1H, H 3), 3.85 (s, 3H, CH 3 O), 4.05 (ab quartet, 2H, CH 2), 4.2 (m, 2H, CH-O, H 4), 5.25 (s, 2H, CH 2 CO 2), 7.5 (d, 2H, aromatic), 8.25 (d, 2H, aromatic ).

Calcd for C25H34Cl2N2O8Si: C, 50.93; H, 5.81; N, 4.75; Cl, * '12.03. Found: C, 51.34; H, 5.76; N, 4.65; Cl, 11.97.

Example 23 [3S- [3β (S *), 46]] -3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2-oxo-4- (2-propynyl) -35 1-Azetidineacetic acid, (4-methoxyphenyl) methyl ester

To a suspension of 0.164 g of prewashed sodium 56 100327 hydride (in 60% oil) in 5 ml of anhydrous tetrahydrofuran was added, with stirring under argon, a solution of 1.0 g of azetidinone from Example 1 in 6 ml. anhydrous tetrahydrofuran at -20 ° C. The mixture was stirred for 5 minutes at 0 ° C, followed by the addition of 1.065 g of (4-methoxyphenyl) methyl bromoacetate in anhydrous tetrahydrofuran at -20 ° C, and the reaction solution was stirred at 0 ° C for 17 hours. 2 ml of solution (1 ml of glacial acetic acid + 9 ml of water) was added to adjust the pH to 4. Mixture 10 was poured onto crushed ice, extracted with ethyl acetate, and the combined organic layers were washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting oil was purified by flash chromatography to give 0.799 g (48%) of the desired product, 15 m.p. 54-57 eC.

Calculated (C 24 H 35 NO 5 S, mp 445.6): C, 64.69; H, 7.92; N, 3.14;

Si, 6.30. Found: C, 64.37; H, 7.78; N, 3.04; Si, 6.29.

1 H NMR (CDCl 3) δ 0.041 (s, 3H, C 13 -Si), 0.063- (s, 3H, CH 3 -Si), 0.856 (5.98, (002) 2-O), 1.24 (d, 3H , CH 3 CH), δ 1.97 (m, 1H, O = 00), 2.56 (m, 2H, CH 2 -C = C), 2.92- (m, 1H, O = C-CH-CH- N), 3; 81 (s, 3H, CH-10), 3.92- (m, 1H, O = C-CH-CH-N), 4.05 (dd, 2H, N-CH2), 4.16- (m , 1H, CH3CH-O), 5; 10 (S, 2H, O-CH2-6), 6.89 (d, 2H, CH3O-C-CH), 7.29 (d, 2H, CH3O-C-CH- CH).

· 25 IR (KBr) 1734, 1758 cm-1.

Example 24 [2R- [2 «(E), 3B (R *)]] - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2- [2-iodo- 3- (Phenylsulfonyl) -2-propenyl] -4-oxo-1-azetidine acetic acid, (4-methoxyphenyl) methyl ester

The title compound was prepared by the method of Example 4 using 3.94 g of the product of Example 23, 2.18 g of sodium benzene sulfinate, 2.24 g of iodine and 1.45 g of sodium acetate. The mixture was purified by chromatography to give 5.29 g (84%) of the desired product as a pale yellow oil.

tl |:; IMI It UH Hii'4 · 100327 57 1 H NMR (CDCl 3) δ 0.070 (s, 3H, CH 3 -Si), 0.078- (s, 3H, CH 3 -Si), 0.873 (s, 9H, (CH 3) 3 -C) ), 1.23 (d, 3H, CH 3 CH), 3.17 (to, 1H, O = C-CH-CH-N), 3.30 (dd, 1H, CHCH 2 “C = C”), 3.71 - (dd, 1H, CH-CH 2 -C = C), 3.76 (S, 1H, N-CH 2), 3.80 (d, 3H, OCH 3), δ 3.94 (s, 1H, NCH 2) , 4.17 (m, 1H, O = C-CH-CH-N), 4.17- (m, 1H, CH 3 CH-O), 5/08 (2di2H, O-CH 2 - (S)), 6, 87- (d, 2H, CH 3 O-C-CH), 7.10 (s, 1H, CH-SO 2), 1.29- (d, 2HiCH 3 O-C-CH-CH), 7.59 (t, 2H , S-CH-CH-CH), 7.68- (t, 1H, S-CH-CH-CH), 7.90 (d, 2H, S-CH-CH).

IR (neat) 1742, 1761 cm-1.

Cl-MS: m / z 714 (M + H) &lt; + &gt; 731 (M + NH4) &lt; + &gt;.

Example 25 [5R- [3E, 5β, 6 «(R *)]] - 6- [1 - [[(1,1-dimethylethyl) di-15-methylsilyl] oxy] ethyl] -7-oxo-3 - [ (phenylsulfonyl) methylene] -1-azabicyclo [3.2.0] heptane-2-carboxylic acid, (4-methoxyphenyl) methyl ester The title compound was prepared by the method of Example 5 using 3.18 g of the product of Example 24, 30 ml of anhydrous tetrahydrofuran, 6.68 ml of 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran, 0.45 ml of glacial acetic acid and 1.5 ml + 15 ml of 1M potassium dihydrogen phosphate. 2.69 g of the isomeric mixture was slurried with 25% ethyl acetate / hexane to give 0.798 g (30.5%) of the exocyclic product as a white solid. The filtrate was concentrated to give 1.83 g (70%) of the endocyclic product as an oil.

1 H NMR (exo) (CDCl 3) δ 0.064 (s, 6H, (CH 3) 2 Si), 0.866 (S, 9H, (CH 3) 3 C), 1; 2 3 (d, 3H, CH-CH), 2.84- (m, 2H, -CH 2 -C CCH-S), 2.95 (m, 1H, O = C-CH-CH-N), . 3.80 (s, 3H, OCH 3), 4.18 (m, 1H, CH 3 CH-O), 5.20- (2d, 2H, O-CH 2 -H), 5.25 (s, 1H, N -CH-COO), 6.34- (s, 1H, C = CH-S), 6.88 (d, 2H, CH 3 O-C-CH), 7.40- (d, 2H, CH 3 O-C- CH-CH), 7.50 (t, 2H, S-CH-CH-CH), 7.63- (t, 1H, S-CH-CH-CH), 7.77 (d, 2H, S- CH-CH).

CI-MS: m / z 586 (M + H) + and 603 (M + NH 4) +.

58 100327

Calculated: (C 30 H 39 NC> 7 SiS, MW 585.8): 0. 61.51; H, 6.71; N, 2.39; Si, 4.79; S, 5.47.

Found: C, 61.78; H, 6.65; N, 2.28; Si, 4.53; S, 5.47.

Example 26 [5R- [3 (E), 5a, 6 «(R *)]] - 6- (1-hydroxyethyl) -7-oxo-3 - [(phenylsulfonyl) methylene] -1-azabicyclo [3.2 .0] heptane-2-carboxylic acid, (4-methoxy-phenyl) -methyl ester The title compound was prepared by the method of Example 6 using 0.50 g of the product of Example 25, 17 ml of tetrahydrofuran, 4.27 ml of 1M tetrabutylammonium fluoride and 0.74 ml of glacial acetic acid. The mixture was purified by flash chromatography to give 0.148 g (37%) of the desired product.

1 H NMR CCDCl 3) bs / 30 (d, 3H, C 13 H 13 CH), 2.88- (m, 2H, -CH 2 -C-CH-S), 3.0 (m, 1H, O = C-CH- CH-N), 3.80- (s, 3H, OCH 3), 4.2 (m, 1H, CH 3 CH-O), 5.20 (2d, 2H, O-CH 2 -N), 5j25 (s, 1H , N-CH-COO), 6.35 (s, 1H, C = CH-S), 6.9- (d, 2H, CH 3 O-C-CH), 7.4 (d, 2H, CH 3 O-C) -CH-CH), 7.52-20 (t, 2H, S-CH-CK-CH), 7.65 (t, 1H, S-CH-CH-CH), 7.77- (d, 2K , S-CH-CH).

Example 27 [5R- [5e, 60 (R *)]] - 6- (1-hydroxyethyl) -7-oxo-3 - [(phenylsulfonyl) methyl] -1-azabicyclo [3.2.0] hept 2-ene-2-carboxylic acid, (4-methoxy-phenyl) -methyl ester

The title compound was prepared by modifying the method of Example 8. A solution of 0.281 g of the exocyclic product of Example 26 and 1.72 ml of diisopropylethylamine in 2 ml of methylene chloride was gently stirred at reflux under argon for 13 hours and then stored at 0 ° C for 18 hours. The reaction was diluted with 50 mL of ethyl acetate, washed with 4 x 10 mL of 0.5 M potassium hydrogen phosphate and dried over magnesium sulfate.

35 The organic layer was concentrated to give a quantitative yield of endocyclic product.

2: s 1: 1 H 1: Ml 100327 59 1 H NMR (CDCl 3) δ 1.34 (d, 3H, CH 3 -CH), 3.08- (2d, 1H, -CH 2 -C-CH 2 -SO 2 - ), 3.20 (m, 1H, O = C-CH-CH-N), 3; 31 (2d / 1H, -CH2-C-CH2-SO2-), 3r81 (S, 3H, OCH3), 4 , 22-5 (m, 1H, CH 3 CH-O), 4.22 (m, 1H, O = C-CH-CH-N), 4.31- (d, 1H, -CH 2 -SO 2), 4, 66 (d, 1H, -CH 2 -SO 2), 4.94- (2d, 2H, O-CH 2 -O 2), 6.89 (d, 2H, CH 3 O-C-CH), 7.28- (d, 2H, CH 3 O-C-CH-CH), 7.46 (t, 2H, S-CH-CH-CH), 7.56- (t, 1H, S-CH-CH-CH), 7.78 (d, 2H, S-CH-CH).

IR (neat) br. 1729 cm-1.

CI-MS: m / z 489- (M + NH 4) +.

Example 28 [5R- [5β, 60 (R *)]] - 6- (1-hydroxyethyl) -7-oxo-3 - [(phenylsulfonyl) methyl] -1-azabicyclo-15 [3.2.0] hept-2 -ene-2-carboxylic acid, monosodium salt

To a stirred solution under argon of 0.132 g of the product of Example 27 in 2.24 mL of anisole and 0.56 mL of methylene chloride was added 0.0955 g of sublimed aluminum trichloride at -60 ° C. The reaction mixture was stirred at -60 ° C for one hour. 8.4 ml of 5% sodium bicarbonate was added at -60 ° C, followed by 25 ml of ethyl acetate. The reaction mixture was allowed to warm to room temperature and filtered. The collected solid was washed with ethyl acetate and water. The organic layer was washed with water and the combined aqueous layers were washed with 20 ml of ethyl acetate. The aqueous layer was chromatographed to give 0.074 g (71%) of the desired product.

1 H NMR (DO) δ 1.27 (d, 3H, CH-CH), 2.96-30 Z 3 (2d, 1H, -CH 2 -C-CH 2 -SO 2), 3.07 (2d, 1H, -CH 2 -). C-CH 2 -SC> 2), 3.3 δ (m, 1H, O = C-CH-CH-N), 4.13 (m, 1H, O = C-CH-CH-N), 4, 19 (m, 1H, CH 3 CH-O), 4.78 (2d, 2H, CH 2 -SO 2), 7.64- (t, 2H, S-CH-CH-CH), 7.79 (t, 1H, S-CH-CH-CH), 7.88- (d, 2H, S-CH-CH).

35 IR (KBr) 1756 cm -1.

CI-MS: m / z 391 (M + NH 4) +.

100327 60

Example 29 [2R- [2a (Z), 3B (R *)]] - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2- [2-iodo-3 - [[4- (trifluoromethyl) phenyl] sulfonyl] -2-propenyl] -4-5 oxo-1-azetidineacetic acid, (4-nitrophenyl) methyl ester

The title compound was prepared by the method of Example 4 using 4.6 g of 4-nitrobenzyl ester prepared as described in Example 3A, 4.2 g of 4- (tri-10-fluoromethyl) benzenesulfinic acid, 1.5 g of sodium acetate, 0.84 g of sodium bicarbonate , 2.0 g of iodine, 75 ml of ethyl acetate and 35 ml of water. The mixture was purified by chromatography to give 7.7 g (95%) of the desired product.

NHR (CDCl 3) δ 0.067 (d, 6H), 0.087 (S, 9H), 3.25 (t, 1H), δ 3 and 27 (m, 1H), 3.76 (q, 1H), 4.04 -4.17 (m, 2H), 4-21-4; 23 (m, 2H), 5.27 (s, 2H), 7f08 (s, 1H), 7.54 (d, 2H), 7, 87 (d, 2H), 8fO 3 (d, 2H), 8.21 (d, 2H).

IR: 17 60 cm-1 (broad).

Example 30 [5R- [3 (E), 5β, 6a (R *)]] - 6- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -7-oxo-3- [[[4- (Trifluoromethyl) phenyl] sulfonyl] methylene] -1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid, (4-nitro-phenyl) -methyl ester The title compound was prepared according to the method of Example 5. using 7.0 g of the product of Example 29, 75 ml of anhydrous tetrahydrofuran, 11.3 ml of a 1M solution of lithium bis (trimethylsilyl) amide, 0.94 ml of acetic acid, 12.2 ml of potassium dihydrogen phosphate and 180 ml of ethyl acetate.

The reaction mixture gave 6.2 g (93%) of exocyclic: endocyclic product. A 2 g sample was purified by chromatography to give 0.15 g (9%) of exocyclic product as colorless crystals. A 1.5 g fraction was isolated from a mixture of exocyclic: endocyclic compound which was reacted in Example 35 31.

61 100327 1 H NMR (CDCl 3) δ 0.07 (d, 6H), 0.88 (s, 9H), 1.24 (d, 3H) / 2.99 (m, 2H), 3.80 (m, 1H), 4.20 (t, 2H), 5.27 (s, 1H), 5.3 δ (s, 2H), 6.37 (s, 1H), 7.67 (d, 2H), 7 .82 (d, 2H), 7.94 (d, 2H), 8.2 (d, 2H).

IR: 1773, 1750 cm -1.

Example 31 [5R- [5β, 6e (R *)]] - 6- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -7-oxo-3 - [[[4- (trifluoro-10-methyl) phenyl] sulfonyl] methyl] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, (4-nitro-phenyl) methyl ester 1.1 g of the endo- and a mixture of exo products in 60 ml of methylene chloride was treated with 5 ml of diiso-15-propylethylamine at 5 ° C for two days. The reaction mixture was concentrated to give 1.0 g (90%) of the desired endocyclic product.

1 H NMR (CDCl 3) δ 0.06-0.08 (d, 6H), 8.5 (S, 9H), 1.25 (d, 3H), 3.22-3.25 (m, 2H) δ 25 (m, 2H), 4.36 (d, 1H), 4.69 (d, 1H), 4.97 (d, 1H), 5T11 (d, 2H), 7.26 (d, 2H); , 7 and 80 (d, 2H), 8; 18 (d, 2H), 8.21 (d, 2H).

IR: 1773, 1720 cm-1.

Example 32 [5R- [5a, 6a (R *)]] - 6- (1-hydroxyethyl) -7-oxo-3-25 [[[4- (trifluoromethyl) phenyl] sulfonyl] methyl] -1-azabicyclo [ 3.2.0] hept-2-ene-2-carboxylic acid, (4-nitrophenyl) methyl ester

The title compound was prepared by the method of Example 6 using 0.62 g of the product of Example 31, 18 ml of anhydrous tetrahydrofuran, 0.79 ml of glacial acetic acid and 4.6 ml of a one molar solution of tetra-n-butylammonium fluoride. The reaction mixture gave 0.57 g (100%) of product which was used immediately in Example 33 without further purification.

35 62 100327

Example 33 [5R- [50,6 «(R *)]] - 6- (1-hydroxyethyl) -7-oxo-3 - [[[4- (trifluoromethyl) phenyl] sulfonyl] methyl] -1-azabicyclo [ 3.2.0] hept-2-ene-2-carboxylic acid, 5 monosodium salt

A mixture of 0.57 g of the product of Example 32, 20 ml of dioxane, 5 ml of water, 0.078 g of sodium bicarbonate and 0.150 g of palladium hydroxide was hydrogenated on a Parr apparatus at 21 lbs. in psi for one hour. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with water and diethyl ether. The aqueous layer was extracted with 20 mL of diethyl ether and 2 x 20 mL of ethyl acetate. The aqueous phase was filtered through a pad of diatomaceous earth and lyophilized to give 0.255 g of a pale yellow solid. The solid was purified by reverse phase chromatography to give 0.020 g of the desired product as a white solid.

1 H NMR (D 2 O) δ: 1.27 (t, 3H), 2.45 (m, 2H), 2.78 (m, 1H), 4.18 (m, 2H), 4.48 (m, 3H) ), 7.82 (d, 2H), 8.06 (d, 2H).

Example 34 [2R- [2-e, 3B (R *)]] - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2- [2-iodo-3 - (2-Quinolinylsulfonyl) -2-propenyl] -4-oxo-1-azetidine acetic acid, 2-chloro-2-propenyl ester A mixture of 4.20 g of 2-chloro-2-propenyl ester from Example 3, 4.52 g of sodium quinoline-2-sulfinate, 2.67 g of iodine, 2.58 g of sodium acetate in 50 ml of ethyl acetate and 50 ml of water were treated as described in Example 4 to give 1.68 g (22%) the desired 30 compounds.

Δ NMR (CDCl 3) δ O 6 (s, 6H), 0.88 (S, 9H), 1T24 (d, 3H), 3.25 (m, 1H), 3f4 (m, 2H), 3; 85 -4r25 (m, 6H), 4.69 (s, 2H), 5.44 (0.28), 7.4 δ (s, 1H), 7.75-8.47 (m, 6H).

IR (neat) 1760 cm'1 (broad peak).

35

t I ϊΗ ι lii M I i I II

100327 63

Example 35 [2R- [2α, 3E, 5β, 6α (R *)]] -6- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -7-oxo-3 - [ (2-Quinolinylsulfonyl) methylene] -1-azabicyclo-5-ol [3.2.0] heptane-2-carboxylic acid, 2-chloro-2-propenyl ester

A solution of 1.68 g of iodosulfone (see Example 34) in 20 ml of tetrahydrofuran was treated with 3.50 ml of 1.0 M lithium bis (trimethylsilyl) amide solution 10 as described in Example 5 to give 0.78 g (57%) product.

1 H NMR (CDCl 3) δ 0.07 (s, 6H), 0.87 (s, 9H), 1.22 (d, 3H), 3 j 80 (dd, 1H), 4.20 (m, 2H) , 4.80 (q, 2H), 5.4 (d, 2H), 5.61 (S, 1H), 4.85 (s, 1H), 7.73-8, 44 (m, 6H).

15 IR (neat) 1771 cm 1.

Example 36 [2R- [2a, 3E, 5a, 6a (R *)]] -6- (1-hydroxyethyl) -3 - [(2-quinolinylsulfonyl) methylene] -1-azabicyclo [3.2.0] heptane 2-carboxylic acid, 2-chloro-2-pro-20 penyl ester

The title compound was prepared by the method of Example 7 using 0.78 g of the exo compound of Example 35 and aqueous hydrogen fluoride in acetonitrile to give 0.48 g (76%) of product. The 300 MHz nuclear magnetic resonance spectrum of this compound was essentially identical to that described in the example, except that the ± -butyldimethylsilyl group was absent.

Example 37 [5R- [5a, 6a (R *)]] -6- (1-hydroxyethyl) -7-oxo-3 - [(2-quinolinylsulfonyl) methyl-1-azabicyclo [3.2.0] hept 2-ene-2-carboxylic acid, 2-chloro-2-propenyl ester

A solution of 0.48 g of the compound described in Example 36 in 15 ml of ethyldiisopropylamine and 35 ml of methylene chloride was treated as described in Example 8 to give 0.33 g (69%) of product.

100327 64 1 H NMR (CDCl 3) δ 1.35 (d, 3H), 3.35 (m, 2H), 4.15 (m, 1H), 4.4 (m, 2H), 4.8 (dd, 2H), 5.8 (d, 2H), 7.7-8.4 (m, 6H).

Example 38 [5R- [5α, 6 «(R *)]] - 6- (1-hydroxyethyl) -3 - [(2-quinolin-5-yl) sulfonylmethyl-7-oxo-1-azabicyclo [3.2.0 ] hept-2-ene-2-carboxylic acid, monopotassium salt

A solution of 0.32 g of ester (see Example 37) in 3 ml of methylene chloride was treated as described in Example 10 to give 0.030 g of the desired compound.

1 H NMR (D 6 MSO) δ 1.15 (d, 3H), 2.65 (m, 1H), 3.1 (m, 1H), 3.88 (m, 1H), 7.5-8.8 ( m, 6H).

Example 39 [2R- [2a (E) 738 (R *)]] - 2- (2,3-dichloro-4-methoxy-4-oxo-2-butenyl) -3- (1-hydroxyethyl) 4-Oxo-1-azetidineacetic acid, (4-nitrophenyl) methyl ester From a mixture of 5.6 g of the product of Example 21, 29.0 g of copper (II) chloride and 9.16 g of lithium chloride in 300 ml of acetonitrile , degassed and purged under argon at 80-85 ° C for 24 hours. The reaction mixture was concentrated in vacuo, extracted with ethyl acetate and water, and dried over sodium sulfate. The resulting gum was purified by flash chromatography (ethyl acetate: -2 hexane) to give 1.54 g (30%) of the desired product.

1 H NMR δ 1.28 (d, 3H), 2.15 (d, 1H), 3.10 (m, 3H), 3.86 (s, 3H), 3.89 (d, 1H), δ , 28 (m, 3H), 5.27 (s, 2H), 7.58 (d, 2H), 8.2 (d, 2H). CI-MS: m / z 492 (M + NH 4) +. The identification of other column fraction yields gave:. 30 (a) 2.9 g (45.5%) [2R- [2a (E), 3 (3 (R *)]] -2- (2,3-dichloro-4- · · methoxy-4- oxo-2-butenyl) -3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -4-oxo-1-azetidineacetic acid, (4-nitrophenyl) methyl ester.

1 H NMR (CDCl 3) δ 0.05 (d, 6H), 0.85 (s, 9H), 1.22 (d, 3H), δ 3.09 (m, 3H), 3.85 (s, 3H) ), 4.1 (m, 4H), 5.26 (s, 2H), 7.5 (d, 2H), 8.2 (d, 2H). CI-MS: m / z 606 (M + NH 4) + 65 100327 (b) 0.544 g (8.5%) [2R- [2 «(2), 38 (R *)]] - 2- (2, 3-dichloro-4-methoxy-4-oxo-2-butenyl) -3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -4-oxo-1-azetidineacetic acid, (4-nitrophenyl) methyl ester. CI-MS: m / z 5,606 (M + NH 4) +; and (c) 0.212 g (4%) of [2R- [2 '(E), 3B (R *)]] - 2- (2,3-dichloro-4-methoxy-4-oxo-2-butenyl) - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -4-oxo-1-azetidineacetic acid, (4-nitrophenyl) methyl ester. CI-MS: m / z 10,492 (M + NH 4) +.

Example 40 [2R- [2e (E), 3f (R *)]] - 2- (2,3-dichloro-4-methoxy-4-oxo-2-butenyl) -4-oxo-3 - [ 1 - [[(phenylmethoxy) carbonyl] oxyethyl] -1-azetidineacetic acid, 15 (4-nitrophenyl) methyl ester To a degassed cooled solution under argon with 1.19 g of the product of Example 39 in 20 ml of methylene chloride , 0.478 g of benzyl chloroformate and 0.342 g of 4-dimethylaminopyridine were added.

The reaction temperature was maintained at 0-5 ° C throughout the reaction sequence.

After one and four hours, 0.478 g of benzyl chloroformate and 0.342 g of 4-dimethylaminopyridine were added and the reaction was allowed to continue for another two hours (total time 6 hours). The reaction mixture was diluted with 40 mL of methylene chloride and washed with 0.5 M potassium hydrogen phosphate, water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography to give 1.06 g (70%) of the desired product.

1 H NMR (CDCl 3) δ 1.43 (d, 2H) f 3.02 (m, 2H), 3r22 (dd, 1H), 3.78 (s, 3H), 4 r1 (q, 2H), δ , 13 (d, 2H), 5r17 (s, 2H), 5.24 (s, 2H), 7.35 (s, 5H), 7.50 (d, 2H), 8f22 (d, 2H). CI-MS: m / z 626 (M + NH 4) +.

35 66 100327

Example 41 [2R- [2β, 3 (Ζ), 5β, 6β (R *)]] - 3- (1-chloro-2-methoxy-2-oxoethylidene) -7-oxo-6- [1 - [[ (phenylmethoxy) carbonyl] oxy] ethyl-1-azabicyclo [3.2.0] heptane-2-5 carboxylic acid, (4-nitrophenyl) methyl ester in a solution at -78 ° C under argon with 0.117 g of the product of Example 40 In 3 ml of anhydrous tetrahydrofuran, 0.2 ml of 1M lithium bis (trimethylsilyl) amide was added. The reaction temperature was maintained at -78 ° C for 90 minutes, followed by the addition of 0.035 ml of glacial acetic acid. The reaction mixture was treated with 1 mL of 0.5 M potassium hydrogen phosphate and diluted with 20 mL of ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo.

The resulting oil was purified by flash chromatography (ethyl acetate: hexane) to give 0.020 g (18%) of the desired product.

1 H NMR (CDCl 3) δ 1.4 (d, 3H), 2.75 (m, 1H), 3.23 (dd, 1H), 3.35 (dd, 1H), 3.75 (s, 3H) , 3.85 (m, 1H), 4.97 (d, 1H), 5.14 (m, 1H), 5.17 (s, 2H), 5.32 (s, 2H), 7; (s, 5H), 7.6 (d, 2H), 8.25 (d, 2H).

Example 42 [2r- [2a, 3 (R * or s *), 5a, 6a (R *)]] - α-chloro-2 - [[(4-nitrophenyl) methoxy] carbonyl] -7-oxo-6 - [1 - [[(phenyl-25-methoxy) carbonyl] oxy] ethyl] -1-azabicyclo [3.2.0] hept-3-ene-3-acetic acid, methyl ester The title compound was prepared by the method of Example 41 using 0.45 g the product of Example 40, 5 ml of tetrahydrofuran, 1.6 ml of 1M sodium bis (trimethylsilyl) amide, 0.2 ml of glacial acetic acid, 10 ml of 0.5M potassium hydrogen phosphate and 20 ml of ethyl acetate. The reaction mixture was purified by flash chromatography to give 0.165 g (39%) of the desired product.

100327 67

Example 43 [2R- [2e, 3 (R * or S *), 5β, 6e (R *)]] -3- (1-chloro-2-methoxy-2-oxoethylidene) -7-oxo-6 - [1 - [[(phenylmethoxy) carbonyl] oxy] ethyl] -1-azabicyclo [3.2.0] heptane-2-carboxylic acid, (4-nitrophenyl) methyl ester

The title compound was prepared by the method of Example 41 using 0.165 g of the product of Example 42, 0.041 g (40 μΐ) of 1,8-diazabicyclo [5.4.0] undec-7-ene, 20 ml of di-10 ethyl ether. The organic layer was concentrated in vacuo to give 0.140 g (85%) of product as a white foam.

Δ NMR (CDCl 3) δ 1.4 (d, 3H), 2.8 (m, 1H), 3.25 (m, 2H), 3.75 (s, 3H), 4; O (m, 1H), 5.15 (m, 1H), 5.17 (s, 2H), 5.28 (d, 2H), 5.68 (d, 1H), 7.4 (s, 5H) ), 7.5 (d, 2H), 8.25 (d, 2H).

Example 44 (2R- [2 «, 3 (R * or S *), 5«, 6a (R *)]] - 3- (1-chloro-2-methoxy-2-oxoethylidene) - 6- (1-Hydroxyethyl) -7-oxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, 20 monosodium salt

The title compound was prepared by the method of Example 33 using 0.134 g of the product of Example 43, 0.050 g of 10% palladium hydroxide / carbon, 0.021 g of sodium bicarbonate, 2.5 mL of dioxane and 2.5 mL of water at 40 lbs.psi for one hour. The aqueous layer was purified by reverse phase chromatography (water: ethanol, 95: 5). The aqueous extract was lyophilized to give 0.020 g of the desired product.

1 H NMR (D 2 O) δ 1.38 (d, 3H), 3.10 (m, 1H), 3.36 (m, 2H), 3.92 (s, 3H), 4.13 (m, 1H ), 4.33 (m, 2H), 5.52 (s, 1H).

Example 45 [2R- [2e (E), 3B (R *)]] -3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl 2- [3 - [(4- (fluorophenyl) sulfonyl] -2-iodo-2-propenyl] -4-oxo-1-acetyl-35-acetic acid, (4-nitrophenyl) methyl ester

In the same manner as described in Example 4, 100327 6δ 1.1 g of terminal acetylene prepared in Example 3A was reacted with 0.61 g of iodine and 1.05 g of sodium 4-fluorophenylsulfinate to give 1.45 g of the desired product in a water treatment. and after cleaning.

Δ NMR (CDCl 3) δ 0.07 (s, 3H, CH 3), 0.08 (S, 3H, CH 3), 0.87 (s, 9H, 3 CH 3), 1.25 (d, 3H, CH 3), 3.22 (dd, 1H, H3), 3.35 (dd, 1H, allyl CH), 3.8 (dd, 1H, allyl CH), 4.05 (dd, 2H, CH2CO2), 4.2 ( m, 2H, H 4 + CHOSi), 5.25 (s, 2H, CH 2 O), 7.25 (t, 2H, aromatic), 7.5 (d, 2H, aromatic), 7.9 (dd, 2H , aromatic), 8.2 (d, 2H, aromatic).

IR (neat) 1760 cm-1.

Example 46 [2R- [2e, 3 (E), 5B, 60 (R *)]] - 3 - [[(4-fluorophenyl) sulfonyl] methylene-6- [1 - [[(1,1- dimethylethyl) dimethyloxy] ethyl] -7-oxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, (4-nitrophenyl) methyl ester

In the same manner as described in Example 5Ά, 1.4 g of iodovinyl sulfone from Example 46 was reacted with 1.3 equivalents of lithium bis (trimethylsilyl) amide at -78 ° C for one hour to give 0.675 g of the desired product.

1 H NMR (CDCl 3) β 0.08 (S, 6H, 2CH 3), 0.88 (s, 9H, 3CH 3), 1.23 (d, 3H, CH 3), 2.6-3.0 (m, 3H , H6 + 2H1), 3.8 (m, 1H, H5), 4.2 (p, 1H, CHOSi), 5.25 (s, 1H, H3), 5.4 (s, 2H, CH2O) , 6.35 (s, 1H, vinyl), 7.2 (t, 2H, aromatic), 7.68 (d, 2H, aromatic), 7.8 (dd, 2H, aromatic), 8.2 (d , 2H, aromatic).

IR (KBr) -1765, 1745 cm -1.

Example 47 [5R- [5β, 6 «(R *)]] - 3 - [[(4-fluorophenyl) sulfonyl] methyl] -6- (1-hydroxyethyl) -7-oxo-1- azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, (4-nitrophenyl) methyl ester 35 In the same manner as in Example 7, 0.25 g of the exocyclic carbapenem prepared in Example 46 was reacted with hydrogen fluoride. dissolved in acetonitrile to give the exo-6- (1-hydroxyethyl) derivative used in the diisopropylethylamine-5 isomerization step in the same manner as described in Example 8 to give 0.138 g of the desired product.

NMR (CDCl 3) - 1.35 (d, 3H, CH 3), 3.15 (dd, 1H, H), 3.3 (dd, 1H, H 6), 3.35 (dd, 1H, Hx), δ , 3 (m, 2H, H5 and CHO), 4.52 (dd, 2H, CH2S), 5.15 (dd, 2H, CH2O), 7.15 (t, 2H, aromatic), 7, 55 (d, 2H, aromatic), 7.85 (dd, 2H, aromatic), 8.23 (d, 2H, aromatic).

IR (KBr) - 3534, 1782, 1717 cm-1.

Example 48 [5R- [5 α, 6a (R *)]] -3 - [[(fluorophenyl) sulfonyl] methyl] -6- (1-hydroxyethyl) -7-oxo-1-azabicyclo lo [3.2.0] hept-2-ene-2-carboxylic acid, monosodium salt

In the same manner as described in Example 33, 0.173 g of the carbapenem prepared in Example 47 was reacted with hydrogen (at 2 atmospheres) and 0.059 g of palladium hydroxide catalyst for 0.75 hours to give 0.12 g of the desired product.

1 H NMR (D 2 O) -1.3 (d, 3H, CH 3), 3.05 (dddd, 2H, allyl CH 2), 3.4 (dd, 1H, H 6), 4.17 (m, 2H, CHO and Hs), 4.65 (dd, 2H, CH 2 S), 7.4 (t, 2H, aromatic), 7.4 (dd, 2H, aromatic).

IR (KBr) - 3470 (broad), 1740, 1667, 1660 cm-1.

Example 49 [2R- [2α, 38 (R *)]] - 2- [4- (4-bromophenyl) -4-hydroxy-2-butynyl] -3- [1 - [[(1,1-dimethylethyl) dimethyl-30-silyl] oxy] -4-oxo-1-azetidineacetic acid, diphenylmethyl ester to a -78 ° C solution under argon with 0.3 g of the product of Example 2 in 4.5 ml of dry tetrahydrofuran was added dropwise , with stirring, 1.2 ml of 1.6M 35 n-butyllithium. After one hour, a solution of 70.0325 containing 0.205 g of p-bromobenzaldehyde in 0.4 ml of tetrahydrofuran was added and the reaction mixture was stirred for 45 minutes at -78 ° C. The cold bath was allowed to warm to -50 ° C, whereupon the reaction mixture was cooled with 1 mL of saturated ammonium chloride. The cold bath was removed and the mixture was diluted with ethyl acetate, water and 0.05 mL of glacial acetic acid. After vigorous stirring, the mixture was partitioned and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.

The crude product was dissolved in 3 ml of tetrahydrofuran and treated with 0.18 g of solid diphenyldiazomethane. When the detectable signs of nitrogen formation had ceased, the reaction was heated to 60 ° C for 45 minutes.

The mixture was cooled to room temperature, concentrated in vacuo and chromatographed on silica gel with 20% ethyl acetate / hexane to give 0.174 g (28%) of the desired product.

1 H HMR (CDCl 3) δ 0 ^ 03 (d, 6H), 0r82 (s, 9H), lt2 (d, 3H), δ 2j4-2t65 (m, 3H), 2; 85 (m, 1H), 3, Δ (m, 1H), 4.1 (m, 3H), 5.18 (m, 1H), 6/9 (d, 1H), 7.2-7, 4 (m, 14H).

Example 50 [2R-2e, 38 (R *)] -2- [4- (4-bromophenyl) -4-oxo-2-butynyl] -3- [1 - [[(1,1-dimethylethyl) Dimethylsilyl-25 N-oxy] ethyl] -4-oxo-1-azetidineacetic acid, diphenylmethyl ester

A solution of 0.106 g of the product of Example 49 in 5 ml of methylene chloride was combined with 1 g of diatomaceous earth, followed by 0.104 g of pyridinium chlorochromate.

After stirring for 15 hours, the reaction was diluted with 3 mL of 50% ethyl acetate / hexane and filtered through silica gel, washing with 50% ethyl acetate / hexane and ethyl acetate. The filtrate was concentrated in vacuo to give 0.087 g (80%) of the desired product as a yellow oil / foam.

»! 1 H NMR (CDCl 3) δ 0.05 (d, 6H), 0.85 (s, 9H), 1.25 (d, 3H), 2.88 (m , 2H), 3.05 (m, 1H), 4.08 (m, 1H), 4.18 (s, 2H), 4 r 2 (m, 1H), 6, 85 (S, 1H), 7 .3 (m, 10H), 7.6 (d, 2H), δ 7f 9 (d, 2H).

Example 51 [2R- [2α (α), 3B (R *)]] - 2- [4- (4-bromophenyl) -2-iodo-4-oxo-2-butenyl] -3- [1 - [[ (1,1-Dimethylethyl) dimethylsilyl] oxy] ethyl] -4-oxo-1-azetidine-10-acetic acid, diphenylmethyl ester in a solution at -78 ° C under argon with 0.087 g of the product of Example 50 in 2 ml of methylene chloride -dia, 0.037 ml of trimethylsilyl iodide was added. After 20 minutes, the reaction mixture was cooled with 1 mL of 50% diethyl ether / water. The mixture was diluted with methylene chloride / water, partitioned and the organic layer was washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 20% ethyl acetate / hexane to give 0.059 g (57%) of the desired product as a yellow foam.

1 H NMR (CDCl 3) O 8 (d, 6H), 0.85 (s, 9H), 1f 25 (d, 3H), 2.95 (m, 1H), 3.0-372 (m, 2H), 4, 1 (q, 2H), 4.18-4.3 (m, 2H), δ 6.85 (5.1 * 1), 7.3 (m, 10H), 7.6 (d, 2H), 7, .75 (d, 2H).

Example 52 [5R- [5 «, 6« (R *)]] - 3- [2- (4-bromophenyl) -2-oxoethyl] -6- [1 - [[(1,1-dimethylethyl) dimethylsilyl] -30 oxy] ethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, diphenylmethyl ester in a solution at -78 ° C under argon with 0.059 g of Example 51 product in 2 ml of tetrahydrofuran, 0.088 ml of 1M lithium bis (trimethylsilyl) was added. After 15 minutes, an additional 0.073 mL of 72,100327 IM lithium bis (trimethylsilyl) amide was added and the reaction mixture was stirred for 15 minutes at -78 ° C. The reaction was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel with 10% ethyl acetate / hexane to give 0.010 g (20%) of the bicyclic endocyclic product.

2 H NMR (CDCl 3) δ 0.1 (d, 6H), 0.9 (s, 9H), 1.25 (d, 3H), δ 2.82-3.05 (m, 2H), 3.18 (m, 1H), 4.15 (d, 1H), 4.25 (m, 2H), 4.5 (d, 1H), 6.85 (s, 1H), 7.2-7.45 ( m, 8H), 7.55 (m, 4H), 7.8 (d, 2H).

IR (neat) 1776, 1711 cm-1.

«[Slit li K hia

Claims (8)

100327 73 1. 4-Propargyl-2-oxo-1-azetidineacetic acid derivative, characterized in that it has the formula 5 R1 W \ / Lm \ r30 10. wherein R 1 is 1-hydroxyethyl which may be substituted by benzyloxycarbonyl or t-butyldimethylsilyl, R 3 is p-methoxybenzyl, p-nitrobenzyl, 2-chloro-2-propenyl or sodium or potassium ion, R 30 is hydrogen, -CO 2 R 16, - (C = O) -R 17 or -CHOH-R 17, R 16 is a straight or branched lower alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, and R17 is a phenyl ring optionally substituted with halogen. 2. A compound according to claim 1, which is [3S- [3a (S *), 4B]] -3- [1 - [[1,1-25 dimethylethyl) dimethylsilyl] oxy] ethyl] - 2-oxo-4- [2-propynyl-1-azetidineacetyrra. A compound according to claim 1, characterized in that it is [3S- [3ot (S *), 4β]] -3- [1 - [[1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2-oxo-4- [2-propynyl-l-azetidineacetic. 3. A compound according to claim 1, which is [3S- [3a (S *), 4β]] -3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] - 2-Oxo-4- (2-propynyl) -1-30 azetidineacetyr, 2-chloro-2-propenyl ester. Compound according to Claim 1, characterized in that it is [3S- [3a (S * J, 4B]] -3- [1 - [[(1,1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2 -oxo-4- (2-propynyl) -1-azetidineacetic acid, 2-chloro-2-propenyl ester. 74 100327 4. A method according to claim 1, which comprises [3S- [3a (S *), 4β]] -3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] - 2-Oxo-3- (2-propynyl) -1-azetidineacetyr, (4-nitrophenyl) methyl ester. 76 100327 Compound according to Claim 1, characterized in that it is [3S- [3a (S *), 4β]] - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2- oxo-3- (2-propynyl) -1-azetidineacetic acid, (4-nitrophenyl) methyl ester. 5. A compound according to claim 1, which is [2R- [2a, 3fl (R *)]] - 3- [1 - [[(1,1-dimethyl) dimethylsilyloxy] ethyl] -2- (4-Methoxy-4-oxo-2-butynyl) -4-oxo-1-azetidineacetyl, (4-nitrophenyl) methyl ester. 6. A preferred embodiment of claim 1, which is [3S- [3a (S *), 4fi]] - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2-OXO-4- (2-propynyl) -1-azetidineacetyr, (4-methoxyphenyl) methyl ester. Compound according to Claim 1, characterized in that it is [2R- [2α, 3β (R *)]] - 3- [1 - [[(1,1-dimethyl) dimethylsilyloxy] ethyl] -2- (4 -methoxy-4-oxo-2-butynyl) -4-oxo-1-azetidineacetic acid, (4-nitro-phenyl) -methyl ester. Compound according to Claim 1, characterized in that it is [3S- [3a (S *), 4β]] - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2- oxo-4- (2-propynyl) -1-azetidineacetic acid, (4-methoxyphenyl) methyl ester. 7. A compound according to claim 1, which is [2R- [2a, 3fi (R *)]] -2- [4- (4-bromophenyl) -4-hydroxy-2-butynyl] - 3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4-oxo-1-azetidineacetyrra, diphenylmethyl ester. Compound according to Claim 1, characterized in that it is [2R- [2α, 3β (R *)]] - 2- [4- (4-bromophenyl) -4-hydroxy-2-butynyl] -3 - [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4-oxo-1-azetidine acetic acid, diphenylmethyl ester. Compound according to Claim 1, characterized in that it is [2R- [2α, 3β (R ')] -2- [4- (4-bromo-phenyl) -4-oxo-2-butynyl] -3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -4-oxo-1-azetidine acetic acid, diphenylmethyl ester. mtg I »«: rl «MI 1t 1 * 100327 75 1. 4-propargyl-2-oxo-1-azetidinecarboxylic derivatives, converted to the formulation / yN \ R30 10 oi co2r3 i vilken R1 is 1-hydroxyethyl, vilken which may be substituted by benzyloxycarbonyl or t-butyldimethylsilyl, R3 is p-methoxybenzyl, p-nitrobenzyl, 2-chloro-2-propenyl or sodium or potassium ion, R30 is derived, -CO2R16, - (C = O) -R17 or -CHOH-R17, R16 is and the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, and R17 is phenyl, which may be substituted with halogen. 8. A compound according to claim 1, which comprises [2R- [2α, 3B (R *)] -2- [4- (4-bromophenyl) -4-oxo-2- butynyl] -3- [1 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -4-oxo-1-azetidineacetyrra, diphenylmethyl ester. Il I I *! Ill I Ml M ί