NL8001012A - ANTIBACTERIALS AND BETA-LACTAMAS INHIBITORS AND THEIR PREPARATION. - Google Patents

Description

/ '"V

VO 130

Title: Antibacterial agents and ö-lactamase inhibitors as well as their preparation.

The invention relates to lactam-containing compounds, their preparation and preparations containing these compounds.

In particular, the invention relates to penem carboxylic acids of the formula 1 of the formula sheet, wherein n 0 or 1, R "" is hydrogen, alkyl, acetonyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methaxy -benzyl, phenyl, p-nitrophenyl or benzhydryl or represents a group which undergoes metabolic activation in vivo and has useful pharmacokinetic properties, eg acetoxymethyl, pivaloyloxymethyl, phthalidyl or a group of the formula -CH-OCOOCgH ^ or -CHgMCOR "", wherein R "" is alkyl of 1-5 carbon atoms, cycloalkyl or aryl; Z is hydrogen, halogen, hydroxy, amino, carbamoyloxy, mercapto or a pyridium group or a group of the formula OR ', OCOR', ICHOR 'or SR ", wherein R' and R" are each alkyl, aryl or a hetero-15 represent a cyclic ring, each of which may or may not be substituted; and R '' is hydrogen, alkyl, alkoxy, cycloalkyl or hydroxyalkyl, most preferably hydroxyalkyl, wherein the alcohol function of the hydroxyalkyl group is free or protected and the protecting group is most preferably p-nitrobenzyloxycarbonyl or dimethyl-t-butylsilyl, and wherein the substitution in the 6 th form or the form, the o form being preferred.

Examples for the R "" residues, which are known to undergo metabolic activation in vivo and possess useful phanaacokinetic properties, are acetoxymethoxy, pivaloyloxymethyl and phthalydyl, as well as groups of the formulas -CHjDCOOCgH ^ and -CHgRHCOR "".

ch3

When R 'and R "are hetero rings, these are preferably 5- or 6-rings, such as 5-Jaethyl-1,3,3-thiadiazol-2-yl, 1-methyltetrazol-5-yl, 1,2 , 3-triazol-5-yl or pyrazinyl. Examples for R ''.

30 are methyl, ethyl, methoxy, 1-hydroxyethyl and 1- (p-nitrobenzyloxy-carbonyloxy) -ethyl.

These compounds have a broad spectrum of antibacterial activity as well as an β-lactamase inhibiting activity. It should be noted that the stereochemistry at the atom of the present compounds as well as that of the 80 0 1 0 12 -2 intermediates formed during preparation is the same as naturally occurring penicillins and cephalosporins.

Pharmaceutically suitable salts of penem carboxylic acids of the formula 1, such as the sodium, potassium, benzathine, procaine and the like salts, which are usually formed with penicillin and cephalosporin, are all within the scope of the invention.

The invention further relates to methods of preparing the present compounds, the intermediates formed thereby and pharmaceutically suitable preparations containing these compounds in admixture with conventional carriers for oral and parenteral administration.

The scheme A of the formula sheet shows the preparation of the compounds of the formula 1.

When RM 'is hydrogen, the compounds of formula II are derived from (5R) -6-aminopenicillanic acid or β-ΑΡΖ according to e.g. the known Cignarella process reported in the Journal of Organic Chemistry, 27, 2668 and Nature 201, 112U.

When R'M is alkyl, cycloalkyl or hydroxyalkyl, the group R 'can be introduced according to Journal of Organic Chemistry U2, 2960 (1977).

If R '' is alkoxy, this group R '' according to Helv.-Chem.

Acta 50, 1327 (1967) and Tetrahedron Letters 11, 995 (1978) are introduced at 6-APZ in the 6-position.

Alternatively, compounds of formula 2 wherein R "1 is H 25 may be converted to compounds of formula 2 wherein R" 1 is alkyl, cycloalkyl or hydroxyalkyl using the substituent. of a strong base is introduced at position 6, as further illustrated in the following examples.

Compounds of formula II, wherein R 1 'is alkyl, cycloalkyl or hydroxyalkyl, may also be prepared from suitable esters of penicillanic acid S-oxide as further illustrated in the examples. The substitution at position 6 is directed stereospecifically to the β ^ derivatives.

The ester of penicillanic acid S-oxide (2) (R is alkyl and R "has the meanings shown above) can be in an inert solvent, such as benzene or toluene, usually at 70-100C, with a suitable acetylene - r 80 0 1 0 12 it Ψ -3- * derivative of the formula X'C = CY, where X 'is a group of the formula CHgZ', and Z 'is hydrogen, halogen, hydroxy, amino, carbamoyloxy or a group of the formula OR ', OCOR' or 'ICHOR', and Y is hydrogen, alkyl, cyano or a group of the formula COOR or CH 2 Z ', wherein R 5 and Z' have the above meanings are heated. If X 'has a different meaning, it can be converted into a group X by known substitution reactions, wherein X represents a group of the formula GHgZ, in which Z has the meaning shown above.

The compound 3 can be used with a base up to. of the compound b are isamerized, which can be converted into the final compound 1 in two different ways. According to the first method, the compound b at the isopropenyl double bond can be selectively ozonized to yield the compound 5 (n = 1), which is converted to the compound with suitable reducing agents such as phosphorus trichloride or sodium iodide in acetyl chloride. 5 (n = 0) can be reduced, which is then hydrolysed to compound 6 (n = 0) under mild basic conditions or over silica gel. When condensed with a suitable ester of glycolic acid, the compound 7 (n = 0) is obtained, which with a chlorinating agent, such as thionyl chloride and pyridine, in the chloro-derivative 8 (n = 0) and then in the phosphorane 9 (n * 0) can be set.

Moreover, the same reaction sequence is also carried out starting from the unexpected compound Ij (n = 1), which is stable if Y does not represent a highly cleavable group. In compounds 9 (n = 0), the compound can be selectively ozonized as the phosphonium salt under acidic conditions to give the compound 11, which is readily heated by heating in an inert solvent such as toluene at 50-100 ° C to a compound 1 is cycled.

In compounds 11 (n = 1), the compound must be reduced to compound 10 and then selectively ozonized to compound 11 to yield compound 1.

According to the second method, the compound U can be reduced under the usual conditions to a compound 12, which is ozonized on both double bonds, whereby the compound 13 and, after hydrolysis, the compound 1U are formed. According to the method already indicated above 80 0 1 0 12 -1 + - a glyoxylation of the compound lU yields a compound 1-5, which can be converted into the chlorine derivative 16 and then into the phosphorane 11, the latter a general intermediate for both methods.

If R '' is hydroxyalkyl, the reaction sequence is preferably carried out under the protection of the alcohol function.

Compounds of compound 1 in which R '' 'is hydrogen can be obtained by hydrolysis or hydrogenolysis of the corresponding esterified compounds. Compounds of formula 1, wherein 10 is n = 1, are readily prepared from compounds of formula 1, wherein n = 0, by known oxidation processes. Preferably, peracids can be used, most preferably m-chloroperbenzoic acid and peracetic acid.

The above methods all fall within the scope of the invention.

A series of in vitro experiments were performed on the activities of (5R) -acetoxymethyl 1-2-acetoxymethyl 1-2-penem-3-carboxylate (FCE / 200T7 / Bl + 0/31 + 1), (5R) -acetoxymethyl 2- / 11-Methyl-1H-tetrazol-5-yl) -thicmethyl-2-penem-3-carboxylate (Compound A) and two reference compounds. Table A below shows the results of these tests with their MRC values.

25 30 35 800 1 0 12 '2 * -5-

Table A: MRC jig / ml

StamΡ0 / 20077 / Β ^ 0/3 ^ 1 | connection a | ampicillin *. cefoxitin Staphylococcus aureus 209P 0.39 0.39 / 0.19 0.78

St aphyloc occus aureus 153 1.56 0.78 1.56 0.78

Staphylococcus! aureus FV2) 0.39 0.78 v <0.19 0.78 i. St a-phyloc occus aureus

Smith ATCC 13709 1 ^ 0.19 0.39 \ 0.19 0.78

Streptococcus pyo-; genes ATCC 1238¼ j 3.12 0.78 3.12 1.56

Escherichia eoli B ί 1.56 0.78 0.39 1.56

Escherichia coli VlU j 1.56 0.78 1.56 3.12

Escherichia, coli V23 | 3.12 0.78 3.12 12.5

Enterohacter sp. V19 | 12.5 ^ 100> 100 12.5

Klebsiella pneumoniae! ATCC 10031 - 3.12 50 0.78

Klebsiella sp. R2 25 - 50 12.5

Proteus vulgaris V15 3.12 6.25 1.56 0.78

Proteus mirabilis V15 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 s {0.19 0.78

Pseudomonas aeruginosa 3.12 0.39 25 6.25

Salmonella typhimurium 1.56 0.78 0.78 3.12

Salmonella panamae F15 1.56 0.78 0.78 1.56

Salmonella Saint Paul F20 1.56 0.78 0.78 3.12

Salmonella derby Flh 3.12 0.78 0.78 3.12

Salmonella montevideo

F1 6 3.12 0.78 0.78 3.12

80 0 1 0 M

-6-

The following examples further illustrate the invention.

Example I: 1 + 1-vinylthio- (1,2-diacetoxymethyl) -1- (1H-ethoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide. Schedule B.

5 A solution of 2.0 g of methylpenicillanate-S-oxide and 2.8 g

O

butindiol diacetate in 1 + 0 cnr toluene was refluxed for 2b hours. The title compound could be purified by column chromatography over silica gel, eluting with 91% dichloromethane: ethyl acetate. Thus, 1.1+ g of the title compound were obtained.

10 MR (CDC13): 2.03 ^ (s, CH3-Ö-), 2.15 and 2.20 ^ (two s, 2 C ^ CO), 2.88 § (dd, Jgem = ll + Hz, Jvic cis = 1+ Hz, C-3-HbO, 3> 38 J * (dd, Jgem = 11 + Hz, Jvic trans = 2 Hz, C-3-H0), 3.83 (s, CH30), 1+, 88 <? (Jvic * 6 Hz,

CH ^), 1 +, 92 J (broad s, CH2-C =) 1 +, 93 - 5.33iP (m, = CH2 and -N C

15 ^ CE), 5.32 $ (dd, Jvic = 1+ and 2 Hz, C-1 + -H), 6.1 + 7 $ (t, Jvic = 6 Hz, ioo = <jc (h2)) .

H

Example II: 20 1+ / Winylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-on-S-oxide (Scheme C).

1.7 g 1 + r ^ -vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-

O

methyl 2-propenyl) -azetidin-2-one-S-oxide was dissolved in 80 cm 2 of dichloromethane 3. 0.5 cm of triethylamine was added and this solution was stored at room temperature for several hours. After distilling off the solvent, the title compound was obtained pure in quantitative yield.

MR (CDCLi): 2.13 (9H) and 2.32 (3H) J (two s, 2 CH3CO and 2 CH3-C =), 2.92 $ (dd, Jgem = 15 Hz, Jvic cis = 5 Hz , C-3-Hoty, 3.38 $ (dd, Jgem = 15 Hz,

Jvic trans = 2.5 Hz, C-3-HP), 3.82 $ (s, CH30), l +, 88 $ (d, Jvic = 6.5 Hz, 30 CH2-C =), 1 +, 92 (s, CH2-C =), 5.15 $ (dd, Jvic = 5 and 2.5 Hz, C-1 + -H), 6.50 $ (t, Jvic = 6.5 Hz, = 9- (H2)).

Example III: 1 + $ - vinylthio- (1,2-diacetoxymethyl) -1-methoxyoxaloyl-azetidin-2-one-S-oxide. (scheme D).

2.0 g i + A-viylthiO0.2 -deacetoxymethyl) -1- (1-methoxycarbonyl-2 - 8001 -7-. 3 methyl-1-propenyl-azetidin-2- on -S-oxide was dissolved in 150 cm dichloromethane and after cooling at -78 ° C with a streak of ozone in oxygen by blowing until a faintly bluish color appeared, this solution was brought to room temperature, shaken with an aqueous HagSgO2 solution. 5 and dried with HagSO 4 The organic phase obtained gave 1.1+ g of the title compound after distilling off the solvent in vacuo.

KMR (CDC13: 2.05 and 2.08 # two s, 2 Cl 3 CO 2), 3.03 (dd, Jgem 17 Hz, J cic cis = 5.5 Hz, C-3-Hck), 3.50 dd, Jgem * 17 Hz, Jvic trans = 3 Hz, C-3-Hβ), 3.90 i (s, CHoO), 1 +, 82 S (d, Jvic * 6.5 Hz, CEL-C-) , 1 +, 9θ | (s, 10 CH2-C =), 5.32o (dd, Jvic = 5.5 and 3 Hz, C-1 + -H), v 1 6, l + 7 <£ (t, Jvic = 6.5 Hz, = 0-0 (¾)).

H

IR (CB ^ CXg): 1830 cm-1 ft-lactam C = 0 1750 cm-1 * ester 0 = 0 15 1715 cm-1 amide C = 0.

Example 17: 1 + fA-vinylthio- (1,2-diaceto3cymethyl) -1-methoxyoxaloyl-azetidin-2-one (Scheme E).

A solution of 1.1+ g of 1+ -vinylthio-1,2-diacetoxymethyl) -1-. . . 3 ...

Methoxyaxaloyl-azetidin-2-on-S-oxide with 10 cm anhydrous dimethylformamide was cooled to -25 ° C and 0.9 cm2 of phosphorus trichloride was added.

After 10 minutes, the mixture was diluted with ethyl acetate and washed twice with a saturated sodium bicarbonate solution. After drying with sodium sulfate and distilling off the solvent, 0.9 g of the title compound 25 were obtained.

HMR (CDC13): 2.07 £ (s, 2 CH3C0), 3.17 £ (dd, Jgem * 19 Hz »Jvic trans = 3.5 Hz, C-3-Ηβ), 3.65 $ (dd, Jgem = 19 Hz, Jvic cis * 5 Hz, C-3- Hrf), 3.90 $ (s, 0¾ 0), 1 +, 73 $ (d, Jvic = 6.5 Hz, ΟΗ2 ~ 9 =) l + .88 ^ (broad s, CH2- <? = 0.53v (dd, Jvic = 5 and 3.5 Hz, ^ C-1 + -H), 6.25cT (t, 30 Jvic = 6.5 Hz, -9- (0 (¾)).

H

IR (CHCl 3): 1815 cm-1 α-lactam 0 = 0 17 I + 5 cm ester 0 = 0 1710 cm -amide 0 = 0.

Example V: 800 1 -12 -8- 1+ -vinylthio- (1,2-diacetoxymethyl) -azetidin-2-one.

(schedule F).

1.5 g of Ι + β-vinylthio- (1,2-diacetoxymethyl) -1-methoxy-oxaloyl-azetidin-2-one were dissolved in 100 ml of methanol and a few grams of silica gel were added with good stirring. After 1 hour, this silica gel was filtered off and the methanol solution evaporated, yielding 0.8 g of the title compound.

ME (CDCL ^): 2,255 (s, 2 CH ^ O), 2.98 <f (dd, Jgem = 15 Hz, Jvic trans * 2 Hz, C-3-H), 3, Wi (dd, Jgem 15 Hz, Jvic cis = 1 +, 5 Hz, C-3-Hp), U, 78cT 10 (d, Jvic = T Hz, CH2-C =), 1 +, 87 ƒ (s, CHg-C »), 5 .03 (dd, Jvic * l +, 5 and 2 Hz, <! C-1 + -H), 6.02 (f (t, Jvi £ èi 7 Hz, = 9-0 (Η2)), 7.13 ^ (broad s, IH).

IR (CHCl 3): 1770 cm-1 f-lactam H C = 0 1711 cm-1 ester C = 0.

Example VI: 15 + Fvinylthio- (1,2-diacetoxymethyl) -azetidin-2-one-S-Oxide. (scheme G).

0.800 g of vinylthio- (1,2-diacetoxymethyl) -1-methoxy-oxaloyl-3-azetidin-2-one-S-oxide was dissolved in 80 cm @ 3 of methanol and a few grams of silica gel were added with stirring. This silica gel was filtered off for 1 hour and 0.5 g of the title compound were obtained after distilling off the solvent.

MR (CDCl ^): 2.13 ^ (s, 2 CH ^ CO), 3.0 to 3.3 <^ (m, 2 protons at C-3), 1 +, 70 S (m, CUH), b, Q8 $ (d, Jvic = 6 Hz, CH ^ s), U, 93 cf (s, CHg-C *), 6.53? (t, Jvic = 6 Hz, -9-C (ï2) ), 7.23 <P (s, 1H).

IR (CHCl 3): 1790 cm -1 "-lactam C = 0 25 171 + 5 cm" 1 ester C = 0.

Example VIII:

Onion acetylglycolylthio-1-acetaxymethylaxyaloyl-azetidin-2-one. (scheme H).

0.8 g U ^ -vinylthio- (1,2-diacetoxymethyl) -1- (1-acetozymethyloxycar-

O

bonyl-2-methyl-1-propenyl) -azetidin-2-one was dissolved in 80 cm @ 3 of dichloromethane, cooled to -78 ° C and blowing a stream of ozone into oxygen until a blueprint occurred. This solution was dried after shaking with an aqueous I2S2O2 solution with sodium sulfate to yield 0.1 + 5 g of the title compound.

MR (CDC] ^): 2.10 and 2.13 $ (two s, 2 CH3C0), 3.20 ^ (dd, Jgem * 17 Hz, 35 Jvic trans = 3.5 Hz, C-3-Hj &) , 3.77 f (dd, Jgem = 17 Hz, Jvic cis = 800 1 0 12 -9- 5.5 Hz, C-3-H 3 O, ^, 73 <? (S, -CO ^ -CHg-OCO-) r 5.73 (dd, Jvic = 5.5 and 3.5 Hz, CUH), 5.87c5 * (s, C00-CH2-OCO).

Example VIII: Acetylglycolylthio-azetidin-2-one (Scheme J).

0.6 g of U-acetylglycolylthio-1-methoxyoxaloyl-azetidin-2-one were dissolved in 100 ml of methanol and a few grams of silica gel were added with stirring. After 1 hour, the silica gel was filtered off and the resulting solution yielded 0.35 g of the title compound after distilling off the solvent.

10 NMR (CDCl 3): 2.20? (S, C 1 C 3 CO), 3.03 P P (dd, Jgern 16 16 Hz, Jvic trans * 2.5 Hz, C-3-H), 3.50 ((da, Jgern = lö Hz, Jvic cis = k, 5 Hz, C-3-Ηύί), ^ .77 ^ (8, -CO-CHg-OCO-), 5.32 $ (dd, Jvic * h, 5 and 2 .5 Hz, CUH), 6tkoS (broad s, NH).

Example IX: 15 K-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one. (scheme K).

0.7 g of acetoxymethyl glyoxylate (freshly prepared by an ozonolysis of

O

diacetoxymethyl fumarate) was dissolved in 30 cm of benzene and the resulting solution with. Cook a Dean-Stark device for 20 min.

After cooling at 50-60 ° C, 0.7 g! + Ö-vinylthio (1,2-diacetoxy-

O

methyl) -azetidin-2-one dissolved in 10 cm benzene, added and the resulting solution boiled for 2 hours. The title compound was obtained in almost quantitative yield and could be used as a crude mixture in the next step. A pure sample was obtained by preparative thin layer chromatography for analytical purposes.

NMR (CDCl3): 2.Q7 $ (s, 3 ClO ^ O), 2.97cT (dd, Jgern = 18 Hz, Jvic trans = 2 Hz, C-3-H (>>), 3. ^ 0 $ (dd, Jgem = 18 Hz, Jvic cis = U Hz, C-3-Ifc0, ^, 70iP (d, Jvic = 6 Hz, CHo-CJ k, n $ (s, 0Ho-C =), 5.0 -5, lvc? (M, CUH, and £ * -N-CH-C00-), 5.77 ^ (s, -COO-CH0-OCO-), 6.12 ^ (t, Jvic = 6 Hz, -CC (H0)).

6 (H) 1 Example X: U-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxy-carbonyl-1-chloromethyl) -azetidin-2-one (Scheme L).

0.6 g U2-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxy-)

O

carbonyl-1-bydroxymethyl) -azetidin-2-one, dissolved in 15 cm of tetrahydro-

O

Furan, was cooled to 0 ° C, 0.115 g pyridine and 0.10¼ cm thionyl chloride 800 1 0 12 -10- were added and this mixture stirred for 10 min. The insoluble material was filtered off and the solution evaporated in vacuo at room temperature to yield the title compound in high yield.

For analytical purposes, a sample was purified by preparative thin-layer chromatography, however the crude mixture could be used for the next step without purification.

HMR (CDC13): 2.1hS (s, 3 CH3C0), 3.10ƒ (dd, Jgem = 15.5 Hz, Jvic trans = 2 Hz, C-3-Ηβ), 3.55 (dd, Jgem = 15 .5 Hz, Jvic cis = 5 Hz, C-3-HdO, U, 7T ^ (d, Jvic = 6.5 Hz, CHg-p *), l +, 83i? (S, CHg-C *), 5 , 1 * -10 5.9 Cl * -H and -JT-CHCl-C00-), 5.88 ^ s, -COO-CHg-OCO-), 6.133 (t,

Jvic = 6.5 Hz, = C-C (H2)).

Example XI: 1 * (1-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethylaxycarbony 1-1-triphenylphosphoranylidenemethyl) -azetidin-2-one (Scheme M).

15 A solution of 0.1 * 30 g of l * £ -vinylthio- (1,2-diacetoxymethyl) -

O

1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one in 5 cm 3.

tetrahydrofuran and 5 cm dioxane with a content of 0.520 g trxphenylphosphine and 0.08 car pyridine were stirred overnight at 50 ° C. The resulting phosphorane was purified by column chromatography over silica gel, eluting with 70:30 dichloromethane-ethyl acetate. 0.1 * 00 g of the title compound were thus obtained.

MR (CDCl ^): 2.05 <F (e, 3 CH3C0), l *, 70 «P (d, Jvic = 6.5 Hz, CHg-q ·), l *, 73 <? (S, CHg -q *), 5.77 ^ (s, -COO-CHg-OCO), 5.90 ≤ f (t, Jvic * 4¾ Hz.

-G-C (H 2)), 7.1-8.0 <5 * (m, 3 CgH4.

25 "

Example XII: 1 * Acetylglycolylthio-1- (1-acetoxymethyloxycarbonyl-1-triphenylphos-foranylidenemethyl) -azetidin-2-one (scheme II).

0.7 g of 1 * Ê-vinyl lthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxy-

O

Carbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one was dissolved in 1 * 0 cm dichloromethane and, after cooling to -20 ° C, added 50 cm3 of a 10 # solution of trifluoroacetic acid in dichloromethane.

After a few minutes, a stream of ozone in oxygen was purged at -20 ° C until a light blue coloring occurred. At this time, the reaction was stopped and a few drops of trimethylphosphite added. The 800 1 O 12 -11 organic solution was washed with a saturated sodium carbonate solution and dried with sodium sulfate to obtain 0.550 g of the title compound.

HMR (CDCl3): 2.10 and 2.15 ^ (two d, 2 CH3CO), U, 72 <f (s, -CO-CHg-OCO-), 5 5.61 ^ (3, -COO-CH2 -OCO), 7.1 to 8.0 <T (m, 3 C ^).

Example XIII; (5R) -acetaxymethyl-2-acetoxymethyl-2-penem-3-carboxylate (Scheme 0).

0.7 g b β-acetylglycolylthio-1- (1-acetoxymethyloxyc arbonyl-1-

O

triphenylphosphoranylidenemethyl) -azetidin-2-one was dissolved in 30 cnr anhydrous toluene and boiled for 2 hours. This reaction mixture, consisting of the title compound and triphenylphosphine oxide, was purified by short column chromatography over silica gel, eluting with 79/3 dichloromethane: ethyl acetate; thus 0.25 g of the title compound was obtained.

HMR (CDC13): 2.11 and 2.13 ^ (two s, 2 CHgCO), 3. ^ 9 ^ (dd, Jgem * 16.5 Hz, Jvic trans = 2 Hz, C-6-Hp, 3 , 86 ^ * (dd, Jgem = 16.5 Hz, Jvic cis = 3.8 Hz, C-6-H *), 5.12 and 5MS (two d, Jgem = 15.5 Hz, * C-CH2 ), 5.68 µ (dd, Jvic = 3.8 and 2 Hz, C-5-H), 5.87 ^ (s, -COO-CHg-OCO).

IR (CHCl 3): 1800 cm -1 of lactam C = 0 20 1750-1725 cm -1 ester C = UV (EtOH): λ v 325 nm.

UlaA

MS: m / e 315.0 ^ 108 (M) calc. for C ^ H ^ NO ^ S 315.0 µl27.

Example XIV: k1 -vinylthio- (1,2-diacetoxymethyl) -1- (1-p-nitrobenzyloxycarbonyl-1-25 hydroxymethyl) -azetidin-2-one (Schea P).

The title compound was obtained according to Example IX using p-nitrobenzyl glyoxylate freshly prepared by an ozonolysis of p-nitrobenzyl fumarate.

HMR (CDClg): 2.1 <T (s, 6ï), 2.8 - 3.7 ^ (m, 2H), kfJ - (a, 5H), 5.1 - 5.6 <f (m .2H), 5.2- (m, 1H), 6.1? (A, 1H), 7.5 - 8.3 if (m, UH). Example XV: -vinylthio- (1,2-diacet oxymethyl 1) - (1-nitrobenzzyloxycarbonyl-1-chloromethyl) -azetidin-2-one (scheme Q).

The title compound was prepared according to Example X.

35 EMR (CDOL1): 2.1S (s, 6H), 2.8-3, Ti (m, 2H), lt, 7-1 (.9 ^ (m, 11H), 800 1 0 12 -12 - 5.2 - 5, kS (m, 1H), 5M (m, 2H), 6.1 - 6.3 cT (m, 2H), 7.5 - 8, UcP (m, UH) Example XVI 1 (V-vinylthio- (1,2-diacetoxymethyl) -1- (1-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one (Scheme R).

5 The title compound was prepared according to Example XI.

Example XVII: β-acetylglycolthio-1- (1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoryl-deenmethyl) -azetidin-2-one (Scheme S).

This title compound was prepared according to Example XII.

Example XVIII: (5R) -p-nitrobenzyl-2-azetaxymetbyl-2-penem-3-carboxylate.

(scheme T).

This title compound was prepared according to Example XIII.

RMR (CDClg): 3.75 £ (IB, dd, J = 2.3 Hz, l6.8JIz, Η-6 <λ), 3.87 S 15 (1H, dd, J = 3.6 Hz, 16 , 8 Hz, H-6 £), 5.11 ^ (1H, d, J = 15.8, = C-CH ^ O), 5.50 (1H, d, J = 15.8 Hz, = C-CH 2 O), 5.71 ^ (^, dd, J * 2.3 Hz, 3.6 Hz, H-5).

/ el / D + 87 ° (c = 1.2 in CHCl 3).

IR (CHCl 3): 1800 (? 3-lactam), 1750 and 1720cm -1.

UV (EtOH): 265 (£ 11000) and 322 (6 7000) nm.

M.S .: m / e 378 (M +).

Mp. 122 to 123 ° C.

Example XIX: (5R) -2-Acetoxymethyl-2-penem-3-acetic acid (Scheme U).

200 mg (5R) -p-nitrobenzyl-2-acetoxymethyl-2-penem-3-carboxylate,. 3 prepared analogous Example XVIII, m 12 cm ethyl acetate was dissolved.

O

8 cur of a 0.2 M sodium bicarbonate solution and 100 mg 10 Pd / C were added and the resulting phase mixture shaken under hydrogen for 60 min. After filtering off the catalyst, the aqueous phase was acidified with 5% aqueous citric acid and extracted three times with methylene chloride. The organic layers were dried with sodium sulfate and evaporated to give 60 mg of the title compound.

IR (CHCl 3): 1790 (--lactam, 1735 and 1700 cm -1).

35 Uv (EtOH): 300 nm.

80 0 1 0 12 -13-

Example XX: 1+ - (1-hydroxymethyl) -vinylthio-1- (1-methoxy-carbonyl-2-methyl-1-2-propenyl) -azetidin-2-one-S-O 2 (scheme V).

o 1+ g of penicillanic acid methyl ester S-oxide were added in 15 cm of toluene

O

5 dissolved and boiled for 8 hours with 15 cm propargyl alcohol. After evaporation in vacuo, the residue was purified by a short silica gel column chromatography, eluting with dichloromethane-ethyl acetate (1: 1). Thus, 2.8 g of the title compound were obtained.

HMR (CDC13): 1.96 h (broad s, 3H, C-CHg), 2.91 and 3.35 lb (dd, 2H, J = 2 Hz, 10 5 Hz, 15 Hz, CO-CHg-CH -S), 3.78 <T (s, 3H, GOOCHS), 1 +, 36 cT (broad s, 2H, CHgOH), 1 +, 90 - 5.25 ^ (m, 3H, CH-C00CH3-CC = CH2), 5.35 ^ (m, 1H, CH2-OT-S), 5.88 (s, 2H, CH2 = CS).

Example SCI: 1+ (1-hydroxymethyl) -rinythio-1- (1-methoxycarbonyl-2-methyl-1-pro-15-penyl) -azetidin-2-on-S-oxide (Scheme W).

3.0 g (1-hydroxymethyl) -vinylthio-1- (1-methoxycarbanyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide were dissolved in 100 cm of dichloromethane and left at room temperature for several hours kept. After the solvent was billed off, the residue consisted of pure title-20 compound, which was obtained in a quantitative yield.

HMR (CDCl3): 2.08 $ (s, 3H, J-Cgg), 2.18 (s, 3H, = -Cl3), 2.7 - 3.6 (m, J = 2 Hz, 5 Hz, 16 Hz, CO-CHg-CH-S), 3.7S (s, 3H, COOCHg), 1 +, 35 (s, 2H, CHgOH), 5.32 (m, 1H, C 1 -S), 5, 90 (broad s, 2H, = ¾).

Example XXII; 1 + P- (1-bromethyl) -vinylthio-1- (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one. (schedule X).

1.8 g l + £> - (1-hydroxymethyl) -vinylthio-l- (1-methoxycarbony1-2-

O

methyl-1-propenyl) -azetidin-2-one-S-oxide was dissolved in 1 + 0 cm dimethylform amide and cooled to -20 ° C, 0.7 cm 3 pyridine and 3.0 cm 3 PBr 3 were added and the mixture stirred for 15 min. Ethyl acetate was added and the organic layer shaken with a saturated sodium bicarbonate solution, washed with water and then dried with sodium sulfate to yield 1.6 g of the title compound after distilling off the solvent.

35 BME (CDClj): a.Oltits, 3H,, 2.21 ^ (., 3H,), 800 1 0 12 -Ολ ο 3.2l; S (ad, J = 2.8, 5.16 Hz, 2Η, ö-CHg-CH), 3.75 (a, 3Η, OCH3), 1 *, 02 (s, 2Η, CHgBr), 5.2U (broad s, 1H, = CH), 5.31 S ( dd, J = 2.8 Hz, 5 Hz, 1H, CH 2 -CH-S), 5.6o (Wide s, 1H, = CH).

Example XXIII: 5k (1-methyl-1H-tetrazol-5-yl) -t-hiomethyl-1-vinylthiol? -1- (1-methoxy-carbonyl-2Hiethyl-1-propenyl) -azetidin-2-one. (scheme Y).

1, ¾. g of bb- (1-bromethyl) -vinylthio-1- (1-methozycarbonyl-2-methyl-1-proxy) -azetidin-2-one were dissolved in 25 cm of tetrahydrofuran and cooled to 0 ° C. 0.8 g of 1-methyl-5-thiol-tetrazole sodium salt was added and this mixture was stirred at room temperature for 3 hours. After filtering out the insoluble material, this mixture was diluted with ethyl acetate, washed with water, dried with sodium sulfate and evaporated. The residue consisted of 2.0 g of pure title compound.

MR (CDCl 3): 2.0 £ (s, 3H, = i-CH3), 2.22 tf (s, 3H, = δ-CH3), 2.70-3.80 <f 15 (m, 2H , J = 2 Hz, 5 Hz, 15 Hz, CO-CHg-CH-S), 3.72 <P (s, 3H, COOCHg), 3.95 i (a, 3H, N-CHj, ^, 10 ^ (s, 2H, ^ -S), 5.18i (broad s, 1H, kc = CH), 5.36 <T (m, 1H, CH2-CH-S), 5.57 J * (broad s , II, Sb =--H).

Example XXIV: 1 + P- (1-methyl-1H-tetrazol-5-yl) -thioacetyl-thio-1-methoxyoxaloyl-azeti-20 din-2-one (Scheme Z).

1.8 g U f- / 1- (1-methyl-1-tetrazol-5-yl) -thimethyl / -vinylthio-1- (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2- on was dissolved in 200 ml of dichloromethane and cooled to -78 ° C. Once-ozonized oxygen was blown through the solution until bleaching occurred.

Some drops of P (0CH3) 3 were added, the mixture brought to room temperature and evaporated. yielding 1.3 g of the title compound.

ME (CDC13): 2.9 - 3.7 (f (m, 2H, COCHgCHS), 3.85 ^ (s, 3H, COOCHg), 3.98 (s, 3H, N-CHg), h, 35 (a, 2Ξ, CHgS), 5.75 (m, 1H, CHgCHS).

Example XKV: kf- (1-methyl-1H-tetrazol-5-yl) -thioacetyl-thio-azetidin-2-one (scheme AA), 1.2 g ^ - (1-methyl-1H-tetrazol-5 -yl) -thioacetylthio-1-methoxy-axaloyl-azetidin-2-one were dissolved in a 1: 1 mixture of ethyl acetate-methanol and a few grams of silica gel were added with vigorous stirring. After 1 hour, the insoluble material was filtered off and the 80 0 1 0 12 -15 solution evaporated in vacuo. The title compound crystallized from methanol / ethyl ether. Yield 0.6 g.

Example XXVI: (1-methyl-1H-tetrazol-5-yl) -thioacetylthio-1- (1-acetoxymethyloxy-carbonyl-1-hydroxy-axymethyl) -aze tin-2-one. (Schedule BB).

1.5 g of tm1-methyl-1H-tetrazol-5-yl) -thioacetylthio-azetidin-2-one were boiled in 50 cur benzene with 1.2 g of acetoxymethyl glyoxylate (freshly prepared by an olysis of diacetoxymethyl fumarate). The reaction was after 3 hours. past. The oily material obtained after distilling off the solvent could be used for the next step without further purification. A sample was purified thin-layer chromatographically for spectroscopic data.

HMR (CDC13): 2.05 ^ (s, 3H), 2.7 - 3.8 (m, 2H), 3.95J (s, 3H), U, 30 ^ (s, 2H), 5, ^ 0 i (s, 1H), 5.50 <F (m, 1H), 5.80 <P (s, 2H).

Example XXVII; (1-methyl-1H-tetrazol-5-yl) -thioacetylthio-1- (1-acetoxymethyloxy-arbyl-1-chloromethyl) -azetidin-2-one (scheme CC).

The oil obtained according to the previous example, which is obtained from crude (1-methyl-1H-tetrazol-5-yl) -thio-acetylthio-1- (1-acetoxymethyloxy-

O

Carbonyl-1-hydroxymethyl) -azetidin-2-one existed, was dissolved in 20 cm of anhydrous tetrahydrofuran and treated with an equimolar amount of pyridine and thionyl chloride at 0 ° C until the total starting material disappeared. After filtering off the insoluble material, the filtrate was used immediately for the next step.

Example XXVIII: 1-methyl-1H-t etrazol-5-yl) -thioacetyl-thio-1- (1-acetoxymethyloxy-carbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one (Scheme DD).

To a solution containing crude Ufu (1-methyl-1H-tetrazol-5-yl) -thio-acetylthio-1- (1-acetoxymethyl-2-carbonyl-1-chloromethyl) -azetidin-2-one-3 was added 800 mg of triphenylphosphine and 0Λ cm pyridine added and the resulting mixture heated at 60-70 ° C for several hours. The phosphoran was purified on silica gel, eluting with dichloromethane / ethyl acetate (1: 1).

Example XXIX: 35 (5R) -acetoxymethyl-2- / 71-methyl-1H-tetrazol-5-yl) -thicmethyl / -2-penem-800 100 -16-3-carboxylate (Scheme EE).

0.500 g U / 3- (i-methyl-1H-tetrazol-5-yl) -thicmethylacetylthio-1- (1-aetaxymethyloxycarbonyl-1-triphenylphosphanyl-liderethyl) -azetidin-2-one were dissolved in 30 canol toluene and 2 hours heated to 100 ° C. The title-5 compound was purified by short column chromatography over silica gel of PPh 2 O, eluting with dichloromethane-ethyl acetate (8: 2).

NMR (CDCl3): 2.15 <£ (s, 3H, COCHj, 3.30 - 1 + .03 5 (m, J * b Hz, 2 Hz, -CH2- (6), 3.975 (s, 3H, -HCHj), 1 +, 56 δ (d, J = Ih Hz, 1H, HCH-S), 10 + 1, 81 + f (d, J = 11 + Hz, 1H, HCH-S), 5.65 ^ (d <1, J = 1+ Hz, 2 Hz, 1H, HJ *), 5.88 (s, 2Ξ, COOCHgO).

Example XXX: (5R) -2- (1-methyl-1H-etr azol-5-yl) -thimethyl-2-penem-3-carbonic acid. (schedule EF).

The title compound was prepared according to Example XIX. The (5R) -p-nitro-benzoyl-2- (1-methyl-1'-etr azol-5-yl) -thi-ethyl-2-penem-3-carbaxylate was obtained analogously to the previous examples.

IE (CHCl 3): 1800 (g-lactam), 1750 and 1720.

Example XXXI: 20 Methy 1-6- (1'-hydroxyethyl) -penicillanate-S-oxide. (schedule GG).

A solution of 2.3 g of methylpenicillanate-S-oxide in 50 ml of vessel-free tetrahydrofuran is cooled to -78 ° C. Lithium diisopropylamide (freshly prepared from 5 ml of diisopropylamine and 20 ml of a 1.6 M BuLi-hexane solution), dissolved in anhydrous tetrahydrofuran, was added and this mixture was stored at -78 ° C for 10 min. 5 ml of acetaldehyde was gradually added and the whole was stirred for 15 minutes. The reaction mixture was then quenched with a saturated aqueous NH 2 Cl solution, extracted with ethyl acetate, washed twice with water and dried with sodium sulfate. After distilling off the solvent, the residue was purified briefly by silica gel column chromatography, eluting with dichloromethane / ethyl acetate (1: 1). Yield 1 ^ 5 g · The title compound consisted of a 2: 3 mixture of epimers, at the carbon-bearing hydroxyl group, determined by NMR, the new Cg-Cg bond being worst under the conditions used due to the stereospecificity of the reaction. -standard.

80 0 1 0 12 -17- 3SME (CDC13): 1.27 <f (s, 3H, 3 (- (¾), 1.1 + θ £ (d, 3H, J = 5.7 Hz, CH ^ -CHOH) main isomer, 1,18 <f (d, 3H, J = 5,7 Hz, CH 2 -CHOH) gerings * is amer, 1,70 <ƒ * (s, 3H, P-CH 3), 3, 1+ - 3.8 <? (M, IB, H-6), 3.80 ƒ (s, 3H, COOCE,), 1 +, 1 - l +, 7 <T (m, IB, CHOH), 4 .50 ^ (s, IB, H-3), ^, 98 ^ (d, J = 1.9 Hz, 5 IB, H-5), lower isamer, 5.50 (d, J = 1.9 Hz , 1H, H-5) main isomer Example XXXII:

Methyl 6- (1-hydroxyethyl) -3-penillillate (sherm HH).

3

A slight excess of lithium diisopropylamide was added to -78 ° C under nitrogen to a solution of 2.2 g of methylpenicillanate in 30 an anhydrous tetrahydroforan. An acetaldebydeoveimate was added dropwise, the mixture stirred for 5 min, quenched with a trace of acetic acid, poured into water and extracted with methylene chloride.

The organic layers dried with sodium sulfate and evaporated in vacuo gave 0.8 g of the title compound.

Example XXXIII:

Methyl -6- (1-p-nitrobenzyloxy-carbonyloxyethyl) -3-penicillanate (Scheme JJ).

O

1.2 g of methyl 1-6- (1-hydroxyethyl) -3-penicillanate was dissolved in 1 + 0 cm of tetrahydrofuran, cooled to -78 ° C and treated with an equivalent of butyl-20 lithium. 1.2 equivalents of p-nitrobenzyloxycarbonyl chloride were added to this mixture. After standing at -78 ° C for 30 min, the reaction mixture was stored at room temperature for 60 min, poured into water and extracted with methylene chloride. After drying with sodium sulfate and evaporation, 1.1+ g of the title compound were obtained.

Example XXXIV:

Methyl 1- 6- (1-p-nitrobenzyloxycarb onylaxyethyl) -3-penillillanate S-oxide. (scheme KEC).

1.8 g of methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate were dissolved in 50 ml of methylene chloride and treated with 1.5 equivalents of m-chloroperbenzoic acid at 0 ° C. The organic phase was shaken with saturated NaHCO 3 solution, extracted with NagSO 2, dried and evaporated. Thus, 1.1+ g of sulfoxide were obtained.

Example XXXV: b -vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxyearbonylaxy-35 ethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one -S-oxide (scheme LL).

800 1 0 12 -18-

A solution of 2.0 g of methyl 6- (1-p-nitrobenzyloxycarbonyloxy-

O

ethyl) -3-penicillanate-S-oxide and 2.1+ g hutindiol dioetate in 50 cm toluene were boiled for 2 hours. The inclusion compound was then purified by chromatography, eluting with 9: 1 dichloromethane / ethyl acetate. Thus, 1.1 g of the title compound were obtained.

Example XXXVI: 1 + 1 vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonylaxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-on-S -oxide. (schedule MM).

10. 1.3 g l + p-vinythi o- (1,2-diacetoxyme t hy 1) -3 - (1-p-ni trobenzy laxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-2 -propenyl) -azetidin-2- o 3 on-S-oxide was dissolved in 80 cm of dichloromethane. 0.3 cm triethylamine. and this mixture was kept at room temperature for 2 hours.

The pure title compound was obtained in a quantitative yield by distilling off the solvent.

Example XXXVII: 1 + vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonylaxyethyl) -1-methoxyoxaloyl-azetidin-2-one-S-oxide (Scheme M).

A solution of 1.1 g of l + (Winylthio- (1,2-diacetoxymethyl) -3-20 (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2Hnethyl-1-propenyl) -azetidin-2-on-S- Oxide in 100 ml of chloromethane was cooled to -78 ° C. Ozone in oxygen was purged until blue coloring occurred.

This solution was shaken with an aqueous sodium bisulfite solution and dried with sodium sulfate. After evaporation, 0.5 g of title compound 25 was obtained. Example XXXVIII: 1+ p-vinylthio- (1,2-diacetoxymethyl-1) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one (scheme 00).

A solution of 0.8 g of l + | () - vinylthio- (1,2-diacetaxymethyl) -3- (1-p-n-trobenzy loxycarbonyloxyethyl) -1-methoxycxaloyl-azetidin-2-one in 15 ml of anhydrous dimethylformamide was cooled to -20 ° C and 0.6 cm 2 phosphorus ribromide added. This reaction mixture was diluted with ethyl acetate after 10 min and washed twice with sodium bicarbonate solution. The organic phase dried and evaporated with sodium sulfate gave 0.1+ g of the reduced compound.

Example MIX: 80 0 1 0 12 -19- 1+ (J-vinylthio- (1,2-diacet oxymethyl) -3-C1-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one (Scheme EP).

1.2 g of {i-vinylthio- (1,2-diacetaxymethyl) -3- (1-p-nitrobenzylaxy-carbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one were dissolved in methanol 5 and 2 g of silica gel was added thereto . After 60 min, the insoluble material was filtered off and the organic phase evaporated.

A short column chromatography gave 0.1 µg of the title compound. Example XL: 1 * ^ -vinylthio- (1,2-diacetaxymethyl) -3- (1-p-nitrobenzzylaxycarbonyloxy-10 ethyl) -1- (1-acetaxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one . (schedule QQ).

0.6 g of Up-vinylthio- (1,2-diacetoxymethyl) -3- (1-piitr-obenzylaxycar.-bonylaxyethyl) -azetidin-2-one, dissolved in 30 cm of benzene and 0.6 g of acetoxymethylglyoxylate (freshly prepared by ozonolysis of diacetoxymethyl-15 fumarate) was refluxed. The reaction ended after 2 hours. The condensation product could be used for the next step without further purification.

Example XLI; l; (Winylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -20 l- (1-acetaxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one (scheme ER). 0.5 g ^ β-vinyl lthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxy-carbonylaxyethyl) -1- (1-acetaxymethylaxycarbonyl-1-hydroxymethyl) -3 azetidin-2-one became anhydrous 12 cm tetrahydrofuran dissolved and cooled to 0 ° C. 1.1 equivalent pyridine and 1.1 equivalent thionyl chloride 25 were added This mixture was stirred for 10 min The insoluble material was filtered off and the solution evaporated at room temperature, leaving the title compound in substantially Quantitative yield was obtained This product could be used for the next step without further purification.

Example gJI; 1 * & -vinylthi o- (1,2-diacet oxymethyl) -3- (1-p-nitrobenzzyloxy carbonyloxyethyl) -1- (aetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one (scheme SS ).

A solution of 0.60 gk fWinylthio- (1,2-diacet oxymethyl) -35 3- (1-p-nitrobenzo oyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl- 800 1 0 12 -20- 3 3 1- hydroxymethyl) -azetidin-2-one in 10 cm tetrahydrofuran and 10 cm diaxan diluted with 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine overnight at 50 ° C. The phosphoran was purified by a silica gel column chromatography, eluting with 7: 3 dichloromethane / ethyl acetate. U80 g of the title compound were obtained.

Example XLIII: 1'-acetylglycolylthio-3- (1-p-nitrohenzyloxycarhonylaxyethyl) -1- (1-acetoxymethyl-mcycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one. (schedule TT).

10 0,1 * 5 µl * - - vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxy-carbonyloxyetbyl) -1- (acetoxymethyloxycarhonyl-1-trifenylphosphanylidene-3 methyl) -azetidin- 2-one was dissolved in 50 cm dichloromethane and cooled to -20 ° C. 30 ml of a solution of trifluoroacetic acid in dichloromethane was added. After a few minutes, ozone in oxygen was purged until a light blue coloration occurred. This reaction was stopped and a few drops of inimethylphosphite were added. The organic phase was washed with a saturated sodium bicarbonate solution and dried with sodium sulfate. Thus, 260 mg of the title compound were obtained.

Example XLIY: 1 *--viethylthio- (1,2-diacetaxymethyl) -3- (1-p-nitrobenzyloxycarbonylaxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidin- 2-on.

(scheme UU).

1.5 g of vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzylaxy-carbynyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-prapenyl) -azetidin-2-one

5 O

S-oxide was dissolved in 10 cc anhydrous dimethylforamide and at -20 ° C

cooled. 0.8 cm of phosphorus tribramide was added, this mixture stirred for 10 min, diluted with ethyl acetate and washed twice with a saturated sodium bicarbonate solution. The organic layer dried with sodium sulfate and evaporated gave 1.1 g of the title compound.

Example XLV: 1 * f-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxalyl-azetidin-2-one (Scheme W).

1,1 * g 1 * Ji-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxy-35-carbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2- on 80 0 1 0 12 -21- in 120 cm 2 of dichloromethane were cooled to -78 ° C. Ozone in oxygen was purged to a blue color cptrad. This solution was shaken with an aqueous sodium bisulfite solution and dried with sodium sulfate. After evaporation, 0.8 g of the title compound were obtained.

Example XLVI: 1 * -AetylglycolylthiO-3 - (1-nitrobenzyloxycarbonyloxyethyl.) -Azetin-2-one (scheme WW).

0.800 gk of acetylglycolylthi-3- (1-nitrobenzyloxycarbonyloxy-3-ethyl) -1-methoxyoxalyl-azetidin-2-one was dissolved in 50 cm @ 3 of methanol and one gram of silica gel was added. the insoluble material was filtered off and the filtrate gave 0.3 g of the title compound on evaporation. Example XLVII: k F-acetyl glycol 3 thio-3 - (1-p-nitrobenzyloxycarbonyloxyethyl) -1-15 (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one (Scheme XX).

0.5 g of ^ - acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxy-ethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one 3 and 0.5 g of acetoxymethylglyoxylate in 30 cm of benzene cooked until the reaction was complete (2 hours). The title compound obtained could be used for the next step without further purification. Example XLVIII: fc ja-acetylgly colylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one (Scheme YY).

0.35 g of acety lgly coly lthi o-3- (1-p-nitr obenzyloxyc arbonyloxy-ethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one Λ in anhydrous tetrahydrofuran at 10 ° C Dissolved at 0 ° C. 1.1 equivalent of pyridine and 1.1 equivalent of thionyl chloride were added.

This mixture was stirred for 10 min. The precipitate was filtered off and the filtrate, after evaporation, gave the title compound in a quantitative yield. This crude product was used as such for the next step.

Example XLIX; 1+ Ö-acetylglyc olylthio-3- (1-nitroenzyloxy earbony laxyet hy 1) -1- (1-acetaxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-35 2-one (scheme ZZ).

800 1 0 12 -22- Q, hOQ g U (1-acetylglycolylthio-3- (1-nitrobenzyloxycarbonylaxyethyl) -1- (1-acetoxymethyloxycartonyl-1-chloromethyl). -Azet idin-2-one 3 was added in 20 of a 1: 1 mixture of tetrabydrofuran and dioxane dissolved 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine were added and this mixture was stirred overnight at 50 ° C. The title compound was purified by silica gel column chromatography. 7: 3 Dichloromethane / ethyl acetate was eluted, 0.280 g of the phosphorane formed was thus obtained.

Example L: 10 (5R) -acetoxymetbyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxy-methyl-2-penem-3-carboxylate (Scheme AB).

0.210 g of U 2 -acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acet axymethylQxycarbonyl-1-triphenylphosphanylidenemethyl) -3 azetidin-2-one were dissolved in 7 cm toluene and this solution 2 boiled for 15 hours. Purification via a short column chromatography eluting with 95: 5 dichloromethane-ethyl acetate gave 50 mg of the title compound.

Example LI: (5R) -acetoxymethyl-6- (1-hydroxyethyl) -2-acetoxymethyl-2-penem-3-carbaxylate 20 (scheme AC), 0.060 g of 5R-acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) - 2-Acetoxy-methyl-2-penem-3-carboxylate was poured into a mixture of water, ethanol and KgHPO4 and hydrogenolysed with 10% Pd / C. Rapid cleaning by silica gel column chromatography gave 0.015 g of the title compound.

Analogously, using 5-methyl-2-thiol-1,3, Wthiadiazole, 5-thiol-1,2,3-triazole or thiolpyrazine instead of 1-methyl-5-thioltetrazole: (5R) -2 - /, ( 5'-metby 1 - 1 ', 3', -, - thiadiazol-2, -yl) -thicmethyl-7-penem-3-carboxylic acid, (5R) -2 - / * (1 ', 2', 3, -triazol-5-yl) -thicmethyl-7-penem-3-car-30 carboxylic acid, (5R) -2- (pyrazinyl) -thiamethyl-2-penem-3-carboxylic acid, (5R) —β— (1 ' -hydroxyethyl) -2- '(5'-methyl-1 ", 3", k'-thiadiazol-2 "-yl) -thiomethyl / i-2-penem-3-carboxylic acid, (5R) -6- (1'-bydroxyetbyl) -2- / T1 ", 2", 3 "-triazol-5'-yl) -thicmethyl / -2-penem-3-carboxylic acid (5R) -6- (1 '-hydroxye thyl) -2- (pyrazinyl) -thi omethyl-2-penem-3-carboxylic acid.

Analogously, but with reduction of the methyl 6- (1-hydroxyethyl) -80 0 1 0 12 -23-3-penicillanate by corresponding "known methods", the 6-ethyl derivatives "were prepared.

0ππ1n 19

Claims (13)

1. Compounds of the formula 1 of the formula sheet, wherein n 0 or 1, R "" hydrogen, 2,2,2-trichloroethyl 1, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p- is nitrophenyl or benzhydryl or a group which undergoes metabolic activation in vivo and has useful pharmacokinetic properties, Z hydrogen, halogen, hydroxy, amino, carbamcylaxy, mercapto, a pyridinium group or a group of the formula OR ', 0C0R', RHCOR "or SR", wherein R "and R" are each alkyl, aryl or a heterocyclic ring, each of which is unsubstituted or substituted, and R "is hydrogen, alkyl, alkoxy, cycloalkyl or hydroxy alkyl, wherein the 10 alcohol function of the hydraxyalkyl group is free or protected, as well as salts thereof. 2. Compounds according to claim 1, characterized in that the radical, which undergoes metabolic activation in vivo and has useful pharmacokinetic properties, is an acetoxymethyl, pivaloyloxymethyl or phthalidyl group or a group of the formulas -CH-QC00CoHc or -CHOHHCOR ”” '1 2 5 2 ch 3, wherein R 1' '' alkyl of 1-5 carbon atoms, cycloalkyl or aryl. Compounds according to claim 1 or 2, characterized in that the heterocyclic ring has a 5-methyl-1,3thiadiazol-2-yl-, imethyl-tetrazol-5-yl-, 1,2,3-triazol-5- yl or pyrazinyl group. h. Compounds according to claims 1-3, characterized in that R "is methyl, ethyl, methoxy, 1-hydraxyethyl, 1- (p-nitrobenzyloxycarbonyloxy) -25 ethyl or 1- (dimethyl-t-butylsilyloxy) -ethyl. Compounds according to claims 1 to 1, characterized in that R 1 'is 1-hydroxyetbyl. 6. Process for preparing compounds according to claim 1, characterized in that a compound of the formula 2, wherein R 30 is alkyl and R "'has the meaning as defined in claim 1, has an acetylene derivative of the formula X' C = CY, wherein X 'is a group of the formula CHgZ', wherein Z 'represents halogen, hydrogen, hydroxy, amino, carbamoyloxy or a group of the formula OR', OCOR ', IHC0R' and Y represents hydrogen, alkyl, cyano or a group of the formula C00R or CHgZ ', where R and Z' have the meanings shown above, in a compound of the formula 3 wherein R, R '' , X 'and Y have the meanings shown above, which is then electromerized under basic conditions in a compound of the formula k, wherein R, R' ', X' and Y have the meanings shown above, wherein X 'when these have a has other meaning, can be converted into X by a substitution reaction, which represents a group of the formula CB ^ Z wherein Z has the above-indicated meaning, and then a) reduces the compound of the formula k to a compound of the formula 1¾, wherein R 1 and X have the meanings shown above, reduces, ozonates and hydrolyses, which then with a suitable ester of glyoxylic acid of the formula CHOCORAL "", wherein R "" has the above-defined meaning into a compound of the formula 15, wherein X, R "" and R ", T have the meanings shown above, the latter being converted into the chlorine derivative of the formula 16, wherein X, R '' and R'm having the above-mentioned meanings is converted, the latter of which is subsequently converted into the phosphorane of the formula II, in which X, R '' and R '' 'have the above-mentioned meanings, which compound finally becomes a compound of the formula 1 is cyclized, or b) the compound of the formula U is selectively ozonized to a compound of the formula 5 wherein n = 1 and X, Y, R and R "have the meanings shown above, which is then reduced to a compound 5> where n * 0 is hydrolyzed, the latter compound to a compound of the formula 6 wherein X, Y and R '' have the meanings shown above and n = 0, and the latter with a suitable ester of glyoxylic acid of the formula ΟΠΟ ^ ΟΗ "”, wherein R "" has the meaning shown above, in a compound of the formula 7, wherein X, Y, R "" and R "" have the meaning shown above and n = 0 is converted, which is then converted into the chl an ear derivative of the formula 8 wherein X, Y, R '' and R, m have the meaning shown above and n = 0 is converted, the latter into the phosphorane of the formula 9 wherein R '', R T, X and Y have the meanings shown above, Ph is phenyl and n = 0 is converted, the latter to a compound of the formula 11 wherein R 1, R, n, X and Ph are the above -35 has the meaning shown is ozonized and finally cyclized to an 800 1 0 12 -26 compound of the formula 1, or c) the compound of the formula k selectively into a compound of the formula 5, wherein n = 1 and X, Y, R and R '' have the meanings shown above, are ozonized, then hydrolyzed to a compound of formula 6, wherein X, Y and R "* have the meanings shown above and η * 1, the latter with a suitable ester of glyoxylic acid of the formula CIOOCOQR "", where Rm 'is as defined above, in a compound of the formula 7 »in which X, Y, R" "and R" "have the meanings shown above and n = 1 is converted, 10 the latter in the chlorine derivative of the formula 8, wherein X, Y, R" "and R" " have the above-indicated meaning and n = 0, the latter is converted into the phosphorane of the formula 9, wherein R '', R ,,,,, X and Y have the above-indicated meaning, Fh is phenyl and n = 1 , which last compound is then reduced to a compound 15 of the formula 9 wherein n = 0, the last compound is converted into a compound of the formula 11, wherein R 1,?, R "", X and Fh having the above-mentioned meaning is ozonized, and the latter is finally cyclized to a compound of the formula 1. 20 · 7. (5R) -2-acetoxymethyl-1-2-penem-3-carboxylic acid. 8. (5R) -2-Acetoxy-methyl-6-ethyl-2-penem-3-carboxylic acid. 9. (5R) -2-Acetoxy-methyl-1-6 - (-'-hydroxyethyl) -2-penem-3-carboxylic acid. 10.5 (R) -2 - / (1'-methyl-1'-H-tetrazol-5'-yl) -thicmethyl7-2-penem-3-carboxylic acid. 11. (5R) -2 - / (1'-methyl-1'-H-tetrazol-5-yl) -thianethyl-6-ethyl-2-penem-3-carboxylic acid. 12. (5R) -6- / 11-hydroxyetbyl-7-2- / t 1 "-methyl-1" -Ht etr azol-5 "-y 1) -thi anethyl-2-penem-3-carboxylic acid. (5R) -2 - / (51-methyl-1 ', 3', k'-thiodiazol-2'-yl) -thiaethyl 7-2-3 0 penem-3-carboxylic acid. 1U. (5R) -2- / (51-methyl-1 ', 31,11 -thiadiazol-2'-yl) -thiamethyl-1,7-6-ethyl-2-penem-3-carboxylic acid. 15 (5R) -6 -1' '-hyd oxye thy17-2- / 15 "-methyl-1", 3 ", U" -thi adi azol-2 "-yl) -thianethyl7-2-penem-3-carboxylic acid. 16. (5R) -2 - / (1 *, 2 ', 3' -triazol-5 '-yl) -thicmethyl / -2-penem-3-carboxylic acid. 800 1 0 12 -27-m 17. (5E) ~ 2- / J1 ', 2', 31, triazol-5'-yl) -thicmethyl-6-ethyl-2-penem-3-carboxylic acid. 18. (5R) -6- / ′'-hydroxyethyl / -2 - /] [1 ", 2", 3 "-triazol-5" -yl) -thi-amethyl · / - 2-penem-3-arb on sour. 5 19. (5R) -6- / 1 '-hydroxyethyl / -2- / (pyrazinyl) -thicmethyl7-2-penem-3-carboxylic acid. 20. (5E) -2- (Pyrazinyl) -thimethyl-2-penem-3-carboxylic acid. 21 (5R) -2- / Tpyrazinyl) -thicmethyl-7-6-ethyl-2-penem-3-carboxylic acid. 22. A compound according to any of the preceding claims, prepared according to the method of claim 6. A compound of formula 9, wherein Ph is phenyl, R "'and R" "have the meaning as defined in claim 1, X is a group of the formula CH 2 Z, wherein Z has the meanings shown in claim 1, Y hydrogen alkyl with 1-5 carbon atoms, CE or C00R, wherein 15. has the meaning as defined in claim 6, or is CHgZ, where Z has the meaning as defined in claim I, and n = 1 or 0. 2h. Compound of the general formula II, wherein X and R '' have the meanings shown above. 25. A compound of formula 6, wherein R '*, X and Y have the meanings defined above and n = 1 or O-. 26. A compound of formula 17, wherein R 1, R, X and Y have the meanings shown above. A compound of the formula 18, wherein R 1, R, X and Y have the meanings shown above. Pharmaceutical composition, characterized in that it contains a compound according to claim 1 or a pharmaceutically suitable salt thereof mixed with a pharmaceutically suitable diluent or an appropriate carrier. 29. Treatment of infectious diseases, characterized in that a therapeutically active amount of a compound according to claim 1 or a pharmaceutically suitable salt thereof is administered. 35 80 0 1 0 12