CH651570A5 - ANTIBACTERIAL PENEM COMPOUNDS WITH BETA LACTAMASE ACTIVITY AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The present invention relates to β-lactam-containing compounds, to processes for their preparation and compositions containing these compounds.

The invention relates to the penemcarboxylic acid compounds of the formula

r '

"coor" v where n = 0 or 1, R "" signifies hydrogen, lower alkyl, acetonyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl or benzhydryl or ace-toxymethyl, pivaloyloxymethyl, phthalidyl or a group of the formula

-CH-OCOOC2H5 or -CH2NHCOR "'"

I.

CHj where R '"" is alkyl of 1-5 C atoms, cycloalkyl or aryl; Z is hydrogen, halogen, hydroxy, amino, carbamoyloxy, mercapto or a pyridinium group or a group of the formula OR ', OCOR', NHCOR 'or SR ", where R' and R" are each lower alkyl, aryl or a heterocyclic ring mean, which are each optionally substituted; and R '"is hydrogen, lower alkyl, lower alkoxy, cycloalkyl or hydroxyalkyl, preferably hydroxy lower alkyl, the alcoholic function of the hydroxyalkyl group being free or protected and the protecting group preferably p-nitrobenzyloxycarbonyl or Is dimethyl-tert-butylsilyl.

The substituent in position 6 has the a configuration or the β configuration. The a configuration is preferable. Examples of residues for R "" which are known to undergo metabolic activation "in vivo"

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

651 570

gene, and have useful pharmacokinetic properties, are acetoxymethoxy, pivaloyloxymethyl and phthalide and groups of the formulas

-CH-OCOOC2H5 and -CH2NHCOR '""

I.

CHj

When R 'and R "are heterocycles, they are preferably 5- or o-membered heterocyclic rings, such as 5-methyl-1,3,4-thiadiazol-2-yI, 1-methyltetrazol-5-yl, 1,2,3- Triazol-5-yl or pyrazinyl. Examples of R '"are methyl, ethyl,

Methoxy, 1-hydroxyethyl and l- (p-nitrobenzyloxycarbonyloxy) ethyl.

These compounds have a broad spectrum of antibacterial activity and a β-lactamase inhibitory activity. It should be pointed out that the stereochemistry on the Cs atom of the compounds according to the invention and that of all the intermediates formed in the course of their preparation are the same as in the naturally occurring penicillins and cephalosporins.

Pharmaceutically acceptable salts of penemic carboxylic acids of general formula (1), such as sodium, potassium, ben-5-zathin, procain and the like salts, which are usually formed with penicillins and cephalosporins, also fall within the scope of the present invention .

The invention also relates to the processes for the preparation of Verbin-10 fertilizers of the formula (I) as defined in claims 20-26, and the pharmaceutical compositions which comprise a compound according to claim 1 or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable Contain diluents or carriers.

15 The following diagram shows an overview of processes for the preparation of compounds of the formula (I), the processes according to the invention also being encompassed according to claims 20-25.

651 570

6

(vii)

(xiv)

v

(0)

r r "1

no jzttx

\ / i \ y y n \ j ^ oh coor "" coor ""

(viii) (xv)

0

R "1"

■ \ \ >> Sx ^ X

XX, ~; = u> v coor ""

(x)

| PPh3

coor "" (ix)

I.

coor ""

(xvi)

(xi)

(I)

(xi)

If R '"is hydrogen, compounds of the general formula (II), starting from (5R) -6-aminopenicillanic acid, ie 6-APA, according to the known general method of Cignarella et al., Journal of Organic Chemistry, 27 , 2668, and Evrard et al., Nature 201, 1124.

When R '"is lower alkyl, cycloalkyl or hydroxyalkyl, the group R'" can be introduced according to the method of Di Ninno et al., Journal of Organic Chemistry 42, 2960 (1977).

When R '"is lower alkoxy, the group R'" can be according to the method of Hauser et al., Helv. Chem. Acta 50, 1327 (1967), and Giddings et al., Tetrahedron Letters 11,995 (1978), starting from 6-APA to position 6.

On the other hand, compounds of formula (II) in which R '"is H can be converted into compounds of general formula (II) in which R'" denotes lower alkyl, cycloalkyl or hydroxyl, the substituent using a strong base is inserted into position 6, as explained in the following examples.

Compounds of the formula (II) in which R '"denotes lower-alkyl, cycloalkyl or hydroxyalkyl can also be prepared starting from a suitable ester of penicillanic acid S-oxide, as explained in the following examples. Substitution of position 6 is stereospecifically directed to the 6a derivatives.

The ester of penicillanic acid S-oxide (II) (R is alkyl and R '"has the above meaning) can in an inert solvent such as benzene or toluene, usually at a temperature of 70 to 140 ° C, with a suitable acety -45 lender derivative of the general formula XC = CY, where X is a group of the formula CHiZ ', where Z' is hydrogen, halogen, hydroxy, amino, carbamoyloxy or a group of the formula OR ', OCOR' or NHCOR ', and Y is hydrogen , lower alkyl, cyano or a group of the formula so represents COOR or CH2Z ', where R and Z' have the meaning given above, if X in the end product is CH2-Z ", where Z" -SH, Pyridinium or SR ", where R" is lower alkyl, aryl or a heterocyclic radical, the group CH2-Z 'can be converted into a group of the formula CH2Z "by substitution" 55 reactions with a Z "introducing agent, in which Z "has the meaning given above.

The inclusion compound (III) can be isomerized with a base to give the compound (IV), which can be converted into the final compound (I) in two different ways. According to the first type, the compound (IV) can be selectively ozonized on the isopropenyl double bond, whereby the compound (V) (n = 1) is obtained, which with suitable reducing agents, such as phosphorus tribromide or sodium Jo-65 did in acetyl chloride, to give the compound (V. ) (n = 0) can be reduced, which is then hydrolyzed under mild basic conditions or on silica gel to give the compound (VI) (n = 0). In the case of condensation with a suitable

7

651 570

Esters of glyoxylic acid will give compound (VII) (n = 0) which, with a chlorinating agent such as thionylchloride and pyridine, is converted into the chlorine derivative (VIII) (n = 0) and then into the phosphorane (IX) (n = 0) can be transferred.

In addition, the same reaction sequence is also carried out starting from the unexpected compound (VI) (n = 1), which is stable when Y is not a strong cleavable group. In the case of Compounds (IX) (n = 0), the compound can be selectively ozonized as a phosphonium salt under acidic conditions to give Compound (XI), which is easily obtained by heating in an inert solvent such as toluene at one temperature cyclized from 50 to 140 ° C to the compound (I).

In the case of compounds (IX) (n = 1), the compound to compound (X) must be reduced and then selectively ozonized to compound (XI), which gives compound (I).

According to the second type, the compound (IV) can be reduced under the usual conditions to the compound (XII) which is ozonized on both double bonds, the compound (XIII) and, after hydrolysis, the compound (XIV) being obtained. According to the same procedure as described above, the glyoxylation of the compound (XIV) gives the compound (XV) which is in the chlorine derivative

(XVI) and then can be converted into the phosphorane (XI), which is a general intermediate for both types of process.

If R '"denotes hydroxyalkyl, the reaction sequence 5 is preferably carried out while protecting the alcoholic function.

Compounds of the general formula (I) in which R "" denotes hydrogen can be obtained by hydrolysis or hydro-genolysis of the corresponding esterified compounds. Compounds of general formula (I) in which n = 1 are easily prepared starting from compounds of general formula (I) in which n = 0 according to the well known oxidation methods. Peracids can advantageously be used; 15 m-chloroperbenzoic acid and peracetic acid are preferred.

A number of experiments were carried out in vitro to determine the efficacy of (5R) -acetoxymethyl-2-acetoxy-methyl-2-penem-3-carboxylate (laboratory code FCE / 20077 / B40 / 341), (5R) -acetoxymethyl- Compare 2 - [(1-methyl-1 H-tetra-20 zol -5-yl) thiomethyl] -2-penem-3-carboxylate (Compound A) and two reference compounds. Table I below shows the results of the above experiments on MIC (minimum inhibitory concentration).

Table I: MIC ng / ml

tribe

FCE / 20077 / B40 / 341

Compound A

Ampicillin

Cefoxitin

Staphylococcus aureus 209P

0.39

0.39

<0.19

0.78

Staphylococcus aureus 153

1.56

0.78

1.56

0.78

Staphylococcus aureus PV2

0.39

0.78

<0.19

0.78

Staphylococcus aureus Smith ATCC 13709

<0.19

0.39

<0.19

0.78

Streptococcus pyogenes ATCC 12384

3.12

0.78

3.12

1.56

Escherichia coli B

1.56

0.78

0.39

1.56

Escherichia coli V14

1.56

0.78

1.56

3.12

Escherichia coli V23

3.12

0.78

3.12

12.50

Enterobacter sp. V19

12.50

> 100

> 100

12.50

Klebsiella pneumoniae ATCC 10031

-

3.12

50

0.78

Klebsiella sp. R2

25th

-

50

12.50

Proteus vulgaris VI 5

3.12

6.25

1.56

0.78

Proteus mirabilis VI 5

0.39

0.78

<0.19

0.78

Proteus mirabilis 525

3.12

0.78

0.39

1.56

Shigella flexneri

0.39

0.39

<0.19

0.78

Pseudomonas aeruginosa

3.12

0.39

25th

6.25

Salmonella typhimurium

1.56

0.78

0.78

3.12

Salmonella panamae Fl5

1.56

0.78

0.78

1.56

Salmonella Saint Paul F20

1.56

0.78

0.78

3.12

Salmonella derby F14

3.12

0.78

0.78

3.12

Salmonella montevideo Fl6

3.12

0.78

0.78

3.12

The following examples are intended to explain the present invention in more detail.

Example 1 :

4ß- (1,2-diacetoxymethyl-vinylthio) -1 - (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide cooch ocochj ococh,

"COOCH.

A solution of 2.0 g of methylpenicillanate S-oxide and 2.8 g of butynediol diacetate in 40 ml of toluene was heated to the reflux temperature for 24 hours. The compound mentioned in the title could be purified by column chromatography on silica gel, eluting with 96: 4 dichloromethane-ethyl acetate. 1.4 g of 4β- (l, 2-diacetoxymethyl-vinylthio) -l-

651 570

Obtained (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide.

NMR (CDCh): 2.03 8 (s, CH.1-C-), 2.15 and 2.20 8 (two s, 2 CHaCO), 2.88 8 (dd, Jgem = 14 Hz, Jvic eis = 4 Hz, C-3-Hct), 3.38 8 (dd, Jgem = 14 Hz, Jvic trans = 2 Hz, C-3-Hß),

3.83 (s, CH3O), 4.88 8 (Jvic = 6 Hz, CH27gf1, 4.92 8 (broad l «)

I II

-n c

CH2-C =), 4.93-5.33 8 (m, = CH: and CH), 5.328

coo

8th

(dd, Jvic = 4 and 2 Hz, C-4-H), 6.47 8 (t, Jvic = 6 Hz, = c-c (h9>).

k

5 Example 2:

4ß- (1,2-Diacetoxymethyl-vinylthio) -1 - (1 methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one-S-oxide

10th

0

1.7 g of 4β- (l, 2-diacetoxymethyl-vinylthio) -l- (l-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide were dissolved in 80 ml of dichloromethane. 0.5 ml of triethylamine was added and the solution was left to stand at room temperature for a few hours. After evaporation of the solvent, the compound mentioned in the title was obtained purely in quantitative yield.

NMR (CDCb): 2.13 (9H) and 2.32 (3H) 8 (two s, 2

CHjCO and 2 CH3-Ò =), 2.92 8 (dd, Jgem = 15 Hz, Jvic eis = 5 Hz, C-3-Ha), 3.388 (dd, Jgem = 15 Hz, Jvic trans

= 2.5 Hz, C-3-Hß), 3.828 (s, CH30), 4.885 (d, Jvic = 6.5 Hz,

25 cn_-ç =), 4.92 (s, CHj-C =), 5.15 8 (dd, Jvic = 5 and 2.5 Hz, (H)

C-4-H), 6.50 8 (t, Jvic = 6.5 Hz, = £ ~ (B2)> *

30 Example 3:

4ß- (1,2-diacetoxymethyl-vinylthio) -1-methoxyoxaloyl-azetin-din-2-one-S-oxide

2.0 g of 4β- (1,2-diacetoxymethyl-vinylthio) -1 - (1-methoxycarbonyl -2-methyl-l-propenyl) -azetidin-2-one-S-oxide were dissolved in 150 ml of dichloromethane and after cooling at - 78 ° C a stream of ozone was bubbled through in oxygen until a pale blue color appeared. The solution was brought to room temperature, shaken with an aqueous NaaSaOs solution and dried over NaaSO *. The organic phase obtained gave, after evaporation of the solvent in vacuo, 1.4 g of the compound mentioned in the title.

NMR (CDCh): 2.05 and 2.08 8 (two s, 2 CH3CO), 3.03 8 (dd, Jgem = 17 Hz, Jvic eis = 5.5 Hz, C-3-Ha), 3, 50 8 (dd, Jgem = 17 Hz, Jvic trans = 3 Hz, C-3-Hß), 3.90 8 (s, CH3O),

ch2-c =),

4.82 8 (d, Jvic = 6.5 Hz, (H) 4.90 8 (s, CHi-C =), 5.32 8 (dd, Jvic = 5.5 and 3 Hz, C-4- H), 6.47 8 (t, Jvic = 6.5 Hz, = cc (h.)).

50 h

IR (CH2Ch): 1830 cm-1 β-lactam C = 0.1750 cm-1 ester C = 0.1715 cm -'AmidC = 0.

55 Example 4:

4ß- (1,2-diacetoxymethyl-vinylthio) -1-methoxyoxaloyl-azeti-din-2-one

9

651 570

A solution of 1.4 g of 4ß- (l, 2-diacetoxymethyI-vinylthio) -l-methoxy-oxaloyl-azetidin-2-one-S-oxide in 10 ml of anhydrous dimethylformamide was cooled to - 25 ° C and 0.9 ml of phosphorus tribromide was added. After 10 min the mixture was diluted with ethyl acetate and washed twice with a saturated NaHCOj solution. After drying over NaaSOj and evaporation of the solvent, 0.9 g of the compound mentioned in the title was obtained.

NMR (CDCh): 2.07 S (s, 2 ChhCO), 3.17 S (dd, Jgem = 19 Hz, Jvic trans = 3.5 Hz, C-3-Hß), 3.65 8 (dd, Jgem = 19 Hz,

Jvic eis = 5 Hz, C-3-Ha), 3.90 ô (s, CH3O), 4.73 5 (d, Jvic = 6.5 Hz, CH2 ~ ^ =) '4.88 5 (broad s , CH2-Ç =), 5.52 5 (dd, Jvic = 5

and 3.5 Hz, C-4-H), 6.25 8 (t, Jvic = 6.5 Hz, =? "C (H2)) * 5 h

IR (CHCh): 1815 cm-1 β-lactam C = 0.1745 cm-1 ester C = 0.1710 cm-1 amide C = 0.

10 Example 5:

4ß- (1,2-diacetoxymethyl-vinylthio) -azetidin-2-one

. I S * S ~ ^ r | ^^ OCOC H3

j_N> 0 "CoCOC. ^

cooch,

P

N \

Ti ococh3 '^ • OCOCHq

1.5 g of 4β- (l, 2-diacetoxymethyl-vinylthio) -l-methoxyoxa-loyl-azetidin-2-one was dissolved in 100 ml of methanol and a few g of silica gel were added with stirring. After 1 h, the silica gel was filtered off and the methanolic solution was evaporated to give 0.8 g of 4β- (1,2-diacetoxyme-thvl-vinylthio) -azetidin-2-one.

"NMR (CDCh): 2.25 5 (s, 2 CHjCO), 2.98 S (dd, Jgem = 15 Hz, Jvic trans = 2 Hz, C-3-Hß), 3.48 8 (dd, Jgem = 15 Hz, Jvic cis = 4.5 Hz, C-3-Ha), 4.78 8 (d, Jvic = 7 Hz, CH2-g-),

20 4.87 8 (s, CH2-C =), 5.03 8 (dd, Jvic = 4.5 and 2 Hz, C-4-H), 6.02 8 (t, Jvic = 7Hz, = cc (H,)), 7.13 8 (broad s, NH).

25th

IR (CHCh): 1770 cm-C = 0.

β-lactam C = 0.1740 cm-1 ester

Example 6:

4ß- (1,2-diacetoxymethyl-vinylthio) -azetidin-2-one-S-oxide f-f * s ^ rj ^ 0C0CH3 i-N ^ 0 ^ 0C0CIi3

V

cooch,

O II

rf X

■ P N \

ococh3 ococh,

0.800 g of 4ß- (l, 2-diacetoxymethyl-vinylthio) -l-methoxy-oxaloyl-azetidin-2-one-S-oxide was dissolved in 80 ml of methanol and a few g of silica gel were added with stirring. After 1 h the silica gel was filtered off and 0.5 g of 4β- (1,2-diacetoxymethyl-vinylthio) -azetidin-2-one-S-oxide was obtained after evaporation of the solvent.

NMR (CDCh): 2.13 8 (s, 2 CHjCO), 3.0 to 3.3 8 (m, 2 protons at C-3), 4.70 8 (m, C-4-H), 4 , 88 8 (d, Jvic = 6 Hz,

CH2- £ =), 4.93 8 (s, CH2-C =), 6.53 8 (t, Jvic = 6 Hz,

= c-c (h,)),

6 z

7.23 8 (s, NH).

IR (CHCh): 1790 cm "C = 0.

β-lactam C = 0.1745 cm -1 ester

Example 7:

4β-acetylglycolylthio-1-aceto xymethyloxyoxaloyl-azetidin-2-one

ococh3 _ k rf t ococh3

ococh3 *

L.1 0

coocii2ococh3 cooch2ococii3

0.8 g of 4β- (l, 2-diacetoxymethoxy-vinylthio) -l- (l-acetoxy-methyloxycarbonyl-2-methyl-1-propenyl> azetidin-2-one was dissolved in 80 ml of dichloromethane, to -78 ° C After cooling with a stream of ozone in oxygen until a blue color appeared, the solution was dried over Na2S04 after shaking with an aqueous NaaSaOs solution to obtain 0.45 g of the title compound.

NMR (CDCh): 2.10 and 2.13 8 (two s, 2 CHsCO), 3.20 8 (dd, Jgem = 17 Hz, Jvic trans = 3.5 Hz, C-3-Hß), 3, 77 8 (dd, Jgem = 17 Hz, Jvic eis = 5.5 Hz, C-3-Ha), 4.73 8 (s, -CO-CH2-OCO-), 5.73 8 (dd, Jvic = 5.5 and 3.5 Hz, C-4-H), 5.87 8 65 (s, COO-CH2-OCO).

Example 8:

4ß-AcetyIgIycolylthio-azetidin-2-one

651570 10

| —Ococh3 ^ r ~ f Y "0C0CH3

> -N> ° 0 o ^ - ^ H

"r

COOCH

0.6 g of 4β-acetylglycolylthio-l-methoxyoxaloyl-azetidin-2-one was dissolved in 100 ml of methanol and a few g of silica gel were added with stirring. After 1 h, the silica gel was filtered off and the solution obtained, after evaporation of the solvent, gave 0.35 g of the compound mentioned in the title.

r — SS ^ f ^ ° cocn3

\ N \ ^ OCOCilj c? II

NMR (CDCh): 2.20 8 (s, ChhCO), 3.03 8 (dd, Jgem = 16 Hz, Jvic trans = 2.5 Hz, C-3-Hß), 3.50 5 (dd, Jgem = 16 Hz, io Jvic eis = 4.5 Hz, C-3-Ha), 4.77 8 (s, -CO-CH2-OCO-), 5.32 5 (dd, Jvic = 4.5 and 2 , 5 Hz, C-4-H), 6.40 8 (broad s, NH).

Example 9:

4ß- (1,2-diacetoxymethyl-vinylthio) -1 - (1 -acetoxymethyloxy-carbonyl-1-hydroxymethyl) -azetidin-2-one n ^ X

0 1

ocochj ococh,

COOCI ^ OCOCI ^

0.7 g of acetoxymethylglyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate) was dissolved in 30 ml of benzene and the solution obtained was refluxed for 20 minutes using a Dean-Stark device.

After cooling to 50 to 60 ° C., 0.7 g of 4β- (1,2-diacetoxymethyl-vinylthio) -azetidin-2-one, dissolved in 10 ml of benzene, were added and the solution obtained was kept under reflux for 2 hours. The compound mentioned in the title was obtained in almost quantitative yield and could be used as a crude mixture for the next step. A pure sample was prepared for preparative analytical purposes. Obtain thin layer chromatography.

NMR (CDCh): 2.07 8 (s, 3 CH3CO), 2.97 8 (dd, Jgem = 18 25 Hz, Jvic trans = 2 Hz, C-3-Hß), 3.40 8 (dd, Jgem = 18 Hz, Jvic eis = 4 Hz, C-3-Ha), 4.70 8 (d, Jvic = 6 Hz, CH2-c =), 4.775

(H)

(s, CH2-Ç =), 5.0-5.4 8 (m, C-4-H and -n-ch-coo-), 5.77 8

Ó (H)

(s, -COO-CH2-OCO-), 6.12 8 (t, Jvic = 6 Hz, = c-c (h_)).

h z

Example 10:

4ß- (1,2-diacetoxymethyl-vinylthio) -1 - (1 -acetoxymethyloxy-35 carbonyl-1-chloromethyl) -azetidin-2-one

> rf it000 '"3

J N ^ -OH ^ ~ '0C0CK3 N ^ cx "^ OCOCH3

cooch2ococh3 cooch2ococh3

0.6 g of 4β- (l, 2-diacetoxymethyl-vinylIthio) -1- (1-aceto-xymethyloxycarbonyl-l-hydroxymethyl) -azetidin-2-one, dissolved in 15 ml of tetrahydrofuran, was cooled to 0 ° C .; 0.115 g pyridine and 0.104 ml thionyl chloride were added and the mixture was stirred for 10 minutes. The insoluble material was filtered off and the solution was evaporated in vacuo at room temperature, the compound mentioned in the title being obtained in high yield. For analytical purposes, a sample was purified by preparative thin layer chromatography, but the crude mixture could be used for the next step without purification.

45 NMR (CDCh): 2.14 8 (s, 3 CHjCO), 3.10 8 (dd,

Jgem = 15.5 Hz, Jvic trans = 2 Hz, C-3-Hß), 3.55 8 (dd, Jgem = 15.5 Hz, Jvic eis = 5 Hz, C-3-Ha), 4.77 8 (d, Jvic = 6.5

HZ 'CH2 ^ ")' 4.83 5 (S 'CH2 ~ C =)' 5'4" 5'9 5 (m 'C-4-H

50 and -N-CHC1- COO-), 5.88 8 (s, -COO-CH2-OCO-), 6.13 8 (t, Jvic = 6.5 Hz, = <j> c (H2)) .

Example 11:

55 4ß- (1,2-Diacetoxymethyl-vinylthio) -1 - (1 -acetoxymethyloxy-carbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one cooch2ococh3 cooch2ococh3

A solution of 0.430 g of 4ß- (1,2-diacetoxymethyl-vinyl-thio) -1 - (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azeti-din-2-one in 5 ml of tetrahydrofuran and 5 ml of dioxane with one

The content of 0.520 g of triphenylphosphine and 0.08 ml of pyridine was stirred at 50 ° C. overnight. The phosphorane obtained was purified by column chromatography on silica gel

11

651 570

nigt, eluting with 70:30 dichloromethane-ethyl acetate; 0.400 g of the compound mentioned in the title were obtained.

NMR (CDCh); 2.05 5 (s, 3 CHjCO), 4.70 8 (d, Jvic = 6.5

Hz, CH, -ç =) f 4.73 8 (s, CH: -Ç =), 5.77 8 (s, -COO-CH2- (H) T

OCO-), 5.90 8 (t, Jvic = 6.5 Hz, = <j-C (H2)), 7.1-8.0 0 (m, 3 OHs).

Example 12:

4β-Acetylglycolylthio-1 - (1-acetoxy methoxyoxycarbonyl-1-tri-phenylphosphoranylidenemethyl) -azetidin-2-one

OCOCH3 OCOCH,

COOCU2OCOCH3

XOCH,

r ~ f o ^ - ^ PPh,

COOCILOCOCII,

0.7 g of 4ß- (l, 2-diacetoxymethyl-vinylthio) -l- (l-acetoxyme-thyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azeti-din-2-one were dissolved in 40 ml of dichloromethane and after cooling to - 20 ° C 50 ml of a 10% solution of trifluoroacetic acid in dichloromethane were added. After a few minutes, a stream of ozone in oxygen was bubbled through at -20 ° C until a slight blue color appeared. At this point the reaction was stopped and a few drops of trimethyl phosphite were added. The organic solution was washed with a saturated 20 NaHCO ^ solution and dried over NaSO- to give 0.550 g of the compound mentioned in the title. NMR (CDCh): 2.10 and 2.15 8 (two d, 2 CH3CO), 4.72 8 (s, -CO-CH2-OCO-), 5.64 8 (s, -COO-CHa-OCO ), 7.1 to 8.0 8 (m, 3 CaHs).

25th

Example 13:

(5R) -acetoxymethyl-2-acetoxymethyl-2-penem-3-carboxylate rT'V "-

Y — N>

OCOCH,

> PPh3

COOCH2OCOCH3

* l-fir

OCOCH3

Y — N

O ^ COOCH2OCOCH3

0.7 g of 4β-acetylglycol thio-1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one were dissolved in 30 ml of dry toluene and heated to reflux temperature for 2 hours. The reaction mixture, which consisted of the compound mentioned in the title and triphenylphosphine oxide, was purified by brief column chromatography on silica gel, eluting with 97: 3 dichloromethane-ethyl acetate; 0.250 g of acetoxymethyl-2-acetoxy-methyl-2-penem-3-carboxylate were obtained.

NMR (CDCh): 2.11 and 2.13 8 (two s, 2 CH3CO), 3.49 8 (dd, Jgem = 16.5 Hz, Jvic trans = 2 Hz, C-6-Hß), 3, 86 8 (dd, Jgem = 16.5 Hz, Jvic eis = 3.8 Hz, C-6-Ha), 5.12 and 5.45 8

(two d, Jgem = 15.5 Hz, = Ç-C Ha), 5.68 8 (dd, Jvic = 3.8 and 2 Hz, C-5-H), 5.87 8 (s, -COO -CH2-OCO-).

IR (CHCh): 1800 cm'1 β-lactam C = 0.1750-1725 cm- 'ester C = 0.

40 UV (EtOH): Xmax 325 nm.

MS: m / e 315.04108 (M +) calculated for CnHuNOrS 315.04127.

45 Example 14:

4ß- (1,2-diacetoxymethyl-vinylthio) -1 - (1-p-nitrobenzyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one

OAc OÄC

YE

OAC OAc

COOCH.

K °>

NO.

The title compound was obtained by the method described in Example 9 using p-nitrobenzylglyoxylate which had been freshly prepared by ozonolysis of p-nitrobenzyl fumarate.

NMR (CDCh): 2.1 8 (s, 6H), 2.8-3.7 8 (m, 2H), 4.7-4.9 8

(m, 5H), 5.1-5.6 8 (m, 2H), 5.2 S (m, IH), 6.1 8 (m, IH), 7.5-8.3 8 (m , 4H).

Example 15:

60 4ß- (1,2-diacetoxymethyl-vinylthio) - (1-p-nitrobenzyloxycarbonyl -1 -chloromethyl) -azetidin-2-one

651 570

12

The title compound was prepared according to the procedure described in Example 10.

NMR (CDCh): 2.1 Ô (s, 6H), 2.8-3.7 Ô (m, 2H), 4.7-4.9 5 (m, 4H), 5.2-5.4 ô (m, 1H), 5.4 5 (m, 2H), 6.1-6.3 8 (m, 2H), 7.5-8.4 8 (m, 4H).

Example 16:

4ß- (1,2-Diacetoxymethyl-vinylthio) -1 - (1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one

The title compound was prepared according to the procedure described in Example 11.

COOCH

OAc OAC

"N ^ | = PPh3 j ^

K °>

NO,

Example 17:

4β-Acetylglycolylthio-1 - (1-p-nitrobenzyloxy carbonyl-1-tri-15 phenylphosphoranylidenemethyl) -azetidin-2-one

OAc

: PPh-

COOCH.

; <ö>

NO "

The title compound was prepared according to the procedure described in Example 12.

Example 18:

25 (5 R) -p-nitrobenzyl-2-acetoxymethyl-2-penem-3-carboxylate

I-3Ac s ^ j = PPh3

COOCH2 "^ Oy ~ No2

OAc

COOCH.

> - © ~

NO "

The title compound was prepared according to the procedure described in Example 13.

NMR (CDCh): 3.75 ô (1H, dd, J = 2.3 Hz, 16.8 Hz, H-6a), 3.87 8 (1H, dd, J = 3.6 Hz, 16.8 Hz, H-6ß), 5.14 8 (1H, d, J = 15.8, = C-CHjO-), 5.50 8 (1H, d, J = 15.8 Hz, -Ó-CHzO) , 5.71 8 (1 H, dd, J = 2.3 Hz, 3.6 Hz, H-5).

[a] D + 87 ° (c = 1.2 in CHCh).

IR (CHCh): 1800 (β-lactam), 1750 and 1720 cm-1. UV (ÄtOH): 265 (e 11000) and 322 (8 7000) nm. M.S .: m / e 378 (M +).

40 mp 122 to 123 CC.

Example 19:

(5R) -2-acetoxymethyl-2-penem-3-carboxylic acid rOpüac ^ -> rfjP * 0

}> \ & N

O COOCH2- ^ O) ~ n02 0 COOH

200 mg (5R) -p-nitrobenzyl-2-acetoxymethyl-2-penem-3-carboxylate, prepared as described in Example 18, were dissolved in 12 ml of ethyl acetate. 8 ml of a 0.2M NaHCCb solution and 400 mg of 10u / o Pd / C were added and the resulting two-phase mixture was shaken under hydrogen for 60 minutes. After filtering the catalyst, the aqueous phase was acidified with 20 ml of 50% aqueous citronic acid and extracted three times with methylene chloride. The organic layers were measured over Na: SC> 4

dried and evaporated to give 60 mg of the title compound. 55 IR (CHCh): 1790 (β-lactam), 1735 and 1700 cm-1. UV (EtOH): 300 nm.

Example 20:

4ß- (1-Hydroxymethyl-vinylthio) -1 - (1-methoxycarbonyl-bo2-methyl-2-propenyl) -azetidin-2-one-S-oxide

P-Ï - * AT

u H COOCH, H COOCH,

13

651 570

4 g of methyl penicillanate S-oxide were dissolved in 15 ml of toluene and refluxed for 8 hours with 15 ml of propargyl alcohol. After evaporation in vacuo, the residue was purified by short column chromatography on silica gel, eluting with dichloromethane-ethyl acetate (1: 1). 2.8 g of the compound mentioned in the title were obtained.

NMR (CDCh): 1.96 5 (broad s, 3H, C-CH.Q, 2.91 and 3.35 5 (dd, 2H, J = 2 Hz, 5 Hz, 15 Hz, CO-ch2-CH -S), 3.78 8 (s, 3H, COOCHj), 4.36 8 (broad s, 2H, ch2oh), 4.90-5.25 8 (m, 3H, CH-COOCH3- C-Ò = ch2), 5.35 8 (m, 1H, 5 ch2-CH-S), 5.88 8 (s, 2H, ch2 = Ò-S).

Example 21:

4ß- (1-hydroxymethyl-vinylthio) -1 - (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one-S-oxide fÇP "~ P?"

h cooch,

3 cooch3

3.0 g of 4β- (l-hydroxymethyl-vinylthio) -1- (1-methoxycarbonon-2-methyl-2-propenyl) -azetidin-2-one-S-oxide were dissolved in 100 ml of dichloromethane and a few h at room temperature. After evaporation of the solvent, the residue consisted of the pure compound mentioned in the title, which had been obtained in quantitative yield.

20 NMR (CDCh): 2.08 8 (s, 3H, = '- CH3), 2.18 (s, 3H, =' - CHj), 2.7-3.6 (m, J = 2 Hz, 5 Hz, 16 Hz, CO-ch2-CH-S), 3.78 (s, 3H, COOCH3), 4.35 (s, 2H, ch2oh), 5.32 (m, 1H, CH-S), 5.90 (broad s, 2H, = CHz).

25 Example 22:

4ß- (l-Bromomethyl-vinylthio ') - 1 - (l-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one

J-i f "oh cooch,

J

0 y "

cooch,

1.8 g of 4β- (1-hydroxymethyl-vinylthio) -1- (1-methoxycarbo-nyI-2-methyl-l-propenyl) -azetidin-2-one-S-oxide were dissolved in 40 ml of dimethylformamide and added to - Chilled to 20 ° C. 0.7 ml of pyridine and 3.0 ml of PBn were added and the mixture was stirred for 15 minutes. Ethyl acetate was added and the organic layer was shaken with a saturated NaHCCh solution, washed with water and then dried over Na2SC> 4, whereby 1.6 g of the compound mentioned in the title were obtained after evaporation of the solvent.

NMR (CDCh): 2.04 8 (s, 3H, = ^ CH3), 2.24 8 (s, 3H,

O

= SCR3] '3.24 8 (dd, J = 2.8, 5, 16 Hz, 2H, c-ch2-ch),

40 3.75 (s, 3H, OCH3), 4.02 (s, 2H, CHaBr), 5.24 (broad s, 1H, = CH), 5.37 8 (dd, J = 2.8 Hz, 5 Hz, 1 H, ch2-CH-S), 5.60 (broad s, 1H, = CH).

45 Example 23:

4β- [1 - [(1-Methyl-1 H-tetrazol-5-yl) thiomethyl] vinylthio] -1 - (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one

n n

N

ch,

cooch,

cooch,

1.4 g 4ß- (l-bromomethyl-vinylthio) -l- (l-methoxycarbonyl- 60 (NMR (CDCh): 2.00 8 (s, 3H, = Ö-CH3), 2.22 8 (s, 3H,

2-methyl-l-propenyl) -azetidin-2-one were dissolved in 25 ml of tetra- = C-CHî), 2.70-3.80 8 (m, 2H, 3 = 2 Hz, 5 Hz, 15 Hz, Dissolved CO-hydrofuran and cooled to 0 ° C. 0.8 g l-methyl-5-thiol-ch2-CH-S), 3.72 5 (s, 3H, COOCH3), 3.95 8 (see 3H , N-CH3),

Tetrazole sodium salt was added and the mixture 3 h 4.10 8 (s, 2H, ch2-S), 5.18 8 (broad s, 1h, S-C = 6h), 5.36 8

stirred at room temperature. After filtering off the insoluble (m, 1H, CHi-CH-S), 5.57 8 (broad s, 1H, S-Ó = Ó-H).

The mixture was diluted with ethyl acetate, 65

washed with water, dried over Na2SC> 4 and used- Example 24:

steams. The residue consisted of 2.0 g of the pure 4ß _ [(1-methyl-1 H-tetrazol-5-yl) thioacetyl-thio] -1-methoxy

named connection. xaloyl azetidin-2-one

651 570

14

cooch.,

n-sY "

<? - n '\ _ "

O] = 0

cooch,

n— n

I o I

-S- "

I.

ch,

1.8 g of 4β- [l - [(l-methyl-1H-tetrazol-5-yl) thiomethyl] vinyl thio] -1 - (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidine- 2-ones were dissolved in 200 ml dichloromethane and cooled to -78 ° C. A stream of ozonized oxygen was bubbled through the solution until blue color appeared. A few drops of P (OCH3) j were added, the mixture was brought to room temperature and evaporated to give 1.3 g of the compound mentioned in the title.

NMR (CDCh): 2.9-3.7 ô (m, 2H, COCHiCHS), 3.85 ô (s, iO 3H, COO-CHs), 3.98 (s, 3H, N-CH3), 4 , 35 (s, 2H, CH2S), 5.75 (m, 1H, CH2CHS).

Example 25:

4ß - [(1-Methyl-1 H-tetrazol-5-yI) thioacetyl-thio] -azetidin-2-one n n rfs- ~ TsX-V

^ NYo CH3

COOCH-

n n

-H

1.2 g of 4β - [(1-methyl-1 H-tetrazol-5-yl) thioacetylthio] -1-methoxyoxaloyl-azetidin-2-one were dissolved in a 1: 1 mixture of ethyl acetate-methanol and a few g of silica gel were added with vigorous stirring. After 1 h the insoluble material was filtered off and the solution was in

Evaporated vacuum. The compound mentioned in the title crystallized from methanol-ethyl ether. Yield 0.6 g.

Example 26:

3o 4ß - [(1-Methyl-1 H-tetrazol-5-yl) thioacetylthio] -1 - (1-acetoxy-methyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one

1 °

# H

n - n 1

ch3

n n r-fV-1? *

g N-n ^ oh

COOCH ,. OCOCH,

ch,

1.5 g of 4β - [(1-methyl-1 H-tetrazol-5-yl) thioacetylthio] -azeti-din-2-one were dissolved in 50 ml of benzene with 1.2 g of acetoxymethylgly-oxylate (freshly prepared by ozonolysis of diacetoxyme-thyl fumarate) is kept at reflux. The reaction was complete after 3 hours. The crude oil obtained after evaporation of the solvent could be used for the next step without further purification. A sample was purified by thin layer chromatography for spectroscopic data.

NMR (CDCh): 2.05 5 (s, 3H), 2.7-3.8 (m, 2H), 3.95 5 (s, 3H), 4.30 ô (s, 2H), 5, 40 5 (s, 1H), 5.50 8 (m, 1H), 5.80 8 (s, 45 2H).

Example 27:

4β - [(1-Methyl-1 H-tetrazol-5-yl) thioacetylthio] -1- (1 -acetoxy-methyloxycarbonyl-1-chloromethyl) -azetidin-2-one n n n n

J, —Ny ^ n CH3) - 'cn3

COOCH2OCOCH3 COOCH2OCOCH3

The oil obtained according to the previous example, which consisted of crude 4β - [(1-methyl-1H-tetrazol-5-yl) thioacetylthio] -l- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one, was dissolved in 20 ml of anhydrous tetrahydrofuran and treated at 0 ° C. with equimolar amounts of pyridine and thionyl chloride until all of the starting material had disappeared. After filtering off the insoluble matter, the filtrate was immediately used for the next step.

65 Example 28:

4ß - [(1-Methyl-1 H-tetrazol-5-yl) thioacetyl-thio] -1 - (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one

15

651 570

N —N

c i O I

r-r "

Cl ch,

cooch2ococn3

> PPh3 cooch ococh

N I

ch,

The solution containing the crude 4β - [(1-methyl-1H-tetrazol-5-yl) thioacetylthio] -1 - (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one was 800 mg of triphenylphosphine and 0.4 ml of pyridine are added and the mixture obtained is heated to 60 to 70 ° C. for a few hours. The

Phosphorane was purified on silica gel, eluting with dichloro-methane-ethyl acetate (1: 1).

Example 29:

(5R) -acetoxymethyl-2 - [(1-methyl-1 H-tetrazol-5yl) thiomethyl] -2-penem-3-carboxylate

0

N --_

> PPh3 coocii2ococh3

I.

ch,

n n

0 cooch2ococh3

0.500 g of 4β - [(1-methyl-I H-tetrazol-5-yl) thiomethylacetyl-thio] -1 - (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one was dissolved in 30 ml of toluene and heated to 100 ° C for 2 h. The title compound was purified from PPI13O by short column chromatography on silica gel, eluting with dichloromethane-ethyl acetate (8: 2).

N-H

I.

ch,

cooch.

NMR (CDCh): 2.15 5 (s, 3H, COCH3), 3.30-4.03 S (m, J = 4 Hz, 2 Hz, -CH2- (6), 3.97 ô (s, 3H, -NCH3), 4.56 8 (d, 25 J = 14 Hz, 1 H, HCH-S), 4.84 8 (d, J = 14 Hz, 1 H, HCH-S), 5.65 8 (dd, J = 4 Hz, 2 Hz, 1 H, H-5a), 5.88 8 (s, 2H, COOCH20).

Example 30: 30 (5R) -2 - [(I-methyl-1 3-carboxylic acid

H-tetrazol-5-yl) thiomethyl] -2-penem-

cooh

N

J,

no.

The title compound was obtained according to the procedure described in Example 19. The (5R) -p-nitrobenzoyl-2 - [(1 -methyl-1H-tetrazol-5-yl) thiomethyl] -2-penem-3-carboxylate was obtained by a procedure similar to that described in U.S. Pat previous examples.

40 IR (CHCh): 1800 (β-lactam), 1750 and 1720. Example 31:

Methyl 6a- (1'-hydroxyethyl) penicillanate S-oxide lf 'COOCH,

Oli ch i H

N -

O

h ii

" 1

0 7 4 / - '/ COOCH,

A solution of 2.3 g of methylpenicillinate S-oxide in 50 ml of anhydrous tetrahydrofuran was cooled to -78 ° C. Lithium diisopropylamide (freshly prepared from 5 ml diisopropylamine and 20 ml of a 1.6M BuLi-hexane solution) dissolved in anhydrous tetrahydrofuran was added and the mixture was left at -78 ° C for 10 minutes. 5 ml of acetal dehyde was gradually added and the whole was stirred for 15 minutes. Then the reaction mixture was quenched with a saturated aqueous NH4C1 solution, extracted with ethyl acetate, washed twice with water and dried over NazSOj. After evaporation of the solvent, the residue was briefly purified by column chromatography on silica gel, eluting with dichloromethane-ethyl acetate (1: 1). Yield 1.5 g. The connection mentioned in the title consisted of a 2: 3

Mixture of epimers bearing the carbon atom-55 the hydroxyl group, based on NMR, the new Cö-Cä bond is only in the a-position due to the stereospecificity of the reaction under the conditions used.

NMR (C DCh): 1.27 8 (s, 3 H, a-CHj), 1.40 8 (d, 3 H, J = 5.7 Hz, CH3-CHOH) major isomer, 1.48 8 (d , 3H, J = 5.7 Hz, bo CH3-CHOH) lower isomer, 1.70 8 (s, 3H, ß-CH3), 3.4-3.8 8 (m, 1H, H-6), 3.80 8 (s, 3H, COOCH3), 4.1-4.7 8 (m, 1 H, CHOH), 4.50 8 (s, 1 H, H-3), 4.98 8 (i.e. , J = 1.9 Hz, 1H, H-5) lower isomer, 5.05 8 (d, J = 1.9 Hz, IH, H-5) major isomer.

65

Example 32:

Methyl 6- (1-hydroxyethyl) -3-penicillanate

651 570

16

OH

A weak excess of lithium diisopropylamide was added at -78 ° C. under nitrogen to a solution of 2.2 g of methylpenicillanate in 30 ml of anhydrous tetrahydrofuran. An excess of acetaldehyde was added dropwise, the mixture was stirred for 5 min, quenched with a trace of acetic acid, poured into water and extracted with methylene chloride. The dried over NaaSCh and in vacuo

vaporized organic layers gave 0.8 g of the compound mentioned in the title.

Example 33:

Methyl 6- (l-p-nitrobenzyloxycarbonyloxyethyl) -3-penicilla-nat

1.2 g of methyl 6- (l-hydroxyethyl) -3-peniciIlanat were dissolved in 40 ml of tetrahydrofuran, cooled to -78 ° C and treated with 1 equivalent of butyllithium. 1.2 equivalents of p-nitrobenzyloxycarbonyl chloride were added to the resulting mixture. After 30 minutes at -78 ° C., the reaction mixture was left to stand at room temperature for 60 minutes, poured into water and extracted with methylene chloride.

After drying over NasSO 4 and evaporation, 1.4 g of the compound mentioned in the title were obtained.

25th

Example 34:

Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicilla-nat-S-oxide

1.8 g of methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3- Example 35:

penicillanate were dissolved in 50 ml of methylene chloride and at 40 4ß- (l, 2-diacetoxymethyl-vinylthio) -3- (l-p-nitrobenzyloxycar-

0 ° C treated with 1.5 equivalents of m-chloroperbenzoic acid. bonyloxyethyl) -l- (l-methoxycarbonyl-2-methyl-2-propenyl) -

The organic phase was shaken with saturated NaHCCb solution azetidin-2-one-S-oxide, extracted, dried over NaCl and evaporated. 1.4 g of the expected sulfoxide were obtained.

oMTa m OCO0PNB °

Y * "V ^ SvX) COCH3

H "'COOCH3

A solution of 2.0 g of methyl 6- (l-p-nitrobenzyloxycar-bonyloxyethyl) -3-penicillanate-S-oxide and 2.4 g of butynediol diacetate in 50 ml of toluene was kept under reflux for 24 hours. The inclusion compound was then purified by column chromatography, eluting with 9: 1 dichloromethane-ethyl acetate. 1.1 g of the compound mentioned in the title were obtained.

Example 36:

55 4ß- (l, 2-Diacetoxymethyl-vinylthio) -3- (l-p-nitrobenzyloxycar-bonyloxyethyl) -1 - (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one-S-oxide

17th

651 570

1.3 g of 4ß- (1,2-diacetoxymethyl-vinylthio) -3- (lp-nitrobenzyloxycarbonyloxyethyl) -1 - (methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide were used dissolved in 80 ml dichloromethane. 0.3 ml of triethylamine was added and the mixture was left to stand at room temperature for 2 hours. The pure,

The compound mentioned in the title was obtained in quantitative yield when the solvent was evaporated off.

Example 37:

5 4ß- (r, 2-diacetoxymethyl-vinylthio) -3- (1-p-nitrobenzyloxycar-bonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one-S-oxide oco2pnb

Cococh3 ococn3

o ocojpnb d ococh3

ococh,

A solution of 1.1 g of 4ß- (1,2-diacetoxymethyl-vinylthio) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (methoxycarbonyl-2-methyl-l-propenyl) -azetidin-2-one-S oxide in 100 ml dichloromethane was cooled to -78 ° C. Ozone in oxygen was bubbled through until blue color appeared. The solution was poured with an aqueous Na2S20s solution20

and dried over Na2S04. After evaporation, 0.5 g of the compound mentioned in the title was obtained.

Example 38:

4ß- (1,2-diacetoxymethyl-vinylthio) -3- (1-p-nitrobenzyloxy car-bonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one

OCOjPNB

tCC

cooch,

ococh3 ococii.

OCOjPNBjjj! ^

Xccoch3

ococh,

cooch,

A solution of 0.8 g of 4β- (1,2-diacetoxymethyl-vinylthio) - NaHCOj solution was washed. The one dried over Na2SÛ4

3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one in 15 ml of anhydrous dimethylformamide was cooled to -20 ° C. and 0.6 ml of phosphorus tribromide were added. The reaction mixture was diluted with ethyl acetate after 10 min and twice with an evaporated and evaporated organic phase gave 0.4 g of the reduced compound.

Example 39:

4ß- (1,2-diacetoxymethyl-vinylthio) -3- (1-p-nitrobenzyloxycar-bonyloxyethyl) -azetidin-2-one oco2pnb ococh,

oc02pnb ococh ococii.

1.2 g of 4ß- (1,2-diacetoxymethyl-vinylthio) -3- (1-p-nitroben- 55 short column chromatography gave 0.4 g of the title zyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one were in Dissolved methanol and 2 g of silica gel was added to the solution. After 60 min the insoluble material was filtered off and the organic phase was evaporated. A named connection.

Example 40:

4ß- (1,2-diacetoxymethyl-vinylthio) -3- (1-p-nitrobenzyloxycar-60 bonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl -1-hydroxy-methyl) -azetidin-2-one

OCOjPNB

cocii3 coch,

oco2pnb

à

° I

oodch3 ococil,

651 570

18th

0.6 g of 4ß- (l, 2-diacetoxymethyl-vinylthio) -3- (lp-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one, dissolved in 30 ml of benzene, and 0.6 g of acetoxymethylglyoxylate (freshly prepared by ozonolysis of Diacetoxymethyl fumarate) were refluxed. The reaction was complete after 2 hours. The

Condensation product could be used for the next step without further purification.

Example 41:

5 4ß- (1,2-diacetoxymethyl-vinylthio) -3- (1-p-nitrobenzyloxy-carbonyloxyethyl) -1 - (1 -acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one coch3

ococh,

cooch2ococh3

0c02pnb

0c0ch3 ococh,

N \ ^ rCl cooch20c0ch3

0.5 g of 4β- (l, 2-diacetoxymethyl-vinylthio) -3- (lp-nitrobenzyloxycarbonyloxyethyl) -1 - (1-acetoxymethyloxycarbonyl-l-hydroxymethyl) -azetidin-2-one was dissolved in 12 ml of anhydrous tetrahydrofuran and cooled to 0 ° C. 1.1 equivalents: pyridine and 1.1 equivalents of thionyl chloride were added. The mixture was stirred for 10 minutes. The insoluble material was filtered off and the solution was evaporated at room temperature, the compound mentioned in the title being obtained in almost quantitative yield. The product could be used for the next step without further purification.

Example 42:

4ß- (1,2-diacetoxymethyl-vinylthio) -3- (1-p-nitrobenzyloxycar-bonyloxyethyl) -1 - (acetoxymethyloxycarbonyl-1-triphenyl-phosphoranylidenemethyl) -azetidin-2-one oco2pnb ococh,

cooch2ococh3

OCOjPNB

coch3

ococh, PPlï ^ 3

N \ j>

cooch, ococh

A solution of 0.760 g of 4β- (1,2-diacetoxymethyl-vinylI-thio) -3- (1-p-nitrobenzoyloxycarbonyloxyethyl) -1 - (1-acetoxymethyloxycarbonyl-l-hydroxymethyl) -azetidin-2-one in 10 ml of tetrahydrofuran and 10 ml of dioxane was stirred with 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine at 50 ° C overnight. The phosphorane was purified by column chromatography on silica gel, with dichloro-

35 methane-ethyl acetate was eluted. 0.480 g of the compound mentioned in the title were obtained.

Example 43:

4ß-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxy-40 ethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one coocH2ococh3

0.45 g of 4ß- (l, 2-diacetoxymethyl-vinylthio) -3- (lp-nitrobenzyloxycarbonyloxyethyl) -1 - (acetoxymethyloxycarbonyl-1-tri-phenylphosphoranylidenemethyl) -azetidin-2-one were dissolved in 50 ml of dichloromethane and cooled to - 20 ° C. 30 ml of a solution of trifluoroacetic acid in dichloromethane was added. After a few minutes, ozone was bubbled through in oxygen until a slight blue color appeared. The reaction was stopped and a few drops of tri-methyl phosphite were added. The organic phase coocii2ococh3

was washed with saturated NaHC03 solution and dried over Na2S04. 0.260 g of the compound mentioned in the title were obtained.

Example 44:

4ß- (1,2-Diacetoxymethyl-vinylthio) -3- (1-p-nitrobenzyloxycar-bonyloxyethyl) -1 - (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one

19th

651 570

1.5 g of 4ß (1,2-diacetoxymethyl-vinylthio) -3- (lp-nitrobenzyloxycarbonyloxyethyl) -1 - (methoxycarbonyl-2-methyl-l-propenyl) -azetidin-2-one-S-oxide were used in 10 ml of anhydrous dimethylformamide dissolved and cooled to - 20 ° C. 0.8 ml of phosphorus tribromide was added, the mixture was stirred for 10 min, diluted with ethyl acetate and washed twice with saturated NaHCCb solution. The about Na: SC> 4

dried and evaporated organic layer gave 1.1 g of the compound mentioned in the title.

Example 45:

4β-acetyglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxy-ethyl) -1-methoxyoxalyl-azetidin-2-one oco2pnb

ococh3 .ococh,

coocii ..

oco2pnb

—I * s "^ v ^ ococh.

. N-V ^ .0

O y cooch.

net. Evaporation gave 0.8 g of the compound mentioned in the title.

1.4 g of 4ß- (l, 2-diacetoxymethyl-vinylIthio) -3- (lp-nitrobenzyloxycarbonyloxyethyl) -1 - (methoxycarbonyl-2-methyl-l-propenyl) -azetidin-2-one in 120 ml of dichloromethane cooled to -78 ° C. Ozone in oxygen was blown through. 20 Example 46:

until a blue color appears. The solution was washed with 4β-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxy-

seriger NaiSjOs solution shaken and dried over NaiSOj-ethyl) -azetidin-2-one oco2pnb

/ - "Y °

ococh.

cooch,

oco-pnb

ococh,

0.8 ^ g of 4β-acetylglycolyIthio-3- (l-p-nitrobenzyloxycarbonyloxyethyl) -l-methoxyoxalyl-azetidin-2-one was dissolved in 50 ml of methanol and a few g of silica gel were added. The mixture was left to stand at room temperature for 60 min, the insoluble material was filtered off and the filtrate, after evaporation, gave 0.300 g of the compound mentioned in the title.

Example 47:

35 4ß-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxy-ethy 1) -1 - (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one oco2pnb

ri ococh,

- "s o '1!

oco2pnb

I '0

o ^ ny ° "

coch,

c00cii20c0cii3

0.5 g of 4β-acetylglycolylthio-3- (lp-nitrobenzyloxycarbonyl-oxyethyl) -1 - (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one and 0.5 g of acetoxymethylglyoxylate in 30 ml of benzene were kept under reflux, until the reaction was complete (2 h). The compound obtained, named in the title, could be used for the next step without further purification.

Example 48:

4β-AcetyIglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxy-ethyl) -1 - (1 -acetoxymethyloxycarbonyl-1-chloromethyl) -azeti-din-2-one

50

0c02pnb ococh.

u ^

cooch2ococh3

oco2pnb

: ~ tT <

ococh.

^ I ^ C1

cooch ococh,

0.35 g of 4β-acetylglycolylthio-3- (I-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one was dissolved in 10 ml of anhydrous tetrahydrofuran at 0 ° C. 1.1 equivalents of pyridine and 1.1 equivalents of thionyl chloride were added. The mixture was stirred for 10 minutes. The precipitate was filtered and the filtrate after evaporation gave the title

Compound in quantitative yield. The crude product was used as such for the next step.

65 Example 49:

4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxy-ethyl) -1 - (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one

651 570

20th

0C02PNB

coch,

cooch2ococh3

OCOjPNB

/ ìj "P

? N \ -sspph,

ococh,

T

COOCH2OCOCH3

0.400 g of 4β-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1 -acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one was dissolved in 20 ml of a 1: 1 mixture of tetrahydrofuran and dioxane. 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine were added and the mixture was stirred at 50 ° C. overnight. The compound mentioned in the title was purified by column chromatography on silica gel, eluting with 70:30 dichloromethane / ethyl acetate. 0.280 g of the phosphorane was obtained.

Example 50:

(5R) -acetoxymethyl-6- (l-p-nitrobenzyloxycarbonyloxyethyl) -15 2-acetoxymethyl-2-penem-3-carboxylate oco2pnb ococh3

j, Nv ^ PPh3

Y

cooch "ococh,

oco2pnb

»JJ

Y N

r ococh,

'cooch2ococh3

0.210 g of 4β-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbo- 25, eluting with 95: 5 dichloromethane-ethyl acetate,

nyloxyethyl) -1 - (1-acetoxymethyloxycarbonyl-1-triphenyl-phosphoranylidenemethyl) -azetidin-2-one were dissolved in 7 ml of toluene and the solution was kept under reflux for 2 hours. By cleaning using short column chromatography,

0.050 g of the compound mentioned in the title were obtained. Example 51:

(5R) -acetoxymethyl-6- (1 -hydroxyethyl) -2-acetoxymethyl-30 2-penem-3-carboxylate oco2pnb ococh,

cooch2ococh3

ococh,

cooch2ococh3

0.060 g of 5R-acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate was poured into a mixture of water, ethanol and K2HPO4 and hydrogenolyzed with 10% Pd / C. Rapid purification by column chromatography on silica gel gave 0.015 g of the compound mentioned in the title.

When working as in the preceding examples, but using 5-methyl-2-thiol-l, 3,4-thiadiazole, 5-thiol-l, 2,3-triazole or thiolpyrazine instead of l-methyl-5 thioltetrazole were (5R) -2 - [(5'-methyl-l ', 3', 4'-thiadiazol-2'-yl) -thiomthyl] -2-penem-3-carboxylic acid, (5R) -2- [(r, 2 ', 3'-triazol-5-yI) -thiomethyl] -2-penem-3-carboxylic acid, (5R) -2- (pyrazinyl) -thiomethyl-2-penem-3-carboxylic acid,

(5R) -6- (1 '-hydroxyethyl) -2 - [(5 "-methyl-1", 3 ", 4" thiadiazol-40 2 "-yl) -thiomethyl] -2-penem-3-carboxylic acid, (5R) -6-

(1'- Hydroxy ethy l) -2 - [(1 ", 2", 3 "-triazol-5" -yl) -thiomethyl] -2-penem-3-carboxylic acid and (5R) -6- (l '-Hydroxyäthyl) -2- (pyrazinyl) -thiomethyl-2-penem-3-carboxylic acid obtained.

When working as described above, but with reducing 45 the methyl 6- (P-hydroxyethyl) -3-penicillanate according to the well-known method, the corresponding 6-ethyl derivatives were obtained.

Example 52:

50 trichloroethyl ester S-oxide 6a-methoxypenicillanate c »3 ° \

// —N "

COOCH CCI 2 3

C "3 °%

00CH CCJ '3

800 mg of trichloroethyl 6a-methoxypenicillanate, prepared according to Giddings et al, Tetrahedron Letters, 11, 995 (1978), were dissolved in 20 ml of dichloromethane and treated in portions with 570 mg of m-chloroperbenzoic acid at room temperature. The organic phase was washed with a saturated solution of NaHCCb and evaporated. The desired compound was recrystallized from ethyl ether. 650 mg were obtained.

, M.p. 120-121 ° C.

NMR (CDCh) S: 1.35 (s, 3H, a-CRi); 1.75 (s, 3H, β-CHa): 3.58 (s, 3H, OCH3); 4.52 (s, IH, 3-H); 4.70-5.00 (two d, 2H, J = 9 Hz, CH2CCI3): 4.97 (d, 1 H, J = 1.5 Hz, H-5); 5.07 (d, 1H, J = 1.5 Hz, H-6).

Example 53:

3a-Methoxy-4ß- (î, 2-diacetoxymethyl-vinylthio) -1 - (trichloro-ethoxycarbonyl -2-methyl-2-propenyl) -azetidin-2-one-S-oxide

21st

651 570

CH, 0%

O

CHgO /,

//

4 '' fcoOCH CCI H

* tCP

cochj coch,

550 mg of trichloroethylester S-oxide 6a-methoxypenicile ilic acid were dissolved in 25 ml of toluene, 1.2 g of butynediol diacetate were added and the resulting mixture was refluxed for 10 hours. The reaction mixture was then chromatographed on a silica gel column and eluted with 10% ethyl acetate-dichloromethane.

450 mg of the desired compound were obtained.

0

jj c00ch2cc13

NMR (CDCh) S: 2.01 (bs, 3H,

io 2.08-2.10 (two s, 6H, ococh3) 3.45 (s, 3H, OC Hb);

4.75-5.00 (multiple, 8H); 5.18 (bs, 2H, = CH2); 5.27 (d, 1H,

r-

15

J = 1.5 Hz, H-3); 6.57 (t, 1H, J = 6.0 Hz, =

Example 54:

3a-methoxy-4ß- (1,2-diacetoxymethyl-vinylthio) -1 - (1-trichloroethoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one S-oxide

400 mg of 3a-methoxy-4ß- (1,2-diacetoxymethyl-vinylthio) -l- (trichloroethoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide were dissolved in 10 ml of dichloromethane and at room temperature stirred with a few drops of triethylamine for 2 h. After evaporating off the solvent, the pure desired compound was obtained.

NMR (CDCh) S: 2.10 (s, 6H, = J-3, OCOCHs); 2.14

(s, 3H, OCOCHs); 2.40 (s, 3H,

= / ~ "3),

3.49 (s, 3H, OCHj);

4.82-4.88 (two s, 4H, "^ ococh ^ ch2cci3); 4.91

(d, 2H, J = 6.0 Hz, = (".) 5 4.95 (d, 1H, J = 2.0 Hz, H-4);

30, h

5.23 (d, 1H, J = 2.0 Hz, H-3); 6.60 (t, 1 H, J = 6.0 Hz, ■ = (-) •

Example 55:

35 3a-methoxy-4ß- (1,2-diacetoxymethyl-vinylthio) -1-trichloro-ethoxy-ocaloyi-azetidin-2-one-S-oxide

CK3 ° '"" j | ^ Sv- | 0

ocochg ococh,

cooch2cci3

2 g of 3a-methoxy-4ß -. (1,2-diacetoxymethyl-vinylthio) -1 - (1-trichloroethoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one-S-oxide were dissolved in 200 ml of dichloromethane and cooled to -70 ° C. Ozone in oxygen was passed through the solution until a blue color appeared. Then a few drops of trimethyl phosphite were added and after evaporation of the solvent the pure desired compound was obtained.

coch3

ococh,

coochgcclj

NMR (CDCh) 8: 2.10-2.12 (two s, 6H, OCOCH3); 3.58

CH ,;

(s, 3H, OCHs); 4.75-5.05 (m, 6H, CH2CCI3,

50

töi-);

ch a y

C «3 or. y> k / ^ C0CH3

I [^ ° C

T

COOCHjCClj

OCOCH,

5.07 (d, 1H, J = 3.0 Hz, H-4); 5.22 (d, 1H, J = 3.0 Hz, H-3); 6.61 (t, 1H, J = 6.0 Hz, hA / J-

55 Example 56:

3a-methoxy-4ß- (1,2-diacetoxymethyl-vinylthio) -1-trichloro-ethoxyoxaloyl-azetidin-2-one ococ »3

coch,

800 mg of 3a-methoxy-4β- (1,2-diacetoxymethyl-vinylthio) - cooled. 0.5 ml of PBn was added and the mixture of l-trichloroethoxyoxaloyl-azetidin-2-one-S-oxide in 30 ml was stirred for 10 min. Then the reaction water-free dimethylformamide was dissolved and poured into a mixture at -20 ° C. in ethyl acetate and several times with water

651 570

22

Washed, whereupon the residue obtained after drying over Na2SO4 essentially gave the desired compound, which was used in the next reaction step without further working up.

NMR (CDCh) 8: 2.08-2.11 (two s, 6H, OCOCH3); 3.61 (s, 3H, OCH3); 4.5-5.0 (m, 7H); 5.38 (d, 1H, J = 3.0 Hz, H-3);

6.28 (t, 1H, J = 6.5 Hz,

Example 57:

3a-methoxy-4ß- (1,2-diacetoxymethyI-vinyIthio) -azetidin-2-one.

T ^ C

cooch2ccl3

The crude residue from the previous example was dissolved in 100 ml of methanol and 3 g of silica gel were added with stirring. The mixture was stirred for 2 hours and after filtering over SÌO2 the residue was chromatographed on a silica gel column eluting with 20% ethyl acetate-dichloromethane to give 400 mg of the desired compound.

NMR (CDCh) 8: 2.08-2.11 (two s, 6H, OCOCH3); 3.55

(s, 3H, OCH3); 4.68 (d, j = 6.5 Hz, 2H, H ^^ ÇH

);

CH ~ ° NT ^^ ococh,

f TI OCOCHj I OCOCHj

4.81 (bs, 3H, h-4); 4.86 (d, j = 2.0 Hz, 1H, H-3);

20 6.04 (t, j = 6.5 Hz, 1 H, h ch., '; 6.50 (bs, 1 H, NH).

Example 58:

25 3a-methoxy-4ß- (1,2-diacetoxymethyl-vinylthio) -1 - (1 -acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one

CH3 ° X

V 0

Co.

COCH,

ococh-.

250 mg of 3a-methoxy-4β- (1,2-diacetoxymethyI-vinylthio) -azetidin-2-one were dissolved in 20 ml of benzene and refluxed for 3 hours with 300 mg of acetoxymethylglyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate). The crude mixture was purified by column chromatography on silica gel and eluting with 40% ethyl acetate-dichloromethane.

CH3 ° "'i OCOCHj

> I k ^ OCOCHj

// N-yWfcH

c00ch20c0ch3

tended to give 150 mg of the pure desired compound as a mixture of diastereoisomers.

Example 59:

3a-Methoxy-4ß- (1,2-diacetoxymethyl-vinylthio) -1 - (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one

CH3OV /> S vs ^ \ 0C0CH3

COOCH2OCOCH3

ococh,

COOCH OCOCH, 2 3

150 mg of 3a-methoxy-4β- (1,2-diacetoxymethyl-vinylthio) -1-ace residue was obtained, which was used without working up in the toxymethyloxycarbonyl-l-hydroxymethyl) -azetidin-2-one, the next step.

dissolved in 10 ml of anhydrous tetrahydrofuran and cooled to −20 ° C. 50, stoicheiometric proportions of pyridine and thio. Example 60:

nyl chloride was added and the mixture was stirred for 10 3a-methoxy-4β- (1,2-diacetoxymethyl-vinylthio) -1 - (1-ace-min. Then the insoluble matter was filtered off over zelith and toxoxymethyloxycarbonyl-1-triphenylphosphoranylidene was measured and evaporated at room temperature, with a thyl) -azetidin-2-one

CH 0 * \ 3

// "^ <1

coch,

COCH,

cooch2ococh3

l

Cococh3 ococh,

Ph,

COOCH OCOCH, 2 3

The crude residue from the preceding example, consisting of almost pure (3a-methoxy-4ß- (1,2-diacetoxy-methyl-vinylthio) -1 - (1 -acetoxymethyloxycarbonyl-1-chloro-ethyl) -azetidin-2-one ) was dissolved in 10 ml of toluene. 200 mg of triphenylphosphine were added and the resulting solution was refluxed under nitrogen for 2 hours. The phosphorane was chromatographed on a short silica gel column and eluted with 40% ethyl acetate-dichloromethane to give 180 mg of the desired compound.

65 Example 61:

3a-methoxy-4β-acetylglycolylthio-1 - (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenmethyl) -azetidin-2-one

23

651 570

ch3 ° \ njcochj

;

r coch,

'Ph,

cooch ococh, 2 "»

CHjOv

ococh,

»>:

O PPh,

coochgocochj

230 mg 3a-methoxy-4- (1,2-diacetoxymethyl-vinylthio) -. 1 - (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -azetidin-2-one were dissolved in 50 ml of dichloromethane and, after cooling to -20 ° C., 0.5 ml of trifluoroacetic acid were added. Ozone in oxygen was passed through the solution until a permanent blue color appeared, whereupon a few drops of trimethyl phosphite were added, the reaction mixture was diluted with dichloromethane and washed several times with a saturated NaHCO 3 solution. After drying over Na: S04 and evaporation of the solvent, the residue gave 180 mg of the pure desired compound.

Example 62:

(5R) -acetoxymethyl-6a-methoxy-2-acetoxymethyl-2-penem-3-carboxylate

CHjCk,

ococh,

_N \.

rpph3

cooch ococh, 2 3

ch3o ococh,

cooch ococh 2 3

^ -CHn,

180 mg3a-methoxy-4ß-acetylglycolythio-l- (l-acetoxy-2s dd2H Ii 2 5.55 (d, J = 1.7 Hz, 1H, H-3); 5.86 (s, 2H,

methyloxycarbonyl-1-triphenylphosphoranylidenmethyl) -azeti-din-2-one were dissolved in 20 ml of toluene and refluxed under nitrogen for 2 h. The desired compound was purified by column chromatography on silica gel while eluting with 5% ethyl acetate-dichloromethane. 50 mg were obtained.

NMR (CDCh) 5: 2.11 (s, 6H, OCOCH3); 3.56 (s, 3H, OCH3); 4.94 (d, J = 1.7 Hz, 1H, H-4); 5.26 (center of

COOCH2OCOCH3);

1R (CHCh) 1795 (β-lactam), 1745-1720 (ester).

Example 63:

30 (5 R) -acetonyl-6cc-methoxy-2-acetoxy-methyl-2-penem-3-car-boxylate ch30 "- /

N

ococh,

coochgcochj

Using the same procedure as in Examples 58, 59, 60, 61 40 IR 1800.1745, 1710. (CHCh)

and 62, but using acetonyl glyoxylate

Instead of acetoxymethylglyoxylate in Example 58, Example 64 was obtained:

above connection. (5R) -6a-methoxy-2-acetoxymethyl-2-penem-3-carboxylic acid ococh,

: ooch2coch3

CH30 'or

t

ococh.

cooh

260 mg (5R) -acetonyl-6 "-methoxy-2-acetoxymethyl-2-penem-3-carboxylate were dissolved in 25 ml of tetrahydrofuran, the resulting solution was diluted with 5 ml of water and cooled to 0 ° C. 7.9 ml of a 0.1 N NaOH solution in water were added and the mixture was left to stand at 0 ° C. for 10 minutes. The solution was then washed twice with methylene chloride, the aqueous phase was poured into methylene chloride with stirring and 4 ml of a 20% aqueous solution of citric acid was added. The aqueous phase was washed twice with methylene

50 chloride extracted, the combined organic phases were dried over Na 4 SO 4 and evaporated to give 80 mg of the desired compound.

IR 1795, 1740, 1700. (CHCh).

55 Example 65:

4ß- [1 - (hydroxymethyl) vinylthio] -3a- (1-p-nitrobenzyloxy-carbonyloxyethyl) -1 - (1-methoxycarbonony l-2-methyl-2-propenyl) -azetidin-2-one-S -oxide. Reaction (2) - (3).

OCO-PNB

COOCH.

OCO.PNB

y ^ OH

/ \

COOCH,

651 570

24th

A solution of 2.6 g of methyl 6- (l-p-nitrobenzyloxy-carbonyloxyethyl) -3-penicillinate S-oxide and 8 ml of propargyl alcohol in 20 ml of toluene were refluxed under nitrogen for 40 h. After evaporation of the solvent, the compound obtained was purified by chromatography on a silica gel column, with (9: 1) dichloromethane

oco2pnb than ethyl acetate was eluted and 2.0 g of the title compound were obtained.

Example 66:

5 4ß- [l- (l-hydroxymethyl) vinylthio] -3a- (l -p-nitrobenzyloxy-carbonyloxyethyl) -1 - (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one -S-oxide. Reaction (3) - (4).

oco-pnb

I 2

I.

Oh

cooch,

2.0 g 4ß- [l- (l-hydroxymethyl) vinylthio] -3a- (lp-nitro-benzyloxycarbonyloxyethyl) -1 - (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one- S-oxide was dissolved in 50 ml of dichloromethane and left at room temperature in the presence of a few drops of triethylamine for 12 h.

oco2pnb h cooch3

After evaporation of the solvent, the pure title compound was obtained in quantitative yield.

Example 67:

4β- [1 - (1-Bromomethyl) vinylthio] -3 a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one. Reaction (4) - (12).

oco, pnb

- "k ^ V ^ Br

-, f cooch3

2.0 g of the compound prepared in Example 66 was dissolved in 50 ml of dimethylformamide. After cooling to -20 ° C, 0.7 ml of pyridine and 3.2 ml of PBn were added, and the reaction mixture was left to stir for 15 minutes. Ethyl acetate was added to the mixture and the organic phase was shaken with a saturated NaHCCb solution, washed with water and finally dried over Na2SC> 4. To

Evaporation of the solvent gave 1.7 g of the pure title compound.

Example 68:

4ß- [1 - [1 - (5-methyl-1 -3,4-thiadiazol-2-yl) thiomethyl] vinyl-40 thio] -3a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1 - methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one oco-pnb cooch,

cooch,

1.8 g of the compound prepared in Example 67 was dissolved in 30 ml of tetrahydrofuran. The solution obtained was cooled to 0 ° C; 1.1 g of 5-methyl-1,3,4-thiadiazole-2-thiol sodium salt was added and the mixture was left under stirring for 4 hours. After filtering the insoluble, the filtrate was diluted with ethyl acetate, washed with water, over Na2SO4

dried and evaporated: 2 g of the title compound were obtained.

55

Example 69:

4β- [l - [1 - (1,2,3-triazol-5-yl) thiomethyl] vinylthio] -3a- (1-p-nitro-benzyloxycarbonyloxyethyl) -1 - (1-methoxycarbonyl-2-methyl -1-propenyl) -azetidin-2-one cooch,

cooch,

Starting from 2.5 g of the compound, prepared in Example 67 and proceeding as in Example 68, but using 1,3,3-triazole-5-thiol sodium salt, 2.2 g of the title compound were obtained.

0C02PNB

X

0J—

cooch3

2 g of the compound prepared in Example 68 was dissolved in 250 ml of dichloromethane and cooled to -78 ° C. A stream of ozonized oxygen was bubbled into the solution until a blue color was obtained. A few drops of P (OCH3) 3 were added to the solution and the temperature of the mixture was set to room temperature.

25 651570

Example 70:

4ß - [(5-methyl-1,3,4-thiadiazol-2-yl) thioacetylthio] -3a- (1 -p-

nitrobenzyloxycarbonyloxyäthyl) -l-methoxy-oxaIoylazetidin-

2-on cooch3

15 temperature raised. The mixture was evaporated to give 1.5 g of the title compound.

Example 71:

4ß - [(1,2,3-Triazol-5-yl) thioacetylthio] -3a- (1-p-nitrobenzyl-20 oxycarbonyloxyethyl) -1-methoxy-oxaloyl-azetidin-2-one. Reaction (12) - (13).

;

0c02pnb

F '

i-'nn coochn oco.pnb

X.

? »V

s

H

Np = - ° cooch-

Starting from 1.6 g of the compound prepared in Example 69 and proceeding as in Example 70, 1.1 g of the title compound were obtained.

Example 72:

4ß - [(5-Methyl-1,3,4-thiadiazol-2-yi) thioacetylthio] -3a- (1-p-nitrobenzyloxycarbonyloxyethyl) azetidin-2-one. Reaction 35 (13) - (14).

oco2pnb oco-pnb

1.5 g of the compound prepared in Example 70 was dissolved in a 1: 1 mixture of methanol and ethyl acetate. A few grams of silica were added and the mixture was left at room temperature with vigorous stirring. After filtering off the silicon dioxide, the filtrate was evaporated to give an oil

(8: 2) Chromatographies were obtained to obtain 0.9 g of the pure title compound.

50 Example 73:

4ß - [(1,2,3-Triazol-5-yl) thioacetylthio] -3a- (1-p-nitrobenzyloxycarbonyloxyethyl) azetidin-2-one. Reaction (13) - (14).

which was placed on silica gel with dichloromethane: ethyl acetate OCO2PNB

oco2pnb

'n

0

y °

coocn3

0c02pnb

Starting from 1.5 g of the compound prepared in Example 71 and proceeding as in Example 72, 0.6 g of the title compound was obtained.

65 Example 74:

4ß - [(5-methyl-1,3,4-thiadiazol-2-yl) thioacetylthio] -3a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1 -acetonyloxycarbonyl-l-hydroxymethyl) azetidin-2- on. Reaction (14) - (15).

651 570 26

oco-pnb n n 0c02pnb m n s "y-; r * s ^ s s ^

\ ^ 0H

n 0

nh

CH3

cooch2coch3

0.9 g of the compound prepared in Example 72 were as in Example 75:

dissolved in 40 ml of benzene; 0.6 g of acetonylglyoxylate was 4β - [(l, 2,3-triazol-5-yl) thioacetylthio] -3a- (l-p-nitrobenzyl-

was added and the resulting solution was refluxed for 3 h oxycarbonyloxyethyl) -l- (l-acetonyloxycarbonyl-l-hydroxy. After evaporation of the solvent, the methyl) -azetidin-2-one. Reaction (14) - (15).

raw oil used for the next step without further purification. 15

oco-pnb "0c0, pnb

Ì "J I II g

1 JL H 1 *

i— \ 0 H * £ - \

1

0

I.

h h qy cooch-coch,

Starting from 0.6 g of the compound, produced in example 76:

Game 73 and proceeding as shown in Example 74, 4β - [(5-methyl-l, 3,4-thiadiazoI-2-yl) thioacetylthio] -3a- (l-p-

0.7 g of the title compound were obtained. nitrobenzyloxycarbonyloxyethyl) -l- (l-acetonyloxycarbonyl

3o l-chloromethyl) -azetidin-2-one. Reaction (15) - (16).

h m oco-pnb "

.oco-pnb f f, 2? n x s ch3 a ^ syagigach

> l / - ~ 3 ^^ IT -3

s = c ° -> °

3 xyjwoh o y * "* cl cooch2coch3 t cooch2coch3

The crude oil obtained in Example 74 was dissolved in anhydrous tetrahydrofuran (30 ml) and cooled to 0 ° C. Equimolar amounts of pyridine and thionyl chloride were added to the solution until the starting material disappeared. After filtration of the insoluble material, the filtrate was used immediately for the next step. •

Example 77:

45 4ß - [(1,2,3-triazol-5-yl) thioacethylthio] -3a- (1-p-nitrobenzyl oxycarbonyloxyethyl) -1 - (1-acetonyloxycarbonyl-1-chloromethyl) -azetidin-2- on. Reaction (15) - (16).

OCO-PNB. N OCO-PNB i N

i r »i n

} •. s s • / -s'

i »

i N> i N

ox y 0H ° VC1

COOCH2COCH3 COOCH2COCH3

Starting from 0.7 g of the compound, prepared in Example 75 and proceeding as described in Example 74, the crude chlorine derivative was obtained. The product was used for the next step without further purification.

Example 78:

es 4ß - [(5-methyl-1,3,4-thiadiazol-2-yl) thioacetylthio] -3a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1 -acetonyloxycarbonyl 1 -triphenylphosphoranylidenemethyl) -azetidin-2- on. Reaction (16) - (11).

27th

651 570

0c02pnb

A

n — n

V s ~ s

O

iL ch, ^

oco2pnb

..cl

Y1

cooch2coch3

n n

A iL

SY ^ s s ch3

O

\ ^ PPh3 cooch2coch3

The crude product obtained in Example 76 was dissolved in 20 ml of tetrahydrofuran; 700 mg of tripehylphosphine and 0.35 ml of pyridine were added and the solution obtained

Example 79;

4ß - [(1,2,3-triazol-5-yI) thioacetylthio] -3a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1 -acetonyloxycarbonyloxyethyl-

was 15 l-triphenylphosphoranylidenemethyl) -azetidin-2-one under nitrogen at 70 ° C for a few hours. Reac

warmed up. The title phosphorane was on silica gel by ion (16) - (11).

Elution with dichloromethane: ethyl acetate (1: 1) chromatographed. This gave 0.6 g of the title compound.

oco2pnb

A

»

s

0

n

I.

h y \ ^ - Cl cooch2coch3

0c02pnb cooch2coch3

Starting from the raw chlorine derivative, obtained in Example 30 Example 80:

77 and proceeding as described in Example 78, 0.55 g of the title compound was obtained.

(5R) -acetonyl-2 - [(5-methyI-l, 3,4-thiadiazoI-2-yl) thiomethyl] -6a- (1-p-nitro-benzyloxycarbonyloxyethyl) -2-penem-3-carbo- xylate. Reaction (1 l) - (l).

oco2pnb n n

0c02pnb.

i

Njss PPh3 cooch.coch,

n n

Ii il i 'ML

S ^ Cîî3 N S S CHri

° - »cUn _ -X ^

cooch2coch3

0.6 g of the compound prepared in Example 78 was dissolved in 50 ml of toluene and refluxed under nitrogen for 3 hours. The title compound was purified by short column chromatography from silica gel eluting with dichloromethane: ethyl acetate (8: 2). 0.25 g of the title compound was obtained.

1R: 1795, 1750, 1720.

Example 81:

(5 R) -Acetonyi-2 - [(1,2,3-triazol-5-yl) thiomethyl] -6a- (1-p-50 nitrobenzyloxycarbonyloxyethyl) -2-penem-3-carboxylate.

cooch2coch3

cooch2coce3

Starting from 0.54 g of the compound, prepared in Example 65:

game 79 and proceeding as in Example 80, 0.180 g of the (5R) -acetonyl-2 - [(5-methyl-l, 3,4-thiadiazol-2-yl) thiome-

Received title link. thyl] -6a- (l-hydroxyethyl) -2-penem-3-carboxylate. Reaction (1). IR: 1795, 1750, 1720.

651 570

28

0.450 g of the compound prepared in Example 80 was hydrogenated in 25 ml of acetonitrile containing a few drops of ethanol and over 10% palladium on carbon (400 mg). The catalyst was removed by filtration and the filtrate was chromatographed on silica gel eluting with dichloromethane: ethyl acetate (7: 3) to give 0.18 g of the title compound.

io IR: 3605, 1795, 1745, 1720.

Example 83:

(5R) -Acetonyl-2 - [(l, 2,3-triazole-5-thiomethyl] -6a (l-hydroxyethyl) -2-penem-3-carboxylate. Reaction (1).

Starting from 0.380 g of the compound prepared in Example 81 and proceeding as in Example 82, 0.12 g of the title compound was obtained.

IR: 3610, 1795, 1750, 1720.

Example 84:

(5R) -2 - [(5-methyl-l, 3,4-thiadiazol-2-yl) thiomethyl] -6a- (l-hydroxyethyl) -2-penem-3-carboxylic acid. Reaction (1).

cooch2coce3

cooh

A solution of 0.200 g of the compound, prepared according to Example 82, in acetonitrile (30 ml), which contains a few drops of water, was cooled to 0 CC; 5 ml of 0.1 N NaOH solution was added under nitrogen and the solution was stirred for 10 minutes. The alkaline mixture was washed twice with methylene chloride, acidified with 10% citric acid in aqueous solution and extracted again twice with methylene chloride. The ch i

P

V

Combined organic phases were dried over Na 4 SO 4 and evaporated to give 0.110 g of the title compound.

IR: 3500, 1795, 1665.

Example 85:

45 (5R) -2 - [(1,2,3-triazol-5-y]) - thiomethy]] - 6a- (l-hydroxvethyl) -2-penem-3-carboxylic acid. Reaction (1).

cooch2coch3

OH

A

cooh

Starting from 0.25 g of the compound prepared in Example 83 and proceeding as shown in Example 84, 0.135 g of the title compound was obtained.

IR: 3490, 1795, 1660.

Example 86:

4ß- (1-Carbamoyloxymethyl-vinylthio) -3a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one-S-oxide. Reaction (4) - (5).

oco-pnb

0c02pn3

^ p0C0NE2

cooch.

cooce,

29

651 570

2.2 g of the compound, prepared as in Example 66, were dissolved in 30 ml of acetonitrile and cooled to 0 ~ C. Then 0.8 ml of chlorosulphonyl isocyanate was added under nitrogen and the mixture was stirred for 2 hours. The reaction mixture was poured into a saturated NaHCCh solution, stirred for a few minutes and then extracted with ethyl acetate. After drying over Na: SOj,

Evaporation of the solvent gave 1.5 g of the title compound.

Example 87:

5 4ß- (1-Carbamoyloxymethyl-vinylthio) -3a- (1-p-nitrobenzyl-oxycarbonyloxyethyl) -1 - (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one. Reaction (4) - (12).

oco2pnb y

oconh.

cooch,

oco2pnb

Starting from 1.7 g of the compound prepared in Example 86 and proceeding as in Example 67, 1.4 g of the title compound was obtained.

i

OC02? N3

* oconh.

cooch.

Starting from 2.2 g of the compound, prepared in Example 87 and proceeding as illustrated in Example 70, 1.4 g of the title compound was obtained.

oconh.

Example 88:

4β- (Carbamoyloxy-acetylthio) -3a- (1-p-nitrobenzyloxycarbo-20 nyloxyethyl) -l-methoxyalovl-azetidin-2-one. Reaction (12) - (13).

ocojpnb oconh,

Example 89:

4ß- (Carbamoyloxy-acetyIthio) -3a- (1-p-nitrobenzyloxycarbo-nyloxyethyl) -azetidin-2-one. Reaction (13) - (14).

OCOjPNB

oconh,

Starting from 1.4 g of the compound prepared in Example 88 and proceeding as shown in Example 72, 0.9 g of the title compound was obtained.

oco2pnb

A

J- *

/ ^ Ndconh,

'H

Starting from 0.9 g of the compound obtained in Example 89 and 0.6 g of acetonyl glyoxylate and proceeding as in Example 74, the crude carbinolamide was obtained.

Example 90:

4β- (Carbamoyloxy-acetylthio) -3a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1 -acetonyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one. Reaction (14) - (15).

qco2pnb

À

V

oconh,

&

I w

A> \ ^ OH

o l cooch, coch3

Example 91

4ß- (Carbamoyloxy-acetylthio) -3a- (l-p-nitrobenzyloxycarbo-nyloxyethyl) -1 - (1 -acetonyloxycarbonyl-1-chloromethyl) -acetin-din-2-one. Reaction (15) - (16).

oco2pnb

A

oconh,

V

• oh cooch2coch3

X

0c02pnb

SV "

oconh,

Cl cooch2coch3

651 570

30th

Starting from the raw product obtained in Example 90- Example 92:

and proceeding as in Example 76, the crude 4β- (carbamoyloxy-acetylthio) -3a- (l-p-nitrobenzyloxycarbo-

Get chlorine derivative.

r * "

Y

oconh-

J_S »

^ ycx cooch2coch3

nyloxyethyl) -1 - (1 -acetonyloxycarbonyl-1-triphenylphosphoranylidenemethyl-l) -azetidin-2-one. Reaction (16) - (11).

oco-pnb

A

oconh-

ii

N

sPPh,

cooch2coch3

Starting from the crude product obtained in Example 91 and proceeding as in Example 78, 0.40 g of the phosphorane was obtained.

Example 93:

(5R) -Acetonyl-2-carbamoyloxymethyl-6a- (1-p-nitrobenzyl-oxycarbonyloxyethyl) -2-penem-3-carboxylate. reaction

(H) - (l).

oco2pnb oconh,

cooch2coch3

X

C02PNB

> * s-

0

OCOHH-

cxioaijcoa ^

Starting from 0.4 g of the compound prepared in Example 92 and proceeding as in Example 80, 0.11 g of the title compound was obtained.

Example 94:

(5 R) -acetonyl-2-carbamoyloxymethyl-6a- (1 -hydroxyethyl) -2-penem-3-carboxylate. Reaction (1).

X

OCONHj

1 running

N

Oh

A

1 1

oconh.

cooch2coch3

'cooch2coch

Starting from 0.35 g of the compound prepared in Example 93 and proceeding as in Example 82, 0.11 g of the title compound was obtained.

Example 95:

(5R) -2 (carbamoyloxymethyl) -6a- (1-hydroxyethyl) -2-penem-3-carboxylic acid. Reaction (1).

OH

A

oconh-

^ cooch2coch3

oconh cooh

Starting from 0.11 g of the compound, prepared in Example 96:

Game 94 and proceeding as in Example 84, 0.060 g of 55 (a) 4β-acetylglycolylthio-3a- [l-p-nitrobenzyloxycarbonyloxy- of the title compound were obtained. ethyl] -l- [l-acetonyloxycarbonyl-l-hydroxymethyl] azetidine IR: 3400-3500, 1795, 1700-1650. 2-on. Reaction (14) - (15).

X

OCOjPNB

11 O

O H

ococh-

J

: 02PNB

/ ey ~ "

ococh.

.N

1

rf * oh cooch2coch3

31

651 570

A solution of 1.04 g of 4β-acetylglycolylthio-3a- [l-p-nitrobenzyloxycarbonyloxyethyl] -azetidin-2-one, prepared according to Example 46, and 1.8 g of acetonylglyoxylate in 20 ml of benzene was refluxed for 4 hours. Evaporation of the solvent gave the crude title compound which was used for the next step without further purification.

(b) 4β-AcetylglycolyIthio-3 "- [l-p-nitrobenzyloxycarbonyloxyethyl] -1 - [1 -acetonyloxycarbonyl -1-chloromethyl] -aceti-5 din-2-one. Reaction (15) - (16).

DCOjPNB

ococh,

cooch.coch,

The crude carbinolamide obtained from step (a) was dissolved in 20 ml of anhydrous tetrahydrofuran and cooled to 0 ° C. Equimolar portions of pyridine and thionyl chloride were added until all of the starting material disappeared. The precipitate was filtered; evaporation of the filtrate gave the crude title compound,

oco2phb ococh,

cooch2coch3

? co2pnb ococh.

cooch2coch3

which was used for the next step without further cleaning.

(c) 4β-Acetylglycolylthio-3a- (1-p-nitrobenzyloxycarbo-20 nyloxyethyl] -1- [acetonyloxycarbonyl-l-triphenylphosphoranylidenemethyl] azetidin-2-one. Reaction (16) - (11).

OCOjPNB

A-

/ s o

r ir

O

pph,

coch,

cooch2coch3

The crude chlorine derivative was dissolved in 100 ml of methylene chloride; 1.5 g triphenylphosphine and 10 g silica gel were added to the solvent and the solvent was evaporated under vacuum. The solid material was left overnight at room temperature and poured into a column chromatography column and mixed with 1: 1 dichloro

35 methane-ethyl acetate to give 1.5 g of the title compound.

(d) (5R) -acetonyl-6a- [l-p-nitrobenzyloxycarbonyloxyätyl] -2-acetoxymethyl-2-penem-3-carboxylate. reaction

(H) - (l).

0c02pnb

{3

ococh,

cooch2coch3

jc02pnb ococh.

• cooch2coch3

1.5 g of 4β-acetylglycolylthio-3- [l-p-nitrobenzyloxycarbonyl-oxyethyl] -1 - [acetonyloxycarbonyl-1-triphenylphosphoranyl-denmethyl] -azetidin-2-one were dissolved in 50 ml of toluene and refluxed for 3 hours. Evaporation of the solvent gave an oil, which was purified by short column chromatography on silica gel, eluting with (9: 1) dichloromethane-ethyl acetate. 0.51 g of the title compound was obtained.

Erithro

PMR (CDCb): 1.46 (d, J = 6.5 Hz, 3H, CHjCH), 2.07 (s, 3H, OCOCHi), 2.16 (s, 3H, COCHj), 4.02 (dd , J = 2.0, 4.0 Hz, 1H, H-6), 4.73 (s, 2H, CH2CO), 5.0-5.3 (m, 1H, CHO), 5.12 , 5.38 (dd, J = 15.5 Hz, 2H, CH2OCO), 5.22 (s, 2H, COCHiPh), 7.4-8.5 (m, 4H, PhNOi).

IR (CHCb): 1725 cm-1 C = 0 unsaturated esters, ketones, 1750 cm-1 C = 0 esters, 1800 cm-1 C = 0 ß-lactam.

Threo

PMR (CDCh): 1.45 (d, J = 6.0 Hz, CH3CH), 2.08 (s, 3H, OCOCH3), 2.19 (s, 3H, COCH3), 3.96 (dd, J = 2.0, 7.0 Hz, 1H,, H-6), 4.77 (s, 2H, CH2CO). 5.0-5.4 (m, 1H, CHO), 5.13, 5.42 (d, J = 16.0 Hz, CH2OCO), 5.25 (s, 2H, CH2PI1), 5.66 ( d, J = 2.0 Hz, 1H, H-5), 7.4-8.5 (m, 4H, PhN02).

IR (CHCh): 1725 cm-1 C = O unsaturated esters, ketones, 1750 cm -1 C = 0 esters, 1800 cm-1 C = 0 β-lactam.

Example 97:

(5 R) -acetonyl-6a- [1-hydroxyethyl] -2-acetoxymethyl-2-penem-3-carboxylate. Reaction (1).

651 570

32

(XOjFNB

—J /.

"Ndcoch.

n cooch2coch3 "

Oh

O/;

■ ococh.

cooch2coch3

0.51 g (5R) -acetonyl-6a- [lp-nitrobenzyloxycarbonyloxy-ethyl] -2-acetoxymethyl-2-penem-3-carboxylate, prepared according to Example 96, was in 60 ml (1: 1) acetonitrile: (95 ° or ) Dissolved ethanol mixture. 0.46 g of 10% Pd / C was added and the mixture was stirred under a hydrogen atmosphere for 1 h. After filtering off the catalyst, the filtrate was evaporated and the title compound was purified by silica gel column chromatography, eluting with (8: 2) dichloromethane-ethyl acetate to obtain 0.20 g of the pure product.

Erithro

PMR (CDCh): 1.38 (d, J = 6.5 Hz, CHhCH), 2.09 (s, 3H, OCOCHj), 2.20 (s, 3H, COCHj), 3.86 (dd, J = 2 , 0, 4.0 Hz, 1H.

H-6), 4.22 (dq. J = 6.5, 4.0 Hz, 1 H, CHOH), 4.72 (s, 2H, CH? CO), 5.12. 5.42 (d, J = 15.5 Hz, 2H. CH2OCO), 5.58 (d. J = 2.0 Hz. 1H. H-5).

15 Threo

PMR (CDCh): 1.32 (d, J = 6.5 Hz, 3H, CFbCH), 2.10 (s, 3H, OCOŒh), 2.20 (s, 3H, COCH3), 3.06 (bs , IH, OH), 3.74 (dd, J = 2.0, 7.0 Hz. 1 H, H-6), 4.23 (m, 1 H, CHOH), 4.77 (s, 2H , CHjCO), 5.12, 5.38 (d, J = 16.0 Hz, 2H, CH2OCO), 5.63 20 (d, J = 2.0 Hz, 1H. H-5).

Example 98:

Sodium (5R) -2-acetoxymethyl-6a- (l-hydroxyethyl) -2-penem-3-carboxylate. Reaction (1).

OCOCH.

OH

—U

■ ococh.

cooce2coch3

cf

"N.

COONa

0.21 g (5R) -acetonyl-6a- [l-hydroxyethyl] -2-acetoxy-methyl-2-penbem-3-carboxylate, prepared according to Example 97, was dissolved in 20 ml acetonitrile and 3 ml water. The reaction mixture was cooled to 0: C under a nitrogen atmosphere and 7.4 ml of an aqueous 0.1 NaOH solution was slowly added over 30 minutes.

After evaporating the acetonitrile in vacuo, the residue was extracted twice with cold ethyl acetate. Ci8 reverse phase chromatography (elution with water) of the concentrated aqueous phase gave 0.054 g of the pure title compound.

Erithro

PMR (D: 0) 80mKz: 1.34 (d, J = 6.3 Hz, 3H, CH3CH). 2.14 (s, 3H, OCOCHs), 4.01 (m, 1H, H-6), 4.22 (m, 1H, CHOH), 5.10, 5.44 (i.e. J = 14.0 Hz, 2H, CH2OCO), 5.63 (d, J = 1.0 Hz, 1H, H-5).

UV (ethanol 95%): Ämax 262 nm (s 2000), 308 nm (e 2520) [a] D = 128 (C = 0.92, H2O).

Threo

PMR (D2O): 1.31 (d, J = 6.5 Hz, 3H, CH.3-CH), 2.19 (s, 3H, OCOCHs). 3.92 (dd, J = 1.5, 7.0 Hz. 1H, H-6), 4.21 (m, 40 1H, CHOH), 5.10, 5.44 (d. J = 14, 0 Hz, 2H, CH2OCO), 5.67 (d, J = 1.5 Hz, 1H, H-5).

UV (ethanol 95%): /.mas 262 nm (e 3410), 308 nm (s 4340).

Example 99:

"Sodium (5R, 6S) -6- [l (R) hydroxyethyl] -2 - [(1-methyl-l, 2,3,4-tetrazol-5-yl) thiomethyl] -penem-3-carboxylate

Starting from 2.5 g of the compound which was prepared in Example 67 and proceeding as described in Examples 68, 70.72. 74. 76. 78. 80 and 82. but using 1-methyl-l, 2,3,4-tetrazole-5-thiol sodium salt instead of 5-methyl-l, 3,4-thiadiazole-2-thiol sodium salt and treating the resulting compound as described in Example 98, 0.13 g of the title compound was obtained.

55 UV (H2O): /.max 315 nm.

NMR (D2O): 5ppm 1.28 (3H, dJ = 6.3 Hz), 3.87 (1H, dd. J = 1.4 and 6.3 Hz), 4.10 (3H, s), 4.19 (1H. M), 4.40 (2H, ABq, J = 16.0 Hz, separation of inner lines = 13 Hz), 5.59 (1H, i.e. J = 1.4 Hz).

G

Claims (27)

651 570 PATENT CLAIMS 1. Compounds of the formula 'coor' wherein n = 0 or 1, R "" is hydrogen, lower alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl or benzhydryl or an acetoxymethyl, pivaloyloxymethyl or phtahlidyl group or a group of the formula -CH-OCOOCaHs or -CHiNHCOR '"" I. Is CHs, wherein R '"" is alkyl having 1 to 5 carbon atoms, cycloalkyl or aryl, Z is hydrogen, halogen, hydroxy, amino, carbamoyloxy, mercapto, a pyridinium group or a group of the formula OR', OCOR ', NHCOR' or SR ", where R 'and R" are each lower alkyl, aryl or a heterocyclic ring, which are each optionally substituted, and R "hydrogen, lower alkyl, lower alkoxy, cycloalkyl or Hydroxyalkyl means that the alcoholic function of the hydroxyalkyl group is free or protected. 2. Compounds according to claim 1, characterized in that the heterocyclic ring is a 5-methyl-l, 3,4-thia-diazol-2-yl, l-methyl-tetrazol-5-yi, l, 2,3 -Triazol-5-yl or pyrazinyl group. 3. Compounds according to one of claims 1 or 2, characterized in that R '"methyl, ethyl, methoxy, 1-Hydroxyethyl, l- (p-nitrobenzyloxycarbonyloxy) ethyl or 1 - (dimethyl-tert-butylsilyloxy) ethyl. 4. Compounds according to any one of claims 1 to 3, characterized in that R '"is 1-hydroxyethyl. 5. (5R) -2-acetoxymethyl-2-penem-3-carboxylic acid as a compound according to claim 1. 6. (5R) -2-acetoxymethyl-6-ethyl-2-penem-3-carboxylic acid as a compound according to claim 1. 7. (5 R) -2-acetoxymethyl-6- (1 '-hydroxyethyl) -2-penem-3-carboxylic acid as a compound according to claim 1. 8. (5R) -2 - [(1 '-methyl-1' -H-tetrazol-5'-yl) -thiomethyl] - 2-penem-3-carboxylic acid as a compound according to claim 1. 9. (5R) -2 - [(1 '-methyl-1' -H-tetrazol-5'-yl) -thiomethyl] -6-ethyl-2-penem-3-carboxylic acid as a compound according to claim 1. 10. (5R) -6- [1 '-hydroxyethyl] -2 - [(1 "-methyl-1" -H-tetrazole-5 "-yl) -thiomethyl] -2-penem-3-carboxylic acid as the compound according to Claim 1. 11. (5R) -2 - [(5'-methyl-r, 3 ', 4'-thiadiazol-2'-yl) thiomethyl] -2-penem-3-carboxylic acid as a compound according to claim 1. 12. (5R) -2- [5'-methyl-1 ', 3', 4'-thiadiazol-2'-yl) thiomethyl] -6-ethyl-2-penem-3-carboxylic acid as a compound according to claim 1 . 13. (5R) -6- [l'-HydroxyethyI] -2 - [(5 "-methyl-l", 3 ", 4" thiadiazol-2 "-yl) thiomethyl] -2-penem-3 carboxylic acid as a compound according to claim 1. 14. (5 R) -2 - [(1 ', 2', 3'-triazoI-5'-yl) thiomethyl] -2-penem-3-carboxylic acid as a compound according to claim 1. 15. (5R) -2 - [(1 ', 2', 3'-triazol-5'-yl) thiomethyl] -6-ethyl- 2-penem-3-carboxylic acid as a compound according to claim 1. 16. (5R) -6- [l'-hydroxyethyl] -2 - [(l ", 2", 3 "-triazol-5" -yl) - thiomethyl] -2-penem-3-carboxylic acid as a compound according to claim 1. 17. (5 R) -6- [1 '- Hydro xyäthy l] -2 - [(py raziny l) thiomethyl] -2-penem-3-carboxylic acid as a compound according to claim 1. 18. (5R) -2- (pyrazinyl) thiomethyl-2-penem-3-carboxylic acid as a compound according to claim 1. 19. (5 R) -2 - [(pyrazinyl) thiomethyl] -6-ethyI-2-penem-3-car-bonic acid as a compound according to claim 1. 20. A process for the preparation of compounds of the formula (I) in which R '"and R" "are as defined in claim 1, n = 0 and Z = Z', where Z 'is halogen, hydrogen, hydroxyl, amino, Carbamolyoxy or a group of the formula OR ', OCOR', NHCOR ', characterized in that a compound of the formula coor in which R is alkyl and R' "has the meaning given in Claim 1, with an acetylene derivative of the formula XC = CY wherein X represents a group of the formula CHaZ 'and Y is hydrogen, lower alkyl, cyano or a group of the formula COOR or CHzZ' to a compound of the formula 0 which then converts under basic conditions to a compound of the formula o coor in which R, R '"X and Y have the above meaning isomerized, the compound of the formula (IV) to a compound of the formula r"' \ 0) n \ h ° (xiv) is reduced, ozonized and hydrolyzed, which is then with an ester of glyoxylic acid of the formula CHOCOOR "", to a compound of the formula 2nd 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 3,651,570 is implemented, which in the chlorine derivative of the formula (xv) 5 I »II (viii) which compound is converted into the chlorine derivative of the formula io n »I In front ^ -tKyr * ci (xvi) 5 coor "" which is converted into the phosporan of the formula r "' coor " is converted, which in the phosphorane of the formula R \ 'x JtCC coor "" 20th wherein Ph is phenyl, which is converted to a compound of formula (xi) 25th is converted, which is finally cyclized. 21. A process for the preparation of compounds of formula (1), wherein R '"and R" "are as defined in claim 1, 30 n = 0 and Z = Z', where Z 'is halogen, hydrogen, hydroxy, amino , Carbamoyloxy or a group of the formula OR ', OCOR', NHCOR ', characterized in that the intermediate of the formula IV, as in the process KT " CT Y = PPh, (xi) coor "" is ozonized, which is finally cyclized. 22. A process for the preparation of compounds of the formula (I), in which R '"and R" "are as defined in claim 1, of claim 20, and the compound of the formula 35 is n = 0 and Z = Z', where Z 'is halogen, hydrogen, Hydroxy, amino, carbamoyloxy or a group of the formula OR ', OCOR', NHCOR ', characterized in that the intermediate of the formula IV, as in the process of claim 20, and the compound of the formula (IV) selectively a compound of the formula (IV) to a compound of the formula (O) nCI. •> (v) coor wherein n = 1, is selectively ozonized, which is then reduced to a compound (V), where n = 0, which to a compound of the formula 45 Xx (v) XX (vi) ' coor 50 where n = 1, is ozonized, which then forms a compound of the formula (0), is hydrolyzed, which with a suitable ester of Gly-55 oxylic acid of the formula CHOCOOR "", wherein R "" has the above meaning, to a compound of formula XX (vi) 60 n H I XX (VII) coor "" wherein n = 1, is hydrolyzed with an ester of glyoxylic acid of the formula CHOCOOR "", wherein R "" has the above meaning, to a compound of formula 651 570 4th cóor "" wherein n = 1, is converted, which is converted into the chlorine derivative of the formula coor where n = 1, which is converted into the phosphorane of the formula tSi) coor "" wherein Ph produces phenyl and n = 1, which is then reduced to a compound of formula (IX), wherein n = 0, which to a compound of formula : pph coor ' is ozonized, which is finally cyclized. 23. A process for the preparation of a compound of formula I, wherein n = 0, and R '"and R" "are as defined in claim 1 and Z = Z" where Z is "mercapto, -SR" or pyridinium, where R "Lower alkyl, aryl or a heterocyclic ring, characterized in that the intermediate of formula IV is prepared as in the process of claim 20, in this intermediate the radical X, which is -CH2-Z 'and Z' as in claim 20 is defined, by a substitution reaction with a Z "-introducing agent, converted into a radical X, in which X is -CHa-Z", and the compound of formula IV obtained is further reacted in accordance with the reaction steps specified in the process of claim 20 . 24. A process for the preparation of a compound of formula I, wherein n = 0, and R '"and R" "are as defined in claim 1 and Z = Z", where Z is "mercapto, -SR" or pyridinium, wherein R "denotes lower alkyl, aryl or a heterocyclic radical, characterized in that the intermediate of formula IV is prepared as in the process of claim 21, in this intermediate the radical X, which is -CHi-Z 'and Z' as in Claim 21 is defined, by means of a substitution reaction with a Z "-introducing agent, converted into a radical X, where X is -CH: -Z", and the compound of the formula IV obtained in accordance with the reaction steps given in the process of claim 21 continues to implement. 25. A process for the preparation of a compound of formula I wherein n = 0 and R '"and R" "are as defined in claim 1 and Z = Z" where Z is "mercapto, -SR" or pyridinium, wherein R "denotes lower alkyl, aryl or a heterocyclic radical, characterized in that the intermediate of formula IV is prepared as in the process of claim 22, in this intermediate the radical X which is -CH2-Z 'and Z' as in Claim 22 is defined, by means of a substitution reaction with a Z "-introducing agent, converted into a radical X, where X is -CH2-Z", and the compound of the formula IV obtained in accordance with the reaction steps specified in the process of Claim 22 implements. 26. A process for the preparation of compounds of the formula I in which R '", R" "and Z are as defined in claim 1 and n = 1, characterized in that a corresponding compound of the formula I in which n = 0, is oxidized. 27. Pharmaceutical composition, characterized in that it contains a compound according to claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.