FI70902C - 4-THIO-2-AZETIDINONDERIVAT ANVAENDBARA SOM MELLANPRODUKTER VID FRAMSTAELLNING AV ANTIBAKTERIELLA PENEMDERIVAT - Google Patents

Description

1 70902 4-Thio-2-azetidinone derivatives used as intermediates in the preparation of antibacterial penem derivatives

Divided by application 793905 5

The invention relates to 4-thio-2-azetidinone derivatives of the formula

O

• I

Y 1 10 V _ S-C-X ·

Γ IV

0 ^ Νγ ^, 0.3 CO22 · 15 where Z 'is an ester-forming group, Q is phenyl, X' is methyl, phthalimidobutyl, CH2C (CH-j) = NOCH3 or (CH2) ^ PO (OR) 2, where n is 2 or 3 and R is lower alkyl and Y 'is hydrogen, lower alkyl substituted with Acetoxy, hydroxy or protected hydroxy; HCONHCH 2, C 9 H 8 -CH 2 H (OH), where the hydroxy group may be protected, or 2,2-dimethyl-1,3-dioxolan-4-yl, provided that X 'is not methyl when Y' is hydrogen.

The compounds of formula IV are useful as intermediates in the preparation of the antibacterial penem derivatives described in FI-67853 having the formula

Y

\ _

30 Vo2Z

wherein Z is hydrogen or an ester-forming group, X is methyl, phthalimidobutyl, CH 2 C (CH 3) = NOCH 3 or (CH 2) n PO (OR) 2, where n is 2 or 3 and R is lower alkyl, and Y is hydrogen, lower alkyl substituted with acetoxy or hydroxy; HCONHCH 2, C 6 H 5 CH 2 CH (OH), CH 3 OCH 2 OCH 2 CH (OH) or 2,2-dimethyl-1,3-dioxolan-4-yl, provided that X is not methyl when Y and Z are hydrogen.

70902

The Penem ring system's formula is

tt'V

and may be called systemat iso s + - i 7-oxo-H-thia-1-azabicyclo [3.2.2] oxept-2-ene. For simplicity, it is referred to in this application as "penein" and the numbering system used is as follows: J_s i 10 7 // ± J „· - /. /

"" V

Suitable ester-forming groups Z 'are those commonly used in the β-lactam and peptide fields.

Many such groups are known which have been used to protect the carboxyl group during subsequent chemical reactions and which can be subsequently removed by conventional methods to obtain the free carboxylic acid. Known ester-forming groups include 2,7,2-trichloro-ethyl, tertiary alkyl of 4 to 6 carbon atoms, tertiary alkenyl of 5 to 7 carbon atoms, tertiary alkynyl of 5 to 7 carbon atoms, alkoxymethyl, alkanoylmethyl, having 2 to 7 carbon atoms, N-phthalimim-Dome style, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl, triethylsilyl, 7-triethylsilyl , and groups like these.

The preferred ester-forming group is p-nitrobenzyl ester, which can be easily removed by catalytic hydration. Another preferred mm / locating group of the ester is β-trimethylsilylethyl, which can be removed by treatment with fluoride ions. Physiologically cleavable groups which are known in the art of penicillin and cephalosporin chemistry to be easily cleaved in the body to the parent acid can also be used. Examples of physiologically cleavable groups include indanyl, thalidyl, methoxymethyl, glycyloxymethyl, phenylglyloxymethyl, thienylglyloxymethyl or acyloxymethyl having the formula

O

-ch2-c-y · 10 wherein Y * is C1-C4-alkyl or phenyl. Particularly preferred groups of this type are methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

Preferred compounds of formula IV are those wherein Y 'is hydrogen or hydroxyethyl.

The following reaction schemes describe the preparation of the compounds of the invention and their use as intermediates.

4 70902

Reaction Scheme Ia

NIGHT

\ _ ^ OAc II

Y ~ CH = CH-OAc CS l f XC-SMa <j- N nH 7.5 "

O H

O

y 11 7 "V-rsc'x _> \, -sc-x _.

‘I ™ I SOCl ^

o '"Ni CO 2z' -O 2 -N 2 O 0H

co2 z1 o o

Cp y Y-, H

^ —R w3> —rsc "x :: -> Γ _>

0 p o ^ J

C02Z ‘co2z’

Y

—R \ γ _ „/ -> V; <'Z' group} //

° Vn z-? Oi * to y> - W

co ^ o \ co9h ö '

II

Ac = CH 2 -C 0 = C, H_- 6 3 5 70902

Reaction scheme Ib Y 0

^ -0 Ac M

Y-CH = CH-OAc CSI f CH 2 C-SNa ^ J- N pH. 7.5 ^ O ^ li Y’K’J-r-5Ac _V, V_rSAc _ ^ Γ SOC1-

rn z ’-Mn OH

O XH LU2 co2z · ’

Y Λ, Y

^ -rSrtC PO3 | - ^ S Ac>% tA

i — n cl anas' J— N ^^? 0 ^ * o ^ -p o C02 3 »C02Z '' Y“ V_ ° Y? '' r ~ rs: i x-i- © "v-rsc'x 4 0J-” y * ™ 3 oJ - »^ 03 C02 2 'COn Z'

Y

w r *

| f "\ -x _N

^ Z 'group I // - *' O 'deletion --1 ‘C0o2’ O \

A CO2H

o n X-L- G = acylating agent f-1A = heavy metal salt 70902

Reaction Scheme Ie K, _O Ac Y-C! I = C !! - OAc CSI | Py ^ S.Ia ^ J- N pH 7.5 "

O ^ H

Y -v, Y

I — Tsc03 -> —rSC3 3 -> I, 9110 I SCC1 «/“ 'N, ^ 2Z' 0 ^ —Η \ ^ ° "CO, Ξ 'Y-, Y ^ • \ -rSC03 P'3 _. SCO, 3 v, j 3 ma _M 'rl base "^ // l, v. - ^? Q_ base O 3 co2 Z 'CC, Z' Yv O 9 _ ^ SM II SC-v I: <- c- 0 p-Τ 'Δ 1 --9 »- 3 s? - \ ^ -ν3 ο co2z- <[η 2 '

Y

'—S r * 1 I) -X ^,. ^ S \ / -> - \ \ _ * Deletion of' 'Z' group} // O \) CO „Z 'O \

2 CO H

7 70902

In Reaction Schemes Ia, Ib and Ie, the vinyl ester is converted to U-acetoxy-2-azetidinone by a cycloaddition reaction with chlorosulfonyl isocyanate (CSI) followed by reduction with an organic reducing agent such as sodium sulfite. The CSI reaction is conveniently carried out in an inert organic solvent such as diethyl ether at a temperature of 0 ° C or below. The reduction step can be carried out in an aqueous or aqueous-organic reaction mixture at a temperature of 0 ° or below and the pH slightly on the basic side. After the formation of 4-acetoxy-2-azetidinone, the synthesis can be continued in three different ways. According to Reaction Scheme Ia, azetidinone is reacted with thiolic acid 0 tt X-C-SH, or a salt thereof, in a suitable solvent (e.g., water or an aqueous organic solvent). This displacement reaction is preferably carried out at or below room temperature and with a slightly basic pH (<v 7.5). When Y 1 H, the cis and trans isomers of the resulting azetidinone are preferably separated at this stage of process 20 (e.g. by chromatography). Schemes

Ib and Ie H-acetoxy-2-azetidinone is converted to 4-acetylthio-2-azetidinone and 4-tritylthio-2-azetidinone, respectively, with nucleophilic displacement using thioacetic acid or triphenylmethyl mercaptan (or a salt thereof) such as sodium salt, respectively.

4-Azetidinone is then reacted with a glyoxyl oxide ester HC-CC 2 Z *, where Z 'is e.g. p-nitrobenzyl or trimethylsilylethyl, or its reactive oxo derivative such as a hydrate, in an inert organic solvent ( e.g. in benzene, toluene, xylene or the like) and preferably at a higher than normal temperature (e.g. at 50 ° C - preferably at boiling temperature). When a hydrate of the ester 35 is used, the water formed can be removed azeotropically or using a molecular sieve. The hydroxy ester product 70902 is formed as a mixture of epimers which can be purified chromatographically or used directly in the next step if desired.

Conversion of the hydroxy ester to the corresponding chloro ester 5 is accomplished by reaction with a chlorination reagent (e.g., SO 2, POCl 3, PCl 2, or the like) in an inert organic solvent (e.g., tetrahydrofuran, diethyl ether, methylene chloride, dioxane, dioxane). ) in the presence or absence of a base, preferably in the presence of an aliphatic tertiary amine (e.g. triethylamine) or a heterocyclic tertiary amine (e.g. pyridine or collidine). The reaction is preferably carried out at a temperature between about -10 ° C and room temperature. The chloroester product is obtained as a mixture of epi-15 mers, which can be purified in the next step before use, if desired.

The phosphorane intermediate can be obtained by reacting the chloroester with a suitable phosphine (preferably triphenylphosphine or tri-lower alkylphosphine such as triethylphosphine or tri-n-butylphosphine) in an inert organic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, tetrahydrofuran in dioxane or an aliphatic, cycloaliphatic or aromatic hydrocarbon (e.g. hexane, cyclohexane, benzene, toluene, or the like) in the presence of a base, preferably an organic tertiary amine such as triethylamine, pyridine or 2,6-lutidine. The reaction is preferably carried out at a temperature between room temperature and the boiling point of the solvent system.

In Reaction Scheme Ia, the phosphorane intermediate is converted to the desired penem compound by cyclization in a thermally inert organic solvent at a temperature slightly above room temperature and the boiling point of the solvent system. The cyclization is suitably carried out under boiling conditions. Suitable organic solvents include aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. benzene, toluene, hexane, cyclohexane), halogenated hydrocarbons (e.g. methylene chloride, chloroform, carbon tetrane, diethyl ether, 5-ether), ethers (5). tetrahydrofuran, dimethoxyethane), carboxylic acid amides (e.g. dimethylformamide), di-C 1 -C 6 alkyl sulfoxides (e.g. dimethyl sulfoxide) or C 1 -C 6 alkanol (e.g. methanol, ethanol, t-butanol), or mixtures thereof.

In Reaction Schemes Ib and Ie, phosphorane is converted to ras-10 casmetal mercaptide of the formula _ ^ S__ 15 ^ P (Q> 3 »_ C0R" 2 —I x

III

or 20 _SHrCOOCH, L1 p (Q> 3 CO9R "25 purple

The formation of the mercaptide is carried out by reacting phosphorane with a salt of Hg (II), Pb (II), Cu (II) or Ag (I) or (methoxycarbonyl) mercuric (IDacetate in a methanolic solvent and an organic or inorganic In the presence of a basic base such as aniline, pyridine, collidine, 2,6-lutidine, alkali metal carbonate or the like The preferred base is pyridine The reaction may be carried out at room temperature or, if desired, with moderate cooling or heating. be any anion which forms a salt soluble in the chosen solvent, e.g. NOg, CH2COO, BF2, F, C104, NC> 2, CNO, etc. The mercaptide intermediate is then reacted with an acylating agent capable of attaching a group of 70902 O, wherein X is the desired penem-2 substituent xc The acylating agent 0 may be acid 0 or

(X-C-O) X-C-OH

Its reactive functional derivative such as acid halide (preferably acid chloride), acid azide, acid anhydride, mixed acid anhydride, active ester, active thioester, etc. The acylation is performed in an inert solvent (e.g. in a halogenated hydrocarbon such as methylene chloride or ether) or in diethyl ether), and when an acid derivative is used, in the presence of an acid scavenger such as tri-lower alkylamine (e.g. triethylamine) or a tertiary organic base such as pyridine, collidine or 2,6-lutidine. When the free acid is used, the acylation is carried out in the presence of a suitable condensing agent, for example a carbodiimide such as Ν, Μ'-dicyclohexylcarbodiimide. The acylation of mercaptide can be performed over a wide temperature range, but is preferably performed at -20 ° to + 25 ° C. The phosphorane obtained after acylation is cyclized as described above to give the desired penem ester.

The formation of phosphorane via the mercaptide intermediate (Reaction Schemes Ib and Ie) yields a much better product than that obtained using the more conventional method described in Reaction Scheme Ia.

Once a carboxyl-protected penem compound is formed, the ester-forming group can be removed by conventional methods (e.g., by hydrolysis, hydrogenation, or photolysis) to give an unprotected penem compound.

For example, removal of p-nitrobenzyl ester can be accomplished by hydrogenation from a catalytic catalyst in the presence of a noble metal catalyst such as palladium or rhodium, including derivatives such as oxides, hydroxides or halides, said catalyst optionally bound to a common support such as carbon and diatomaceous earth. In this case, a non-reducing aqueous or non-aqueous inert solvent such as water, ethanol, methanol, ethyl acetate, tetrahydrofuran, diethyl ester or dioxane is used.

n 70902

The hydrogenation can be carried out at atmospheric pressure or higher, and is most conveniently carried out at room temperature for about 1 to 5 hours, depending on the solvent and catalyst used. If an equivalent amount of a base such as an alkali metal or alkaline earth metal hydroxide or amine is used during the hydrogenation, the product can be recovered as the carboxylic acid salt. The removal of the -trimethylsilylethyl group is conveniently carried out by treatment with a fluoride ion-producing compound. Other ester-forming groups can be removed in a similar manner by methods well known to those skilled in the art.

Reaction schemes Ila and Hb 15 ____- SC03 SC0 ~ H _> i s? - n! ..

° '\ 0 ^ \

20 H \ B

Y Y V_ ^ SC03

25 bases ^ I

0 ^ B

deprotection / \ MA / base 30 / \ / \ 35 12 70902

N-- | ^ SC03 YH ^ SM

J Ns / N

0 H O NB

<f «0 O

C ° 2Z 'x-c-0 V Ψ Y "N -_ ^ SC0, Yvv>?

| 3 ^ -pSC-X

—N \ ^ oh J

O

C02ZT

Deprotection of SOC1 V ψ Y 0 ^ _ ^ sc-x r-Cl 1; C02 Z · P03 base v ™ 0 \ / C02R "

rpr, O

I * v_ ^ sc-x J N ^ P03 1 0 * ^ [Λ-CI!

O

CO, Z '· I

CO-, HA 'HA / base V ^ S0C12 70902 ^ _J-x C ° 2 1θ2Ζ 'χ X-C- Θ p03 V emas

0 ^ O

Y ^ _ Sc} _x y ° S Qr-v n ^ nr is - ”\ ^? 03 p,

f, I

C02Z CO ^ 'Δ Δ V V · * N — r ^ s \ Y \ ^ s \ ^' V-x

° '7 t O

C ° 2J C02Z Removal of the 'Z' group Removal of the Z? Group

^ V

Y Vr y * VrA

.yy β> · co h 0 \ 2 C02n B = ring type protection group “70902

In Reaction Schemes IIa and lib, the azetidinone ring nitrogen is protected with a conventional easily removable protecting group such as triorganosilyl (e.g., trimethylsilyl or t-butyldimethylsilyl), methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, and the like. The incorporation of the desired Y substituent at the 1-position of the azetidinone is then accomplished by reacting the appropriate electrophilic compound with the N-protected azetidinone in the presence of a strong base. Thereafter, the synthesis of synth-10 can be continued in two ways, depending on the stage at which azetidinone is deprotected.

According to Reaction Scheme IIa, the N-protected intermediate is deprotected by conventional methods (e.g., hydrolysis with acid) and then converted to the 2,6-penem compound by ester formation, chlorination of the hydroxyester, conversion of the chloroester to phosphorane, conversion of the chloroester to phosphorane, conversion to phosphorane to a heavy metal mercaptide, acylating the mercaptide with a group 0, thermally cyclizing the resulting phosphorane XC-, to give the 2,6-penem ester, and removing the ester-forming group Z *.

According to Reaction Scheme Hb, the N-protected azetidinone is acylated with a group 0, the N-protecting group is removed, the deprotected acetyl-XC-0.25 thidinone is reacted with a glyoxylate ester, chlorinated, the chloroester is reacted with a phosphine to give a phosphorane, the phosphorane is cyclized, a penem ester is obtained and the ester-forming group Z 'is removed to give 2.6-30 penem compounds.

The following examples illustrate the invention.

All temperatures are in degrees Celsius. Some abbreviations have been used in the examples. Of these abbreviations, the meanings of which are not obviously defined are defined below.

15 70902 CSI chlorosulfonyl isocyanate tt i pet.ether petroleum ether b.p. boiling point n.in.r. nuclear magnetic resonance 5 h hour ether diethyl ether (unless otherwise stated)

Celite Jonns-Manville Products Corporation’s buttermilk trademark psi pounds per square inch 10 r.t. room temperature PNB p-nitrobenzyl m.p. melting point LAii lithium aluminum hydride n-öuLi n-butyllithium 15 MIBK methyl isobutyl ketone

Et c 2 H f> -

Tr -C (CrHr) _ h h o

Me CH3-THF tetrahydrofuran 20 Ph phenyl DMF dimethylformamide TEA triethylamine PC3G p-nitrobenzylglyoxylate THP tetrahydropyranyl 25 TFA trifluoroacetic acid HMPT (or hexyl methyl phosphorus triamide.

HHPA)

EtOAc ethyl acetate DMSO dimethyl sulfoxide 30 Ac CH3CO-

Ms CH 3 SO 2 DMAP 1+ -dimethylaminopyridine

Py pyridine LDA lithium diisopropylamide 35 70902 16

Preparation of Compounds of the Invention Example 1? ?

5 Π * - U T

o * "'Y'-} CO pjjb co,?:; a 6 2 10

To a solution of crude compound 8 (463 mg, 0.38 mmol) was added triphenylphosphine (236 mg, 0.9 mmol) and 2,6-lutidine (4 mL). (36 mg, 0.9 mmol) and the mixture was allowed to stand at room temperature for 65 hours. It was then filtered, the filtrate was concentrated and the residual oil was chromatographed on a silica gel column eluting with a mixture of ethyl acetate and 2'-ethanol to give 203 mg (30.6 °) of oil 3 which solidified on standing, m.p. . 12-12-12 ° C.

20 Example 2/0 Ac SAc AC ° η- ^ (Φ) 3Ρ ArO ^ -jf -J, 1 — CHCl 1 dioxane J -— n —c = p (0) o I cr 1 3 CO PNB CO2PN3 25 2 - 6 A mixture of crude compound 5 (1.90 g; 4.27 mmol), triphenylphosphine (1.572 g; 6 mmol) and 2,6-lutidine (0.642 g; 6 mmol) in dioxane (20 mL) was heated At 55 ° for 18 h. Cooled, filtered and evaporated to dryness to give 3.8 g of a crude dark oil.

This was chromatographed on silica gel to give 1.2 g (42%) of compound 6.

Example 3 17 70902

,, ^ SCCCH

r-f 2 2c "3cocl_. 2 f ~ f J A? Ph, pyridine J ->: \ ^ ?? h3

5 ° 3 ° I

I co ?: · ‘b contra 2 II 111 10

A solution of compound II (262 mg, 0.2 nunol), acetyl chloride (35 mg, 0.4 U mmol) and 2 drops of pyridine in 10 mL of dichloromethane was stirred at 5 ° C for 1 h. The precipitated mercuric chloride was then filtered. separated and the filtrate was washed successively with cold dilute hydrochloric acid, sodium hydroxide and finally brine. The organic solution was treated with hydrogen sulfide for 2 minutes at 5 ° C and stirring was continued at this temperature for another 10 minutes to precipitate the last traces of mercury salt. Some charcoal was added to the black mixture and the mixture was then filtered

Through a Celite mattress. Evaporation of the clear filtrate to dryness left 193 mg (80.7%) of compound III as a foam.

IR (CHCl 3) 1755 (^) c = o-lactam) 1692 (?) SCr (CH) 1620 (phenyl). 3 25

Example 4 18 70902 crsY— 'V1 ^ rr - V ^' o V1 / - \ ö ^ fW3 ö °° 2®2 \ P I NO2 CO2CH2 - (5) - NO2. 10 6 1

A solution of compound 6 (21.6 g, 38.8 mmol) in tetrahydrofuran (85 mL, distilled over LAH) was treated with triphenylphosphine (10.2 g, 38.8 mmol) and 2,6-luti-15 didine. (5.0 mL, 42.9 mmol) for 18 h at 40 ° C. The mixture was diluted with benzene-ether 1: 1 (30 mL), washed with water, 1-norm. HCl, saturated NaHCO 3, brine and dried over MgSO 4. Evaporation of the solvent gave a dark brown oil. It was passed through a silica-20 gel (700 g) column (benzene ether mixture) to give 16.0 g (53%) of compound 7 as a thick oil. NMR (CDCl 3) δ 8.2 (2H, d, J = 9 Hz), 7.8 (8H, d, J = 2 Hz), 7.52 (16H, broad s), 5.2 (1H, broad s), 4.78 (1H, 2s), 4.30 - 4.52 (1H, m), 3.5 - 3.8 (2H, m), 2.8 - 3.5 (2H, m) , 2.1 - 2.9 (4H, m), 1.5 - 1.9 (4H, m).

Example 5 19 70902 ii — ocii- ίί — DCM '

Il 3 il J

SCOCH -C-CH, '__ ^ SCCO12-C-CM3 rf - jX., ..

5 ° Γ

1 dO-PNB

A solution of chlorazetidinone M (1.2 g, 2.70 mmol) in THF (20 cm, distilled over LAH) was treated with triphenylphosphine (1.06 g, * 4 .05 mmol, 1.5 eq.) And 2,6-lutidine (318 mg, 0.346 cm, 2.97 mmol, 1.1 eq.). The mixture was stirred for u days at room temperature under a nitrogen atmosphere. Diluted with ethyl acetate, washed with 2% aqueous HCl, 2N aqueous NaHCO 3, water and brine. The solution was then dried over HgSO 4 and the solvent was evaporated. The crude compound 5 was purified on a silica gel (10-fold weight) column (ethyl acetate, 770 mg, 45%).

'i ... (CHCl3) 1755, 1695, V 1530 - 1610, .. 1525.

»3 N u 2 JO 70902

Example G

'A ^ H2C1 * CICOCIIjClljCl - öj_ „vrp * j

CO, fll »C02P" B

5

I II III

A solution of I (1.1 g, 1.6 mmol) and II (0.16 mL, 1.6 mmol) in methylene chloride (30 mL) was cooled in an ice bath and 1 mol was added dropwise. methylene chloride solution of pyridine (1.7 mL, 1.7 mmol). The resulting reaction mixture was stirred at room temperature for 1 h and then filtered through Celite and washed with methylene chloride. The filtrate and washings were combined and washed successively with 1-norm. HCl (5 mL), water (5 mL), 1 mol. NaHCO 3 (5 mL) and brine, and then dried (MgSO 4) and evaporated to dryness in vacuo to give Compound III 900 mg (87%) as an amorphous solid. It was used without further purification in the next step. IR (CHCl 3) 1755, 1G90 cm -1.

MHR (CDCl 3) δ 8.22 (2H, d, J = 9 Hz), 7.55 (15H, m), 6.72 (2H, d, J = 9 Hz), 5.7 (1H, m), 5.0 (2H, 2s), 3.55 (2H, 2s), 2.8 (4H, m).

J3 25. f Corpus o -—P <o —O 2 III IV J-N ρφ O 3

CO PUB

30 2 v n 70902

A mixture of III (1.3 g, 2 mmol) and IV (0.65 mL, 3 mmol) was heated at 80 for 4 h. The reaction mixture was diluted with methylene chloride (10 mL) and washed with water (2 x 5 mL). mL). The organic layer was dried (MgSO 4) and evaporated to dryness in vacuo to give Compound 1.4 g (90 g) as an amorphous solid. It was used without further purification in the next step.

IR (CHCl 3) 1755, 1690 cm -1 NMR (CDCl 3) δ 8.25 (2H, d, J = 9 Hz), δ 7.55 (15 H, m), 6.8 (2H, d, J = 9 Hz), 5.7 (1H, m), 5.1 (2H, 2s), 4.72 (2H, dq J = 12 Hz, J = 6 Hz), 2.6 (4H, m), 1, 4 (6H, s), 1.28 (6H, s).

Example '_ / SAg p .1 1 + C1C (CH.) P (OC.! Lc), -► 15 J_, j J> t · 2 3 2 5 2 0 I 9 co2 ™

Π T

In a cooled (ice bath) mixture of compound 1 (1.324 g, 2 mmol) and compound 2 (0.54 g, 2.2 mmol, crude). (CH 2 Cl 2) (15 mL) was added dropwise. pyridine / CH 2 Cl 2 solution (2.2 mL, 2.2 mmol). The mixture was stirred at room temperature for 1 h and filtered through Celite. The filtrate was washed successively with 0.5 nomr. With HCl, Hailia, 0.5 mol. NaHCO 3 and brine. Dried (MgSO 4) and filtered through Celite to give 0.9 g of oil after evaporation to dryness, the oil was chromatographed on SiO 2 * Ha (10% H 2 O) and eluted with ethyl acetate to give 0.5 g. compound 3. (32.8%). NMR - (ppm, CDCl 3) 7.0-8.4 (m, 19H), 4.8-5.8 (3H, m), 4.1 (411, q), 3.3-4.2 , (211, m) 2.7 (2H, m), 35 1.9 (2H, rn), 1.3 (6H, t).

70902 27

Example 8? / s.

I 0 + (Meo)? - * · '-, α 2 2 o3 ° 3

^ I I

- Corpus co ^ pmb 1 2 3

A mixture of compound 1 (1.07 g, 1.66 mmol) and 10 compound 2 (0.42 g, 3 mmol) in CH 2 Cl 2 (3 mL) was heated at 80 for 5 h. Crude oil chromatographed on SiO 2 (3%

H 2 O) and eluted with ether, ether-ethyl acetate (1: 1) and ethyl acetate and 5% EtOH to give 1.0 g of compound 3 (82%). The oil crystallized on standing, m.p. (from ether) 138-140 °.

MHR δ (ppm, CDCl 3) 8.2 (2H, d) 7.0-8.0 (17H, m), 4.6-8.5 (3H, m), 3.8 (3H, s), 3.6 (3H, s), 1.5-3.5 (6H, m).

Example 9 (1 * R, 3R, 4R and 1'S, 3S, 4S) -4-Acetylthio-3- (1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl-2 Preparation of "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone (Isomer D)

OCO.PiJB

25 OC02phb X / _SShc

Xs ™ '1 CUf.CCl ^ —v I CM Cl, o -'--' 3

0J — 2 - I

υ J co2? :: 3

CO ^ PMD

30

To a stirred solution of silver 3- (1'-paramotro-benzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-acetethinone-4-thiolate (Isomer D) (35 mg, 0.035 mmol) CH 2 Cl 2. In Ci at 2370902 (5 mL) with pyridine (30 μL to 0.37 mmol; Fisher) at 0-5 ° C was added CH 2 COCl (20 μL, 0.28 mmol) and the mixture was stirred at 0 ° C. At -5 ° C for 30 minutes. The precipitate formed was filtered off and washed with CH 2 Cl 2. The filtrate and washings were combined, washed successively with brine, dilute HCl, saturated NaHCO 3 and then brine, dried (Ν32304) and evaporated to dryness to give 7S mg (0.091 mmol, 95% yield of crude compound). compound as a syrup: 1 Hmr (CDCl 3), δ: 2.33 (s, -SOCOCH 6); IR (fine) λ max: 10 1750 (β-lactam, ester), 1695 (thioester), 1520 and 1350 cm -1 (-NO 2).

Example in (1'S, 3S, 4R and 1'R, 3R, US) -1) -acetylthio-3- (1,1-paranitrobenzyldioxycarbonyl-1 * -ethyl) -1- (paranitrobenz-15-silyl-2 "- triphenylphosphoranylidene-2 "-acetate) -2-azetidinone (Isomer C).

OCO.PNB OCOjPNB

SA9 CH3COCl - [^ ° AC

20 ^ 'V 3 35 ^ V

C02P! JB C02? NB

To a cold (ice-MeOH bath) solution of 1'S, 3S, 4R and 1'R, 3R, 4S) -silver-3- (1'-paranitrobenzyl-dioxycarbonyl-1r-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (Isomer C) (1.14 g, 1.30 mmol) in CH 2 Cl 2 (60 mL) was added pyridine (0.6 mL, 0.74 mmol) and by dropwise addition of acetyl chloride (236 mg, 0.213 mL, 3.00 mmol). The reaction mixture was stirred for 1 h at -15 ° C. The precipitate was filtered off and washed with ether. The filtrate was washed with 2% aqueous HCl, water, 2% aqueous NaHCO 3, water and brine and dried over MgSO 4. The residue obtained after evaporation of the solvent was triturated with ether (895 mg, 83.7%). mp 184-185 ° C with decomposition); IR <CHCl 3) max} 1755, 1695 (C = O), 1620 and 1605 en'135 (phosphorane). Anal. Calcd for C 12 H 20 I 3, 3 ° nSSi: C, 61.38; H 4.42; il 5.11; S 3.90; Found: C, 61.26; H 4.49; N 4.88; S 4.26.

Example 11 24 70902 (1'S, 3S, 4R and 1'R, 3R, 4S) -4-Acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethylD-1-industrialanitrobenzyl-2 "- triphenylphosphoranylidene-2 "-acetate) -2-acetyl-4-quinone (Isomer C)

OCO-PHB? C02PNB? C02PtlB

I 1 SAc JL / SAc Φ p, VV - = * · VV VV,

COjPHB ίθ2ΡΗΒ C02PMB

Isomer C of 4-acetylthio-3- (1'-paranitrobenzyl-dioxycarbonyl-15 * -ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) -2-azetidinone (577 mg, 1 mmol) was dissolved to dry THF (10 mL) and pyridine (95 mg, 1.2 N) was added to the solution, the solution was cooled to 0 °, and thionyl chloride (143 mg, 1.2 mmol) was added slowly. .

At 20 ° C, diluted with a small amount of ether and insoluble salts were removed by filtration and washed with ether. The combined filtrates were evaporated to dryness to give a crude mixture of epimers of the C-2 "chloro compound. It was dissolved in TriF (20 ml), triphenylphosphine (314 mg, 1.2 mmol-25) and 2,6-lutidine (129 mg , 1.2 mmol) and the solution was stirred for 4 days at 45 ° C. The solids were removed by filtration, washed with benzene and the combined filtrates evaporated to dryness to leave an oil with spectral properties and tlc behavior identical to 30 samples of the title compound. prepared by acylation of the corresponding silver thiolate.

25 7 0 9 0 2

Example 12 (1'R, 3S, 4R and 1'S, 3R, 4S) -4-Acetylthio-3- (1,1-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2n-triphenylphosphoranylidene-2 "- acetate) -2-azetidinone, 5 (isomer B) i OCO-PUQ OCO ΓΠ0 J 2 SA? J SAc '' · j S ArCl 10 SS "* <r ~ 'γ · Ρίι co,? tia

A solution of (1'R, 3S, 4R and 1'S, R'USi-silver-S-Cl'-paranitrobenzyldioxycarbonyl-11-ethyl) -1-piaranitrobenz-15-yl-2 "-triphenylphosphoranylidene-2" -acetate) 2-azetidinone-4-thiolate (Isomer B) (917 mg, 1.03 mmol) in CH 2 Cl 2 (20 mL) was treated at -15 ° C (ice-MeOH bath) with pyridine (242 μL, 247 mg, 3.13 moles) and was added dropwise to acetyl chloride (142 μL, 157 mg, 2.0 mmol). The mixture was stirred for 15 minutes at -15 ° C and the solid was filtered off and washed with ether. The organic solution was washed with 2% aqueous HCl, water, 2% aqueous NaHCO 3, water and brine and dried over MgSO 4. The residue obtained after evaporation of the solvent was crystallized from ether (710 mg, 80%, m.p. 183-185 ° C; IR (CHCl 3) max: 1755, 1695 (C = O), 1620, 1605 (phosphorane) and 1625 cm -1). -1 (NO 2).

Example 13 26-7 0 9 0 2 (1'R, 3S, 4R and 1'S, 3R, 4S) -4-Acetylthio-3- (1,1-trimethyl-4-silyloxy-1'-ethyl) -1- (paranitrobenzyl -2 '' - triphenylphosphoranylidene-2 "-acetate) -2-azetidinone (Isomer B)

OH o * MS

^ A <3 TMS Cl AcC 1 /'···.,-/SAc 1 ° oJ_il F ^ 3 TEA C5H5N 0J—

C02WB C ° 2PbrB

Suspension of (1'R, 3S, 4R and 1'S, 3R, 4S) -silver-3-15 (1'-hydroxy-11-ethyl) -1- (paranitrobenzyl-1 "-triphenyl-phosphoranylidene-2" acetate (2S) -2-azetidinone-4-thiolate (5 mg, 0.715 mmol) in THF (25 mL) was cooled to -15 ° C (ice-MeOH bath), triethylamine (289 mg, 398 μL) was added dropwise. 2.86 mmol), trimethylchlorosilane (310 mg, 362 μL, 2.85 mmol) and finally imidazole (50 mg, 0.734 mmol) were stirred for 3 h at -15 ° C and room temperature for 16 h (sample tea IR showed no hydroxyl group). The mixture was cooled to -15 ° C, diluted with Cl 2 Cl 2 (20 mL), treated with pyridine (226 mg, 231 μL, 2.36 mmol) and acetyl chloride (168 mg, 152 μL, 2 mL). 14 mmol), stirred for 0.5 h, diluted with ether, washed with dilute aqueous HCl, water, 5% aqueous NaHCO 3, water and brine, and dried. The solvent was removed on a rotary evaporator and the residue was purified by filtration through 30 columns of silica gel (1:10, 3% ether in benzene) to give the title compound (360 mg, 84.2%) which included a small amount of desilylated derivative (30 mg, 7 , 8 i). IR (nos October Ivo), 1750, 1790 (C = U), 1520 (focforan) and 1518 cm (MOj) · 1 - 27 70902

Example 14 (1'R, 3S, 4R and 1'S, 3R, MS) -4-Acetylthio-3- (11-hydroxy-1 * -ethyl) -1- (paranitrobenzyl) -2 "-triphenylphosphoranylidene-2" acetate) -2-azetidinone (isomer B) 5 h

OH

? ™ S ΟΛ 1 S Ac -Vr jL- Vi „άθ2ΡΝΒ 2

A solution of (1 * R, 3S, MR and 1'S, 3R, 4S) -4-acetylthio-3-1'-trimethylsilyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-15 triphenylphosphoranylidene-2" acetate) -2-azetidinone (360 mg, 0.504 mmol) was treated with TFA (3 drops) and stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate, washed with water, dilute aqueous NaHCO 3, water and brine and dried (MgSO 4). ^). Evaporation of the solvent gave the title compound (334 mg, 100%); IR (CHCl 3) 1) k: 1755, 1690 (C = O), 1620, 1605 (phosphorane) and 1520 cm -1 (WO 2).

Example ib (1'S, 3R, 4R and 11R, 3S, 4S) -4-Acetylthio-3- (1 * -methoxymethoxy-25-1 * -ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2 "-acetate) -2-azetidinone (isomer A) 30 OClt-> CCl 3 Orl2ocn1 --- qJ-3 &

T CO.PNB

CO PUB 2 35 28 70902

Isomer A of 4-acetylthio-3- (1'-methoxymethoxy-1'-ethyl) -1- (para-nitrobenzyl) -2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone was prepared as described elsewhere for the paranitrobenzyldioxycarbonyl derivative. isomer C

• For 5, with a yield of 85%. IR (fine) i),: 1750 and 1690 cm -1

vmax J

(C = 0).

Example 16 (1'S, 3R, 4S and 1'R, 3S, 4S) -4-Acetylthio-3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -2-azetide-10-noni (isomer A)

OH

? C "2CC, I1 1 .SM

- "rC.

loPUB cv "B

15 2 Isomer A of 4-acetylthio-3- (1'-methoxymethoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2 '' - acetate) -2-acetidinone (500 mg , 0.68 mmol) was added to a cooled solution (0 ° C) of trifluoroacetic acid (50 ml) and water (10 ml) and stirred for 15 minutes on ice and for 3 h at room temperature The reaction mixture was evaporated to dryness, dichloromethane was added and the solution washed with sodium bicarbonate, water and brine, dried and evaporated to dryness to give the title compound (450 mg, 96%);

25 3400 (OH), 1745 and 1690 cm-1 (C = O). Max

29 70902

Example 17 4-Acetylthio-3- (1 H -acetoxy-1'-ethyl) -1- (β-trimethylsilylethyl 2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone 5 t 0H OAc I SAc

Me 1 | AcCl / pyride im Me jf '10 S — N ^ PPh3 N PPh 0 ^ V 3 SiMe- 0 "νν ^ ™ 3 SiMe, bo2' ^ '3 3 15 A solution of acetyl chloride (70 mg, 0.88 mmol). lia) in methylene chloride (1 ml) was added dropwise to a solution of silver 3- (1'-hydroxy-1'-ethyl) -1 - ([6-trimethylsilylethyl-2 "-triphenylphosphoranylidene-2" -acetate) -2- azetidinone 4-thiolate (267 mg, 0.40 mmol) and pyridine (70 mg, 0.88 mmol) in methylene chloride (5 mL) at 0. The mixture was stirred at 0 for 1.5 h and then For 15 minutes at 23 [deg.] C. The precipitate was filtered off and the solution was washed with 0.1 M hydrochloric acid and 0.1 M sodium bicarbonate solution (10 ml: 1 each) The solvent 25 was evaporated off in vacuo to give the title compound. 153 g (59%); ir 3450 (OH), 1750 (β-lactam and ester) and 1690 cm -1 (thioester; Hmr (CDCl 3), ν max: 7.5-8.2 (m, 15H, Ph), 5.85 (br, 1H, H-4), 3.0-5.0 (unresolved, 4H, OCH, OCH 2, H-3), 2.0-2.6 (3 singlets; 6H, OAc, SAc), 0.9-1.7 (m, 5H, CH 3, CH 2 Si) and 0.20 ppm (s, 9H , SiMe ^).

3 "70902

Example i8

Trans-4-acetylthio-3-formamidomethyl-1- (parano-benzoyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone 5

„_ H H

H 0 ^ - "^ Φ3

10 COjPtIB C02P ,, B

To a cooled solution (ice bath) of trans-silver 3-formamidomethyl-1- (paranitrobenzyl-21-triphenylphosphoranyl-15-diene-2 * -acetate) -2-azetidinone-4-thiolate (800 mg, 1.11 mmol) -lia) in dichloromethane (10 ml) was added dropwise under 1-mol protection. acetyl chloride in dichloromethane (1.33 mL, 1.33 mmol) followed by 1 M. dichloromethane solution of pyridine (1.33 mL, 1.33 mmol). The solution was stirred in a cold bath for 20 h, and then filtered through Celite. The filtrate was washed successively with 1-norm. with hydrochloric acid, water, 1 mol. sodium bicarbonate and brine and the organic layer was dried (HgSO 4) and evaporated to dryness. The residue was purified on a silica gel column (5.0 g) and eluted with mixtures of ethyl acetate-25% to 10% methanol in ethyl acetate to give 4 50 mg (52%) of the title compound; ir (CHCl 3) νmax: 1755, 1685 and 1620 cm -1; Hrnr (CDCl 3) δ: 8.18 (2H, d, J = 9Hz), 7.0-8.0 (20H, m), 6.75 (2H, d, J = 9Hz), 6.3 (1H, m), 5.5 (1H, m), 5.2 (2H, bs), 4.9 (1H, bs), 3.6 (1H, m), 3.0 (1H) , m) and 2.2 ppm (3H, 4 s).

31. to 70902

Example -1¾ (1'S, 3S, 4R and 1'RjSRi ^ SJ-M-acetylthio-S-d'-paranitrobenzyldioxycarbonyl-11-propyl) -1- (paranitrobenzyl-2 "-5 triphenylphosphoranylidene-2" -acetate) -2-azetidinone

. (isomer C) and PNB

OCO PNB 0CO2PMB 1 2 STr λ, „ο3 cH3cl. pt -TOSSB- / -O *, Y3

m i ’CO PNE

1U CO PNB CO PNB 2 2 2

To a hot solution (60 ° C) of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-paranitrobenzyldioxycarbonyl-1'-propyl) -15- (paranitrobenzyl-2 "-triphenylphosphoranylidene 2 "-acetate) -4-tritylthio-2-azetidinone (Isomer C) (1, (g <1.35 mmol) in MeOH (40 mL) was added with stirring a hot solution of AgNO (0.3 g , 1.76 mmol) in MeOH (10 mL) followed by pyridine (0.107 g, 0.11 mL, 1.76 mmol) The silver mercaptide began to precipitate immediately, and the mixture was stirred at room temperature for 15 minutes and at 0 ° C. It was filtered and the solid was washed well with cold MeOH and ether, 1.2 g, (quantitative yield), mp 113-115 ° C with decomposition, ε 1 IR (nujol) j) max: 1740 -1760 cm (wide). This solid was used as such. To a cooled (ice bath) solution of the above mercaptide (1.2 g, 1.35 mmol) in Cl 2 Cl 2 (15 mL) was added acetyl chloride (0.118 g, 0.107 mL, 1.5 mmol) in CH 2 Cl 2 (2 mL). ml) followed by pyridine (0.119 g, 0.122 mL, 1.5 mmol) in Cl 2 Cl 2 (2 mL). The mixture was stirred at 0 ° C for 30 minutes. It was filtered through Celite to remove the silver salt and the filtrate was washed successively with HCl (0.5 M), Hail, NaHCO 3 (0.5 M) and brine. The Cl 2 Cl 2 solution was dried (IlgSO 4) and evaporated to dryness to give 0.94 g of the title compound as an amorphous solid (83.4%). IR (fine) ν max: 1750 cm -1 (broad).

vmax 32

Example 2Π 70902 (1'RjSS ^ R and 1'S, 3R, US) -4-Acetylthio-3- (1'-formyloxy-1'-propyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2 "-acetate) -2-azetidinone (isomer B) 5

PCH0 <pO OCHO

r — r> STr 10 0 ^ 'γ *' '. jj,

CO-PNB 1 T

2 CO PUB CO PNB

* 2 Warm solution (60 ° C) with 0.15 mol. A solution of AgNO 2 -15 CH 2 OH (8.7 mL, 1.3 mmol) was added to a mixture of (1'R, 3S, 4R and 11S, 3R, 4S) -3- (1'-formyloxy). 1'-propyl) -1- (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone (Isomer B) (0.88 g, 1 mmol) and pyridine (0.103 g, 1.3 mmol) in MeOH (5 mL) heated to 60 ° C. The mixture was stirred at room temperature for 15 min. and at 0 ° C for 2 h. It was filtered and washed with cold MeOH to give 0.53 g of silver mercaptide as a yellow solid (71%) which was used as such. To a cooled (ice bath) mixture of the above mercaptide (0.53 g, 0.71 mmol) and pyridine (0.079 g, 1 mmol) in CH 2 Cl 2 (10 mL) was added dropwise CH 2 Cl 2 ( 0.079 g, 1 mmol) in CHCl 3 (5 mL). After stirring at 0 ° C for 1 h, the mixture was filtered. The filtrate was washed well with cold 0.5 mol. With HCl solution, 0.5 mol. MaHCO 3, and w 30 saline. Dried (Na 2 SO 4) and evaporated to dryness to give 0.43 g of an oil, (63%); Ir (fine) \),: 1700-1760 _ n me k s cm (broad „and β-lactam).

-C '5

Example 21 70902 (1'R, 3S, 4R and 1'S, 3R, 4S) - and acetylthio-3- (1'-hydroxy-1 · -propyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranyl-2" acetate) -2-azetidinone (isomer B)

OCHO OH

o,> sac a ..-

HCl / HeOH

10 o 3 0 ^

CO PNB CO PNB

^ «

The formate from the example (1.0 g, 1.45 mmol) in THF (10 mL) was treated at room temperature with HCl / MeOH (10 mL, prepared from 2 mL of concentrated HCl and diluted with MeOH to a volume of 24 ml). The mixture was kept at room temperature for 0.5 h. It was basified with 1 mol. NaHCO 3, extracted with ethyl acetate, washed with brine and dried (Na 2 SO 4). Evaporated to dryness to give 0.9 g of crude title compound. This was chromatographed on Pigs and eluted with ether and ether-ethyl acetate (1: 1) to give 0.6 g of pure title compound as an amorphous solid (62.5%); 1 Hmr (CDCl 3) tf: 82.5 (2H, d), 7.3-6.1 (17H, m, aromatic), 5.6 (H, m), 5.2 (2H), 4.9 (H), 4.4 (H, m), 2.3 (3H, SAc), 1.5 (2H, m) and 0.9 ppm (3H, t).

34 70902

Example 22 4-Acetylthio-3- (1'-formyloxy-2'-phenylethyl) -1- (para-nitrobenzyl-2 "-triphenylphosphoranylidene) N-acetate-methyl-azetidinone (1'R, 3S, 4R- and 1'S, 3R, 4S-enantiomer-5 reja) 10 Ocho „Ocho. H · ... a, 0CH0 SAc

CO PNB COjPMB CO ^ NB

To a boiling solution of 3- (1'-formyloxy-2'-phenylethyl) -1-paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone (1 * R, 3S , 4R and 1S, 3R, 4S enantiomers) (3.6 g, 3.8 mmol) and pyridine (0.33 g, 4.2 mmol) in Cl 2 Cl 2 (30 mL) and MeOH. 20 (30 ml) was added dropwise at 0.15 mol. AgNO 2 / MeOH solution (28 mL, 4.2 mmol). The mixture was stirred at room temperature for 2.15 h. It was concentrated to low volume (1010 mL), cooled and filtered to give the silver mercaptide as a yellow solid (2.3 g, 77%).

To a mixture of this mercaptide and pyridine (0.277 g, 3.5 mmol) in ice-cold CH 2 Cl 2 (20 mL) was added dropwise a solution of CH 3 COCl (0.27 g, 3.5 mmol) in CH 2 Cl 2. in (15 ml). The mixture was stirred at room temperature for 3 h. It was filtered through Celite and the filtrate was washed with cold 1 N HCl, 1 L, 1 mol. NaHCO 3 and brine. Dried over MgSO 4 and evaporated to dryness to give 1.0 g of an amorphous solid (89.8%). Himr (CDCl 3) δ: 8.2 (2H, d), 7.0-8.0 (23H, m ), 4.5-5.7 (4H, m), 2.6-3.3 (3H, m), and 2.3 ppm (2H, d, SAc).

Example 2 3 35 70902 4-Acetylthio-3- (1'-hydroxy-21-phenylethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -5-azetidinone (1'R, 3S , 4R- and 1'SjSR ^ S enantiomers) t 10 H .OCHO. B-..

KX ._ ^ Sac

J = C ·; -

____ CO.PMB

CO 2 PMB 2 15

A solution of the compound from Example 31 (1.8 g, 2.416 mmol) in THF (10 mL) was treated with a 1-norm solution. HCl / MeOH (10 mL) and the mixture was stirred at room temperature for 4 h. It was concentrated to remove methanol, diluted with cold water, basified with 1 M mol. NaHCO 3 and extracted with CHCl 3. The CHCl 3 solution was dried (MgSO 4) and evaporated to dryness to give 1.65 g of an amorphous solid.

This was chromatographed on Pigs and eluted with ether / ethyl acetate to give 1.30 g of the title compound 25 (75%). 1 Hmr (CDCl 3) δ: 8.2 (2H, d), 6.7-8.0 (22H, m), 4.0-6.0 (5H, m), 2.5-3.5 (3H , m) and 2.2 ppm (3H, SAc).

70902 36

Example .2 4 4'R, 3S, 4R and 4'S, 3R, 4S) -3- (2 ', 2'-Dimethyl-β, 3,3-dioxolan-4'-yl) -1- (p-nitrobenzyl) 2 "-trifenyyiifosforanyli.

diene-2 "-aetaphaphth) -4-acetylthio-2-aceticlinone (Isomer C) 5 · r ··: ^

° ν * ·· .._> S, V? CH 2 ClCl / pyr VA_SAC

rt, * nJ — rl P *

"• 0 CO rtlD CO, FNB

2 * ·

To a solution of (4'R, 2S, 4R and 4'S, 3R, 4S) -silver-3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -1- ( p-Nitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thio-15ate (Isomer C) (254 mg, 0.333 mmol) in CH 2 Cl 2 (15 mL) and containing pyridine (100, 1.24 mmol; 3.72 eq.) Acetyl chloride (71, 1.0 mmol; 3.0 eq) was added at 0-5 ° C. The mixture was stirred at 0-5 ° C for 40 minutes. After the precipitate was filtered through Celite, the filtrate was washed successively with brine containing 1-norm. HCl (1.25 mL), saturated NaHCO 3 and then brine, dried (Na 2 SO 4) and evaporated to dryness to give 200 mg of an oil which crystallized from Etoi to give 155 mg (0.222 mmol, yield 66). 7%) of the title compound as white crystals:. 1 Hmr (CDCl 3) δ: 1.23 (s, di-Me), δ 2.20, 2.33 (2s, -SAc) and 7.2-8.3 ppm (m, aromatic Hs): ir (nujol ) l / makg: 1750 (β-lactam and ester) and 1690 cm-1 (thioester). An analytical sample was obtained by crystallization from CH 2 Cl 2 -Et 2: m.p. 177-178 ° C; Analysis calculated for C 37 H 35 N 2 O 8 PS: C, 3.60; H 5.05; N 4.01; S 4.59; Found: C, 63.34; H 5.32; N 3.83; S 4.31.

Rf 0.62 (ethyl acetate).

3 7 70902

Example 25 (4'S, 3S, 4R and 4'R, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl) 2 "-triphenylphosphonanylidene-2" -acetate) -4-acetylthio-2-azetidinone (Isomer B) 5 O ", - CM'CO-1 / pyr. O"., - j-SAc

^ ® CO DMB

CO ^ MB ^ 2 '

The title compound was prepared as described in Example 33 for "Isomer C" (4'S, 3S, 4R and 4'R, 3R, 4S) 15-silver-3 -C 21 J'-dimethyl-1 ', 3'- dioxolan-4'-yl) -1- (p-nitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone 4-thiolate (Isomer B) (2.46 g, 3.22 mmol); yield after purification by column chromatography (SiO 2 32 g, eluent 10% to 50% ethyl acetate = 20 1: 1); 1 Hmr (CDCl 3) δ 1.23, 1.27, 1.30 (3s, di-Me), 2.22, 2.33 (2s, SAc) · and 7.3-8.3 ppm (m, aromatic Hs); ir (fine) y) ^ 2 ^ jticIks 1755 (β-lactam, ester) and 1695 cm (thioester).

70902

Example 26 (1'R, 3S, 4R and lfS> 3R, liS) -3- (1 ·, 2 · -dihydroxyethyl) -1- (p-ni LroL> cnt; silyl-2 "-triphenylphosphoranylidene- 2 "-acetate) -u-acetylthio-2-azetidinone (Isomer C) 5

QH

A s ··.

1-f τΓΛ-ιι ,, α [co ^ priB co ^ pria 10

A solution of (4'R, 3S, 4R and 4'S, 3R, 4S) -3-C2 *, 2 * -dimethyl-1 ', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl -2 "-tri-phenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (Isomer C) (472 mg, 0.676 mmol) in trifluoroacetic acid 15 (1.0 mL) and H 2 O (0, 1 ml) was allowed to stand at room temperature for 30 minutes. The mixture was added dropwise to a cold solution of NaHCO 3 (2.5 g) in He (50 mL) and extracted with CH 2 Cl 2 (3 x 20 mL). The extracts were washed with saturated NaHCO 3 and then brine, dried (Na 2 O 4) and evaporated to dryness to give 458 mg (0.695 mmol, crude yield 100%; purity 97.3%) of the crude title compound as a yellowish foam; 1 Hmr (CDCl 3): 2.20, 2.32 (2s, SAc) and 7.2-8.3 ppm (aromatic Hs); ir (fine) λmax: 3420 (OH), 1745 (y β-lactam, ester) and 1690 cm -1 (thioester), Rf 0.16 (ethyl acetate).

25 70902

Example 27 (1'R, 3S, 4R and 1'S, 3R, 4S) “3- (1'-Hydroxy-2'-methoxymethoxy-1, -ethyl) -1- (p-nitrobenzyl-2" -triphenylphosphoranylidene -2 '' - acetate) -4-acetylthio-2-azetidinone.

5 (Isomer C)

OH? H

H0>. J. ^ SAc. Λν / ··, __> »SAc j nr -,!. 7oc, h'dimet ^ ylaniline ^ 1 | 10 <Λ -!, - γΓί3 C "2C12 0« ί- «γΡ * 3

CO ^ PfiB CO ^ MB

To a solution of (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1 ', 21-di-15-hydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4-acetylthio-2-azetidinone (Isomer C) (291 mg, 0.430 mmol; purity 97.3%) and bromomethyl methyl ether (55.2 mg, 0.442 mmol; 4 drops) in CH 2 Cl 2 (8 mL ), N, N'-dimethylaniline (58.8 mg, 0.483 mmol / 20 drops; 5 drops) was added at 0 ° C and the mixture was stirred at room temperature for 20 h. An exporter of bromomethyl methyl ether (2 drops) and M, N'- dimethylaniline (2 drops), and the mixture was stirred for an additional 4 h. The mixture diluted with CH 2 Cl 2 was washed successively with 1-norm. HCl, saturated NaHCO 3 and brine, dried (Na 2 O 4) and evaporated to dryness. The crude residue was purified by hplc (SiO 2, eluent ethyl acetate) to give the title compound as an oil (31 mg, 0.186 mmol; 42.2% yield);

Rf 0.24 (ethyl acetate; m / z (CDCl 3) i ': 2.20, 2.32 (2s, SAc), 3.30 (s, OCH 2), 4.52 (s, OCH 2 O-) and 7, 4-8.3 ppm (m, aromatic-Hs); ir (fine) t / MaRg: 3420 (OH), 1755 (br, 3-lactam and ester) and 1690 cm-1 (thioester).

Example 78 40 70902 (1'S, 3S, 4R and 1'RjSRjUSJ-S-d'-dihydroxyethyl) -1- (p-nitrobenzyl-2 "-trophenylphosphoranylidene-2" -acetate) -4- acetylthio-2-azetidinone (Isomer B) 5 *

OH

10 r ~ f TV! I '- ^ - ► nJ-l .ρφ

b2Ptm c02Pt, B

The title compound was prepared as described in Example 15 for "Isomer C" (4'S, 3S, 4R, and 4'R, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3 ' -dioxolan-4'-yl) -1- (p-nitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (Isomer B) (1.03 g, 1.47 mmol); yield 970 mg, 1.47 mol, 100%; yellowish foam; 20 1

Hmr (CDCl 3) δ: 2.20, 2.32 (2s, -SAc) and 7.3-8.2 ppm (m, aromatic Hs); ir (fine) ^. : 3410 (OH), 1750 (β-lactam, · · rnci K S / ester) and 1590 cm-1 (thioester): Rf 0.16 (EtOAc).

70902 41

Example t1'S, 3S, 4R and 1'R, 3R, 4S) -3- (11-hydroxy-21-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2 " acetate) -4-acetylthio-2-azetidinone (Isomer E) 5 h

is ° H

^ 3ΛΟ '' O

'J | BrCH 2 -dimethylaniline (

10 o ^ ~ U '^ P'P3 cn2ci2 ”cT

co2pVib <-0

The title compound was prepared as described in Example 36 for "Isomer C" (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1 ', 2'-dihydroxyethyl) -1- (p -nitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (Isomer B) (485 mg, 0.736 mmol); yield 205 mg, 0.292 mmol, 39.6%; oil; m / m (CDCl 3) δ: 2.22, 2.33 (2s, SAc), 3.32 δ (s, OCH 3), 4.57 (Sj-OCHgO-) and 7.2-8.3 ppm (aromatic Hs) and (fine) λmax: 3420 (OH), 1755 (γ-lactam, ester) and 169Q (thioester) Rf 0.32 (EtOAc).

Use of compounds of the invention as intermediates Example I

6-acetoxymethyl-2-methylpenem-3-carboxylic acid SAc v-w e

Aco ^ 'v] r __> acikn — j' \ 30 L H-C.P («3 C ° 2PNB co0pnb 6 1 2

A solution of crude compound 6 (1.20 g; 1.79 mmol) in toluene (15 mL) was boiled for 5 h. It was cooled to 35 and evaporated to dryness to give an oil which was chromatographed on SiO 2 (30 g). and eluted with Bent fungus to give 0.4 g of compound 7 (57%). Anal. Calcd for C 18 H 16 N 2 O 7 S: C, 52.04; H 4.11; N 7.14; Found: C, 51.77; H 4.08; N 7.30.

Separation of the cis and trans isomers was performed by careful chromatography on silica gel (60 g) eluting with benzene. cis-isomer: δ (ppm, CDCl 3): 7.5-8.5 (4H, aromatic), 5.67 (1H, d, J = 5, H-5), 5.28 (2H, AB quartet, benzyl), 4.33 (2H, d, AcOCH 2), 4.20 (1H, dt, 10H-6), 2.31 (3H, s, CH 2), 2.0 (3H, s, CH 2 CO 2). yv 1770, 1740, 1730 cm-1. Trans-isomer: ε (ppm, CDCl 3): 7.5-8.5 (4H, aromatic), 5.53 (1H, d, J = 2, H-5) , 5.30 (2H, AB quartet, benzyl), 4.32 (2H, d, AcOCH 2), 4.27 (1H, dt, J = S, J - 2, H-6), 2.31 (3H , s, CH 3), 2.0 (3H, s, CH 3 CO). 1770, 1740, 1730 cm -1.

g

Aco ^ r — r V CH3 Il2Pd / C Accr "Y-r s __ ^ NaHLO3 ^ \ —tl // CH3 20 ^ C0;; PNB ° \ 2 C0„ Na 1 8

To a solution of trans-7 (119 mg; 0.3 mmol) in ethyl acetate (15 mL) and water (7 mL) was added 25 NaHCO 3 (25.2 mg, 0.3 mmol) and Pd / C (110 mg) and this was hydrogenated at 30 psi for 4.5 h. The mixture was filtered and the layers were separated. The aqueous layer was washed with ether and lyophilized to give 40 mg of solid 8 (48%). Λ max = 1765, 1740, 1600 cm -1. (Ppm, D 2 O): 5.52 (1H, H-5 ), 4.85 (2H, AcOCH 2), 4.0 (1H, H-6), 2.65 (3H, CH 2), 2.40 (3H, CH 3 CO).

s __ ^ S

Αοθ '' 'Λ'Ί r 5 ^ ™ .. Ac ° I /) - CHg J-N »/ ^ 3 - *

35 \ \ 0H

C09Na LJ2i1 8 11 70902 43

Example II

2-methylpenem-3-p-nitrobenzyl carboxylate ^ 5COX- Λ, -r "'S v 5 n>. □ /) - 013 / ΝγΜ3 ° / κ ^ nco? ™ b

C0, PNB

Phosphorane 2 (75 mg, 0.126 mmol) was boiled in toluene (10 cm) for 2.5 hours under a nitrogen atmosphere. Evaporation of the solvent and purification of the residue gave a crystalline derivative (25 mg, 63%) whose physical and spectral values were in complete agreement with the values of the title product.

Example III

2- (4'-Phthalimido-1'-butyl) penem-3-carboxylic acid 20 n JL 9 1-6 δ Uyy 25 2 2 '-' 1 -Solution with phosphorane 7 (5.0 g , 6.4 mmol) in toluene (35 ml) was boiled at 3 H. Evaporation of the solvent gave a residue which was passed through a silica gel (100 g) column. Elution with benzene followed by ether gave 600 mg of ester 8 as an oil, i.r. (fine 1790, 1710, 1520 cm-1, nmr (CDCl 3) 8.22 (2H, d, J = 9Hz), 7.82 (4H, d, J = 2Hz), 7.65 (2H, d, J = 9Hz), 5.69 (1H, dd, Jcis = 4Hz,

Jtrans = 2Hz) '5'35 (2H' 2s) '4'12 (1H' dd 'Jgem = 16Hz> Jcis = 35 4Hz), 3.50 (1H, dd, Jgem = 16Hz, Jtrans = 2Hz), 3 , 1-3.8 (2H, m), 2.5-3.0 (2H, m), 1.4-2.0 (4H, m).

t * 70902 o rrs— '~ ϋο). rr € Θ J-H-V / -> y) ^ - X '0 cr \ / - \ o \ 5 XC0? CH? - \ O / -no2 co? h 8 9

A biphasic mixture of ester 8 (196 mg, 0.39 mmol) in ether (2 mL), tetrahydrofuran 10 (4 mL) and sodium bicarbonate (32 mg, 0.39 mmol) in water (2 mL) was hydrogenated 30% with palladium / diatomaceous earth (190 mg) on a Parr shaker at 40 psi Hj, after 4.5 hours it was filtered through a pad of Celite and the pad was washed with water and tetrahydrofuran. The filtrate and washings were combined and the organic phase was separated. The aqueous solution was washed with ether, acidified to 1-norm. HCl (3 x 0.4 mL) and extracted (after each addition of acid) with ethyl acetate (4 x 2 mL). The organic extracts were washed with brine, dried over MgSO 4, and the solvent removed by evaporation to dryness to give 9.67 mg (47%) of the acid as a yellow solid, i.r. (nujoli) 1775, 1705, 1 696 cm -1.

n.m.r. (DMSO), δ $ 7.92 (4H, s), 5.71 (1H, dd, Jcig-4Hz, Jtrans = 2Hz), 3.90 (1H, dd, Jgejj) = 16 Hz, Jcis = 4Hz ), 3.47 (1H, dd 'Jgem = 16 Hz' Jtrans = 2Hz) »3» 3-4.3 (3H, m), 2.7 - 3.05 (2H, m), 1.5 - 2.0 (4 H, m).

Example IV

Sodium 2- (acetonylmethyloxime) -penem-3-carboxylate 3 0 N ~~~ 0CH3 SCOCH2-C-CH3 __ ^ - SN— OCH ^ -r / \ I "0 I ^ _zi ——> 1 σι ..- c-cHo | Pd.,. - - N --- ^ 2 3 | -N 3 toluene 0-,.

& | X co2pnb

C0oPNB

35 2 3 and 45 70 9 O 2

Phosphorane 5 (700 mg, 1.05 mmol) was boiled in toluene for 4.5 h. Evaporation of toluene gave a residue which was passed through a silica gel (1:15) column (4% ether-benzene). There was thus obtained compound 5 as a crystalline substance (251 mg, 62%, m.p. 116-125 °).

Analysis calculated for C 18 H 18 N 3 O 3 S: C, 52.17; H 4.38; N 10.74; Found: C, 51.15; H 4.18; N 10.33.

Ε (ppm, CDCl 3) 7.70 (2H, d, Hm aromatic) 7.12 (2H, d, 10 Ho aromatic), 5.00 (2H, s, CH 2 PNN), 4.85 (1H, m, H -5), 3.75-2.70 (7H, m, CH 2 O, CH 2, H-6), 1.77, 1.72, 1.65 (3H, s, CH 3) CHCl 3) 1787> 17 ^ 2, 1705, y? NO 1530.

U.V. (EtOH) max 318 (<f = 8420), 262 (E = 12.539).

15 .o N - OCH ,, _S! J "^ 3

Γ \ ch -C-CH --- y — CH -C-CH

jJj //? 13 NaHCO 3 -N-N 6 -N-CO 2, Na co 2 pnb 1 6 7 20 A mixture of ester 6 (151 mg, 0.386 mmol) in THF (20 cm 3), ether (40 cm 3) and NaHCO 3 (32 mg, 0.381 mmol) in water (20 cm) was shaken on a Parr hydrogenator for 3 h at 35 psi H 2 using a 30 Iris Pd / Celite catalyst (200 mg) as a catalyst. The resulting aqueous mixture 3 was washed with ether (3 x 60 cm) and lyophilized (32 mg, 30%)., ζ (ppm, DMSO) 5.50 (m, H-5), 3.75 (s, OCH, ), 0.77 (s, CH 2).> Pc-o (nu y rate 1770, 1600, 1400. UV (H 2 O 2 makn 300 (£ = 2,800), 255 (£ = 2.400) 3 0 Example V - : - ^ m

I V ^ N-P (0 - O

X CO2H

rr’Y'- "" - '"I— * <Γ'V“ · __. s, „5 co9pnb I - P (o-o2

v o ^ ~ H

VI co2pnb 1.6 70902

A solution of V (1.6 g, 2.06 mmol) in toluene (60 mL) was heated at reflux for 5 h.

The solvent was evaporated in vacuo and the residual oil was chromatographed on a silica gel column (30 g). Eluting with benzene and then ether, the non-polar material was removed first and then eluted with ethyl acetate to give VI, 620 mg (62%) as a white solid, m.p. 83-4 ° C crystallized from ether.

IR (CHCl 3) 1790, 1710 cm -1. NMR: (CDCl 3) t (8.2 (2H, d, J = 9Hz), δ 7.6 (2H, d, J = 9Hz) 7.5 (2H, s), 5.65 (1H, dd, J = 4Hz,

Jcis = 2Hz), 5.22 (2H, 2s), 4.75 (2H, dq, J = 12Hz, J = 6Hz), 3.85 (1H, dd, J = 15Hz, J = 2Hz) ), 3.5 (1H, dd, J = 15Hz,

Already. = 2H7), 2.8-8.3 (2H, m), 1.4 (6H, s), 1.28 (6H, s).

Clb ΛΛ 15 -r "" S \. , ς 0

^ - P (0— ^). 1-r 'M

«W -> - * co2pnb u nco? H

VI VII

To a solution of compound VI (2CO mg, 0.4 mmol) in tetrahydrofuran (8 mL) and ether (4 mL) was added sodium hydrogen carbonate (34 mg, 0.4 mmol), water (4 mL) and 30% Pd. / Celite catalyst (200 mg) was then hydrogenated at 40 psit for 2 h. The mixture was filtered and the layers were separated. After washing with methylene chloride (2 x 5 mL), the aqueous phase was cooled with ice, acidified to 1-norm. HCl (1 mL), and extracted with chloroform (5 x 5 mL). The organic extracts were dried (MgSO 4) and evaporated to dryness in vacuo to give compound VII, 76 mg (52%) as an oil. IR (CHCl 3) 1790, 1710 cm -1. NMR (CDCl 3) -S 9.5 (1H, ws), 5.65 (1H, dd, Jtrans = 1 + Hz, Jcis = 2Hz), 4.72 (2H , dq, J = 12Hz, J = 6Hz), 4.2-5.1 (2H, m), 3.4-4.1 (2H, m), 2.7-3.4 (2H, m) , 1.35 (6H, s), 1.25 (6H, s).

Example VI

35 I-r-S n & \ co2h 47 70902 | _ (OEt) 2 'Z -Δ' 0 ^ -ΝΎΦ3 5 CO.PNB _Sv ^ n

\ θ PNB

'1

Compound 3 (0, + + g, 0.52 mmol) was boiled in toluene (35 mL) for 4 h and evaporated to dryness to give an oil of 3, 4 and 03P = O. This was chromatographed on SiO 2 (10% 10%) and eluted with ethyl acetate to give 0.1 g of pure compound 4, followed by 0.15 g of compounds 3 and 4. NMR δ (ppm, CDCl 3). 8.3 (2H, d), 7.67 (2H, d), 5.7 (H, q), 5.33 (2H, d), 4.2 (4H, q), 3.83 (H , q), 3.4 (H, q), 2.9 (2H, m), 1.9 (2H, m), 1.3 (6H, t), IR (fine) δ 1790 cm -1 (/ 5-lactam) 1710 cm -1 (ester).

j— (pEt) 2 ___— v 25 0 ^ "co PNB —f — s \ / s. / Nji?> 2 | p (OEt) 2 ~ ° co2h 5 30

A mixture of compound 4 (0.1 g, 0.207 mmol).

30% Pd / Celite catalyst (0.1 g) and NaHCO 3 (17 mg, 0.207 mmol) in THF (10 mL), ether (5 mL) and water (5 mL) were hydrogenated for 2 h at initial pressure. 40 psi. The mixture was filtered using Celite and the layers were separated. The basic aqueous layer 48 70902 was washed well with ethyl acetate and acidified to 1-norm. HCl. Extracted with CH 2 Cl 2 and dried (MgSO 4). The CH 2 Cl 2 solution was evaporated to dryness to give 48 mg of compound 5, (66.5%). IR spectrum ε 1790 (β-lactam) 50 1700 (-C-OH).

Example VII

0 _S P (0Me) „CK \ CO2Na 0 0 n, S \ P <OMe) 2 ^ ^ ^ P (OMe) 2 15 xx i toiiiee - v> \ Ay ^

3 I U 4 C09PNB

co2pnb

Compound 3 (0.5 g, 0.69 mol) was boiled in toluene (30 mL) for 4 h. It was evaporated to dryness, chromatographed on SiO 2 (3% H 2 O) and eluted with ET 2 O: EtOAc (1: 1). ) followed by EtOAC-ID% EtOH to give 0.18 g of compound 4 (58%). NMR δ (ppm, CDCl 3), 8.25 (2H, d), 7.6 (2H, d), 5.65 (H, q), 5.3 (2H, d), 3.8 ( 3H, s) 3.6 (3H, s), 2.7-3.6 (2H, m), 1.5-2.5 (4H, m).

0 I-P (0Me} 2 30% Pd / Celite ^ 30> - N ^ .7 NaHCO2;

M

u ___S ^ P (0Me) o - n v 35 ° \ o Ma C * 49 70902

A mixture of compound 4 (50 mg, 0.112 mmol), NaHCO 3 (9.125 mg) and 30% Pd / Celite catalyst (50 mg) in THF (5 mL), Et 2 O (2.5 mL) and water (2.5 mL) was hydrated at an initial pressure of 40 psi (2 hours). The mixture was filtered using Celite and the layers were separated. The basic aqueous layer was washed well with ethyl acetate and freeze-dried under high vacuum to give 28 mg of compound 5 (75.9%) (hygroscopic). IR (KBr) 1770 cm-1 (O-lactam), 1610 cm-1 (-C00-).

10 Example VIII

(1'R, 5R, 6R and 1'S, 5S, 6S) -Potassium and sodium 6- (1'-hydroxyethyl) -2-methylpenem-3-carboxylate

15 0C0oPNB

oco2pnb r 2 ^ ^ Ac toluene j Γ "" \ TC »,

(f "CO2PNB

20 CO2PNB

A solution of the above acetylthioacetidinone (74 mg, 0.09 mmol) in toluene (30 mL) was heated at reflux under N 2 for 7 h. After evaporation of the solvent, the residue was purified by H 2 Cl 2 (SiO 2; eluent: Bent). fungus: ether = 3: 1) to give 24 mg (0.044 mmol, 49% yield) of the penem ester as a syrup. (Note: this oil could be crystallized from THF-ether or CH2Cl-ether): BHmr (CDCl3) ^: 1.40 (3H, d, J = 6.5 Hz, 1'-CH3), 2.38 ( 3H, s, 2-CH 2), 4.07 (1H, dd, J & 6 = 4Hz, Jg 1 = 4Hz, Jg 1 = 9Hz, 6-H), 5.05-5.30-5.34-5 .59 (2H, AB type, 3-CO 2 CH 2 -Ar), 5.30 (2H, s, 1'-CO 2 -CH 2 -Ar), 5.1-5.6 (1H, m, 1'-H ), 5.68 (1H, d, Jg g = 4Hz, 5-H), 7.49-35 7.64-8.18-8.33 (4H, Aj'B ^, aromatic Hs), 7, 53-7.68-8.18- 50 70902 8.33 (UH, A2 ', B2' »3-aromatic Hs); ir (fine) Ymax: 1/80 (β-lactam), 1750 (-CO 2>, 1710 (ester), 1520 and 1350 cm-c 2).

.5 OH

oco2pnb f s AVv vpd-ceiite_. "o"> «, ether-H 2 O o 'CO_PHB 2 10 2

A solution of the above penem ester (24 mg, 0.044 mmol) in THF (5 mL) was stirred with ether, (10 mL), H 2 O (5 mL), phosphate buffer (1.00 mL, 0.05 mL). mol., pH 7.00: 15 Fisher) and 30% Pd-Celite catalyst (50 mg, Engelhard). This mixture was hydrogenated at 35 psi for 21.5 hours at room temperature. After removal of the catalyst (Celite), the aqueous layer was separated, washed with ether and lyophilized to give 12 mg of a mixture of the title sodium and potassium salts as a white powder: 1 Hmr (D 2 O 2: 1.2 3 (3H, d, J = 6Hz, 1'-CH 3 ), 2.27 (3H, s, 2-CH 3), 3.85 (1H, dd, J 8 β = 4Ηζ, Jg ^ ΘΗζ, 6-H), 4.3 (1H, m, 1 * - H) and 5.65 ppm (1H, d, * J5 6 = 4Hz, '5-H); ir (nujol) λmax: 1755 (lactam) and 1570 cm-1 (-CO2); uv ( H 2 O) jipmyg1 297 (C 2300, calc. K-salt), 258 (£ 1900, calc. K-salt) This substance was identical to the title compound prepared by aldol condensation of acetaldehyde using 2-methylpenem. Dianonone of 3-carboxylic acid (1Hmr, ir, uv).

Example IX

(1'S, 5R, 6S and 1'R, 5S, 6R) β-Trimethylsilylethyl 6- (1'-30-acetoxy-1'-ethyl) -2-methylpenem-3-carboxylate OAc

OAc I H H

I SAc Mp / M— J — N. , PPh3 ^ 0 Vq x ^^ SlWe3 3 5 0 ^ ^, 3. SlMe3 t02 • C0? "^ 5i 70902

A solution of the above phosphorane (150 mg, 0.23 mmol) in toluene (15 mL) was heated at reflux for 2 h. The solution was stirred with 1 g of silica gel and the solvent was evaporated in vacuo. The silica gel was applied to a 5 g aliquot of silica gel on a column (dry) and eluted with ether. The first 5 ml fraction (one spot of high Rf on a tlc plate) gave, by evaporation of the solvent, 65 mg (76%) of the title compound as a waxy solid. IR λ max: β-78 β (β-lactam), 1740 (ester) and 1700 cm -1 (OAc); 1 Hmr (CDCl 3) δ: (d, J = 2Hz, 1H, H-5), 5.4 (m, 1H, H-1 '), 4.3 (m, 2H, OCH 2), 3.90 (q, J = 2Hz, 4Hz, 4Hz, 1H, H-7), 2.37 (s, 3H, 2-CH 3), 2.11 (s, 3H, OAc), 1.42 (d, J = 6.5 Hz, 3H, 2'-CH 3), 1.1 (m, 2H, CH 2 Si) and 0.05 ppm (s, 9H, SiMe 3). The product was found to be a single isomer.

15 Example X

Paranitrobenzyl 6-formamidomethyl-2-methylpenem-3-carboxylate 20 ° SAc ° HO ^ "H ->« CM I |, ._ CH3 co2pnb co2pnb 25

A solution of trans-4-acetylthio-3-formamido-methyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone (450 mg, 0.686 mmol) in toluene (10 mL) was heated to reflux. hours. Evaporate to 30% dryness and purify on a silica gel column eluting with ether -> 10% methanol in ether to give 100 mg (39%) of the penem compound as an amorphous solid.

IR (CHd 3) y 2 max: 1780 0a 1690 cm -1; 1 Hmr (CDCl 3) δ ': 8.2 (2H, d, J = 9Hz), 8.2 (1H, s), 7.6 (2H, d, J = 9Hz), 6.9 (1H, m ), 35 5.55 (1H, s), 5.35 (2H, 2s), 3.3-4.1 (3H, m) and 2.33 ppm (3H, s).

70902

Example XI

6- (11-hydroxy-21-phenylethyl) -2-methylpenem-3-carboxylic acid (1'R, 5R, 6S and 1'S, 5S, 6R enantiomers) c h.

5 H-> 0H $ --v * c • ° Vr “- O ^ -Νγ ™ 3 0 \ o2? Nb

CO PNB

A solution of the above phosphopran (1.2 g, 1.67 mmol) in toluene (80 mL) was heated to reflux (10 mL was distilled off to remove moisture present and the low boiling solvent) for 6 hours. Evaporated to dryness and the crude product was chromatographed on Pigs. The title compound 15 was obtained by eluting the column with ether to give 0.65 g of an amorphous solid (89%). 1 Hmr (CDCl 3) δ: 8.2 (2H, d), 7.6 (2H, d), 5.4 (H, d), 5.2-5.4 (2H, d), 4.0 -4.5 (H, m), 3.7-4.0 (H, dd), 3.0 (2H, d), and 2.3 ppm (3H, s).

20

H OH

H '· ..> 0H <Κ "> ν

Jo ^ -Qh_CH5

"S 'cO H

co2pnb 1 30 A mixture of paranitrobenzyl ester (0.33 g, 0.75 mmol), 0.05 mol. buffer solution (pH 7, 17.4 ml), THF (30 ml),

Et 2 O (30 mL), distilled water (60 mL), and 30% Pd / Celite catalyst (0.69 g) were hydrogenated for 24 h at an initial pressure of 50 psi. The mixture was filtered through Celite and the organic layer was washed with water. The combined aqueous layer was washed several times with ethyl acetate and lyophilized for 18 h to give the title compound as a yellow solid salt. This was treated with 53 7 0 9 0 2 with a small amount of water, acidified with cold 1-norm.

HCl and extracted well with CHCl 3. The CHCl 3 solution was dried (MgSO 4) and evaporated to dryness to give a solid residue. This was treated with ether and filtered to give 30 mg of a white solid (13.2%), m.p. 165-167 ° C; IR (nujol) γ, max: 3580 (OH, sharp), 1660 and 1760 cm-1; uv (MeOH) -v. : 310 (£ .5490) and 254 (£ 4880).

J r> max J

Example XII

(4'R, 5R, 6S and 4'S, 4S, 6R) -6- (2 ', 2'-dimethyl-1,2,3'-10 dioxolan-4'-yl) -2-methylpenem-3-carboxylic acid 0 SAc qs ^ ί- * tolup.p.ni - Γ \ 0 I o \

ΟΟ ,, ΓΝΒ C02PNB

A suspension of (4'R, 3S, 4R and 41S, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan-41-yl) -1- (p- nitrobenzyl-20 '- 2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (Isomer C) (443 mg, 0.634 mmol) in toluene (70 mL) was heated at reflux under N 2 for 6 h. Evaporation of the solvent gave a white solid which was purified by column chromatography (SiO 2 10g; eluent 10% Et 2 O in benzene) to give 247 mg (0.587 mmol, 92.7% yield) of the title compound as a white solid: 1 Hmr (CDCl 3). ^ ': 1.42 (6H, s, di-Me), 2.38 (3H, s, 2-CH 2), 3.8-4.5 (4H, m, H-6, H-4 · and H-5 '), 5.02-5.25-5.33-5.57 (2H, AR type, -OCH 2 AR), 5.57 (1H, d, 30 J = 1.8 Hz, H-5 ) and 7.52-7.67-8.12-8.27 ppm (4H, A 2 B 2, aromatic H 5); IR (nujol) β 2: 1760 (β-lactam) and 1700 cm -1 (ester). An analytical sample was obtained by crystallization from CH 2 Cl 2 -Et 2 O: m.p. 167-168 ° C, uv (EtOH) δ max: 265 (£ 14,000) and 314 nyu (£ 10,000).

Analysis calculated for C 19 H 20 N 2 O 7 S: C, 54.28; H 4.79; N 6.66; S 7.63; Found: C, 54.15; H 4.78; N 6.54; S 7.65;

Rf 0.62 (benzene-Et 2 O = 1: 1).

54 70902 Ö ^ Q - / - ¾ H./Pd-Cl ^, —r “S \ nu ΓΓ / 3 r> J-L / 3 (T \ ° \ C02PNB co2h

Solution of (4'R, 5R, 6S and 4'S, 5S, 6R) -nitrobenzyl-6- (2 ', 21-dimethyl-1', 3'-dioxolan-4-yl) -2 methyl penem-3-carboxylate (Isomer C) (195 mg, 0.454 mmol) in THF (20 mL) was stirred in Et 2 O (20 mL), H 2 O (20 mL), NaHCO 3 (39 mg, 0 mL). , 45 mmol) and 10% Pd / C catalyst (200 mg, Engelhard). This mixture was hydrogenated at 35 psi for 4 h at room temperature. After removal of the catalyst (using Celite) the aqueous layer was washed with ethyl acetate (2 times), saturated with NaCl, acidified to 1-norm.

HCl (0.47 mL) and immediately extracted with ethyl acetate (3 x 20 mL). The brine washed extracts were dried (Na 2 SO 4) and evaporated to dryness to give 94 mg of a yellowish solid which was rinsed with pentane to give 89 mg (0.31 mmol, 67% yield) of the title compound as a yellowish solid: m.p. 132-133 ° C; Rf 0.60 (acetone: HOAc = 5: 0.7); 1 Hmr (CDCl 3) δ: 1.37, 1.43 (6H, 2s, di-Me), 2.36 (3H, s, 2-CH 2), 3.9-4.6 (4H, m, H- 6, H-4 · and H-5 T) and 5.59 ppm (1H, d, J = 1.7 Hz, H-5); IR (nujol) δ max: 1760 (β-lactam) and 1660 cm -1 (CO 2 H); uv (EtOH) max: 309-6,300) and 263 m / u (13800).

Example XIII

(1 * R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxy-2'-methoxymethoxy-21-ethyl) -2-methylpenem-3-carboxylic acid 30 T. SAc f I I toluene ^ | ^ S \ _ / "f3 Δ"

> υ C0 „PNB

35 C02PNB t 55 7 0 9 0 2

A solution of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-hydroxy-2'-methoxymethoxy-1 * -ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene -2 "-acetate) -4-acetylthio-2-azetidinone (Isomer C) (167 mg, 0.238 mmol) in toluene (30 mL) was heated at reflux under N 2 for 8 h. Evaporation of the solvent in vacuo gave an oily residue. which was purified by hplc (SiO 2, eluent ethyl acetate) to give 68 mg (0.16 mmol, 67% yield) of the title compound as an oil; Rf 0.61 (ethyl acetate), 0.15 (benzene: Et 2 O = 1: 1); 1 Hmr (CDCl 3) δ: 2.38 (3H, s, 2-CH 3), 3.35 (1H, br, OH), 3.40 (3H, s, OCH 3), 3.6-3.8 ( 2H, m, H-2 »), 3.90 (1H, dd, Jg_5 = 2Hz, Jg_lf = 4Hz, H-6), 4.18 (1H, m, H-11), 4.67 (2H, s, -OCH 2 O-), 5.03-5.27-5.38-5.62 (2H, ABq, OCH 2 Ar), 5.65 (1H, d, J = 2Hz, H-5) and 7.55 -7.70-8.15-8.30 ppm (4H, A2, B2, aromatic H5); IR (fine) ν: 3450 (OH), 1785 (β-lactam), 1710 (ester) and 1520 cm -1 (NO 2); uv (EtOH) ft max ‘266 13000) and 313 ny u (£ * 9100).

Analysis calculated for C 18 H 28 N 2 O 8 S: C, 50.94; H 4.75; N 6.60; Found: C, 51.13; H 4.77; N 6.36.

OH? H

Nco2PNB xco2h

A solution of (1, R, 5R, 6S and 1'S, 5S, 6R) -p-nitro-benzyl-6- (1'-hydroxy-2'-methoxymethoxy-2 * -ethyl) -2-30 methylpenem- 3-Carboxylate (Isomer C) (51 mg, 0.12 mmol) in THF (10 mL) was stirred in Et 2 O (10 mL), H 2 O (10 mL), NaHCO 3 (10 mg, 0 mL). 12 moles) and 10% Pd / C catalyst (50 mg, Engelhard). It was hydrogenated at room temperature at 32 psi for 3 h. After filtering off Catalyst 35 using Celite, the separated aqueous layer was washed with Et 2 O (3 times) and saturated with NaCl. The aqueous phase, which was acidified at 0 ° C with 0.1-norm. HCl .. e 70902 (1.2 mL) was immediately extracted with ethyl acetate (3 x 15 mL). The extracts were washed with brine, dried (Na 9 SO 4) and evaporated to dryness to give 22 mg of a yellowish solid which was rinsed with a small amount of Et 2 O to give 20 mg (0.069 mmol; 58% yield) of the title compound as a slightly yellow solid; 1 Hmr (DMSO-d 6), δ: 2.28 (3H, s, 2-CH 2), 3.27 (3H, s, OCH 9), 3.49 (2H, d, J = 6.2 Hz, 2 1 -H), 3.87 (1H, dd, J 8 = 1.7 Hz, J 1 = 3.3 Hz, 6-H), 4.58 (2H, s, -OCH 2 O-) and 5.55 ppm (1H, d, J = 1.7 Hz, 5-H); IR (KBr) ^ 'maky: 31 <1ϋ (CH)>

1755 (β-lact Aarn) and 1655 cm -1 (CO 2 H); uv (EtOH) ^ · 30B

(£ 6,800) and 262 nyu (£ 4,200), m.p. 137-8 ° C (dec.).

Claims (2)

57 7 0 9 0 2 1. A 4-thio-2-azetidinone derivative useful as an intermediate in the preparation of antibacterial penem derivatives of the formula Y N_ 10 \ CO 2z wherein Z is hydrogen or an ester-forming group, X is methyl, phthalimidobutyl, CH 2 C ( CH3) = NOCH3 or (CH2> nPO (OR) 2, where n is 2 or 3 and R is lower alkyl and Y is hydrogen, lower alkyl substituted by acetoxy or hydroxy; HCONHCH2, C8H5CH2CH (OH), CH3OCH2OCH2CH (OH) or 2,2-dimethyl-1,3-dioxolan-4-yl, provided that X is not methyl when Y and Z represent hydrogen, characterized in that it has the formula 20 O SCX ' / - Νγίρ (°> 3 CO 2 Z 'wherein Z * is an ester forming group, Q is phenyl, X' is methyl, phthalimidobutyl, CH 2 C (CH 3) = NOCH 3 or (CH 2) n PO (OR) 2, where n is 2 or 3 and R is lower alkyl, and Y 'is hydrogen, lower alkyl substituted with Acetoxy, hydroxy or protected hydroxy; HCONHCH 2, C 9 H 9 CH 2 CH (OH), where the hydroxy group may be protected, or 2,2-dimethyl-1,3-dioxolan-4-yl, provided that X 'is not methyl when Y' is hydrogen. 4-Thio-2-azetidinone derivative according to Claim 1, characterized in that Y 'is hydrogen or hydroxyethyl.