FI70716C - METALLMERKAPTID SOM AER ANVAENDBAR SOM MELLANPRODUKT VID FRAMSTAELLNING AV 4-TIO-2-AZETIDINONDERIVAT - Google Patents

Description

1 70716 Metal mercaptide useful as an intermediate in the preparation of 4-thio-2-azetidinone derivatives

Divided by application 793 903 5

The invention relates to a metal mercaptide having the formula! Y -S - Y SHgC00CH3 10; γγ "ti ^ ---- N P (Q) j M or J______N P (Q) i 0 '3! O"' 3

! I i I

; co „z. co ~ z L · Δ J t l III Ula 15 0

II

wherein Y is hydrogen, IICNHCl ·, -, 2,2-dimethyl-1,3-dioxolan-4-yl or lower alkyl which may be substituted by hydroxy, protected hydroxy, azido or phenyl, Q is phenyl, Z is an ester-forming group, t is 1 or 2 and M is Cu (II), Pb (II) or Hg (II) when t is 2, or Ag (I) when t is 1.

The metal mercaptides of formulas III and IIIa are useful as intermediates in the preparation of 4-thio-25 2-azetidinone derivatives of formula 0

Y S-C-X

X_____ 30 0J— "γ" "» co2z where Y, Q and Z are as defined above and X is 35 methyl where m is 1-4, phthalimidobutyl, 2,70716 (OR) -PO (CH-) -, where n is 2 or 3 and R is lower alkyl, 6 ^ n N3- <0 ^ or \ CH2 -] - ~ -CH2 · ~ 'N 1 = 0 5 ^ 0 ^

The compounds of the formula IV can be used as intermediates in the preparation of the antibacterial 2-substituted and 2,6-di-10-substituted penem compounds described in FI publication 67853.

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 Kemi-15 reactions and which, if desired, can be subsequently removed by conventional methods to obtain the free carboxylic acid. Known ester protecting groups include 2,2,2-trichloroethyl, 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-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benz-25-hydryl, trityl, trimethylsilyl, triethylsilyl, β-trimethylsilylethyl, and the like element.

The preferred ester-forming group is p-nitrobenzyl, which can be easily removed by catalytic hydrogenation. Another preferred ester-forming group is β-trimethylsilylethyl, which can be removed by treatment with fluoride ions. Easily removable ester-forming groups are also those known in the art of penicillin and cephalosporin chemistry to readily cleave in the body to parent acid.

Il 3 70716

Examples of such physiologically cleavable groups are indanyl, thalidyl, methoxymethyl, glyclyloxymethyl, phenylglyloxymethyl, thienylglyloxymethyl or acyloxymethyl of formula 5

O

M

-CH 2 C-Y '10 wherein Y' is C 1 -C 4 alkyl or phenyl. Particularly preferred groups of this type are methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

Preferred compounds of formula III or IIIa are those wherein Y is hydrogen or lower alkyl substituted with N-hydroxy.

The following reaction schemes describe the preparation of the compounds of the invention and their use as intermediates in the preparation of the compounds of formula IV and of these the penem compounds described in FI-67853.

4,70716

Reaction scheme Ia Y, Ο

^ _ ^ OAc II

Y-CH = CH-OAc CSI Γ CU C-SNa

c -> 1 —-- X

.1— N pH 7 5 ^ O ^ Il Ίη Y ~ ^ V rSA c. Y-v 10 p ^ SAc _v.

I CHO T cnr1 ^ -n * m soci ^

O CO2Z 0> -N \ ^ ° H

co9z 15 V | -rSAC 5Ac

'3 v, i MA

, _ to η GJMclG "^ o" V ^ - 1 „^ L \ ^ P03

20 | J

C02Z CO „Z

y * v ° 9 25 ΠΓ X-C- ©, I-Γ Δ 0 ^ ~ 3 O- ^ L-N \ f ^ p03 C02Z C022

III, Ilia IV

30 v x '"H ..

- ^ 1 \ -x ^ -V Group 7 I // O \ ixDist.o,} - N /

35 CO2z O

CO 2 H

O

Il _ X-C- o = acylinyl: iaiiio MA = rarjasmetallic.uola 5 7071 6

Reaction scheme 1b - ^ OAc / CSNa 5 Y-CH = CH-OAc CSI. | 3 4— N Pfi 1.5

0 ^ H

.0 y -, y ^ -1-rSC03 -> \ -rSCi53 -> CHO I soci2 NH ο ^ “Νγ-ΟΗ CO-, Ζ .5 \ -rSC03 P0-, ^ ~ r — f'SCC53 ma, 0 JN Cl ^ JN ^ P03 «^ s Ο o C02z CC9z 0 Yv 0 V Ί -5 SM N _ SC - X a

^ -Χ --- ^ Θ> “T -U

O ^ N P 0 3 ^ N P 0 3

υ O I

co_, z co0z * · L ·.

iO III, Ilia IV

Y ^ -v_ C Y

I - \ _ x ^ __ • // __ 7 \ x y) -N Z group I // 35 q poioto /? - N - CO.Z O \

1 CO H

6 70716

According to the procedure described in Reaction Schemes Ia and Ib, the vinyl ester is converted to 4-acetoxy-2-azetidinone by cycloaddition reaction with chlorosulfonyl isocyanate (CSI) followed by reduction with an organic reducing agent such as sodium sulfyl. 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 performed in an aqueous reaction mixture containing water and 10 organic substances at a temperature of 0 ° or below and a slightly basic pH.

The resulting 4-acetoxy-2-azetidinone is converted to 4-acetylthio-2-azetidinone (Reaction Scheme Ia) or 4-tritylthio-2-azetidinone (Reaction Scheme Ib) upon nucleophilic displacement using thioacetic acid or triphenylmethyl mercaptan (or triphenylmethyl mercaptan, respectively). the sodium salt).

4-Thioazetidinone is then reacted at 20 ° C

t1 with the glyoxylate ester HC-CC 2 Z, where Z is as defined above or with a reactive oxo derivative such as a hydrate in an inert organic solvent (e.g. benzene, toluene, xylene or the like) and mainly at a higher temperature than normal (e.g. at 50 ° C - preferably at boiling temperature). When an ester hydrate is used, the water formed can be removed azeotropically or using a molecular needle. The hydroxy-30 ester product is formed as a mixture of epimers which can be purified by chromatography or used directly in the next step if desired.

Conversion of the hydroxy ester to the corresponding chloro ester is carried out in a reaction with a chlorination reagent, e.g. SOCl 2, 35 PCl 3, PCI .. or the like.

ό D

In a reaction in an inert organic solvent, e.g. tetrahydrofuran, diethyl ether, methylene chloride, dioxane or the like, in the presence or absence of a base, preferably an aliphatic tertiary amine (e.g. triethylamine) or a heterocyclic tertiary amine (e.g. 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 epimers which, if desired, can be purified in the next step before use.

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, dimethylformoxane, dimethylsulfoxide, dimethylsulfoxide, -phosphate, 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.

The phosphorane obtained is converted into a heavy metal mercaptide of the invention having the formula 8 70716

CIS

! CO_Z

i 2

- X

III

10 or Y SHgCOOCH3

j I

15 ° -N 2 P (Q, 3 CO 2 R ”

The formation of mercaptide is carried out by reacting phosphorane with a salt of Hg (II), Cu (II) or Ag (I) or (methoxycarbonyl marker (II) acetate in a methanol-lipoir solvent and an organic or inorganic 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 The anion (A) of the heavy metal salt may be any an anion which forms a soluble salt in the chosen solvent, e.g. NO 2, CH 2 COO, BF 2, F, ClO 2, NO 2 f CNO, etc. The mercaptide intermediate is then reacted with an acylating agent capable of coupling.

It 35 to this group X-C-, where X is the desired penem-2-substituent 9 70716 o o

Il II

substituent. The acylating agent (XC- +) may be an acid XC-OH or a reactive functional derivative thereof such as an acid halide (preferably an acid chloride), an acid azide, an acid anhydride, a mixed acid anhydride, an active ester, an active thioester, etc. The acylation is performed in an inert solvent. such as methylene chloride or ether such as dioxane, tetrahydrofuran or diethyl ether) and, when an acid derivative is used, an acid scavenger such as tri-lower alkylamine (e.g. triethylamine) or a tertiary organic base such as pyridine, collidine or 2,6- in the presence of 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, Ν'-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 the acylation is thermally cyclized to the penem compound as described in FI publication.

Reaction schemes Ha and Hb SC03 ^ SC03 25 ΓΊ _> n

0> - '' - E

Yv ^ _

30 * -¾ I

“^ ^ -N

base \ β deprotection <V ^ MA / einäs 35/7071 6 γ γ

Ν -_ ^ SC03 V

-Ns / 7 Νχ Ο Η Ο Β 5 CHO Ο Τ ιι co ζ x-c- Θ

ψ V

10 ο

"'I- | -SCZ> 3, _pSC-X

-N OH J-N

O

15 CO 2 Z

protection removal V 2 v

O

Y γ H

20 "V rsc03 Y v, _rsc -: <* —tVAyxl 0J — N \

o 0 \ H

co2z 25 P03 v j ”0

\ [C02Z

30 Υ "γ-γ = ε03 Y. SL

-Η \ ^ Ρ03 γ o ^ "N V5"

co9z I

1 CO z

35 Y

‘•• v SQC1- \ / V 2 I) 7071 6 11 o ςΜ Υ"

V_ SC-X

Ν \ ^ Ρ03 J-N C1 υ 0

5 C02Z C02Z

O

11 Λ Ρ0,. , x-c- Θ.? ψ o md s 1 ° o o

K J V V II

. ^ SL ~ X '-u_ ^ sc-x O - ^ - N ^ PO3 O ^ ~ N ^ PO3

15 C02Z C02Z

Δ Δ

V V

Y

\ r —- r / \ Y v 20 I Vx Γ Vx J— O \ o \

co2z CO Z

^ ^ group deletion Deletion of the Z group V ψ

YM r- Y

N — r "\ x v_ 3 ° i — 1" -— f J_N /

O '· Q

CO2H02H

3 5 B = rongas- i: yyp j n bog and group i2 7071 6

In Reaction Schemes Ha and lib, the azetidinone ring type is protected with a conventional easily removable protecting group such as triorganosilyl (e.g., trimethylsilyl or t-butyldimethylsilyl) methoxy-5-methyl, methoxyethoxymethyl, tetrahydropyranyl, or the like. Coupling 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 can be continued in two ways, depending on the stage at which the azedione is deprotected.

According to Reaction Scheme Ha, deprotection of the N-protected intermediate is accomplished by conventional methods (e.g.

Hydrolysis with acid), which is then converted to the 2,6-penem compound by formation of an ester, chlorination of the hydroxy ester, conversion of the chloroester to phosphorane, conversion of the chloroester to phosphorane, conversion of phosphorane to heavy metal mercaptide, acylation

20 O

Capsid with X-C - (+), thermally cyclizing the phosphorane to give 2.6 penem ester.

According to the reaction scheme Hb, the N-protected azetidinone is converted to a heavy metal mercaptide, the mercaptide is acylated at 25 ° C.

with the group X-C - (+), the N-protecting group is removed, the deprotected azetidinone is reacted with a Glyoxylate ester, chlorinated, the chloroester is reacted with phosphine to give phosphorus-30. the phosphorane is cyclized to give the penem ester.

The following examples illustrate the invention. All temperatures are in degrees Celsius. Some abbreviations have been used in the examples. Of these abbreviations, the meaning of which is not obvious is defined below.

13 7071 6 CSI chlorosulfonyl isocyanate tt i pet.ether petroleum ether b.p. boiling point n.m.r. nuclear magnetic resonance 5 h hour ether diethyl ether (unless otherwise stated)

Celite Jonns-Manville Products Corporation's diatomaceous earth trademark psi pounds per square inch L5 r.t. room temperature PNB p-nitrobenzyl m.p. melting point LAH 1 i t iumalum.iniumhydr idi.

n-BuLi n-butyllithium 2Q HIBK methyl isobutyl ketone

Et C 2 H 2 -

Tr -C (CrHr) _ G a 3

Me CH3-THF tetrahydrofuran 25 Ph phenyl DMF dimethylformamide TEA triethylamine PCBG p-nitrobenzylglyoxylate THP tetrahydropyranyl; 3Q TFA t ri f luorietic acid HMPT (or hexamethylphosphoric triamide HMPA)

EtOAc ethyl acetate DM30 dimethyl sulfoxide

Ac CH ^ CO- 35 Ms Cll3sn2 υΜΛΡ Ί-di me styliam inopyridi i n i

Pyr pyridine in LDA 1i thiium diisopropylamide 14 7071 6

Preparation of compounds of the invention

Example 1 1- (p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4-silver mercaptidyl) -2-azetidinone 5 ^ SAg οΌ'γ * ·

C02PNB

10 - STr OAc —j TrSH __ ^ - |

N NaOMe J— N

OH OH

15 1 2

The methanol (90 cm -1) suspension of triphenylmethyl mercaptan (13.8 g, 0.05 mol) was degassed by passing a stream of nitrogen through it for 0.5 hour. The mixture was cooled to 0 ° C and sodium hydride (2.4 g, 0.05 mol, 50% oil dispersion) was added portionwise. The resulting solution was stirred for 5 min. and 4-acetoxyazetidinone (7.7 g, 0.059 mol) dissolved in water (55 cm) was added rapidly. Precipitation of 4-triphenylmethyl-mercapto-azetidinone (2) occurred immediately. The mixture was stirred for 4 h at room temperature. The solid was filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution was washed with dilute HCl, water, aqueous sodium bicarbonate, water and brine and dried over MgSO 4 (89.8%, mp 146.5-147.5 ° C).

Anal. Calcd for C22H19N®®: C, 76.49; H, 5.54; N, 4.05; S, 9.28; Found: C, 76.54; H, 5.60, N, 4.00; S, 9.36.

<3 (ppm, CDCl 3) 7.60 - 7.10 (15H, m, H-trityl), 4.62 (1H, bs, NH), 4.40 (1H, dd, J 1 - = 3.0 , J, = 5, H-4), 3.24 35 UH, ddd, W1S.444c1, -5. H-3 ". 2.83 (1H, ddd, Jgem - 15, J3.4 trans = 3.0, J3.NH = 1.2, H-3) 0 c = o <CHCl3> 1760 '^ NH 3340 · tt is 7071 6

CHO

_ / STr CO, PNB „^ STr ^ STr ΓΤ - * - ΠΓ + pT ^ -H. J— N J3H J - N ^ on O H 0 0 5 co2pnb co2pnb 2 3

Hydrated p-nitrobenzylglyoxylate (4.54 g, 0.02 mol) and azetidinone 2 (6.90, 0.02 mol) were boiled in benzene using a Dean Stark condenser filled with a 3 A molecular sieve for 24 hours. I drive. Additional glyoxylate (2 x 454 mg, 2 mmol) was added with a boiling time of 18 h after each addition. The mixture was diluted with ether, washed with 5% aqueous HCl, water, 5% aqueous NaHCO 3, water and brine. Dried over MgSO 4 (12 g, quantitative). A small portion of the epimeric mixture (CH 2 Cl 2 -ether 6: 4) was separated on a silica gel plate. Isomer A.

Rf = 0.87, m.p. = 170.5 - 171.5 ° 20 £ (ppm, CDCl 3) 8.07 (2H, d, J = 9, Hm aromatic), 7.45 (part of d, Ho aromatic), 7.40- 7.00 (15H, m, trityl), 5.25 (2H, s, CH 2 PNB), 4.75 (1H, s, HCO), 4.37 (1H, dd, J 3 -4 trans 3 'J 3 -4 cis = 4 'H-3)' 2'83 (1H 'dd' V = 16 'J4-3 cis = 4, H-4), 2.10 (1H, dd, Jgem = 16, J4.3 trans = 3 , H-4), δ 1.42 (bs, OH). \ J (CHCl 3) 1770, 1760 (shoulder), V N0 1525, V oh 3475 · C 2

Isomer B:

Rf = 0.75, m.p. 152-153 ° (ppm, CDCl 3), 8.13 (2H, d, J = 9, Hm aromatic), 7.47 (2H, d, J = 9, Ho aromatic), 7.40-7 .00 (15H, m trityl), 5.30 (3H, S, CH 2 -PNB, HCO), 4.45 (1H, t, J = 3.5, H-4), 2.90 - 2.70 (2H, AB portion of ABX, H-4), 1.55 (bs, OH).

C = 0 (CHCl 3) 1767, 1755 (shoulder), J NQ ^ 1525, V QH 3500.

35 16 7071 6 STr .STr ΓΤ soci2 Π J-N, OH -y J-N. Cl pyridine 0 5 co2pnb co2pnb 3 4

To a cold (-15 °) solution of azetidinone 3 (12 g, 21.7 mmol) in THF (150 ° C, dried on molecular sieve) was added pyridine (1.9 g, 24.1 mmol, 1.94 cm 2) and 3 by dropwise addition of thionyl chloride (2.86 g, 24 mmol, 1.88 cm) under a nitrogen atmosphere. The mixture was stirred for 45 min. -15 ° C. The precipitate was filtered off and washed with benzene. Evaporation of the solvent gave a residue which was dissolved in benzene and treated with activated charcoal (11.7 g, 94%, crystallized from chloroform).

Δ (ppm, CDCl 3) 8.17 (2H, d, J = 8, Hm aromatic), 7.67-7.00 (17H, m, Ho aromatic, Tr-H), 5.80 (s, HC -Cl), 5.37, 5.33 (2s, HC-Cl, CH 2 -PNB), 4.81 (1H, m, H-4), 3.27-2.40 (2H, 20 m, H -3) (KBr film 1785, 1770 \? 1525.

c = o r N02 STr STr

1 I

J-N Cl --- J, -N -P0

2 ^ O 2,5-lutidine O

co2pnb co2pnb 4 5 30 A solution of chlorazetidinone 4 (11.6 g, 20.2 3 mmol) in THF (100 cm, distilled over LAH) was treated with triphenylphosphine (7.86 g, 30.0 mmol) and With 2,6-lutidine (2.36 g, 2.56 cm, 22.0 mmol). The mixture was boiled and washed with ether. The organic solution was washed with 2% aqueous HCl and 5% aqueous bicarbonate and dried over MgSO 4. Evaporation of the solvent gave a residue which was purified on a pad of silica gel (200 g). The desired phosphorane was eluted with 30, 40 and 50% ether-benzene (11.4 g, 70.4%, mp 201-202 °). Anal. Calcd for C 18 H 18 N 2 O 2 O 2 -SP: C, 73.57; H, 5.04; N, 3.50; S, 4.01; Found: C, 73.58; H, 4.91; N, 3.44; S, 3.87.

^ (CHCl) 1740, NT phosphorane (1620, 1610), ^ 1525.

U J INU / s 10 2 __STr S Ag

AgN03 I

N 2 -PO 3 pyridine '- N 2 PO 3

1 I

15 co2pnb co2pnb 5 6 4-Trityl mercaptoazetidinone 5 (1.6 g 2 mmol) 3 was dissolved in CH 2 Cl 2 (20 cm) and the solvent was rinsed off at 55-60 °. Phosphorane 5 at 55-60 ° was dissolved in preheated (55-60 °) methanol (32 cm 3).

Immediately after forming a methanol solution of compound 6, it was treated with a preheated (55-60 °) mixture of 0.15 mol. a solution of silver nitrate in methanol (16 cm, 1.2 eq.) and pyridine (174 mg, 178 μL, 2.2 mmol, 1.1 eq.). Immediately thereafter, the heating bath was removed. The mixture was stirred at room temperature for 2 h and at 0 ° C for 1 h. Silver mercaptide 6 was filtered off, washed twice with cold (0 °) methanol and three times with ether. (1.12 g, 84.5%, m.p .: 130-135 ° (dec.)).

JC = Q (CHCl 3) 1795, 1725 (shoulder), V phosphorane (1620, 1605), VNo 2 153 ° * 35 is 70 71 6

Example 2 1- (p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone 5 SCOCH- _SAg r ~ f K2CQ3.AgNQ3 ^ r ~ f

Me0H ^ o ^ N \ C = PPh3 I 3 I 3

10 COOPNB COOPNB

7 6

A solution of phosphorane 7 (1.796 g, 3.0 mmol) in chloroform (3 mL) was diluted with methanol (90 mL), cooled to 0 ° under a nitrogen atmosphere, and silver nitrate (0.51 g, 3.0 mmol) was added sequentially. ) and potassium carbonate (0.33 g, 2.4 mmol). The reaction mixture was stirred (protected from light) at 0 ° C for 15 min, after which the cooling bath was removed and stirring was continued for 3 h. The reaction mixture was cooled to -10 ° C, stirred for 1 h and filtered; the silver mercaptide was washed successively with cold methanol and ether; 1.91 g, m.p .: 138-145 ° C with decomposition, 96%. IR (nujol) cm -1: 1748, 1620 25 and 1605. An analytical sample was obtained by preparative TLC (ethyl acetate); mp: 140-5 ° C (dec.); Calculated for C 30 N 24 N 2 O 5 SPA 2: C, 54, 31; H, 3.65; N, 4.22; S, 4.83; Found C, 54.11; H, 3.48; N, 3.92; S, 4.62.

30 li 19 7071 6

Example 3 1- (p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone A. Use of aniline as base 5'SCOCH-_____SAg ^ Aniline, AgNO 2 | O 'xC = PPh MeOH ^ C = PPh I 3 I 3

1Q COOPNB COOPNB

7 6

A solution of phosphorane 7 (1.8 g, 3.0 mmol) in chloroform (4 mL) was diluted with methanol (90 mL), cooled to -15 ° C under nitrogen, and silver nitrate (0.56 mL) was added sequentially. g, 3.3 mmol) and aniline (1.5 mL, 16.5 mmol). The reaction mixture was stirred (protected from light) at -15 ° C for 0.5 h and then the cooling bath was removed and stirring was continued for 24 h. The reaction mixture was cooled to -10 ° C and stirred before filtration for 1 h; the silver mercaptide was washed successively with cold methanol and ether; 1.55 g, m.p. 114-115 ° C with decomposition; 77.9%. IR (Nujol) cm identical to the compound of Example 7.

Silver 1- (paranitrobenzyl-21-triphenylphosphoranyl-25-diene-21-acetate) -2-azetidinone-4-thiolate B. Use of 4-dimethylaminopyridine (DMAP) as base SCOCH, SAg X 3/30 -f AgNO 2 / DMAP 0 ^ - CH2Cl2 / CH3OH> J-

C02PNB C02PNB

35 20 7 0 71 6

A solution of the above S-acetylphosphorane (17.96 g, 30 mmol) in methanol and dichloromethane (1: 2, 450 mL) was purged with nitrogen (5-10 min) »cooled to 5 ° C: Silver nitrate (5.35 g, 31.5 mmol) and 4-dimethylaminopyridine (3.85 g, 31.5 mmol) were added sequentially, the ice bath was removed and the solution was boiled vigorously for 2 h and then stirred at room temperature for 1 h. The colored reaction mixture was treated with charcoal, filtered and evaporated to dryness, the residue was redissolved in mini-10 dichloromethane and added dropwise with stirring to cold methanol (300 ml), the precipitated silver salt was collected by filtration, washed with ether and dried at 18 g (91%); (CHCl 3): 1745 (β-lactam C = 0) and 1607 cm -1 (ester C = O).

15 SCOCH, „Π - ^ -» rx *

S — N. £ 0- DBU, MeOH ^ N

20 0 'f ° Y

C02PNB co2pnb

The above S-acetylphosphorane (36.0 g, 0.060 mol) was dissolved in methylene chloride (120 mL). The solvent was removed to give an oil. The resulting oily residue was dissolved in warm (35 ° C) methanol (240 mL) and treated rapidly with a solution of silver nitrate (10.68 g, 0.0628 mol) in methanol (420 mL). The resulting solution (or suspension) was stirred at room temperature for 5 min, cooled (in an ice bath) for 30 min, and a solution of DBU (8.96 mL, 0.060 mol) in methanol (20 mL) was added over 5 min. The mixture was stirred for 5 min. The solid was filtered off, washed once with cold (0 ° C) methanol and ether and dried in vacuo; 37.0 g (93%); 35 IR (nujol phase) λ max (c = °) 3a 16 °° cm -1 (phosphorane).

5 21 7071 6 D. Use of pyrrolidine as a base

Silver 1- (paranitrobenzyl 2'-triphenylphosphoranylidene-2 "-acetate) -2-azetidinone-4-thiolate ^ / SO2CH3 SAg

I— [Pyrrolidine ^ I

J — N AgNO> —N.

O ^ C = PPh, J 0 X> PPh, I 3 I 3

10 COOPNB COOPNB

To a cold (0 ° C) solution of 4-acetylthio-1-para-nitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone (0.60 g, 1.0 mmol) in CH 2 Cl 2 (2 mL) was added 15 MeOH (4 mL), a solution of AgNO 2 in MeOH (0.14 N, 7.86 mL, 1.1 mmol) and a solution of pyrrolidine (0.92 mL, 1 , 1 mmol) in MeOH (2 mL). The cooling bath was removed and the reaction mixture was stirred for 1.75 h, cooled to -10 ° C, stirred for 0.25 h and filtered. The solid was washed with cold 20 MeOH and dried in vacuo; 0.548 g, m.p. 115 ° C, 82.4%.

IR (nujol) νmax: 1755 (C = O) and 1600 cm-1 (aromatic).

Example 4

Mercury (II) - [2'-triphenylphosphoranylidene-2'-2,5-acetate] -2-azetidinone-4-thiolate (STr ^ S) 2Hg 2 Π Hg (OAc) 2 ^ L i 30 ^ -N ^ J— N pph .

0 C = PPh_ O 3

I I

C02PNB C02PNB

35

II

22 7071 6

A solution of Compound I (2.4 g, 3 mmol) in dichloromethane (15 mL) was cooled to 5 ° C and treated with a solution of mercuric acetate (0.525 g, 1.65 mmol) dissolved in methanol (15 mL). mL). After stirring at 5 ° C for 2 h, the solvent was evaporated and the residue was redissolved in dichloromethane and washed with cold water. After drying (MgSO 4) and treatment with charcoal, the organic solution was evaporated to dryness to give a foam which crystallized from triturate in ether. Yield: 1.73 g (91%). Sp. 123-127 ° C, IR (CHCl 3) 1745 cm -1 (β) (β-lactam), 1608 cm -1 (phenyl).

Example 5 Silver cis- and trans-3-ethyl-1- (p-nitrobenzyl-2'-triphenylphosphoranylidene-21-acetate) -2-azetidinone-4-thiolates

Solution of cis- and trans-3-ethyl-1- (p-nitrobenzyl-2'-phosphoranylidene-2'-acetate) -4-acetylthio-20 2-azetidinone (1.88 g, 3.0 mmol) in chloroform (4 mL) was diluted with methanol (90 mL), cooled to 0 °, and treated sequentially with finely ground silver nitrate (0.51 g, 3.0 mmol) and potassium carbonate (0.33 g, 2.4 mmol). The mixture was stirred vigorously for 15 min.

At 25 ° C, 3 h at room temperature and 1 h at -10 ° C. The precipitated silver mercaptide was collected by filtration, washed with methanol and ether and dried in vacuo. The title product was obtained as an off-white solid, m.p. 112-135 ° C with decomposition. C = 0 1750, 1620, 1605.

30 23 7071 6

Example 6

Silver cis- and trans-3-acetoxymethyl 1- (p-nitrobenzyl 2'-triphenylphosphoranylidene-2'-acetate) -2-acetidinin-4-thiolate.

5 Crude cis- and trans-3-acetoxymethyl-1- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidione (8.5 g, 10 mmol) was dissolved in hot methanol (55 g). -60 °). A hot solution of silver nitrate (2.04 g; 12 mmol) and pyridine (0.87 g, 11 mmol) in methanol (80 mL) was added. The mixture was allowed to cool to room temperature over 2 hours and stirred for a further 1 h at 0 ° C. The silver mercaptide was collected by filtration, washed with ice-cold methanol and then ether (5.7 g, 82%, with melt decomposition), ψ 1745, 1740, 1625 cm-1. 0 = 0

Example 7 (1 * S, 3R, 4R and 1'R, 3S, 4S) -Silver 3- (1'-methoxymethyl-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2 "-acetate) -2-azetidinone-4-thiolate (Isomer 20 A) OCH2OCH3 0CH2 ° CH3 I JL SAg __ yKry J- \ ^„ o / Vp «. / 3

25 / J CO2PNB

Silver 3- (1'-methoxymethyl-1'-ethyl) -1- (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -3-30 tritylthio-2-azetidinone (Isomer A) was prepared

yield as described for isomer C of the paranitrobenzyldioxycarbonyl derivative Yield 50%. IR

(fine) Λ: 1745 cm-1 (C = O).

max 7071 6 24

Example 8 <1'S, 3S, 4R and 1'R, 3R, 4S) -Silver-2- (1'-methoxy-methyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenyl-phosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate 5 (Isomer C) OCH 2 OCH-, OCIUOCHt,

XrfSTr _> rf J_N ΡΦ -N. ^ ΡΦ.

10 o * 0 3

CO PNB C02PNB

(1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methoxymethyloxy-15''-ethyl) -1-1 (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4 -tritylthio-2-azetidinone (887 mg, 1.0 mmol) was first dissolved in hot (40 ° C) methanol (30 mL), treated with pyridine (103 g, 0.105 mL, 1.3 mmol) and, after cooling, treated with silver nitrate. 20 0.15 mol. with methanol solution (8.7 mL, 1.3 mmol).

The mixture was stirred for 1 h at 23 ° C, cooled (ice bath) and stirred for 20 minutes. The salt was filtered off and washed successively with cold methanil and ether (3 times, 671 mg, 87%). IR (CHCl 3) δ: 1745 (C = O), 25 1 605 (phosphorane) and 1520 cm -1 (NO 2)

Example 9

Preparation of silver 3- (1'-parinitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate 30 oco2pnb oco pnb ΑΛα ^ ____ - e 1.0 1'Nli CO PN3 35 2 2 7071 6 25 "Isomer B" (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-paranitrobenzylcarbonyldioxy-1'-ethyl) -1 - (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" acetate) -4-tritio-2-azetidin-5-one (1.02 g, 1 mmol) was first dissolved in Cl 2 Cl 2 (3 mL) and diluted with hot (55 ° C) with MeOH (20 mL) The hot solution was first treated with pyridine (120 mL, 117 mg, 1.48 mmol) and hot (55 ° C) 0.15 M silver nitrate in methanol (8 mL, The mixture was stirred at room temperature for 15 min, then at 0 ° C for 2 h, then concentrated to a 10% solution on a rotary evaporator (no bath) The mercaptide was filtered off, washed twice with cold (-15 ° C) methanol and three times with ether (917 mg, 100%) IR (nujol phase) ^> J majiS: 1745 (C = O), 1600 (phosphorane) and 1517 cm -1 (NC ^) · "Isomer C"

Silver 3- (1 "'paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2" -triphenylphosphoranylidene-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone 4-thiolate, "Isomer C" , was prepared as described above for "Isomer B"; IR (nujol) δ: 1745 (C = O) and 1600 cm (phosphorane). max

Example 10 (1'R, 3S, 4R and 1'S, 3R, 4S) -Silver-3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" - acetate) -2-azetidinone-4-thiolate (Isomer B)

OH OH

30 X — sstr

0) -l SV

CO PNB CO PNB

2 * 7071 6 26

A solution * of (1 * R r 3S, 4R and 1'S, 3R, 4S) -3- (11-hydroxy-1'-ethyl) -1- (paranitrobenzyl) -2 "-triphenylphosphoranylidene-2" - acetate) -4-tritylthio-2-azetidinone (1 g, 1.19 mmol) in MeOH (10 mL),

5 with pyridine (124, 121.3 mg, 1.53 mmol) O

and at 10 ° C 0.15 mol. with a solution of silver nitrate in MeOH (15 mL, 2.25 mmol - or until no more precipitation of silver mercaptide occurred). The mixture was stirred for 1 h and concentrated on a rotary evaporator (no bath) to a mixture of about 10%: 10 sex. The solvent was filtered off. The filter cake was washed once with MeOH and 3 times with ether, and treated under high vacuum (954 mg, 100%). IR (nujol phase) δ: 3500-3400 (O-H), 1752 (C = O), 1595 (phosphorane) and 15 cm -1 (NO 2) * 15 * The crystalline substance was first dissolved in C

Example 11

Silver 3- (1'-hydroxy-1'-ethyl) -1 - (N-trimethylsilylethyl 2 ', - triphenylphosphoranylidene-2, ,acetate) -2-azetidinone-4-thiolate

oh CH

„EA — I / STr AQNcypyridine ^ J — N J ^ Ph J N PPh ° I ° Y / ^ SiMe3

C ° 2 CO

25 1

A solution of silver nitrate (425 mg, 2.5 mmol), pyridine (79 mg, 1.0 mmol) and water (10 mL) was added to a solution of 3- (1'-hydroxy-1'-ethyl) - 1-30 (-trimethylsilylethyl-2 "-triphenylphosphoranylidene-2" -acetate) -tritylthio-2-azetidione (403 mg, 0.50 mmol) in ether (10 mL). The mixture was stirred vigorously for 1 h. The precipitate was collected by filtration. and washed with water and ether to give 267 mg (80 *) of the title mer-35 captide. IR 2: 3400 (OH) and 1750 cm -1 (β) -actam and ester).

Example 12

Silver 1- (p-trimethylsilylethyl 2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate 5'-SAcj υ ^ 3 / CHl ΓΗ CH S1-Cil, 2 2 2 \ J ch3 10 Di- - (trimethylsilylethyl fumarate 0 0 fT ^ ci fl C1 HO_

X pyridine (CH) Si X

15 0

To a cold (-10 ° C) ether (20 mL) solution of 2-trimethylsilylethanol (4.73 g, 0.04 mmol). Gerlach Helv. Chim. Acta 60, 3039 (1977)} and pyridine 20 (5.66 mL, 0.07 mmol), protected under nitrogen, were added dropwise (15 min) fumaryl chloride (3.78 mL, 0.035 mmol) dissolved in ether (10 mL). ). The black mixture was stirred for five minutes at -10 ° C and ten room temperature. Charcoal was added and the reaction mixture was filtered through a pad of Celite. The filtrate was washed with sodium hydrogen carbonate (1%) brine (1: 1, 150 mL). The aqueous phase was back-extracted with ether (30 ml). The ether solutions were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to dryness in vacuo to give a brown solid. This compound was purified on a pad of silica gel (30 g, 4 x 5 cm) using benzene (300 mL) as eluent to give an oil (4.855 g, 77%) which solidified on standing; mp 33-34 ° C. Analysis calculated for C 14 H 28 O 4 • 2: 35 C 53.12; H 8.91 found C 53.35; H 8.91.

28 7071 6 'ffinr (CDCl 3, E: 6.78 (2H, s, C = CH), 4.26 (4H, m, CH 2 -O), 1.03 (4H, m, CH 2 -Si) and 0 .06 ppm (18H, s, (CH 2 Cl 2); and (CHCl 3) 2: 1710 (C = O) ester C = O), 1643 (C = C), 1267, 1258-112 and 840 cm -1 (si-C).

5 Trimethylsilylethyl glyoxylate hydrate

O

33 1) 0, CH (OH) / VA J _} _> I 2 ^ 31 (CH) 2, (CH3) 2S 3 3 10

A solution of d-trimethylsilylethyl fumarate (37 g, 0.117 mmol) in methylene chloride (1.1 L) was ozonated at -78 ° C until the blue color persisted.

Excess ozone was purged with nitrogen and dimethyl sulfide (2.57 mL, 0.351 mol) was added. The solution was allowed to gradually warm to 23 ° C. The reaction mixture was diluted with carbon tetrachloride to 2 liters and washed with 1% aqueous sodium carbonate solution (500 mL). The organic phase was dried over sodium sulfate, filtered through Celite and evaporated to dryness (2525 ° C) to give 43.9 g of the title compound (97%); IR (fine) λ max: 3450 (-OH), 1740 (ester, 1255, 860 and 840 cm -1) (eg 1- (β-trimethylsilylethyl 2'-hydroxy-2'-acetate)) -4-tritylthio-2-azetidinone fT; - * γΓ

J_i 2 L · J— N. OH

"" H 0 Si (CH) CO J 3 30 2

Trimethylsilylethyl glybylate hydrate (4,000 g, 11.6 mmol) and 4-tritylthio-2-azetidinone (4.8 g, 24.96 mmol) were boiled in benzene (25 mL) through a 35 Dean-Strak condenser under nitrogen for 24 h. .

29 7071 6

The solvent was evaporated off in vacuo. The product was chromatographed on a silica gel column (450 g, 8.5 x 14.5 cm) and eluted with ethyl acetate: methylene chloride (1:19) until the title compound (r * -> 1.5 L) began to come and then ethyl acetate. -methylene chloride (1: 9, 2 L). The fractions containing the title compound were combined and evaporated to dryness to give 5.415 g (89%) of the title compound.

1 Hmr (CDCl 3) δ: 7.80 - 6.70 (15H, m, trityl), 5.23 and 4.90 (1H, 2s, HCO), 4.50-4.10 (3H, m, H-3 and O-CH2),

2.60 (2H, m, H-2), 0.95 (2H, m, CH 2 -Si and 0.1 ppm (9H, s, Si-CH 3); and (CHCl 3) δ: 3520 (-OH) , 1765 (C = O

(>) lactam), 1740 (C = 9aefter C = O), 1595 (C - H, -1 aromatic), 1257, 860 and 840 cm (C-Si).

1- (β) -Trimethylsilylethyl 2'-chloro-2'-chloro-2'-acetate) -4-tritylthio-2-azetidinone rfSTr sccl> (-rSTr ZO0 ^ · "^ '0" Si «CH3l3 Pyridine) 15 CO C0-, 2 2

A solution of thionyl chloride (0.74 mL, 10.37 mmol) in dry THF (9 mL) was added dropwise with stirring to a solution of 1- (β-trimethylsilyl-ethyl-21-hydroxy-21-acetate). ) -4-tritylthio-2-azetidinone (4.9 g, 9.37 mmol), pyridine (0.84 mL, 10.38 mmol) and dry THF (40 mL) at -15 ° C protected by a nitrogen atmosphere. The mixture was stirred at -15 ° C for 2 h. The precipitate was removed by filtration through a pad of Celite and washed with benzene (50 mL). The filtrate was evaporated to dryness in vacuo at 30 ° C. The residue was dissolved in benzene (100 mL), treated with charcoal and filtered through a pad of Celite. Evaporation of the solvent gave a residue which was purified through a pad of silica gel (100 g, 4m7 x 11 cm); 7071 6 hexane-benzene mixture (1: 1, 400 ml), ether-benzene mixture (1:19, 1 1). Evaporation of the appropriate fractions to dryness gave 4.64 g of the title compound (92%).

1 Hmr (CDCl 3) δ: 7.30 (15H, m, aromatic H), 5.77 and δ 5.43 (1H, 2s, CH-Cl), 4.7-4.2 (3H, m, H-4 and CH 2 -O), 2.85-250 (2H, m, H-3), 1.15, (2H, m, CH 2 -Si) and 0.06 ppm (9H, s, Si-CH 3) ), · Ir (fine) ^: 1760 (C = O), 860 and 840 ~ 1 / n λ · \ iuciks

Cltl (C-Sl).

1- (fb “Trimethylsilylethyl 21-triphenylphosphorus-10 nylidene-21-acetate) -4-tritylthio-2-azetidinone n ^ Tr V ργΤΓ 15 2 2

A solution of the aforementioned chlorazetidone (4.12 g, 7.568 mmol) in dioxane (20 mL) was treated with triphenylphosphine (2.209 g, 8.424 mmol) and 2.6-20 lutidine (0.98 mL, 8.424 mmol). The mixture was boiled for 3.5 hours. The cooled was filtered and the white solid was washed with THF. The filtrate was evaporated to dryness. The residue was purified on a silica gel column (200 g, 4 x 31 cm) using ethyl acetate-hexane (3: 7, 11; 7: 3, 25, 11) to give the title phosphorane (4.836 g, 83%).

Ir (membrane: 1755 (C = O), 1615 (phosphorane), 850 and 830 cm-1 (si-O] F? Analysis calculated for NO 2 PSSi: C 73.89; H &07; N 1, 81 30 Found C 72.18, H 6.08, N 1.83.

Silver 1 - (β-trimethylsilylethyl 2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate _ / SAg _ ^ STr + AgNO + (ηΒυ) N + CF CO H —- - ——► f (- \ 3 3 3 2 0 'ρφ,

«Pv *» ri ^ T

3i 7 0 71 6 1- (β-Trimethylsilylethyl-21-triphenylphosphoranylidene-2'-acetate) -2-azetidinone (7.64 g, 10 mmol) was dissolved in ether (60 mL). Aqueous silver nitrate (0.5 M, 80 mL, 40 mmol) was added, followed by the rapid addition (1 min) of a solution of tributylamine (3 mL, 12.58 mmol) and trifluoroacetic acid ( 0.154 ml: 0.2 mmol) in ether (20 ml). The mixture was stirred mechanically for 19 minutes. The precipitate was filtered, rinsed with ether (200 ml), triturated with water (70 ml), re-filtered and rinsed with ether (100 ml).

The light brown solid was dried in vacuo (suction 10 min and pump 65 min) to give the title compound (6.42 g). Ir (CHCl 3) max: 1862 (C = O), 1630 (phosphorane), 860 and 840 (Si-C).

1 5 Example 13

Trans-silver 3- (formamidomethyl-1- (paranitrobenzyl-2 · -triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate 20 <Τ-Ν · γ * ρ * ι o'LNY -?B

CO 2 PNB e02PNB

25

A solution of trans-3-formamidomethyl-1- (para-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone (550 mg, 0.64 mmol) in dichloromethane (10 ml) was evaporated to dryness and diluted with hot methanol (20 ml). The solution was stirred at 60 ° C and treated with a preheated (60 ° C) solution of 0.15 mol. silver nitrate in methanol (5.7 mL, 0.86 mmol), followed by a solution of 35 1.5 M. methanol solution of pyridine (0.57 mL, 0.86 mmol).

32 7 0 7 1 6

The cream solution was stirred at room temperature for 30 minutes, then in an ice bath for 2 h. The solid was filtered off, washed with cold methanol and ether, and dried to give 300 mg (65%} of ho-5 head salt as a beige solid.

Example 14 OCO.PNB 9C02pnb ^ wSTr λ9 „ο3 νΑργ" * 10 (Λ- "ύ ^ Φ3 Py / MoOH 0 # * - N ΡΦ3

COjPHB CO ^ PNB

Procedural:

To a hot solution (60 ° C) with <1 * S, 3S, 4R

and 1'R, 3R, 4S) -3- (1'-paranitrobenzyldioxycarbonyl-1'-propyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidione ( 1.4 g, 1.35 mmol) in MeOH (40 mL) was added a stirred hot solution of AgNO 2 (0.3 g, 1.76 mmol).

In MeOH (10 mL) followed by pyridine (0.107 g, 0.11 mL, 1.76 mmol). Silver mercaptide began to precipitate immediately. The mixture was stirred at room temperature for 15 minutes and at 0 ° C for 2 h. It was filtered and the solid was washed with very cold MeOH and ether; 1.2 g, (yield quantitative); mp. 113-115 ° C with decomposition; IR (nujol) ν: 1740-1760 cm-1 (broad). max

Example 15 30 PCHO Ocho —► απ "Α9

CO PNB I

2 co2pnb 33 7071 6

Procedure: Warm solution (60 ° C) with 0.15 mol. A solution of AgNO 4 -CH 2 OH (8.7 mc, 1.3 mmol) was added to a mixture of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-formyloxy-5 11-propyl) -1- (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone (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. 2 h. It was filtered and washed with cold MeOH to give 0.53 g of silver mercaptide as a yellow solid (71%).

Example 16 H Ocho H ocno 15 _ / STr ο ^ - “^ \ ^ Ρφ3 0J — Ϊ \ ^ - Ρφ3

CO PNB COPNB

2 2 20

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 1'S, 3R, 4S) (3.6 g, 3.8 mmol) and pvrine-25 (0.33 g, 4.2 mmol) in CH 2 Cl 2 (30 mL) and MeOH (30 mL). was added dropwise at 0.15 mol. AgNO 3 / MeOH solution (28 mL, 4.2 mmol). The mixture was stirred at room temperature for 2.15 h. It was concentrated to low volume (>10 mL), cooled and filtered to give 30 silver mercaptides as a yellow solid (2.3 g, 77%).

Example 17 (4'R, 3S, 4R and 4'S, 3R, 4S) -Silver-3- (21,2'-dimethyl-1 ', 3'-dioxolan-4'-yl) -1- (p -nitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-35 4-thiolate (Isomer C) 7071 6 34 f1 33, ¢ - .34, 3 ^ ··· ^ AgNO ^ -Pyr | -j IJ ρφ HeOH _J — NF (J) cr — N 3 ^ 3

5 CO PNB C02PNB

A solution of (4'R, 3S, 4R and 4'S, 3R, 4S) -3- (α, 2α-dimethyl-1 * -3'-dioxolan-4'-yl) -1- (p-nitrobenzyl 10 '2 "-Triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2-azetidinone (Isomer C) (319 mg, 0.355 mmol) in CH 2 Cl 2 (10 mL) was evaporated to dryness to give an oily residue. redissolved in hot methanol (8 mL; 60 °) To this solution was added 15 hot MeOH in AgNO 2 (0.15 mol, 4.0 mL, 0.60 mmol) at 60 ° C and then pyridine (29 μL, 0.36 mmol). The mixture was stirred at room temperature for 5 h and at 0 ° C for 1 h. The mixture was collected and washed with ice-cold methanol and then cold Et 2 O to give 255 mg (0.334 mmol) of pyridine. 20 [mu] l, yield 94.1%) of the title compound as a brownish solid: Ir (nujol) [delta]: 1750 cm-1 (s, C = O).

Example 18 max (4'S, 3S, 4R and 4'R, 3S, 4R) -Silver-3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl 2 "-triphenyl-25-phosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (Isomer B) & ...

I AgNO ^ -pyr ^ "| ^ 30 ο ^ ~ 'ΝΎ'ΡΦ3 Me0H 0 ^ ~ Νν ^ ΡΦ3

C02PNB C02PNB

The title compound was prepared as described in Example 17 "Isomer C for (4'S, 3S, 4R and 7071 6 35 4'R, 3S, 4R) -3- (21,21-dimethyl-1 ', 3' -dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone (Isomer B) (1.00 g, 1.12 mmol); yield 580 mg, 0.760 mmol, δ 67.8%, mp 129-135 ° C (dec.), IR (nujol) λmax, 1745 cm -1 (γ3 "lactam, ester).

Use of intermediates according to the invention Example I

10 S) 2Hg SCOCH3 1 f 2CH3COCl__ I f J_N PPh-. ,. . . ^ --N .PPh_ 3 pyndin 3

15 C02PNB C02PNB

II III

A solution of compound II (262 mg, 0.2 20 mmol), acetyl chloride (35 mg, 0.44 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 off. 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 pad of Celite. Evaporation of the clear filtrate to dryness left 193 mg (80.7%) of compound III as a foam. IR (CHCl 3) 1755 (Vc = o β "lactam) 1692 (ySCOCH) 1620 (phenyl) · 36. · Νν ττ 7071 6

Example II

SAg SCOCH2N3 f cicoch2n3 f "

-BL CH C1 J-N

O— ^ C = PPh, 2 2 O ^ C = PPh-! 3 I 3

COOPNB COOPNB

A solution of silver mercaptide 1 (1.25 g, 1.99 mmol) in dichloromethane (15 mL), kept under a nitrogen atmosphere, was cooled to 0 ° C and 2-mol was added dropwise. dichloromethane solution of azidoacetyl chloride (1.13 mL, 2.26 mmol). The reaction-15 mixture was stirred at 0 ° C for 1 hour? the cooling bath was removed and stirring was continued for 5 h. The reaction mixture was filtered through a pad of Celite and the solids were washed with dichloromethane (35 mL). The filtrate and washings were combined, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to an orange syrup which was purified by column chromatography. (30 g silica gel 60, eluate: ether-2% ethyl acetate (200 ml), ether-6% ethyl acetate (200 ml) and ether-20% ethyl acetate (500 ml), fraction size: 10 ml). Combining and evaporating to dryness fractions 49-80 gave a yellow powder? 0.73 g, m.p. 61-70 °, 60.8%.

Example III

30 Cis and trans-3-ethyl-1- (p-nitrobenzyl-2'-phosphoranilidene-2'-acetate) -4-azidoacetylthio-2-azetidinone

A solution of the above crude silver cis- and trans-3-ethyl-1- (p-nitrobenzyl-2'-triphenyl-35-phosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate ( 1.31 g, 2 mmol) in dichloromethane (15 ml) was cooled to 0 ° C and treated under nitrogen with a 2 mol solution of azidoacetyl chloride in dichloromethane (1.13 ml, 2.26 mmoo-alcohol). The mixture was stirred at 0 ° C for 1 h and at room temperature for 5 h. The insoluble silver salts were removed by filtration through Celite and sprayed with dichloromethane. The combined filtrates were washed with dilute sodium hydrogen carbonate solution and water, dried and evaporated to dryness. the oily residue was purified by chromatography on silica gel (35 g) eluting with ether-ethyl acetate. The appropriate fractions were evaporated to dryness to give a mixture of cis- and trans-acylated compounds as a semi-solid; 0.62 mg.

V (CDCl 3): 2105, 1760, 1690, 1621 cm -1.

15 Example IV

Cis- and trans-3-acetoxymethyl-4-azidoacetyl-thio-1- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone In the treatment of silver cis- and trans-3-acetoxymethyl -1- (p-nitrobenzyl 2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate (1.4 g, 2 mmol) dissolved in dichloromethane (15 mL) azidoacetyl chloride (2.3 mmol) 0.78 g of the title compound was obtained as a yellow powder.

25 Example V

SAg O

_ ^ | + cic (ch2) 3p (oc2h5) 2 - ^ 30 0 ^ -Ν ^ γΧ03 2 CO2PNB ° 1 / S 3p (OC2H5) 2 f> ° 35 f co2pnb 3 33 7071 6 To a cooled (ice bath) mixture containing compound 1 (1.324 g, 2 mmol) and compound 2 (0.54 g, 2.2 mmol, crude) in CH 2 Cl 2 (15 mL) were added dropwise 1 mol. pyridine / CH 2 Cl 2 solution (2.2 mL, 2.2 5 mmol. The mixture was stirred at room temperature for 1 h and filtered through Celite. The filtrate was washed successively with 0.5 N HCl, H 2 O, 0.5 M NaHCO 3. Dried (MgSO 4) and filtered through Celite to give 0.9 g of oil after evaporation to dryness, the oil was chromatographed

Pigs (10% H 2 O) and eluted with ethyl acetate to give 0.5 g of compound 3. (32.8%. NMR δ (ppm, CDCl 3) 7.0-8.4 (m, 19H), 4.8-5 Δ (3H, m), 4.1 (4H, q), 3.3-4.2 (2H, m), 2.7 (2H, m), 1.9 (2H, m), 1, 3 (6H, t).

15 Example VI

(1'R, 3R, 4R and 11S, 3S, 4S) -4-Acetylthio-3- (1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene -2 "acetate) -2-azetidinone (Isomer D) 20

OC02PNB 0C02PNB

Γ CH2COCl-Pyr Γ 25 0 ^ "γ '" 3 CH2C12 ^ o ^ -N \ / 03

C02PNB C02PNB

To a stirred solution of silver 3- (1'-paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -30 acetate) -2-azetidinone-4-thiolate (Isomer D) (85 mg, 0.095 mmol) in CH 2 Cl 2 (5 ml) with pyridine (30 μΐ, 0.37 mmol; Fisher) was added at 0-5 ° C CH 2 COCl 2 (20 μΐ, 0.28 mmol) and the mixture was stirred at 0-5 ° C for 30 minutes. The resulting precipitate was filtered off and washed with CH 2 Cl 2. The filtrate 39 7071 6 and washings were combined, washed successively with brine, dilute HCl, saturated NaHCO 3 and then brine, dried (NaSO 4) and evaporated to dryness to give 75 mg (0.091 5 mmol, 95% yield of crude compound). as a syrup: 1 Hmr (CDCl 3) +: 2.33 (s, -SOCOCH 2); IR (fine) ^ max: 1350 cm (“NO2”) ·

Example VII

(1'S, 3S, 4R and 1'R, 3R, 4S) -4-Acetylthio-3- (1'-10 paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (para-nitrobenzyl-2 "-triphenylphosphoranylidene-2" - acetate-2-azetidinone (isomer C) oco2pnb oco2pnb 15 SAg SAc j ^ ch3coci ^ <W <f 0 · ^ Nx ^ PO3 CO2PNB co9pnb 20 1

To a cold (ice-MeOH bath) solution of 1'S, 3S, 4R and 1'R, 3R, 4S) -silver-3- (1'-paranitrobenzyl-dioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl- 2 "-25 triphenylphosphoranylidene-2" acetate) -2-azetidinone 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 (MgSO 4). The residue obtained after evaporation of the solvent was triturated with ether (895 mg, 83.7%, m.p. 184-185 ° C with decomposition); 7071 6 40 IR (CHCl 3) ν max: 1755, 1695 (C = O), 1620 and 1605 cm -1 (phosphorane).

Anal .: Calcd for C 42 H 36 N 3 O 11 SSi: C, 61.38; H 4.42; N 5.11; S 3.90; Found: C, 61.26; H 4.49; N 4.88; S 4.26.

Example VIII

(1'R, 3S, 4R and 1'S, 3R, 4S) -4-Acetylthio-3- (1'-para-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-phenylphosphoranylidene-2" acetate) -2-10 azetidinone, (isomer B) oco2pnb oco2pnb ^ SAg ^, SAc '-1 AcCl']] 15 o *** - Ν \ ^ Ρ03 C5H5N ^ ΝΎ ^ Ρ03 co2pnb co2pnb

A solution of (1'R, 3S, 4R and 1'S, 3R, 4S) -silver-3- (11-paranitrobenzyldioxycarbonyl-1'-ethyl) -1 * -20 paranitrobenzyl 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 acetyl chloride (142 μL, 157 mg, 2.0 mmol) was added dropwise. 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. After evaporation of the solvent, the residue obtained was crystallized from ether (710 mg, 80%, m.p. 183-185 ° C; IR (CHCl 3)): mp: 1755 1695 (C = O), 1620, 1605 (phosphorane) and 1625 cm -1 (NO 2). ).

| j 35 4i 7071 6

Example IX

(1'R, 3S, 4R and 1'S, 3R, 4S) -4-Acetylthio-3- (1'-trimethylsilyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate ) -2-azetidinone 5 (isomer B)

° Η OTMS

J. / SAg I SAc ·, —S _ / I TMSC1 AcCl j 10 TEA C5H5N o> —N \ ^ PO3

C02PNB C02PNB

Suspension of (1'R, 3S, 4R and 1'S, 3R, 4S} silver-3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-1 "-tri-15-phenylphosphoranylidene) 2 "-acetate) -2-azetidinone-4-thiolate (505 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 IR showed that it had no hydroxy group). The mixture was cooled to -15 ° C, diluted with Cl 2 Cl 2 (20 mL), treated with pyridine (226 mg, 231 μL, 2.26 mmol / 25) 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 30 and the residue was purified by filtration through a silica gel column (1:10, 3% 10% ether in benzene) to give the title compound (360 mg, 84.2%) which included a small amount of desilylated derivative. (30 mg, 7.8%). IR (liquid film),: md ie s 35 3550, 1790 (OO), 1620 (phosphorane and 1518 cm-1 (NO2)).

7071 6 42

Example X

(1'S, 3R, 4R and 1'R, 3S, 4S) -4-Acetylthio-3- (1'-methoxymethoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenyl-phosphoranylidene-2" -acetate) -2-azetidinone (isomer A) 5 OCH-OCH-, OCH 2 OCH-j A. ^ SAg Jk / SAc Γ _ ^ Π 10

C02PNB C02PNB

Isomer A of 4-acetylthio-3- (1'-methoxymethoxy-1'-ethyl) -1- (paranitrobenzyl) -2 "-triphenylphosphoranylidene-2" -15 acetate) -2-azetidinone was prepared as described elsewhere for paranitrobenzyldioxycarbonyl derivative isomer C in 85% yield. IR (fine) ν max: 1750 and 1690 cm -1 (C = O). Example XI

20 (1'R, 3S, 4R and 1'S, 3R, 4S) -4-Azidoacetylthio-3- (11-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate ) -2-azetidinone (isomer B)

25 OH OH

/ · .. Θ A.

--1 1MSC1 C100CH2N3 iH j 0J N \ ^ 3 TEA r ”

3 0 G02PNB 002PNB

To a cold suspension (ice-MeOH bath) of 1'R, 3S, 4R and 1'S, 3R, 4S) -silver-3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 " -triphenylphosphoranylidene-2 "-35 acetate) -2-azetidinone-4-thiolate (970 mg, 1.37 43 7071 6 mmol, obtained from 1 gram of the corresponding trityl) in THF (40 mL) was added dropwise trimethylchlorosilane (0.695 ml, 595 mg, 5.48 mmol), triethylamine (0.765 mL, 555 mg, 5.49 mmol) and imidazole (50 mg, 0.734 mmol). The mixture was stirred under Nj for 17 h, then cooled to -15 ° C (ice-MeOH bath) and azidoacetyl chloride (406 mg, 3.40 mmol) was added. The mixture was stirred for 30 minutes (monitoring the progress of the reaction by tlc). The solid was filtered off and washed with ether. The filtrate was diluted with more ether, washed with 1% aqueous HCl, water, 1% aqueous NaHCO 3, water and brine and dried (MgSO 4). The residue obtained after evaporation of the solvent was dissolved in moist Cl 2 Cl 2 (50 ml) and the solution was treated with TFA (3 drops, following the cleavage of the TMS ether by road). The methylene chloride solution was then washed with 1% aqueous NaHCO 3, water and brine and dried (MgSO 4). Residue 20 was passed through silica gel (8 times the weight) on a column (benzene ether 1: 1, ether and ethyl acetate ether 1: 1) to give the title compound (565 mg, 69.8%); IR (film) ν max: 3500-3200 (0-H), 2100 (N3), 1755, 1609 (C = O), 1620-1605 (phosphorane) and 1518 cm-1 (NC2) *

Example XII

(1'R, 3S, 5R and 1'S, 3R, 4S) -4- (J "-azidobutanoylthio) -3- (11-hydroxyethyl) -1- (paranitrobenzyl-2" -triphenylphosphoranylidene-2 "-acetate) -2-azetidinone 30 44 7071 6

OH OH

X J ** '+ Λ / S-C (CH) N

/ ··.-S 'THSC1 N3 (CH2) 4CO01 H' V-S * 4 3

1-N TEA, Im. CcHcN H ~ 0 J-N

5 0 ^ ^ C = PPh3 5 5 2 0 ^ ^ C = PPh3

COOPNB COOPNB

Solution of (1'R, 3S, 4R and 1'S, 3R, 4S) silver 3- (1'-hydroxyethyl) -1- (paranitrobenzyl) -2 "-triphenyl-10-phosphoranylidene-2" acetate) - 2-Azetidinone-4-thioate (3.03 g, 4.28 mmol) in dry THF (55 mL) under nitrogen was cooled to -25 ° C and treated sequentially with triethylamine (2.39 mL, 17.12). mmol), trimethylchlorosilane (2.18 mL, 17.12 mmol-15) and imidazole (0.10 g, 1.47 mmol). The reaction mixture was stirred at -25 ° C for 0.25 h, the cooling bath was removed, and stirring was continued for 16 h. The reaction mixture was cooled to 0 ° C and diluted with CH 2 Cl 2 (55 mL); it was then treated sequentially with pyridine (0.73 mL, 9.0 mmol) and a solution of 4-aminobutanoyl chloride (1.36 g, 8.56 mmol) in CH 2 Cl 2 (10 mL). The reaction mixture was stirred at 0 ° C for 1 h and filtered through a pad of Celite.

The mattress was washed with CH 2 Cl 2 (25 mL); the filtrate and washings were combined and diluted with ethyl acetate (300 mL). The organic solution was washed with 1-norm. HCl solution, H 2 O, saturated NaHCO 3 solution and H 2 O, dried over anhydrous MgSO 4 and evaporated on a rotary evaporator to give an orange syrup (3.83 g). Syrup was dissolved in CH 2 Cl 2 (75 mL) and water (4 mL) and TFA (0.2 mL) were added; the reaction mixture was stirred at 23 ° C for 1.5 h, washed with NaHCO 3 and H 2 O, dried over anhydrous Na 2 SO 4 and evaporated to an orange syrup (3.4 g). Purification of the syrup was performed by column chromatography (silica gel G 60, 80 g;

II

45 7071 6 eluent: ethyl acetate (CH 2 Cl 2 (10% → 5%).

Evaporation to dryness gave the appropriate fractions as an oil; 2.14 g, 67.7%. Analysis Calculated for C 37 H 36 N 5 O 7 SP: C, 61-23; H 5'00> N 9.65; S 4.42; Found: C, 61.17; H 5.10; N 10.02; S 3.71.

Example XIII

° H 0 OH O

A. r9 * <sL <v *, „♦ pr. v-3> r · —i ___N TEA, Im C H H O J-N.

Cr> sOPPh, 5 5 O C = PPh I 3 I 3

COOPNB COOPNB

Solution of (1'R, 3S, 4R and 1'S, 3R, 4S) silver-15- (1'-hydroxyethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) - 2-Azetidinone-4-thioate (1.01 g, 1.43 mmol) in dry THF (25 mL), protected under a nitrogen atmosphere, was cooled to -40 ° C and treated sequentially with triethylamine (0.80 mL, 5.74 mmol), trimethylchlorosilane (0.726 mL, 5.72 mmol) and imidazole (0.10 g, 1.47 mmol). The reaction mixture was warmed to -15 ° C, stirred for 3 h, the cooling bath was removed and stirring was continued for 18 h. The reaction mixture was cooled to -15 ° C and diluted with CH 2 Cl 2 (25 mL); it was then treated with pyridine (0.15 mL, 1.85 mmol) and trans-3-azidocyclobutanoyl chloride (0.274 g, 1.72 mmol). The cooling bath was removed and the solution was stirred for 1 h and treated with pyridine (0.15 mL, 1.85 mmol) and trans-3-azidocyclobutanoyl chloride (0.274 g, 1.72 mmol). The reaction mixture was stirred at 23 ° C for 1 h and filtered through a pad of Celite. The filtrate was diluted with ethyl acetate (100 mL) and washed with 1N norm. HCl, H 2 O, saturated NaHCO 3 solution and 35 mL, dried over anhydrous MgSO 4 and evaporated on a rotary evaporator to give an orange syrup (1.47 g). To a solution of the syrup in CH 2 Cl 2 (50 mL) was added 1N Orta (2 mL) and TFA (0.2 mL). The reaction mixture was stirred at 23 ° C for 2 h, washed with saturated NaHCO 3 solution and IVO, dried over anhydrous Na 2 SO 4 and evaporated to dryness to an orange syrup (1.1 g). Purification of the syrup was performed by column chromatography (silica gel 60, 20 g; eluent EtOAc-ether 35% to 70%). Evaporation of the appropriate fractions to dryness gave the title compound as an oil; 0.77 g, 74.4% IR (fine) max>: 3440 (OH), 2100 (N?), 1755 (C = O / 3-lactam), 1735 (C = O), 1680 J C = 0) and 1625 cm (aromatic).

Example XIV

15 4-Acetylthio-3- (1'-acetoxy-1'-ethyl) -1- (p-trimethylsilylethyl 2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone? H OAc L .SAg 1 SAc 20 Me \ -f AcCl / pyridliniMe X] - JN ^ PPh. JN ^ PPh_ 0 ^ 3 OM 3] SiMe \ SiMe., Co2 / J co2 / \ / -3 A solution of acetyl chloride (70 mg, 0.38 mmol) in methylene chloride (1 mL) was added dropwise to a solution of silver. -3- (1'-hydroxy-1'-ethyl) -1 - ([3-trimethylsilylethyl 2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate 30 (267 mg, 0, 40 mmol) and pyridine (70 mg, 0.88 mmol) in methylene chloride (5 mL) at 0 ° C. The mixture was stirred at 0 ° C for 1.5 h and then at 23 ° C for 15 minutes.

The precipitate was filtered off and the solution was washed with 2.1 mol. with hydrochloric acid and 0.1 mol. with sodium bicarbonate solution 35 (10 ml each). The solvent was evaporated in vacuo to give the title compound 153 mg (59%); li 4.7 7071 6 1750 (β-lactam and ester) and 1690 cm 3 (thioester) and IR max: 3450 (1H) -1Hmr (cdc13) 0: 7.5-3.2 (m 15H,

Ph), 5.85 (br, 1H, H-4), 3.0-5.0 (unresolved, 4H, OCH, OCH 2f H-3), 2.0-2.6 (3 singlets; 6H, OAc ), 0.9-1.7 δ (m, 5H, CH 2 / CH 2 Si) and 0.20 ppm (s, 9H, SiMe 2).

Example XV

(1'R, 3S, 4R and 1'S, 3R, 4S) -4-acetylthio-3- (11-azido-11-ethyl) -1- (paranitrobenzyl-2 "-triphenyl-phosphoranylidene-2" -acetate) - 2-azetidinone (iso-10 mere B) N3 N3 N3 Λ / ^ 3 Λ / S> 2 «9 X ^ SCOCHj rf -> ΓΊ | 1 15 o'1— "y ** o 002PNB CX) 2PNB co2pnb A cooled solution (5 ° C) containing (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-azido- 11-ethyl) -1- (paranitrobenzyl-20'-2 "-triphenylphosphoranylidin-2" -acetate) -4-tritylthio-2-azetidinone (3.9 g, 10.25 mmol) in dichloromethane (30 mL ) was treated with a solution of mercuric acetate (2.12 g, 6.66 mmol) in methanol (30 mL) After stirring at 5 ° C for 0.5 h and at room temperature for 1.5 h, the solvent was evaporated. off and the crude mercury salt was redissolved in dichloromethane and washed with dilute NaHCO 3 solution and brine.After drying (MgSO 4) the solution was cooled to 5 ° C and treated directly with pyridine 30 (1.66 g, 21 mmol) and by dropwise addition of acetyl chloride (1.65 g, 21 mmol) The reaction mixture was stirred at 5 ° C for 1 h, the precipitated mercuric chloride was filtered off and the filtrate was washed successively with dilute HCl, NaHCO 3 and brine. organic solution impregnation was charged at 5 ° C with hydrogen sulfide 48 7071 6 to precipitate the remaining mercury impurities as mercuric sulfide. The crude thioester obtained after evaporation of the solvent was purified on a silica gel column (8.5 x 9 cm) eluting with dichloromethane (500 ml) and 15% acetonitrile - dichloromethane; 5.1 g (74.6%); 1 Hmr (CDCl 3) *: 3.70 (1H, m, H-11), 2.98 (1H, m, H-3), 2.33 and 2.20 (3H, 2s, acetyl), 1.28 (3H, d, J = 6.2 Ha, H-2 '); IR ν max (CHCl 3: 2115 (Nj), 1758, 1693 and 1620 cm -1) (C = O).

10 Example XVI

Trans-4-acetylthio-3-formamidometyyli-L- (para-nitrobenzyl-2'-triphenylphosphoranylidene-2 -'- acetate acetate) -2-azetidinone

q c _ H H H H

° f -SAg «I f ^ SAo HCiT \ -HCN" ^ M-

H I -H I

J-N, P0, J-N

3 O ** \ / 3

CC ^ PNB C02PNB

To a cooled solution (ice bath) of trans-silver 3-formidomethyl-1- (paranitrobenzyl) -2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate (800 mg, 1.11 mmol) in dichloromethane (10 mL) was added dropwise under 1 N mol. dichloromethane solution of acetyl chloride (1.33 mL, 1.33 mmol) followed by 1-mol. dichloromethane solution of pyridine (1.33 mL, 133 mmol). The solution was stirred in a cold bath for 1 h, and then filtered through 30 Celite. The filtrate was washed successively with 1-norm. with hydrochloric acid, water, 1 mol. sodium hydrogen carbonate and brine and the organic layer was dried (MgSO 4) and evaporated to dryness. The residue was purified on a silica gel column (5.0 g) and eluted with mixtures of ethyl acetate - 10% methanol in ethyl acetate to give 450 mg (62%) of the title compound; IR (CHCl 3),:

λ i ΓΠ3 K S

1755, 1685 and 1620 cm -1 Hmr (CDCl 3) δ $ 8.18 (2H, d, J = 9Hz), 7.0-8.0 (20H, m), 6.75 (2H, d), J = 9 Hz), 6.3 (1H, m), 5.5 (1H, m), 5.2 (2H, bs), 4.9 (1H, bs), 3.6 δ (1H, m ), 3.0 (1H, m) and 2.2 ppm (3H, 4 s).

Example XVII

(11S, 3S, 4R and 1'R, 3R, 4S) -4-Acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1'-propyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -10 acetate) -2-azetidinone (isomer C) oco2pnb oco2pnb SAg '1 I AgNO3 [| 0J-Py / MeOH? N \ / P03

CO_PNB CO_PNB

2 o X 2

II

CH3CC1 Ty ^ / MeOH

OCO-PNB

20 ^ 0J-N \ XP03

C02PNB

25

To a hot solution (60 ° C) of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (11-paranitrobenzyldioxycarbonyl-1'-propyl) -1-paranitrobenzyl-2 "-triphenylphosphoranylidene- 2 "-acetate) -4-tritylthio-2-azetidinone 30 (Isomer C) (1.4 g, 1.35 mmol) in MeOH (40 mL) was added with stirring a hot solution of AgNO 3 (0.3 g, 1.76 mmol) in MeOH (10 mL) followed by pyridine (0.107 g, 0.11 mL, 1.76 mmol). Silver mercaptide began to precipitate immediately. The mixture was stirred at room temperature for 15 minutes and at 0 ° C for 2 h. 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; IR (nujol) ν max: 1740-1760 cm -1 (broad).

This solid was used as such. To a cooled (ice bath) solution of the above mercaptide (1.2 g, 1.35 mmol) in CH 2 Cl 2 (15 mL) was added acetyl chloride (0.118 g, 0.107 mL, 1.5 mmol) in Cl 2 Cl 2. (2 mL) followed by pyridine (0.119 g, 0.122 mL, 1.5 mmol) in CH 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), IVO, NaHCO 3 (0.5 M) and brine. The CH 2 Cl 2 solution was dried (MgSO 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 3 (broad).

Example XVIII

(1'R, 3S, 4R and 1'S, 3R, 4S) -4-acetylthio-3- (1'-formyloxy-1'-propyl) -1- (paranitrobenzyl-2 "-tri-20-phenylphosphoranylidene-2" - acetate) -2-azetidinone (isomer B)

OCHO OCHO OCHO

J. .STr J SAg. J. ^ .SAc 25 n ^ ··· ._s · [_f "—f

.-N P 0, J --- N. .P0, -N

0 ^ 3 3 3 co2pnb co2pnb co2pnb 30 A warm solution (60 ° C) with 0.15 mol. A solution of AgNO 4 - CH 3 OH (8.7 mL, 1.3 mmol) was added to a mixture of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-formyloxy-1'- propyl) -1- (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone 35 (Isomer B) (0.88 g, 1 mmol) and pyridine (0.103 g,

II

51 7071 6 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). mmol) in CH 2 Cl 2 (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. NaHCO 3 and brine. Dried (Na 2 SO 4) and evaporated to dryness to give 0.43 g of an oil, (63%); IR (hie-15 no) V? mafcg5 1700-1760 cm-1 (broad and β-lactam).

Example XIX

4-acetylthio-3- (1'-formyloxy-2'-phenylethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -2q acetate) -2-azetidinone (1'R, 3S, 4R- and 1'S, 3R, 4S-enantiomer)

H y0CH0 H .OCHO

0 STr ^ SAg 25 T- ^ -> n Ο ^ -ΝγΡ03 0> - '»^ 3 C02PNB co2pnb 30 /„ OCHO ^

"S

0 '<jr aSAc 35 N \ ^ P03

C02PNB

52 7 0 7 1 6

To a boiling solution of 3- (1'-formyloxy-21-phenylethyl) -1-paranitrobryl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-acetidinone (1 ' R, 3S, 4R and IS, 3R, 4S enantiomers) (3.6 g, δ 3.8 mmol) and pyridine (0.33 g, 4.2 mmol) in CH 2 Cl 2 (30 mL) and MeOH: a (30 ml) was added dropwise 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 2 Cl 2 (0.27 g, 3.5 mmol) in CH 2 Cl 2 (15 mL). mL). The mixture was stirred at room temperature for 3 h. It was filtered using Celite'S and the filtrate was washed with cold 1-norm. HCl, H 2 O, 1 mol. NaHCO 3 and brine. Dried (MgSO 4) and evaporated to dryness to give 4 l of 1.0 g of an amorphous solid (89.8%). Hmr (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 XX

4'R, 3S, 4R and 4'S, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 31-25-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "- triphenylphosphoranylidene-2 "-acetate) -4-acetylthio-2-azetidinone (Isomer C) Λ Λ 30 ^" \ (^ Ag ^ SAc J CH3COCl / pyr I | 0 ^ -CH2C12 35 CO2PNB co2pnb

II

53 7 0 7 1 6

To a solution of (4'R, 3S, 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-thiolate (Isomer C) 5 (254 mg, 0.333 mmol) in CH 2 Cl 2 (15 mL) and containing pyridine (100 μL). , 1.24 mmol; 3.72 eq.) Was added to 0-5 ° C acetyl chloride (71 μL, 1.0 mmol; 3.0 eq.) · The mixture was stirred at 0-5 ° C. 40 minutes. After the precipitate was filtered through Celite, it was washed successively with 1-norm brine. 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 was crystallized from Et 2 O to give 155 mg (0.222 mmol, yield). 66.7%) of the title compound as white crystals: ^ Hrnr (CDCl 3) δ 1.23 (s, di-Me), 2.20, 2.33 (2s, -SAc) and 7.2- 8.3 ppm (m, aromatic H 5): IR (nujol) ν max: 3 λ 50 (β-lactam and ester) and 1690 cm -1 (thioester). An analytical sample was obtained by crystallization from CH 2 Cl 2 -Et 2 O: 20 m.p. 177-178 ° C; Anal. Calcd for C37H35N2O8PS: C, 63-60; 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).

Example XXI

(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). ^ SAg ^ SAc * Ί-1 CH3COCl / pyr * ·, -f 0J- »y ^ 3 CH2C32 0J — N \ ^ PO3

35 C02PNB C02PNB

54 7071 6

The title compound was prepared as described in Example 33 for "Isomer C" (4'S, 3S, 4R and 4'R, 3R, 4S) -silver-3- (21,2'-dimethyl-1 ', 3'-dioxolane). -4'-yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-5 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 in Cl 2 Cl 2 = 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) V max 1755 (β-lactam, ester) and 1695 cm -1 (thioester).

Example XXII

15 SAg CH ~ --- v + i (c-h- ^ ciz—} 'r o ^ nt ~ 1 ™ 2 ~ / λ, _N P0, pyridine _n?' 'O-1 * o Ύ 3 0 ^

C02PNB C02PNB

20 (III) (IV)

A solution of 1.0 g (0.0015 mol) of compound (III) and 0.12 ml (0.015 mol) of pyridine in 10 ml of 25 methylene chloride under a nitrogen atmosphere was cooled to 4 ° C. A solution of the acid chloride (II) was added to the solution of the compound (III) in one portion, and the reaction mixture was stirred at 4 ° for 5 minutes, then at room temperature for 1.5 h. A thick precipitate formed in the reaction mixture.

The mixture was filtered and the filtrate was diluted with methylene chloride to a volume of 70-90 mL. The organic phase was then washed successively with 70 ml of 0.1-norm. hydrochloric acid, 80 ml of 1% sodium hydrogen carbonate and 30 ml of water. The methylene chloride phase was dried over magnesium sulfate. The solvent was removed in vacuo and the residue

It 55 7071 6 oil was chromatographed on a Mallinckrodt SilicAR CC-7 silica gel using chloroform as eluent to give 0.4 g (30.5%) of compound (IV) as an oil. The infrared and nuclear magnetic resonance spectra were consistent with the values of compound (IV).

Claims (5)

A metal mercaptide useful as an intermediate in the preparation of 4-thio-2-azetidinone derivatives of the formula O II y scx γ-r 1 ° J-Ύ <°> 3 CO 2 Z 15 wherein X is methyl, N 3 - (CH2) m-, where m is 1-4, phthalimidobutyl, (OR) 2PO (CH2) ", where n is 2 or 3 and R is lower alkyl, N3- or # \ -CH2- -N- CH2-, and Y is 20 I! j = oo II hydrogen, HCNHCH2-, 2,2-dimethyl-1,3-dioxolan-4-yl or lower alkyl which may be substituted by hydroxy, protected hydroxy, azido or phenyl, Q is phenyl and Z is ester-forming group, characterized in that the metal mercaptide has the formula 30. S - Y SHgCOOCH, Ί — f. Ί — r J-li P (Q) o M or ^ -n, P (QK co2z co2z 35 - - m ma II 57 70 71 6 where Y, Q and Z have the same meaning as above, t is 1 or 2 and M is Cu (II), Pb (II) or Hg (II) when t is 2, or Ag (I) when t is 1. 58 7 0 71 6 Metal mercapters, which are other than the product in the form of 4- thio-2-azetidinone derivative 5 med formInIn 0 II Y. scx 10 'I (y — γ ™ 3 CO 2 z 15 from X is methyl, from 1 to 4, phthalimidobutyl, (OR) 2? (CH 2) - , där n är 2 eller 3 och R är lägre alkyl, 20 N3—— eller \ / CH2 — u- N-CH2-, och Y är V, === / N J- = 0 0 claim, HCNHCH2-, 2,2-dimethyl-1,3-dioxolan-4- yl or 25 alkyl, which may be substituted by hydroxyl, hydroxy hydroxy, azido or phenyl Q is phenyl and Z is an ester group, kännetecknad därav, att metallmer-kaptiden har formeIn 30 - η Y S-- Y SHgCOOCH- , X_S 'X_s' 3 0J - «^ X (Q, 3 M or 0J- * γ ^«> 3 35 C02Z t C02Z III Ilia II