CS226010B2 - Method of preparing new penemcarboxylic acid derivatives - Google Patents

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DESCRIPTION OF THE INVENTION

PATENT (22) Registered 22 02 80 (21) (PV 1241-80) (32) (31) (33) Priority from 24 02 79 (7906634) and 20 09 79 (7932591) UK (40) Published 24 06 83 (45) Published 15 02 86 226010 (11) (B2) (51) Jnt. Cl? C 07 D 513/04 FOGLIO MAURIZIO, FRANCESCHI GI0VANNI, SCARAFILE COSIMO, MILAN, (72) Author of the invention AHCAMONE FEDERIC0, NERVIAHO MILAN, SANFILLIPO AURORA, MILAN (Italy) (73) Proprietor of FARMITALIA CARLO EHBA S. p. MILAN (Italy) (54) Method for Making New Penemarboxylic Acid Derivatives 1 The present invention relates to a process for the preparation of novel penemarboxylic acid derivatives and their salts.

The present invention provides a process for the preparation of novel penemarboxylic acid derivatives of general formula (I)

in which it is 0 or is hydrogen, C1 -C4 alkyl, 2,2,2-trichloroethyl, acetyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl a group, a benzhydryl group, an acetoxymethyl group, a pivaloyloxymethyl group, a phthalidyl group, a -CH 2 CH 3 -O-COOC 1 H 4 group, or a -CH 3 NHCOR "" group, wherein K 1 "is a C 1 -C 5 alkyl group selected from phenyl, benzyl, or cycloalkyl having 3 to 6 carbon atoms, Z is hydrogen, halogen, hydroxyl, amino, carbamoyloxy, mercapto, pyridinium or OR *, OCOR *. NHCOR2 or SR2, each of R ' and R " is an alkyl group having 1 to 4 carbon atoms, an aryl moiety selected from the group consisting of phenyl and benzyl, 5-methyl-1,3,4-thiadiozole- 2-yl, i-methyl-5-tetrazolyl, 1,2,3-triazole-226010 226010 -2-yl or pyrazinyl and R "'represent a nitrogen atom, an alkyl group of 1 to 4 carbon atoms , (C 1 -C 4) -alkoxy, (C 3 -C 6) -cycloalkyl, or (C 1 -C 4) -hydroxyalkyl, the alcoholic functions of which may be either free or protected with a p-nitrebenzyloxycarbonyl or dimethyl-tert-butyl-butyl group.

The substituent at position 6 may have the configuration a or β. Longer configuration is preferred.

The compounds produced have a broad spectrum of antibacterial activity and further possess the ability to inhibit β-lactamesis. It should be pointed out that the atherochemistry at the carbon atom 5 of the compounds of the present invention, as well as atherochemistry of the other intermediates formed in the preparation of the compounds of the invention, is the same as that of natural penicillins and cephalosporins.

According to the invention, the compounds of the above formula (I) are produced by the fact that the compound of the formula (II) R "

O, S. (II)

COOR wherein R is an alkyl group having from 1 to 4 carbon atoms and B * is as defined above, is reacted with an acetylenic derivative of the formula

x'- C Ξ CY in which X * represents a radical of formula CH2z where Z * represents a hydrogen or halogen atom, a hydroxyl group, an amino group or a radical of formula OR, OCOR 'or NHCOr where R' is as defined above; and Y represents a hydrogen atom, a C 1 -C 4 alkyl group, a cyano group or a COOR or CH 2 Z 2 radical, wherein R and Z * are as defined above,

wherein R, H '', X * e Y are as defined above,

which under isonicity isomerized to a compound of formula (IV) in which 8, R "

(IV)

if different from X, optionally converting the substitution reaction X to form CH 2 Z, wherein, as defined above, the compound sereduces, ozonizes, and hydrolyses to a compound of Formula VII

X 3 226010 (VII) ▼ of which h '”and X are as defined above, which is then reacted with a glyoxylic acid ester of the formula CHOCOOR ", wherein R " "

to form a compound of formula VIII Υ->0> -N \ t

wherein COOR '' X, r '' and R * '' are as defined above,

this compound is converted to a chloro derivative of formula IX

COOR '' in which

Xj r '"and r'" 'are as defined above,

and this is converted to phosphorane of formula X

COOR " wherein X, R " and R " " are as defined above, which is cyclized by heating in an inert solvent to a temperature of 50-140 ° C to give a compound of formula I wherein a is 0, optionally oxidizing to the corresponding compound of formula (I) wherein n is 1. In accordance with the present invention, it is also possible to produce pharmaceutically acceptable salts of penemarbexyl acids of formula (I), such as sodium, potassium, and benzathione salts. under which are usually formed with penicillins and cephalosporins.

The compounds of the present invention are used in the preparation of pharmaceutical compositions containing a compound of formula I or a salt thereof in admixture with a conventional carrier suitable for oral and parenteral administration. The following diagram shows the individual steps in the preparation of the compounds of formula I according to the invention.

226010 4

N PPh,

M COOR R "'

O

II. 'COOR' (I; n = 1)

When R * '' is hydrogen, compounds of formula (XI) are prepared from (5R) -6-aninopeniailane acid, i.e. 6-APA, according to the known general procedure of Cignarella et al., Journal et al. Chemistry, 27, 2668, and Evrard et al., Nature 201. 1, 24.

If R '' is an olefin group, cycloalkyl group or hydroxylene group as defined above, the group R '' may be introduced as described by Di Ninno et al., Journal of Organic Chemistry 42, 2 960 (1977).

If R '' is an alkoxy group as defined above, this group B '' 'can be introduced at position 6 by the procedure of Hauser et al., Helv Chat, Acta 50, 1327, (1967), and Giddings et al., Tetrahedron Letters 11. 995 (1978), using 6-APA as starting material.

In contrast, the compound of formula (II) wherein R '"is hydrogen, convert the compounds of formula (II) wherein R" "is an alkyl group, as defined above, by a cyclealkyl group or a hydroxyl group, wherein the substituent is introduced into position 6 using a strong base, as explained in the following examples.

Compounds of formula II wherein R "'is an alkyl group, a cycloalkyl group or a hydroxyalkyl group as defined above may also be prepared from a suitable penicillanic acid S ester, as illustrated in the following examples. 6.

The penicillanic acid S-oxide ester of formula II (R is a C 1 -C 4 alkyl group and R 11 is as defined above) can be heated in an inert solvent such as 5,226,010 benzene or toluene, usually at 70-140 ° C, and a suitable acetylendative general formula x'c = CX wherein x 'represents a group of formula CH 2 Z, wherein Z' represents hydrogen, halogen, hydrexyl, amino, carbamoyloxy or a group of formula Or ', OCOR' or NHCOR ', and Y is hydrogen, C 1 -C 4 alkyl, cyano, or COOR or GH 3 Z ', wherein R d' are as defined above.

If X is other than X, it can be converted by known substitution reactions of the group X, wherein X is represented by CH 2 Z, wherein Z is as defined above.

The compound of formula (III) can be isomerized with a compound of formula (17) by treatment with a base which can be converted to the final compound of formula (I) by the following procedure.

The compound of formula (IV) can be reduced to the compound of formula (V) under conventional conditions, which is ozonated at both double bonds to give a compound of formula (VI) and, after hydrolysis, a compound of formula (VII). The condensation of the compound with a suitable glyoxyl ester yields a compound of formula VIII which can be converted into a chloro derivative of formula IX and a phosphorane of formula X, by cyclization in a simple manner by heating in an inert solvent such as toluene to a temperature of 50-140 ° C, yielding the product of formula I wherein n is 0.

Compounds of formula (I) wherein β is the number 1 are readily prepared from compounds of formula I wherein n is 0 by a known oxidation process. Peracids may preferably be used as oxidizing agents, with m-chloroperbenzoic acid and peracetic acid being particularly preferred.

When R is a hydroxyalkyl group as defined above, the reaction is preferably carried out under protection of the alcohol function.

Compounds of formula (I) wherein R "is hydrogen may be obtained by hydrolysis or hydrogenolysis of the respective esterified compounds. A number of in vitro experiments have been performed to demonstrate the excellent antibacterial activity of the compounds of the present invention. -2-acetoxymethyl-2-penem-3-carboxylate (laboratory designation FCE / 20077 / - / B4Q / Ϊ41), (5R) -acetoxymethyl-2 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -2-penem-3-carboxylate (compound A) and two comparative compounds The following Table 1 summarizes the results of the above experiments with respect to the minimum inhibitory concentration (MIC).

Table 1

Minimum inhibitory concentration of yug / ml

Strain FCE / 20077 / B40 / 341 Compound A Ampicillin Cefoxitin Staphylececcus aureus 2G9P 0.39 0.39 ^ 0.19 0.78 Staphylococcus aureus 153 1.56 0.78 1.56 0.78 Staphylococcus aureus FV2 0.39 0 , 78 ^ 0,19 0,78 Staphylococcus aureus Smith ATCC 13709 ^ 0, 9 0,39 00,) 9 0,78 Streptococcus pyegenes 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 12.5 Enterobacter sp. Vi 9 12.5> 100> 100 12.5 Klebsiella pneumoniae ATCC 10031 - 3.12 50 0.78 Klebsiella sp. B2 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 ^ 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 1.56 0 , 78 0.78 1, 56 Salmonella Saint Paul F 20 1.56 0.78 0.78 3.12 Salmonella derby Fl4 3.12 0.78 0.78 3.12 Salmonella montevideo Fi6 3.12 0.78 0 , 78 3.12 The following examples serve to illustrate the invention without limiting it in any way. In the following examples, the abbreviations given in the NMR spectra data have the following significance: g = singlet d = dubletdd = double doublet t = triplet = multiplet

Signal positions are given in δ values. Example 1 4P- (1-Hydroxymethyl) vinylthi-1- (1-methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S-oxide

7 226010 4 g of penicillanic acid methyl ester S-oxide is dissolved in 15 ml of toluene and the solution is refluxed for 8 hours with 15 ml of propargyl alcohol.

After evaporation in vacuo, the residue was purified by column chromatography on a short silica gel column using a 1: 1 mixture of dichloroethane and ethyl acetate as eluent. 2.8 g of the title compound are obtained. NMR spectrum (deuterechlorophore): 1.96 (broad s, 3H, C-CH3), 2.91 and 3.35 (dd, 2H, J = Hz, 5 Hz, 5 Hz, CO-Sa2-CH- S), 3.78 (s, 3H, COO-j g), 4.36 (broad s, 2H, CggOH), 4.90 to 5.25 Cm, 3H, OOH-COOCH, C C = CH 2), 5 , 35 (m, 1H, CH 2 --S SS), 5.88 (β, 2H, δ S 2 = CS). Example 2 40- (1-hydroxymethyl) vinylthio-1- (1-methoxycarbonyl-2-ethyl-1-propenyl) azetidin-2-one-S-exid

O

cooch3 3.0 g 4P- (1-Hydroxymethyl) vinyithio-1- (i-methoxycarbonyl-2-methyl-2-propenyl) azetldin-2-one-S-oxide is dissolved in 100 ml of dichloromethane and the solution is allowed to cool. stand at room temperature for several hours. After evaporation of the solvent, the residue contains the pure title compound. The yield of the product is quantitative. NMR spectrum (deuterochloroform): 2.08 (s, 3H, r-CH2). 2.18 (S, 3H,, 2.7 to 3.6 (m, J = 2 Hz, 5 Hz, 16 Hz, CO- H 2 -CH-S), 3.78 (β, 3H, COOS gj) , 4.35 (β, 2H, SSgOH), 5.32 (m, 1H, ε s), 5.90 (broad s, 2H, = 2¾) Example 3 4β- (1-bromomethyl) vinylthio-1 (1-methoxycarbonyl) -2-methyl-1-propenyl) azetidin-2-one

OH o "

Br COOCH, COOCH, 1.8 g of 40- (1-hydroxymethyl) vinylthlo-1- (1-methoxycarbenyl-2-methyl-1-prepenyl) azetidin-2-one-S-oxide is dissolved in 40 ml of dimethylformamide, the solution was cooled to -20 ° C, 0.7 ml of pyridine and 3.0 foeforite bromide were added and the mixture was stirred for 15 minutes. Ethyl acetate was added, the organic layer was shaken with saturated sodium bicarbonate solution, washed with water and then dried over sodium sulfate.

After evaporation of the solvent, 1.6 g of the title compound remains. CH 3, 2.24 (s, 3H, CH-1), 3.24 (dd, NMR spectrum (deuterochloroform): 2.04 (s, 3H, J = 2.8, 5, 16) Hz, 2H, C-CH2CH), 3.75 (s, 3H, OCH3), 4.02 (s, 2H, CH2Br), 5.24 (broad s, 1H, = CH), 5.37 (dd, J = 2.8 Hz, 5 Hz, 1H, CH 2 -CH-S), 5.60 (broad s, 1H, = CH) Example 40- [1- (1-Methyl-1H-tetrazole-5) -yl Hhiomethylvinylthio] -1- (1-methexycarbonyl-2-methyl-1-propenyl) azetidin-2-one 2260.0 8

Dissolve 1.4 g of 4B- (1-bromomethyl) vinylthio-1- (1-methoxycarbonyl-2-methyl-i-propenyl) azetidin-2-one in 25 ml of tetrahydrofuran, cool the solution to 0 ° C, add 1-methyl-5-thitetrazole sodium salt (0.8 g) was added and the mixture was stirred at room temperature for 3 hours. After insoluble matter was filtered off, the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and evaporated. The residue consists of 2.0 g of the pure title compound. NUE spectrum (CDCl3): 2.00 (s, 3H, = C-CH2). 2.22 (s, 3H, = 1-CH 3), 2.70 to 3.80 (m, 2H, J = 2 Hz, 5 Hz, 15 Hz, CO- H 2 -CH-S), 3.72 (s, 3H, COOH4), 3.95 (s, 3H, N-SH3), 4.10 (s, 2H, C8-S), 5.18 (broad s, 1H, SC = 1H), 5 36 (m, 1H, CH 2 -CH-S), 5.57 (broad s, 1H, S-O = CH). Example 5 4β- (1-Methyl-1H-thiazol-5-yl) thioacetylthio-1-methoxyoxaloylazetidin-2-one

1.8 g of 4 (i- [1- (1-methyl-1h-tetrazol-5-yl) thiomethyl] vinylthio-1- (i-methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one are dissolved in 200 ml of dichloromethane, the solution was cooled to -78 ° C and a stream of ozonated oxygen was added thereto until the reaction solution became blue, then a few drops of trimethylphosphite were added, the mixture was allowed to warm to room temperature and evaporated. to give 1.3 g of the title compound: NMR spectrum (CDCl3): 2.9-3.7 (m, 2H, COCH3 CH2), 3.85 (s, 3H, COO-gH3), 3.98 (s, 3H, N-SSg), 4.35 (s, 2H, CH 2 S), 5.75 (m, 1H, CH 2 CH 2).

1.2 g of 4β- (1-methyl-1H-tetrazol-5-yl) thioacetylthio-1-methoxyoxaloylazetidin-2-one are dissolved in a mixture of ethyl acetate and methanol (1: 1) and a few grams of silica gel is added to this solution with vigorous stirring. After one hour, the insoluble material was filtered off and the solution evaporated in vacuo. The title compound crystallized from a mixture of methanol and ethyl ether. The yield was 0.6 g. Example 7 4P-acetylglycolylthio-1-acetoxymethyloxyoxaloylazetidin-2-one 9 2260).

Xfy / 'XOCOCH3N O

Dissolve 0.8 g of N-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxycarbonyl-2-methyl-1-propenyl) azetidin-2-one in 80 ml of dichloromethane. the solution is cooled to -78 ° C and a stream of ozone is bubbled through it until a blue color develops. The solution was shaken with an aqueous solution of Na2SO4 and dried over sodium sulfate and evaporated to give the title compound (0.45 g). NMR spectrum (CDCl3): 2.10 and 2.13 (two s, 2CH2 CO), 3.20 (dd, @ 2 bp1 = 17 Hz, trans = 3'5 Hz 'C'3-HP). 3.77 (dd, Jgem = 17 Hz, Jyic cis = 5.5 Hz, C-3-Ηα), 4.73 (s, -CO-CH 2 -OCO-), 5.73 (dd, Jyic = 5 , 5 and 3.5 Hz, C-4-H), 5.87 (s, COO-CH2-OCO). Example 8 4P-Acetylglycolylthioazetidin-2-one

0.6 g of 4β-acetylglycolylthio-1-methoxyoxaloylazetidin-2-one is dissolved in 100 ml of methanol and a few grams of silica gel are added with stirring. for 1 hour, the silica gel was filtered off and, after evaporation of the solvent, 0.35 g of the title compound was obtained. NMR spectrum (CDCl3): 2.20 (s, CH3 CO), 3.03 (dd, J8a = 16 Hz, Jy ^ c trans = 2.5 Hz, C-3-HR), 3.50 (dd, JgeB = 16 Hz, Jyic cis = 4-, 5 Hz, C-3-Ηα), 4.77 (s , -CO-CH2-OCO-), 5.32 (dd, [alpha] C = 4.5 and 2.5 Hz, C-4-H), 6.40 (broad s, NH). 1-methyl-1H-tetrazol-5-yl) thioacetylthio-1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -

1.5 g of 4β- (1-methyl-1H-tetrazol-5-yl) thioacetylthioazetidin-2-one. is maintained with 50 ml of benzene and 1.2 g of acetoxymethylglyoxylate (freshly prepared by ozonolysis of diacetoxymethylfumerate) at reflux. The reaction is complete after 3 hours. The crude oil obtained after evaporation of the solvent can be used without further purification for the next reaction step. A sample of the product for spectroscopic data is purified by thin layer chromatography. NMR spectrum (CDCl3): 2.05 (s, 3H), 2.7-3.8 (m, 2H), 3.95 (s, 3H), 4.30 (s, 2H), 5.40 ( s, 1H), 5.50 (m, 1H), 5.80 (s, 2H). Example 10 4P- (1-Methyl-1H-tetrazol-5-yl) thioacetylthio-1- (i-acetoxymethyloxycarbonyl-1-chloromethyl) azetidin-2-one 226010 10

qooch2ococh3 cooch2ococh3

The oily product obtained according to the preceding example, which consists of crude 4 - (1- (1-methyl-1H-tetrazol-5-yl) thiacetylthio-1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one, is dissolved in 20 ml of anhydrous tetrahydrofuran and at 0 DEG C., the solution is treated with an equimolar amount of pyridine and thionyl chloride until all of the starting material is removed, and after filtration of the insoluble material, the filtrate is immediately used for the next reaction step. "hyl-1H-tet" Bzol-5-yl) thioacetyl thio-1- (1-acetoxymethyloxycarbonyl) -1-triphenylphosphinoylthienylthioethyl} ethoxy-2-one

To a solution containing crude 4β- (1-methyl-1H-tetrazol-5-yl) thioacetylthio-1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) azetidin-2-one, 800 mg of triphenylphosphine and 0.4 ml are added. pyridine, and the resulting mixture is heated to 60-70 ° C for several hours. The phosphorane was purified by silica gel chromatography using dichloromethane / ethyl acetate (1: 1) as eluent. EXAMPLE 12 COCOCOCCH3COCCH2COC3 (5R) -ACETOXYMYLmethyl-2 - [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] -2-penem-3-carboxylate Ι1Γ

I CHi

e T f = TPh 3> -n 3 COOCH 2 OCO 3

Dissolve 0.500 g of 4β- (1-methyl-1H-tetrazol-5-yl) thiomethylacetylthio-1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidene methyl) azetidin-2-one in 30 ml of toluene and heat the solution with 2 ml. hour and temperature 100 ° C. The title compound was purified by column chromatography on a short silica gel column using dichloromethane / ethyl acetate (8: 2) as eluent. By this purification, the product is freed of triphenylphosphine oxide. NMR Spectrum: (CDCl3): 2.15 (s, 3H, COCH2), 3.30-4.03 (m, J = 4 Hz, 2 Hz, -CH2 (6)), 3.97 (s). , 3H, -NCH 3), 4.56 (d, J = 14 Hz, 1H, HCH-S), 4.84 (d, J = 14 Hz, 1H, HCH-S), 5.65 (dd, J = 4 Hz, 2 Hz, 1H, H-5a), 5.88 (s, 2H, COOCH2 O). EXAMPLE 13 (5R) -Aeetoxymethyl-2-acetoxymethyl-2-penem-3-carboxylate 11 226010 (3) (3), (3) chloro-3-ol.

0.7 g of 4β-acetylglycolcolthio-1- (1-ethoxymethoxycarbonyl-1-triphenylphosphoranylidene-methyl) azetidin-2-one is dissolved in 3% absolute toluene and refluxed for 2 hours. cooler. The reaction mixture consisting of the title compound and triphenylphosphine oxide was purified by column chromatography over a short silica gel column using dichloromethane / ethyl acetate (97: 3) as eluent to give 0.250 g of acetoxymethyl-2- acetoxymethyl-2-penem-3-carboxylate. NMR spectrum (CDCl3): 2.11 and 2.13 (two s, 2CH2 CO), 3.49 (dd, Jgem = 16.5 Hz,

Jvic trane = 2 Hz> C-6 "HW> 3.86 (ad-Jgem = 16.5 Hz> Jvic cis = 3.8 Hz» C-6-Ηα), 5.12 and 5.45 (two d , Jgem = 15.5 Hz, .dbd.J-CH2), 5.68 (dd, Jyic = - 3.8 and 2 Hz, C-5-H), 5.87 (s, -COO-CH2 -); IR spectrum (chloroform): 1800 cm < -1 &gt; C &lt; 0 &gt; C (0-lactam) 1750 to 1725 cm &lt; -1 &gt; C = O (ester). UV spectrum (ethanol): Xmax 325 nm ·

Mass Spectrum: m / e 315.04108 (M +); Calcd for C ^ HH ^ NONO ^S 315.04127. Example 14 (5R) -p-Nitrobenzyl-2-ecetoxymethyl-2-penem-3-carboxylate

The title compound was prepared by the method described in Example 13. NMR spectrum (CDCl 3): 3.75 (1H, dd, J = 2.3 Hz, 16.8 Hz, H-6a), 3.87 (1H, dd, J = 3.6 Hz,, 6.8 Hz, H-6P), 5.14 OH, d, J = 15.8 Hz, = C-CH2 O-, 5.05 OH, d, J = 15.8 Hz, = 0- 0 0, 5.71 OH, dd, J = 2.3 Hz, 3.6 Hz, H-5).

[α] D + 87 ° (c = 1.2 in chloroform). β spectrum (chloroform): 1 β ο (β-lactam), 1750 and 720 cm cm 5. UV spectrum (ethanol): 265 (cil 000) and 322 (ε7,000) nm.

Mass Spectrum: m / e 378 (M +).

Melting point: 122-123 ° C. Excl. 8 d, 5 (5R) -2-ethoxyxyethyl-2-penem-3 "carboxylic acid

88601O12 OAc cooch2 - (O) - o2

200 g of (5R) -p-nitrobenzyl-2-acetoxymethyl-2-pene-3-carboxylate, which was prepared as described in the previous example, was dissolved in 20 ml of ethyl acetate. Then, 8 ml of 0.2M sodium bicarbonate solution and 400 mg of 10% palladium-carbon are added, and the two-phase mixture is shaken for 60 minutes under a hydrogen atmosphere. After filtering off the catalyst, the aqueous phase is acidified with 20 ml of a 2% aqueous citric acid solution and extracted three times with ethylene chloride. The organic layers were dried over sodium sulfate and evaporated to give the title compound (mg). IC spectrum (chloroform): 1790 (β-lactam), 1735 Å 1700 cm -1. PV spectrum (ethanol): 300 nm. Example 16 15? K) -2- (1-methyl-1H-tetrazol-5-yl) thiomethyl-2-penem-3-carboxylic acid

The title compound is obtained by the method described in the previous example: (5R) -p-Nitrobenzoyl-2- (1-methyl-1H-tetrazol-5-yl) thiomethyl-2-penem-3-carboxylate in a manner similar to is described in the above examples. ΐδ spectrum (chloroform): Θ00 (β-lactam), i 750 and 1 720 cm “1. Example 17

Methyl-6α- (1'-hydroxyethyl) penicile-S-oxide

A solution of 2.3 g of methylpenicilane-S-oxide in 50 ml of anhydrous tetrahydrofuran is cooled to -78 ° C, lithium diisopropylamide (freshly prepared from 5 ml of diisopropylamine and 20 ml of a 1.6M solution of butyllithium in hexane) dissolved in anhydrous tetrahydrofuran is added, and the mixture is added. Allow to stand for 10 minutes at -78 ° C. Then acetaldehyde (5 ml) was added portionwise, the reaction mixture was stirred for 15 minutes, treated with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the ethyl acetate extract was washed twice with water and dried over sodium sulphate.

After evaporation of the solvent, the residue was purified by column chromatography on a short silica gel column using dichloromethane / ethyl acetate (1: 1) as eluent. The yield is 1.5 g.

The title compound consists of a mixture of (2: 3) carbon-containing epimers bearing a hydroxyl group (according to NMR spectrum), the new carbon-to-Cg bond being only in the α-position due to the stereospecificity of the reaction under the conditions. 13.26010 NMR spectrum (deuterochlorophore) 1.27 (s, 3H, ct-figj), 1.40 (d, 3H, J = 5.7 Hz, fig ^ -CHOH) major isomer, 1.48 (d, 3H, J = 5.7 Hz, gg ^ -CHOH) minor isomer, 1.70 (s, 3H, β- 83 83), 3.4 to 3.8 (m, H, g-6) , 3.80 (a, 3H, COOH3), 4.1-4.7 (m, 1H, SgOH), 4.50 (s, 1H, g-3), 4.98 (d, J = 1.9 Hz, 1H, g-5) minor isomer, 5.05 (d, J = 1.9 Hz, 1H, g-5) major isomer. Example 18

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

To a solution of 2.2 g of methylpenicillanate in 30 ml of anhydrous tetrahydrofuran is added lithium diisopropylamide at -78 ° C in a slight excess in nitrogen nitrogen, then excess acetaldehyde is added, the mixture is stirred for 5 minutes, then the acid is added in a slight amount. The mixture was poured into water and extracted with methylene chloride. The organic layers were dried over sodium sulfate and evaporated in vacuo. 0.8 g of the title compound is obtained. Example 19

Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate

1.2 g of methyl 6- (1-hydroxyethyl) -3-penicillanate was dissolved in 40 ml of tetrahydrofuran, the solution was cooled to -78 ° C and treated with 1 equivalent of butyllithium. 1.2 equivalents of p-nitrobenzyloxycarbonyl chloride are then added to the reaction mixture. After 30 minutes at -78 ° C, the reaction mixture was allowed to stand at room temperature for 60 minutes, then poured into water and extracted with methylene chloride. After drying over sodium sulfate and evaporation, 1.4 g of the title compound is obtained. Example 20

Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanic S-oxide

Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate (1.8 g) was dissolved in 50 ml of methylene chloride and 1.5 equivalent of m-chloroperbenzoic acid was added to the solution at 0 ° C. The organic phase is shaken with saturated sodium bicarbonate solution, extraction is carried out, the extract is dried over sodium sulfate and evaporated. 1.4 g of the desired sulfoxide are obtained. 226010, 4

The product of my following physicochemical constant:

erythro-configuration: NMR spectrum (CDCl3): 1.20 (s, 3H, u-SH1), 1.55 (d, J = 6.5 Hz, 3H, CH2-CH), 1.70 (s, 3H , 3.82 (s, 3H, COOCH-1), 3.88 (ad, J = 2.0, 4.0 Hz, 1H, H-6), 4.50 (s). , 1H, H-3), 4.85 (d, J = 2.0 Hz, 1H, fl-5), 5.19B, 1H, ClP, 5.31 (a, 2H, d12Ph), 7 4 to 8.4 (a, 4H, -PhNO 2); threo configuration: 1.23 (s, 3H, --CH3); 1.51 (d, J = 6.5 Hz, 3H, CH - CH3), 1.70 (s, 3H, P - H3), 3.77 (dd, J = 2.0, 7.0 Hz, 1H, H-6), 3.81 (s, 3H, COOCH3), 4.51 (s, 1H, H-3), 4, 96 (d, J = 2.0 Hz, 1H, fl-5), 5.28 (m, 1H, E-H), 5.32 (β, 2H, E-H2Ph), 7.4 to 8.4 ( m, 4H, -EfcNOp Example 21 4 1-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S-oxide

oco, pnb9

ococh3 OCOCH, H COOCH3 h '' COOCH3

A solution of 2.0 g of methyl 6 - (- p -nitrobenzyloxycarbonyloxyethyl) -3-penicillanate-S-oxide and 2.4 g of butyldiol diacetate is refluxed in 50 ml of toluene 24. Purification by column chromatography using a 9: 1 mixture of dichloromethane and ethyl acetate as eluent. 1.1 g of the title compound is obtained.

The product has the following physical-chemical constants:

erythro-configuration:

NMR Spectrum (CDCl3): 1.46 (d, J = 6.0 Hz, 3H, CH, CH); 2.06 (s, 9H, OCOCH-, CH- J OCOCH3, X CH3), 3.72 ( s, 3H, COOCH-1, 3.73 (m, 1H, H-6), 4.80 (d, J = 6.0 Hz, 2H, H-2-CH2), 4.87 (s , 2H, CH 2 ° COCH 3), 5.00 (s, 2H, = CH 2>, 5.26 (s, 2H, CO 2 H 2 Ph), 4.9-5.2 (m, 3H, CHOH, H-5 6.42 (t, J = 6.0 Hz, 1H, * yh), 7.4-8.4 (m, 4H, -Ph-NO2); IR spectrum (chloroform): 1; 750 cm &lt; -1 &gt; C = O (esters), 1 780 cm &lt; -1 &gt; C = 0 ([alpha] -lactam).

NMR Spectrum: (CDCl3) 1.40 (d, J = 6.0 Hz, 3H, CH, CH), 1.97, 2.05, 2. 0 (3.H, CH2 OCOCH3, OCOCH3). J = CH 3), 3.64 (m, 1K, H-6), 3.75 (s, 3H, COOCH-1), 4.75 (d, 15,226010 J = 7.0 Hz, 2H, * 4.8, 5.2 (m, 3H, H-5, CHO, SH-COOCH3), 6.43 (t, J = 7.0 Hz, 1H, &quot; U), 7.4 up to 8.4 (m, 4H, PhNO 2); IR spectra (chloroform) 1745 cm -1 / c = 0 (esters)

1,760 cm @ -1 1,785 cm @ -1 C = 0 (beta-lectam) Example 22 4-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2) -methyl-1-propenyl) esetidin-2-one-S-oxide

1.3 g 4β-vinylthio- (1,2-diacetoxymethyl) -3- (p-nitrobenzyloxybonyloxyethyl) -1- (methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S-oxide The residue is dissolved in 80 ml of dichloroethane, 0.3 ml of triethylamine is added and the mixture is allowed to stand at room temperature for 2 hours. Evaporation of the solvent yields the pure title compound in quantitative yield.

The product has the following physical-chemical constants: erythro-configuration:

MIR spectrum (deuterochloroform): 1.50 (d, J = 6.5 Hz, 3H, CH 3 CH), 2.05, 2.07 (s, 9H, 3-OCO 2 H 3, OCOCH 3), 2.27 (s 3.73 (s, 3H, COOCH3), 3.80 (m, 1H, H-6); 4.78 (d, J = 6.0 Hz, 2H, hX <2H2) , 4.83 (s, 2H, CHgOCO), 4.9-5.3 (m, 2H, H-5, CaOH), 5.25 (s, 2H, CH2Ph), 6.42 (t, J = 6.0 Hz, 1H, hJ *), 7.4-8.4 (m, 4H, PH-NO2); IR spectrum (chloroform): 1710 cm @ 1 755 cm @ 1 775 cm @ -1 C = O ((unsaturated ester) C = O (esters) C = O (β-lectures) threo-configuration: MIR spectrum (deuterochloroform) : 1.45 (d, J = 6.0 Hz, 3H, CH-CH);

CH-, CH, J, OCOCH3, - *, 2.28 (s, 3H, - J), 3.70 (dd, J = 2.0, 6.0 Hz, 1H, H-6), 3 , 77 (s, 3H, COO H3), 4.82 (d, J = 7.0 Hz, 2H, C-2000), 4.82 (s, 2H, CH2OCO) 5.10 (d, J = 2, 0 Hz, 1H, H-5), 5.0 to 5.3 (m, 1H, CHO), 5.23 (s, 2H, CH 2 Ph), 6.52 (t, J = 7.0 Hz, 1H) (hJ), 7.4 to 8.4 (m, 4H, PhNO2), spectrum (chloroform): 1710 cm @ -1 C = O (unsaturated ester) 1755 cm @ -1 C = O (esters) 1780 cm 1 C = O (β-lactam). Example 23 4β-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one 226010 16 OCO 3 PNB o

OCOCH 3 OCOCH 3 COOCH 3

OCOCH3 OCOCH3 COOCH3 1.5 g vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) azetifin-2-one-5 The oxide was dissolved in 10 mL of anhydrous dimethylformamide and the solution was cooled to -20 ° C. Then phosphorus tribromide (0.8 ml) was added, the mixture was stirred for 10 minutes, diluted with ethyl acetate and washed twice with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. 1.1 g of the title compound is obtained.

The product has the following physicochemical constants: OCOCH2PhNO2 CH3-C% erythro-configuration:

OCOCH 3 OCOCH 3 COOCH 3 NUR spectrum (CDCl 3): 1.53 (d, J = 6.5 Hz, 3H, C 8 H 2 CH), 2.05 (s, 9H, OCOCH 2 OCOCH 3 = / GH 3), 2.22 ( 3, 3, 3, 3, 3.42, (dd, J = 2.0, 4.0 Hz, 1H, g-6), 3.72 (s, 3H, COOCH3), 4.63 (d, J = 6 Hz, 2H, CH 2 OCO), 4.72 (s, 2H, CH 2 OCO), 5.0 to J 5,6 (r, 2H, H-5, C 8 O), 5.30 (s, 2H, CH 2 Ph), 5.95 (t, J = 6 Hz, 1H, H 2), 7.5 to 8.4 (r, 4H, PgNO 2); IR spectrum (chloroform): 1725 cm @ -1 C = O (unsaturated ester) 1750 cm @ -1 C = O (esters) 1775 cm @ -1 G = O (.beta.-lactam). threo-configuration: MMR spectrum (CDCl 3): 1.53 (d, J = 6.0 Hz, 3H, C 8 H 2 CH), 2.02, 2.03 (s, 9H, OCOCH-1, OGOCH 2 = = 3 2.23 (s, 3H, J = Z-CH3), 3.30 (dd, J = 2.0, 7.0 Hz, 1H, H-6), 3.73 (s, 3H, COOgH3), 4 60 (d, J = 7.0 Hz, 2H, OCO *> 4.70 (s> 2H> -20C0); 5.1-5.3 (m, 1H, CHO); 2H, CH-Ph), 5.38 (d, J = 2.0 Hz, 1 Η, H-5),

H 5.96 (t, J = 7.0 Hz, 1H, @ 2 H), 7.3 to 8.3 (m, 4H, PhNO2); IR spectrum (chloroform): 1725 cm @ -1 C = O (unsaturated ester) 1755 cm @ -1 C = O (esters) 1770 cm @ -1 C = O (β-lactam). Example 24 40-EthylglycOlylthio-3- (1-p-n -trobenzyloxycarbonyloxyethyl) -1-methoxyoxalylazetidin-2-one

OCOjPNB

COOCH 3 OCOCH 3 -OCOCH 3

OCOCH 3 O ° COOCH 3

The 1.4 g of 43-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one in 120 ml of dichloromethane is cooled - 78 [deg.] C., and an ozone stream is carried out in oxygen until a blue color develops. Roztu ». shake with aqueous solution of MgSO 4 and dry over sodium sulfate. Evaporation gave 0.8 g of the title compound. 17 226010 Example 25 4P-Ethylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) azetidin-2-one

OCO2PNB

OCO 3 PNB is 3 COOCH 3 S 2 Y 2 OCOCH 3

0.800 g of 4β-acetylglycolthio 3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxalyl azetidin-2-one was dissolved in 50 ml of methanol and a few grams of silica gel was added. The mixture was allowed to stand at room temperature for 60 minutes, insoluble matter was filtered off and the filtrate was evaporated. 0.300 g of the title compound is obtained.

The product has the following physical-chemical constants:

O

II OCOCH2PhNO2

erythro-configuration:

(CDCl3): 1.48 (d, J = 6.0 Hz, 3H, CH, CH), 2.18 (s, 3H, ococg3), 3.44 (dd, J = 2.0, 5.0) Hz, 1H, H-6), 4.73 (s, 2H, CH 2 OCO), 5.0 to 5.3 (m, 1H, CHO), 5.15 (d, J = 2.0 Hz, H-5), 5.27 (s, 2H, C 8 H 2 Ph), 6.58 (broad s, 1H, MH), 7.4 to 8.4 (m, 4H, -Ph-2 H) 5 (chloroform): 1,705 cm @ -1 sc = 1,775 cm @ -1 C = O (ester) 1795 cm @ -1 C = O (β-lactam) 3,400 cm @ -1 NH threo configuration: NMH spectrum: (CDCl3): 1 , 43 (d, J = 6.0 Hz, 3.39 (dd, J = 2.0, 7.0 Hz, 1H, H-6), 4.72 3H, CH2CH2, 2.17 (s, 5.2, 5.4 (m, 1H, 6.80 (broad s, 1H, CHO), 5.24 (s, 2H, CHgPh), 5, 32 (d, J = 2.0 Hz, 1H, H-5);

NH), 7.4 to 8.4 (m, 4H, -PhNO 2); IR spectrum (chloroform): 1 705 SC = 0 1760 -1 cm C = 0 (ester) 1 785 cm -1 C = O (β-lactam) 3 400 cm -1 NH Example 26 4 1-acetylglycolylthio-3 - (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarboayl-1-hydroxymethyl) azetidin-2-one

OCOCH3

> T ^OCOCH3

OH COOCH2OCOCH3 226010 18 0.5 g 4P-Acetylglycolthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one and 0.5 g acetoxymethylglyoxylate in 30 ml benzene under reflux until reaction is complete (2 hours). The title compound obtained can be used for the next reaction step without further purification. Example 27 4-N-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) azetidin-2-one.

0.35 g of 4β-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one is dissolved in 10 ml of anhydrous tetrahydrofuran at 0 ° C, pyridine (1.1 eq.) and thionyl chloride (1.1 eq.) were added, the mixture was stirred for 10 min. Evaporation of the filtrate gave the title compound in quantitative yield. The crude product may be used as such for the next reaction step. Example 28 4-R-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one

0.400 g of 4-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (- acetoxymethyloxycarbonyl-1-chloromethyl) azetidin-2-one is dissolved in 20 ml of tetrahydrofuran / dioxane ( 1: 1), two equivalents of triphenylphosphine and 1.1 equivalents of pyridine were added and the mixture was stirred overnight at 50 ° C. The title compound was purified by column chromatography on silica gel, eluting with dichloromethane / ethyl acetate (70:30). 0.280 g of the desired phosphorus is obtained. Example 29 (5R) -acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate oco2pnb

xy ^ xOcocH3o -γρρή3 COOCH2OCOCH3

Dissolve 0.210 g of 4β-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidene methyl) azetidin-2-one in 7 ml of toluene and heat the solution for 2 hours. to reflux. Chromatographic purification on a short column of silica gel using dichloromethane / ethyl acetate (95: 5) as eluent gave 0.050 g of the title compound. 19 226010 Example 30 (5R) -acetoxymethyl-6- (1-hydroxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate

OCOoPNB

OCOCHO COOCH2OCOCH3

OH

0.060 g of 5R-acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate is poured into a mixture of water, ethanol and potassium monohydrogen phosphate and performed under hydrogenolysis in the presence of 10% palladium on carbon . Purification by column chromatography on silica gel gave 0.015 g of the title compound. Example 31 a) 4 (1- (1-hydroxymethyl) vinyl thio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S -oxide

A solution of 2.6 g of methyl 6- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -3-penicillanate-S-oxide and 8 ml of propargyl alcohol in 20 ml of toluene was refluxed under nitrogen for 40 hours. After evaporation of the solvent, the product was purified by silica gel column chromatography using dichloromethane / ethyl acetate (9: 1) as eluent. 2.0 g of the title compound is obtained. b) 4 (1- (1-hydroxymethyl) vinylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl, -2-methyl-1-propenyl) azetidin-2-one- oxide

O

OCO2PNBII XXA1 ^ 0 "vr cooch3 J2r, .D (| COOCH,

SOH 2 g g 4 (1- (1-Hydroxymethyl) vinylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S-oxide dissolve in 50 ml of dichloromethane and allowed to stand for 12 hours in the presence of several drops of triethylamine, after evaporation of the solvent, the pure title compound is obtained in quantitative yield c) 4 (1- (1-bromomethyl) vinylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) ) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one

Dissolve 2.0 g of the compound of b) in 50 ml of dimethylformamide, add 0.7 ml of pyridine and 3.2 of phosphorus tribromide to -20 ° C, stir for 15 minutes, then add ethyl acetate. the organic phase was shaken with saturated sodium bicarbonate solution, washed with water and finally dried over sodium sulfate. Evaporation of the solvent gave 1.7 g of pure title compound. 20 226010 d) 4β- [1- (5-Methyl-1,3,4-thiadiazol-2-yl) thiomethyl] vinylthio-3α - (, - p-nitrobenzyloxycarbonyl-oxyethyl) -1- (1-methoxycarbonyl- 2-methyl-1-propenyl) azetidin-2-one

Jj) CO2PNB

N-N s-— -II u s. 1.8 g of the compound prepared in c) are dissolved in 30 ml of tetrahydrofuran. The solution is cooled to 0 ° C, 1.1 g of 5-methyl-1,3,4-thiadizole-2-thiol sodium salt is added and stirred for 4 hours. After the insoluble matter was filtered off, the reaction solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate and evaporated to give 2 g of the title compound. e) 4β- [N- (5-methyl-1,3,4-thiadizol-2-yl] thioacetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloylazetidin-2-one

The N-N, CH 2 g of the compound of d) was dissolved in 250 mL of dichloromethane, cooled to -78 ° C, and a stream of ozonated oxygen was added until blue. After adding a few drops of trimethyl phosphite, the reaction mixture was allowed to warm. evaporate to room temperature to give 1.5 g of the title compound. f) 40- [1- (5-methyl-1,3,4-thiadizol-2-yl)] thioacetylthio-3α- (1-p -trobenzyloxycarbonylethyl) azetidin-2-one

OCOvPNB

COOCH3 ocO2pnb with CH3 J-CH, 1.5 g of the compound prepared in g) was dissolved in a mixture of equal parts of methanol and ethyl acetate, several grams of silica gel was added and the mixture was vigorously stirred at room temperature. After filtering off the silica gel, the filtrate is evaporated to an oily residue, which is chromatographed on silica gel with dichloromethane / ethyl acetate (8: 2) to give 0.9 g of the pure title compound. g) 4β- D- (5-methyl-1,3,4-thiadiazol-2-yl)] thioacetylthio-3n- (1-p-nitrobenzyloxycarbonyloxy) -1- (1-acetonyloxycarbonyl-1-hydroxymethyl) azetidin-2-one

OCO, PNB

N-N

vv

AND

N-N, AA, " gamma ", γ-ω-chloro, CH CH, 0.9 g of the compound of f) was dissolved in 40 ml of benzene, 0.6 g of acetonitrile glyoxalate were added and the resulting solution was heated to reflux for 3 hours. Evaporation of the solvent, the crude oily residue was used in the next step without further purification. - 21,226010 h) 4β- [1- (δ-methyl-1,3,4-thiadiazol-2-yl) thioacetylthio-3 --- (1-β-trobenzyloxycarbonylloxy) ethyl] -1- (1-acetonyloxycarbonyl) -1-chloromethyl) azetidin-2-one

OCOnPNB N -N 0 3 ch 3

COOCH2COCH3 cooch2coch3

The crude oily product obtained in g) is dissolved in 30 ml of anhydrous tetrahydrofuran, the solution is cooled to 0 DEG C. and equimolar amounts of pyridine and thionyl chloride are added until the starting material disappears. After insoluble matter was filtered off, the filtrate was used immediately in the next step. i) 4P - [1- (5-Methyl-1,3,4-thiadizol-2-yl)] thioacetylthio-3α- (1-p-nitrobenzyloxycarbonyloxy-ethyl) -, - (1-acetonyloxycarbonyl-1-triphenylphosphoranylindenmethyl) azetidin-2-one

cooch2coch3

The crude product prepared in (h) was dissolved in 20 ml of tetrahydrofuran, 700 g of triphenylphosphine with 0.35 ml of pyridine was added, and the resulting solution was heated to 70 ° C under nitrogen for several hours. The phosphorane is then purified by chromatography on silica gel using the same parts of dichloromethane and ethyl acetate as eluent. 0.6 g of the title compound is obtained. j) (5R) -acetonyl-2 - [(5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl] -6α- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-penem-3-carboxylate

OCOoPNB

IN

And 0.6 g of the compound prepared in (i) are dissolved in 50 ml of toluene and the solution is refluxed under nitrogen for 3 hours. The title compound was purified by short column chromatography on silica gel eluting with dichloromethane: ethyl acetate (8: 2). 0.25 g of the desired product is obtained. X-ray spectrum: 1795, 1750, 720 cm @ -1. Example 32 (5-methyl-1,3,4-thiadiszol-2-yl) thiomethyl] -un- (1-hydroxyethyl) -2-penemic acid (10-scetyl-β- - 3-carboxylate).

OCOoPNB

OH N-N

0.450 g of the compound of Example 31 was dissolved in 25 ml of acetonitrile containing a few drops of ethanol and the solution was hydrogenated in the presence of 400 mg of 10% palladium on carbon as catalyst. After filtering off the catalyst, the filtrate is chromatographed on silica gel using a mixture of dichloromethane and ethyl acetate (7: 3) as eluent. 0.18 g of the title compound is obtained. Spectrum: 605, 1795, 1745, 1720 cm -1. 226010 Example 33 22- 54) -2 - [(5-methyl-1,3,4-thiadizol-2-yl) thiomethyl] -6α- (1-hydroxymethyl) -2-penem-3-carboxylic acid

A 0.200 g alousenin prepared in Example 32 in 30 ml of acetonitrile containing a few drops of water was cooled to 0 ° C, 5 ml of a 0.1N sodium hydroxide solution was added thereto under nitrogen, and the resulting solution was stirred for 10 minutes. The alkaline reaction mixture was extracted twice with methylene chloride, then acidified with 10% aqueous citric acid and extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate and evaporated to give the title compound (0.110 g). IR spectrum: 3500, 1795, 1665 cm -1. Example 34 a) 4β- [1- (1,2,3-Trlazol-5-yl) thiomethyl] vinylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) 1- (1-methoxycarbonyl-2-methyl-1-propenyl) azetldin-2-one

2.2 g of the title compound are obtained from 2.5 g of the compound prepared according to Example 31c) according to Example 31d) using 1,2,3-triazole-5-thiol sodium salt. b) 4β- [1- (1,2,3-Triazol-5-yl] thioacetylthio-3α- (1-p-trobenzyloxycarbonyloxyethyl) -1-methoxyoxaloylazetidin-2-one

1.1 g of the title compound is obtained from 1.6 g of the compound prepared in a) according to the procedure of Example 31e). c) 4P- [1- (1,2,3-triazol-5-yl) thioacetylthio-3a (1-p-nitrobenzyloxycarbonylcarbonylethyl) azetldin-2-one

from 1.1 g of the compound prepared in b), 0.6 g of the title compound is obtained according to the procedure of Example 31f). d) 4β- [1- (1,2,3-triazol-5-yl)] thioacetylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-hydroxymethyl) azetidin-2-one 23 226010

From 0.6 g of the title compound. in paragraph c)

0.7 g of 4β- [1- (1,2,3-triazol-5-yl)] thioacetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1--) is obtained by the procedure of Example 31g). acetonyloxycarbonyl-1-chloromethyl) azetidin-2-one

COOCH 2 COCH 3 COOCH 2 COCH 3 From 0.7 g of the compound prepared in column d), the crude material was obtained by the procedure of Example 31 h). This product is used in the next step without further plating. F) 4β- [1- (1,2,3-Triazol-5-yl] thioacetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyloxyethyl) -1-triphenylphosphoranylidenemethyl) azetidin-2-one

cooch2coch3 cooch2coch3

From the crude chloro derivative prepared in e), 0.55 g of the title compound was obtained by the procedure of Example 31 i). g) (5R) -acetonyl-2 - [(1,2,3-triazol-5-yl) thiomethyl] -6α- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-penem-3-carboxylate

COOCH2COCH3

OCOjPNB

From 0.45 g of the compound of f), 0.180 g of the title compound was obtained according to the procedure of Example 3H). IR: 1795, 1750, 1720 cm Example 35 (5H) -acetonyl-2 - [(1,2,3-triazol-5-yl) thiomethyl] -6α- (1-hydroxyethyl) -2- penem-3-carboxylate

From 0.380 g of the compound prepared in Example 34, the procedure of Example 32 gave the title compound (0.12 g). IR spectrum: 3 610, 1 795, 1 750, 1 720 cm @ -1. 226010 24 (36 R) -2 - [(1,2,3-triazol-5-yl) thiomethyl] -6a - (1-hydroxyethyl) -2-penem-3-carboxylic acid

OH

AND

St.

N

II p

COOH COOCH 2 COCH 3 From 0.25 g of the compound prepared in Example 35, 0.135 g of the title compound was obtained by the procedure of Example 33. ifi spectrum: 3,490, 1,795, 1,660 ca-1. Example 37 a) 4β- (1-carbamoyloxymethyl) vinylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one-S-oxide OCO2PNB [| ΌΗ r COOCH, JJCO ^ NB θ

2.2 g of the compound prepared in Example 31b) was dissolved in 30 ml of acetonitrile, cooled to 0 ° C, treated with 0.8 ml of chlorosulfonyl isocyanate under nitrogen and stirred for 2 hours. The reaction mixture was poured into saturated sodium bicarbonate solution, stirred for several minutes and then extracted with ethyl acetate. The solvent was evaporated from the extract after drying with sodium sulfate to give 1.5 g of the title compound. b) 4β- (1-carbamoyloxymethyl) vinylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one

$ OC

ax A o o

II S OCONH,

From 1.7 g of the compound prepared in (a) above, 1.4 g of the title compound was obtained from 1.7 g of the compound prepared in (a). c) 4β- (1-carbamoyloxymethyl) acetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxy-oxaloylazetidin-2-one

OCOnPNB

COOCH3

X-Y Y OCONH, "Y-O-O COOCH 3" From 2.2 g of the compound prepared in b), 1.4 g of the title compound is obtained by the procedure of Example 31e). d) 4β- (1-carbamoyloxyaethyl) acetylthio-3a (1-p-nitrobenzyloxycarbonyloxyethyl) azetidin-2-one 25 226010 oco2pnb 'τ-Y "' OCONH2

J — N O 0> = o COOCHi oco2pnb

’’ From OCONH2N O

H, 1.4 g of the compound prepared in c) was obtained according to the procedure of Example 31f) to yield 0.9 g of the title compound, e) 4β- (1-carbamoxyxymethyl) acetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1-acetonyl-oxycarbonyl-1-hydroxymethyl) -azetidin-2-one

OCOoPNB. oco2pnb OCONH, OCONH, o-

From 0.9 g of the compound prepared in d) and 0.6 g of acetonylglyoxylate and as described in Example 3'g), the crude carbinolamide is obtained. (1-carbamoyloxymethyl) acetylthio-3a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyl oxycarbonyl-1-chloromethyl) azetidin-2-one

OCO, PNB

OCOjPNB OCONH,

i-NOO y-OH

[y "OCONH 2 -NOO 2" → Cl COOCH 2 COCH 3 v1 cooch2coch3

From the crude product prepared in e), a chloro derivative was obtained as described in Example 31h). g) 4β- (1-carbamoyloxymethyl) acetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxyxycarbonyl-1-triphenyl, osoranylidenemethyl) azetidin-2-one oco2pnb

J. OCO2PNB - <T oconh2 _ »

, rCI OCONH, PPh, COOCH2COCH3 [~ -γι_ϊ * 3 cooch2coch3

From the crude product prepared in f), 0.40 g of the desired phosphorous was obtained as in Example 3'i) (5R) -acetonyl-2-carbamoyloxyinethyl-6α- (1-p-nitrobenzyloxycarbonyloxyethyl) -2- penem-carboxylate

OCOjPNB I with Υ'Υ'ΌϋΟ.Η, - ΤγίΤ'-ΟΟΟΝΗ, O7 COOCH2COCWj cooch2coch3. From 0.4 g of the compound prepared in g), the title compound is obtained according to the procedure of Example 3Ί). 226010 Example 38 26 (5R) -acetonyl-2-carbamoyloxymethyl-6α- (1-hydroxyethyl) -2-penem-3-carboxylate

OCOoPNB

OCONHj cooch2coch3

From 0.3b H of the compound prepared in Example 37, 0.11 g of the title compound is obtained by the procedure of Example 32. Example 39 (5R) -2- (carbamoyloxymethyl) -6α- (1-hydroxyethyl) -2-penem-3-carboxylic acid

OH

And oconh2 cooch2coch3

OH

From 0.11 g of the compound prepared in Example 38, the title compound (0.060 g) was obtained by the procedure of Example 33. IR: 400-3500, 1795, 1700-150 cm @ -1. Example 40 a) 4α-Acetylglycolylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1- hydroxymethyl) azetidin-2-one

OGOoPNB

I COOCH 2 COCH 3

A solution of 1.4 g of 4 (1-acetylglycolthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) azetidin-2-one prepared as described in Example 25 and 1.8 g of acetonyl glyoxylate in 20 ml of benzene was heated to boiling for 4 hours. After evaporation of the solvent, a crude compound is obtained which is used in the following reaction step without further purification: b) 4P-Acetylglycolylthio-3o (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1- chloromethyl) azetidin-2-one oco2pnb ococh3 CT 'γ-ΟΗ COOCH2COCH3 oco2pnb • with OCOCHo COOCH2COCH3

The crude carbinolamide obtained in the preceding paragraph is dissolved in 20 ml of anhydrous tetrahydrofuran, the solution is cooled to 0 DEG C. and equimolar amounts of pyridine and thionyl chloride are added until all starting material has disappeared. The precipitate was filtered off and the filtrate evaporated to give the crude title compound which was used in the next reaction without further purification. COOCH 2 COCH 3, (C) 4-acetylglycolylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-triphenylphenylphosphorylidenemethyl) azeylin-2-one;

OCO, PNB

ococh3 cooch2coch3

The crude material was dissolved in 100 ml of methylene chloride, 1.5 g of triphenylphosphine and 10 g of silica gel were added, and the solvent was evaporated in vacuo. The solid material was allowed to stand overnight at room temperature and then applied to a chromatographic column eluting with mixed portions of methylene chloride and ethyl acetate. 1.5 g of the title compound is obtained. d) (5R) -acetonyl-6α- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate

OCCLPNB

Dissolve 1.5 g of 4β-acetylglycolylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one in 50 ml of toluene and heat the solution to reflux for 3 hours. under reflux. Evaporation of the solvent gave an oily material which was purified by chromatography on a short column of silica gel, eluting with a 9: 1 mixture of dichloromethane and ethyl acetate. 0.51 g of the title compound is obtained.

The product has the following physicochemical constants. * 3 CH-,

CH 2 OCOCH 2 PhNO 2 OCOCH, COOCH 2 COCH 3 erythro configuration: HMR spectra (CDCl 3, δ): 1.46 (d, J = 6.5 Hz, 3H, CH 2 CH). 2.07 (s, 3H, OCOCH3), 2.16 (s, 3H, COCH3, 4.02 (dd, J = 2.0, 4.0 Hz, 1H, H-6), 4, 73 (s, 2H, CH 2 CO), 5.0 to 5.3 (m, 1H, CHO), 5.12, 5.38 (dd, J = 15.5 Hz, 2H, CHgOCO), 5, 22 (s, 2H, COCH8Ph), 5.52 (d, J = 2.0 Hz, 1H, H-5), 7.4-8.5 (m, 4H, Ph-NO2); ): 1725 cm1 750 cm " 1800 cm " C = O (unsaturated ester, ketone) C = O (esters) C = O (p-lactam) threo configuration: SMR spectrum (CDCl3): 1.45 (d , J = 6.0 Hz, 3H, CH2CH2, 2.08 (s, 3H, OCOCH3), 2.19 (s, 3H, COCH3), 3.96 (dd, J = 2 7.17 Hz, 1H, H-6), 4.77 (s, 2H, CHgCO), 5.0-5.4 (m, 1H, CHO), 5.13-5.42 (d , J = 16.0 Hz, CHgOCO), 5.25 (s, 2H, CHgPh), 5.66 (d, J = 2.0 Hz, 1H, H -5), 7.4-8.5 (m, 4H, PhNO 2); 1 H spectrum (chloroform): 1725 cm -1 C = O (unsaturated ester, ketone), 1750 cm -1 C = O (esters) 1800 cm -1 C = O ( Example 41 (5R) -acetonyl-6- (1-hydroxyethyl) -2-acetoxymethyl-2-pene-3-carboxylate.

OCOCH ·, COOCH 2 COCH 3

0.51 g of (5R) -acetonyl-α- (1β-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-pene-3-carboxylate, prepared according to Example 40, is dissolved in 60 ml of a mixture of equal parts of acetonitrile and 95% ethanol, 0.46 g of 10% palladium on carbon was added and the mixture was stirred under hydrogen atmosphere for 1 hour. After filtering off the catalyst, the filtrate is evaporated and the title compound is purified by chromatography on silica gel using dichloromethane / ethyl acetate (8: 2) as eluent. 0.20 g of pure product is obtained.

The product has the following physicochemical constants.

octyl erythro-configuration: NMR spectrum (CDCl3): 1.68 (d, J = 6.5 Hz, 3H, CH2CH2), 2.09 (s, 3H, OCOCH2-). 2.20 (s, 3H, COCH3), 3.86 (dd, J = 2.0, 4.0 Hz, 1H, H-6), 4.22 (dd, J = 6.5, 4.0) Hz, 1H, CHOH), 4.72 (s, 2H, CH 2 CO), 5.12, 5.42 (d, J = 15.5 Hz, 2H, CH 2 OCO), 5.58 (d, J = 2, 0 Hz, 1H, H-5). threo-configuration: NMR spectrum (CDCl3): 1.32 (d, J = 6.5 Hz, 3H, CH2CH2), 2.10 (s, 3H, OCOCH2-). 2.20 (s, 3H, COCH-1), 3.06 (broad s, 1H, OH), 3.74 (dd, J = 2.0, 7.0 Hz, 1H, H-6), 4 23 (m, 1H, CHOH), 4.77 (s, 2H, CH 2 CO), 5.12, 5.38 (d, J = 16.0 Hz, 2H, CH 2 OCO), 5.53 (d, J = 2.0 Hz, 1H, H-5); [Α] D = + 135 ° (c = 1.04, chloroform). Example 42

(5R) -2-Acetoxymethyl-6- (1-hydroxy-ethyl) -2-penem-3-carboxylic acid sodium salt

OH

AND

OCOCH ·, COOCH 2 COCH 3

OCOCH · COONa 0.21 g of (5R) -acetonyl-6- (1-hydroxyethyl) 2-acetoxymethyl-2-pene-3-carboxylate, prepared according to Example 41, is dissolved in 20 ml of acetonitrile and 3 ml of water . The reaction mixture was cooled to 0 ° C under nitrogen and 7.4 mL of 0.1N aqueous sodium hydroxide solution was slowly added over 30 minutes. After evaporation of the acetonitrile in vacuo, the residue was extracted twice with cold ethyl acetate. Chromatography of the concentrated aqueous layer on an inverted phase (elution with water) yields 0.054 g of the pure title compound.

Claims (3)

29 226010 The product of my next physicochemical constant. erythro-configuration: NMR spectrum (deuterium oxide, 80 MHz): 1.34 (d, J = 6.3 Hz, 3H, CH 2 CH). 2.14 (s, 3H, OCOCH3), 4.01 (m, 1H, H-6), 4.22 (m, 1H, CHOH), 5.10, 5.44 (d, J = 14.0 Hz, 2H, CHgOCO), 5.63 (d, J = 1.0 Hz, 1H, H-5); [.alpha.] D = + 128 DEG (c = 0.92, water); UV (95% ethanol): λ max = 262 nm (t = 2,000), 308 nm (ε = 2,520). threo-configuration: NMR spectrum (deuterium oxide): 1.31 Cd, J = 6.5 Hz, 3H, CH3-CH), 2.14 (s, 3H, OCOCH3), 3.92 (dd, J = 1, 5, 7.0 Hz, 1H, H-6), 4.21 (m, 1H, CHOH), 5.10, 5.44 (d, J = 14.0 Hz 2H, CH3 OOCO), 5.67 Cd, J = 1.5 Hz, 1H, H-5); UV (95% ethanol): λωβχ = 262 nm (ε = 3,410), 308 nm (ε = 4,340). OBJECT OF THE INVENTION CLAIMS 1. A process for the preparation of novel penemarboxylic acid derivatives of the general formula I wherein n is 0 or 1, R "" is hydrogen, C 1 -C 4 alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl, p-nitrobenzyl, p-methoxybenzyl a phenyl group, a p-nitrophenyl group, a benzhydryl group, an acetoxymethyl group, a pivaloyloxymethyl group, a phthalidyl group, a -CH 2 CH 2 JO-COOC 8 H 8 group, or a -CH 3 NHCOR "group wherein R" "" is an alkyl group having 1 to 5 carbon atoms, an aryl radical selected from phenyl and benzyl, or cycloalkyl having from 3 to 6 carbon atoms, Z is hydrogen, halogen, hydroxyl, amino, carbamoxy, mercapto, pyridine, or OR ', OCOR', NHCOR or SR "wherein each of R" and R "is C 1 -C 4 alkyl, an aryl moiety selected from phenyl and benzyl, 5-methyl-1,3 , 4-triadiazol-2-yl, 1-methyl-5-tetrazolyl, 1,2,3-triazol-5-yl or pyrazinyl, and R "'is hydrogen, C1-C4alkyl , (C 1 -C 4) alkoxy, (C 3 -C 6) cycloalkyl, (C 1 -C 4) -alkyl, the alcoholic function of which may be either free or protected with p-nitrobenzyloxycarbonyl, or dimethyl-tert-butylsilyl, characterized in that the compound of formula II is present (II) wherein R is C 1 -C 4 alkyl and R "'is as defined above, is reacted with an acetylenic derivative of formula X - C = CY wherein X' is CH 2 Z 'where Z' is a hydrogen or halogen atom, a hydroxyl group, an amino group, or an OR ', OCOR' or NHCOR 'radical, wherein R' is as defined above, and Y is hydrogen, C 1 -C 4 alkyl, cyano or a radical of formula COOR or CH 2 Z ', wherein R and Z' are as defined above, to give a compound of formula III wherein (III) R 1, R 2 ', X 2 and Y are as defined above, which is isomerized to a compound of Formula IV under basic conditions COOR (IV) in which R, RX * and Y are as defined above, in which the radical X ', if different from the radical X, is optionally converted by a substitution reaction of a residue X representing CH 2 Z, where, as defined above, this compound sereduces, ozonizes and hydrolyses to a compound of formula VII (VII) wherein R '' and X are as defined above, which is then reacted with a suitable glyoxylic ester of the formula CHOCOOR "wherein R" is as defined above to form a compound of formula VIII Wherein X, K '" and R &quot; " are as defined above, this compound is converted to a chloro derivative of Formula IX (IX) wherein COOR X, R '"and K" "are as defined above, and this is converted to phosphorane of formula X COOR wherein X, R '"and S" "are as defined above, which is cyclized by heating in an inert solvent to a temperature of 50-140 ° C to give a compound of Formula I wherein n is 0, optionally oxidizing to the corresponding compound of formula I wherein n is 1. 2. The process according to claim 1, wherein n is 0, B " is hydrogen, C1 -C4 alkyl, 2,2,2-trichloroethyl; , a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a phenyl group, a p-nitrophenyl group, a benzhydryl group, an acetoxymethyl group, a pivaloyloxymethyl group, atalidyl group, a residue of -CH (CH 3) -O-COOC 2 H 5, or - Wherein R '' '' 'is alkyl. (C 1 -C 5) or aryl radical selected from phenyl and benzyl, Z is as defined in 1 and H "is hydrogen, characterized in that compounds of the above general formula II, acetylenic, are used as starting materials derivatives of formula X '- C = CY and gyloxylates of formula CHOCOOR "" wherein B, X' and Y are as defined in 1 and R '' 'and B "" are as defined above, and the reaction is terminated after cyclization of the compound of formula X. 3- The process according to claim 1, for the preparation of compounds of formula I, wherein n is 0, E '' is hydrogen, C1 -C4 alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl group, p-methoxybenzyl group, 226010 32 phenyl group, p-nitrophenyl group, benzhydryl group, acetoxymethyl group, pivaloyloxymethyl group, -phthalidyl group, radical of formula -CHCCH 3 JO-COOC 8 H 1 or -CH 3 NHCOH "", wherein R '' '' represents an alkyl group having 1 to 5 carbon atoms or an aryl radical selected from the group consisting of phenyl and benzyl, Z is as defined in 1 and R 'is an alkyl group having 1 to 4 carbon atoms, cycloalkyl C 3 -C 6 or C 1 -C 4 hydroxyalkyl, the alcoholic function of which may be either free or protected with p-nitrobenzyloxycarbonyl, or di- methyl tert-butylsilyl radical, characterized in that compounds of the aforementioned general formula (II), acetylenic derivatives of the general formula * X '- C = CY and glyoxylates of the general formula chocoor "" in which Η, X' and Y are as defined in 1, are used as starting materials, R 'and R "are as defined above, and the reaction is terminated after cyclization of the compound of Formula X. 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