FI75163B - FOERFARANDE FOER FRAMSTAELLNING AV NYA PENEMKARBOXYLSYROR ELLER -ESTRAR. - Google Patents

Description

KJM "| m. NOTICE OF PUBLICATION: -, (11) UTLAGGNINGSSKRIFT / 0 100 (51) Kv.tk.Vint.ci * c 07 D 499/00

SUOMI FINLAND

(FI) (21) Patent application - Patentansökning 800493 (22) Application date - Ansökningsdag 19.02.80

National Board of Patents and Registration (23) Start date - Giltighetsdag 19.02.80

Patent-och ragisterstyralsan {41) Publications - Biiv.t offenti.g 25 * 08 * 80 (44) Date of submission and publication. - 09 01 88

Ansökan utlagd och utl.skriften publicerad y '(86) Kv application -Int. trap (32) (33) (31) Claim claimed - Begärd priontet 24.02.79 2Ο.Ο9.79 United Kingdom-Storbritannien (GB) 7906634, 7932591 (71) Farmitalia Carlo Erba SpA, Via Carlo Imbonati 24, Milan, I (1) Maurizio Foglio, Milan, Giovanni Franceschi, Milan,

Cosimo Scarafile, Milan, Federico Arcamone, Nerviano (Milan),

Aurora Sanfilippo, Milan, I ta 1 ia-I ta 1ien (IT) (74) oy Heinänen Ab (54) Method for the preparation of new penemic carboxylic acids or esters -Förfarande för framstä11 Ning av nya penemkarboxy1syror eller -estrar ^ The invention relates to a process for the preparation of new, antibenic for the study of penemic carboxylic acids or esters having the 5R configuration and having the general formula λ: η2ζ Γ 1 (j) / N \ (f ^ COOR ”” 75163 wherein R "'is hydroxy-lower alkyl, Z is triazolyl- thio, methylthiadiazolylthio or OCOR 4, wherein R 11 is lower alkyl, and R "1 is hydrogen or an in vivo hydrolysable ester group such as acetoxymethyl, and for the preparation of pharmaceutically acceptable salts of the compounds of formula.

These compounds have a wide range of antibacterial activity as well as β-lactamase inhibitory activity. In addition, it should be noted that the C-atom of the compounds according to the invention and of all intermediates formed in their preparation steps

O

the stereochemistry is the same as that of naturally occurring penicillins and cephalosporins.

The process of the invention also provides pharmaceutically acceptable salts of penemicarboxylic acids of general formula (I), such as sodium, potassium, benzathine, procaine and the like, which are usually formed with penicillins and cephalosporins.

The compounds of the invention are used in the preparation of pharmaceutical ingredients containing a compound of formula (I) or a salt thereof in admixture with a conventional carrier for oral or parenteral administration.

The first penem derivatives11a prepared by R.B. Woodward, there was a general formula

R-S-NH \ _CH

0 Χΐ_) Γ 3

0 ^ COOR

These 6-amino-substituted compounds disclosed in DE-A-2,655,298 were found to be less potent than other β-lactam compounds (cf. Chem. Weekbl., 1977, p. 299).

DE 75163 DE-A-2 819 655 and EP-A-636 further disclose 2-penem compounds of the formula J1-ILcoor2 wherein R1 is hydrogen, an organic radical or an etherified mercapto group and R_ is hydrogen or a carboxy protecting group, C_ is both the R-2b and S configuration. These compounds have been reported to be antibacterial agents and β-lactamase inhibitors.

The compounds prepared according to the present invention, in contrast to said known compounds, are 6-substituted penem compounds in which the methyl group in the 2-position comprises a specific substituent and the carbon atom in the 5-position is in the 5R configuration. This limited group of compounds of the invention has been found to have broader antibacterial activity as well as greater potency than known compounds.

4 75163

The following Schematic shows the various steps of the process of the invention in the preparation of the compounds of formula (i).

^ X 'f if O o I il - i

0'l> as ~ V-VJ

C00R «^ '" coor T Y

UI) / COOR

f 'K (IV) \ rWtx Ryrv

f * k o ^ 1 — fyklY

/ \ (V) COOR COOR

| r \ (XII) r ~ c ^ <\

1 "s'- ·. / - * v- .. V

0 11 COOR H COOR (Oln 5J R "'ζτγ * v-rr" «N * γ.

COOR

(VI) (o) <XIII>

Il J- n "· Il pη i vry wv 'COOR" "(VII) (XIV) ^. 1

II

5 75163 (VII) (XIV)> / J '<°> n II R "1 R"' U v. O \ -> 1— ^ - 'K ^ ciV Y / N ^ · 0 »COOR" "COOR" "(VIII) (XV) 0 '' H ... R" \ JL · S '* R \

V / y. «VYY tl T

γΐΛ, v ^ - ^ v1

Cr | = ppllj Y COOR ""

COOR "" C00R ,, M

(X) d *> (XVI) .0 / yds

y / ^ V

RM f

VfY WY, _Yrr i — Nv. —N — V V — N \ _ ^ N = PPh3 COOR "" CT P> Ph3 COOR "" COOR ""

(XI) (D <XD

6,751 63

When R "'means lower alkyl, cyclo or alkylalkyls, the group R"' can be attached by the method of Di Ninno et al (Journal of Organic Chemistry 42, 2960, 1977).

On the other hand, compounds of formula (II) in which R "'is hydrogen can be converted to compounds of formula (II) in which R"' is lower alkyl, cycloalkyl or hydroxyl, the substituent being attached at the 6-position using a strong base as in subsequent the examples show.

Compounds of formula (II) wherein R "'represents hydroxyalkyl may be prepared from the appropriate penicillinic acid S-oxide ester, as exemplified. Substituent at the 6-position is stereospecifically directed to 6a-j derivatives.

Penicillinic acid S-oxide ester (II) (R is alkyl and R "means the same as above) can be prepared in an inert solvent, e.g. benzene or toluene, usually at 70-140 ° C, by heating with a suitable acetene derivative which the general formula is X'C = CY when X 'is a group represented by the formula CH2Z', wherein 2 'is hydroxy or a group represented by the formula OCOR ^, and Y is hydrogen or a group represented by the formula CH2Z', wherein Z 'has the same meaning as When X 'means otherwise, it can be converted to X by known substitution reactions, where X is a group of the formula CH 2 Z' where Z is as defined above.

Compound (III) can be isomerized with a base to compound (IV), which can be converted into the final compound (I) in two different ways. According to the first method, the isopropenyl double bond of compound (IV) can be selectively ozonated to give compound (V) (n = 1), which can be reduced with suitable reducing agents such as phosphorus tribromide or sodium iodide in acetyl chloride, to compound (V) (n = 0), which is finally slightly hydrolyzed. conditions or on silica gel to give compound (VI) (n = 0). Condensation of 11a with the appropriate glyoxylic acid ester gives compound (VII) (n = 0), which can be

II

75163 can be used to convert chlorine to a derivative (VIII) (n = 0) and then to a phosphorane (IX) (n = 0) with a chlorinating agent such as thionyl chloride and pyridine.

The same reaction procedure is also carried out starting from the unexpected compound (VI) (n = 1), which is stable when Y is not a strongly cleavable group. In the case of compounds (IX) (n = 0), the compound can be selectively ozonated as the phosphonium salt under acidic conditions to give compound (XI), which can be cyclized to compound (I) simply by heating in an inert solvent such as toluene at 50-140 ° C. .

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

By another method, compound (IV) can be reduced in the usual manner to compound (XII), both double bonds of which are ozonated to give compound (XIII) and, after hydrolysis, compound (XIV). By the same method as described above, compound (XIV) is obtained by glyoxylation of compound (XV), which can then be converted into a chlorine derivative (XVI) and then into phosphorane (XI), which is a common intermediate in both preparations.

When R "'represents hydroxylalkyl, the reaction steps are preferably carried out by protecting the alcohol reaction.

Compounds of general formula (I) when R "" represents hydrogen may be obtained by hydrolysis or hydrogenolysis of the corresponding esterified compounds.

All of the methods described above are within the scope of the present invention.

8 75163

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

_OH

I T _ ^ 0 H COOCH3 q ^ "" "C00CH3

To a solution of 2.2 g of methylpenicillinate in 30 ml of anhydrous tetrahydrofuran was added a small excess of lithium diisopropylamide at -78 ° C under a nitrogen ring. Acetaldehyde was added dropwise in excess, stirred for 5 min, quenched with concentrated acetic acid, poured into water and extracted with methylene chloride. After drying over Na 2 SO 4 and evaporation to dryness in vacuo, 0.8 g of the title compound is obtained organically from the phase.

Example 2 Methyl 6- (1-p-nitrobenzyl oxycarbonyl-oxyethyl) -3-penicillanate

OH OCO ^ PNB

1.2 g of methyl 6- (1-hydroxyethyl) -3-penicyanate were dissolved in 40 ml of tetrahydrofuran, cooled to -78 ° C. and treated with 1 equivalent of butyl lithium. To the resulting mixture was added 1.2 equivalents of p-nitrobenzyl oxycarbonyl chloride. After standing at -78 ° for 30 min, the reaction mixture was allowed to stand for 60 min at room temperature, poured into water and extracted with methylene chloride. After drying over IMa 2 SO 4 and evaporation, 1.4 g of the title compound are obtained.

Example 3 Methyl 6- (p-p-nitrobenzyl (oxycarbonyl-oxyethyl) -3-penicillanate S-oxide

II

9,751 63 o OCO-PNB OCCUPNB li [VSvf} N 7 "'", ^ -N 7 \ ΓηηΓΗ OH C00CH3 0 H # UULM3 1,2, 2-methyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penic the branate was dissolved in 50 ml of methylene chloride a and treated at 0 ° C with 1.5 equivalents of m-chloroperbenzoic acid. The organic phase was shaken with saturated NaHCO 3 solution, extracted, dried over Na 2 SO 4 and evaporated to dryness. 1.4 g of the intended sulfoxide were obtained.

Example 4 4β-Vinylthio- (1,2-diacetoxymethyl-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one S-oxide 0 oqo2pnb ^ OCCUPNB n —f 'X' _ —j ^ xX ^ ococh3 0 ^ H ^^ "'C00CH- 0 0C0CH3' COOCH3

A solution of 2.0 g of methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate S-oxide and 2.4 g of butidine idol diacetate in 50 ml of toluene was kept at reflux for 24 hours. . The resulting compound was then purified by column chromatography eluting with 9: 1 dichloromethane-ethyl acetate. 1.1 g of the title compound were obtained.

Example 5 4'-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one S-oxide

G

f) OCO-, ΡΝΒ II

0C0-PNB II I 2 _: Vr -> H cooch3 cooch3 1υ 7516 3 1.3 g 4-night-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl 2-Methyl-2-propenyl-azetidin-2-one S-oxide was dissolved in 80 ml of dichloromethane. 0.3 ml of triethylamine was added and the mixture was allowed to stand for 2 hours at room temperature. A pure amount of the title compound was obtained by evaporating the solvent.

Example 6 4/3-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one S-oxide 0 0 0CO0PNB II 0CO-PNB ||

ococh3 ^ ^ S ^ _ ^^ 0CO0CH

^ - \ j L / ° coch3 * K.L ™.

° ^ 0CH3 ° LOOCH3

A solution of 1.1 g of 4-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzylcarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) azetidine- 2-one S-oxide in 100 mL of dichloromethane was cooled to -78 ° C. Ozone in oxygen was blown through it until a blue color appeared. The solution was shaken with a solution of Na 2 SO 2 O / water and dried over Na 2 SO 4. After evaporation, 0.5 g of the title compound was obtained.

Example 7 4- [3-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one

: 0C02PNB 0 0C02PNB

^ S ^ ^^ OCOCHj / -N-y> t ^ 0C0CH3 * 1 ^ _dcoch3 0 C00CH3 C00CH3

A solution of 0.8 g of 4H-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one in 15 ml of anhydrous dimethylformamide was cooled. To -20 ° C and 0.6 ml of phosphorus tribromine dia was added. After 10 minutes, the reaction mixture was diluted with ethyl acetate and washed twice with NaHCO 3 solution. 0.4 g of the reduced compound was obtained from the organic phase dried over Na2SO4 and evaporated to dryness.

11 75163

Example 8 4 vinylthio (1,2-diacetoxymethyl) -3-

(1-p-Nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one QC0oPNB OCO-PNB

1 2 a. 2 s 0C0CH3 - ^ * S ^^^ 0C0CH3

j OCOCH * T N>. 1 OCQCH

0 COOCH 2 0 g of 4/3-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one was dissolved in methanol and 2 g of silica gel were added. After 60 minutes, the insoluble material filtered off was removed and the organic phase was evaporated to dryness. Short column chromatography gave 0.4 g of the title compound.

Example 9 4,3-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonylethyl) -1- [acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidine-2 -one oco2pnb oco2pnb ococh3_ ^ ^ ococh3 Jn 1L_ / ococh3 J, -N ^^ OH \ v / OCOCH3 ° ^ H Cl C00CH20CO0CH3 0, G g 4? 1-p-Nitrobenzyloxycarbonyloxyethyl-azetidin-2-one dissolved in 30 ml of benzene and 0.6 g of acetoxymethylglyoxylate (prepared just by ozonolysis of diacetoxymethyl fumarate) were kept under reflux. The reaction was complete after 2 hours. The condensation product could be used for the next step without further purification.

Example 10 4,3-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethylcarbonyl-1-chloromethyl) azetidin-2-one oco2pnb oco2pnb ^ S- ^ ^^ DC0CHQ ^ S ^^^ OCOCH.

I-1 Tl 3 s | --1 (I 3 M ni; \ _OCOCl-L · 7 '^ JL ^ OCOCH- ^ 3} -3; C00CH2COCOCH3 O toOCH2OCOCH3 0.5 g 4/3-vinylthio- 2-Diacetoxymethyl) -3- (1-p-nitrobenzylcarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one was dissolved in 12 ml of anhydrous 12,751,630 tetrahydrofuran. and cooled to 0 [deg.] C. 1.1 equivalents of pyridine and 1.1 equivalents of thionyl chloride were added, stirred for 10 minutes, insoluble matter was removed by filtration and the solution was evaporated to dryness at room temperature to give an almost quantitative amount of the title compound. 1 to the next step of internal cleaning.

Example 1 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one oco C00CH20C0CH3

A solution of 0.760 g of 4- (3-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzoyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one in 1 ml of tetrahydrofuran and 10 ml of dioxane, was stirred overnight with 1.1 equivalents of pyridine at 50 ° C. Phosphorane was purified by flash chromatography on silica gel, eluting with 70:30 d 2 PCI or ethyl acetate. 0.480 g of the title compound was obtained.

Example 12 4H-3-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one

oco2pnb oco2PNB

____ QC0CH3 _> ^ S ^^ rT ^^^ OC0CH

Γ H -> \ 0 J

0.400 g of 4/3-vinylthio- (1,2-diazethoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (acetoxymethyloxycarbonyl-1-triflate) -N-presento (methylene) -azetidin-2-one was dissolved in 50 ml of dichloromethane and cooled to -20 ° C. 30 ml of a dichloromethane solution of trifluoroacetic acid were added. After a few minutes, ozone was bubbled in oxygen until it appeared from the blue staining bulb.

1! 13,751 63

The reaction was stopped and a few drops of trimethyl phosphite were added. The organic phase was washed with saturated NaHCO 3 solution and dried over Na 2 SO 4. 0.260 g of the title compound was obtained.

Example 13 4,3-Vinyl-1- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one oco7pnb 3 oco7pnb 3 ^ - 1.5 g of vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl), ocs, o, o, o, o, o, o, o,,,,,,,,,,,,,,,,,,,,,,,, 2-Methyl-1-propenyl) -azetidin-2-one S-oxide was dissolved in 10 ml of anhydrous dimethylformamide and cooled to -20 ° C. 0.1 ml of phosphorus tribromide was added, the mixture was stirred for 10 min, diluted with ethyl acetate and washed twice with saturated NaHCO 3 solution. After drying over Na 2 SO 4 and evaporation to dryness, 1.1 g of the title compound are obtained from the organic layer.

Example 14 4-N-Acotylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxalyl-azetidin-2-one N, N, N, N, N, N, N, N, N, R J 0 f C00CH3

Solution containing 1.4 g of 4/5-vinylthio- (1,2-diacetosmethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-2-propenyl) azetidine-2- in 120 ml of dichloromethane, cooled to -76 [deg.] C. Ozone was bubbled through the solution in oxygen until a blue color formed, and the solution was shaken with aqueous Na2SO2 and dried over Na2SO4 to give 0.6 g of the title compound. compound.

Example 15 4 P-Acetylglycolylthio-3-p-nitrobenzyloxycarbonyloxyethyl) azetidin-2-one 14,7516 3

OCO, PNB 0C02PNB

'YYS'Y' '' ocoCh3 _ ^ 'V ^ ococh3 oh COGCH3 0.800 g 4 y (5-acetyl liglycolylthio-3- (1-p-nitrobenzyl) carbonyloxyethyl] -1-methoxyoxalyl -azetidin-2-one was dissolved in 50 ml of methanol and a few grams of silica gel were added, the mixture was allowed to stand for 60 min at room temperature, the insoluble matter was removed by filtration, and the filtrate was dried by evaporation to give 0.300 g of the title compound.

Example 16 4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one

0C0? PNB

0CO2PNB y S ^ / ~ \ 0C0CH3 o "^ ΝΤ0Η 0 C00CH20CO0CH3

A solution of 0.5 g of 4/3-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethylcarbonyl-1-hydroxymethyl) azetidin-2-one and 0.5 g of acetoxymethylglyoxy plate in 30 ml of benzene, was maintained at the reflux temperature until the reaction was complete (2 hours). The title compound obtained could be used for the next step without further purification.

Example 17 4- [3-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one

OCO-, ΡΝΒ 0C02PNB

--- f S ^ f ^ 0C0CH3 ^ S ^ p0C0CH3 ^ Ν - γΟΗ * -N - JC1 ^ C00CH20CO0CH3 0 cooch2ococh3

II

0.355 g of 4- (b-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one was dissolved in 10 ml of anhydrous tetrahydrofuran. nai at 0 [deg.] C. 1.1 equivalents of pyridine and 1.1 equivalents of thionyl chloride were added, the mixture was stirred for 10 min, the precipitate was removed by filtration and the filtrate was evaporated to dryness to give a quantitative amount of the title compound.

Example 18 4,3-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one QCO-, S s S - ^ ^ - ^ OCOCHL OCO-, ΡΝΒ ^ S - 0CO0CH, —Γ i 3 f, 3 ~ r? tf-r 3 COOCH2OCOCH3 toOCH2OCOCH3 0.400 g of 4- [3-acetyl] glycolthio-3- (1-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -acetidin-2-one was dissolved in 20 ml to a 1: 1 mixture of tetrahydrofuran and dioxane. 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine were added and stirred overnight at 50 ° C. The title compound was purified by column chromatography on silica gel eluting with 70:30 dichloromethane-ethyl acetate. 0.280 g of phosphorane was obtained.

Example 19 (5R) -Acetoxymethyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate

^ 0CO2PNB ---- OCOCHj ^ CO2PNB

0.200 g of 4β-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidine-2-azetidine-azetidine toluene and the solution were back-distilled for 2 hours. Purification by short column chromatography eluting with 95: 5 dichloromethane-ethyl acetate 11a gave 0.050 g of the title compound.

Example 20 (5R) -Acetoxymethyl-5- (1-hydroxyethyl) * 2-acetoxymethyl-2-penem-3-carboxylate

VV

JN-17 7 J, -N - (OCOCtL · u C00CH2OCOCH3 (J \ Λ C00CH2COCHCH3 0.060 g 5R-acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3- the carboxylate was poured into a mixture of water, ethanol and K 2 HPO 4 and hydrogenated with 10% Pd / C. Rapid purification by column chromatography on silica gel gave 0.015 g of the title compound.

When working according to the above-mentioned examples, however, using 5-methyl-2-1-110-1,3,4-diazo-1, 5-thiol-1,2,3-triazole or thiopyrazine 1-methyl Instead of -5-thioletrazole, (5R) -2 - [(5'-methyl-1 ', 3', 4'-thiadiazol-2, -yl) -thiomethyl] -2-penem-3-carboxylic acid was obtained, (5R ) -2 - [(1 ', 2', 3'-Triazol-5-yl] -thiomethyl] -2-penem-3-carboxylic acid, (5R) -2- (pyrazinyl) -1-methyl - 2-penem-3-carboxylic acid, (SR) -6- [1'-hydroxyethyl) -2- [{5 "-methyl-1", 3 ", 4" -thiadiazole-2 "-yl) -thiomethyl) -2-penem-3-carboxylic acid, (5R) -6- (1'-hydroxyethyl] -2 - [(1", 2 ", 3" -triazol-5 "- yl) - thiomethyl-2-penem-3-carboxylic acid and (5R) -6- [1'-hydroxy-ethyl] -2- (pyrazinyl) -thiomethyl-2-penem-3-carboxylic acid.

By working as described above, but reducing methyl 6- (1 * -hydroxyethyl) -3-penicillanate in a manner known per se, the corresponding 6-ethyl derivatives were obtained.

Il 17 751 63

Example 21 4 '- (1-Hydroxymethyl-vinylthio-N, N-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one S-oxide. Reaction (2) to (3).

OCO „PNB 0 1 s, Γ”

”Λ :: V

H COOCH-. v '3 H COOCH3

A solution of 2.6 g of methyl 6- (1-n-nitrobenzylcarbonyloxyethyl) -3-penicillinate S-oxide and 8 ml of propargyl alcohol in 20 ml of toluene was boiled under reflux for 40 hours. . After evaporation of the solvent, the obtained compound was purified by silica gel flash chromatography eluting with (9: 1) dichloromethane-ethyl acetate to give 2.0 g of the title compound.

Example 22 4- (1-Hydroxymethyl) -vinylthio-3H- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one S-oxide. Reaction (3) to (4).

° C02PNB O 'OCO, PNB? J m I 2 s / yP'S OH ✓ oh i i 1 -> 1 'Λ. * -

0 X 0 I

H COOCH3 COOCH3 18 75163 2.0 g of 4 / 3- (1-hydroxymethyl) vinylthio- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-) dissolved in 50 ml of dichloromethane. methyl-2-propenyl) -azetidin-2-one S-oxide was allowed to stand at room temperature after the addition of a few drops of triethylamine for 12 hours. After evaporation of the solvent, the pure title compound was obtained quantitatively.

Example 23

AFI (1-bromomethyl) -vinyylitio-3 ^ - (1-p-nitrobentsyylioksikar-bonyylioksietyyli) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one. Reaction (4) to (12).

0CO2? NB ft 0CO2pnb \ x J s P / jXs cooch3 cooch3 2.0 g of the compound prepared in Example 22 were dissolved in 50 ml of dimethylformamide. After cooling to -20 ° C, 0.7 ml of pyridine and 3.2 ml of PBr were added and the reaction mixture was stirred for 15 minutes. Ethyl acetate was added to the mixture, and the organic phase was shaken with saturated NaHCO 3 solution, washed with water, and finally dried over Ν3220®. After evaporation of the solvent, 1.7 g of the title compound were obtained.

Example 24 4- [1- (5-Methyl-1,3,4-thiadiazol-2-yl) -1-methyl-7-vinyl-thio] -3- (1- (p-nitrobenzyloxycarbonyloxyethyl)) -1- (1-methylcarbonyl-2-methyl-1-propenyl) azetidin-2-one.

Il 19 751 63

0C02PNB 0C02PNB n-N

1.8 g of the compound prepared in Example 23 was dissolved in 30 ml of tetrahydrofuran. The resulting solution was cooled to 0 ° C; 1.1 g of the sodium salt of 5-methyl-1,3,4-adiazole-2-iol was added and stirred for 4 hours. After the insoluble matter was separated by filtration, the remaining solution was diluted with ethyl acetate, washed with water, dried to Ν3250 x 1: 3 and evaporated to give 2 g of the title compound.

Example 25 4/3 - [1- (1,2,3-Triazol-5-yl) -thiomethyl] -vinylthio-3 - * - (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2- methyl-1-propenyl) -azetidin-2-one.

0C02PNB 0C02PNB (j-N

A., Y '' '' 'Br A.

11 -> 1 L 11 o ^ ~ y- h ~ Ny-COOCH3 COOCH3 Starting from 2.5 g of the compound prepared in Example 23 and proceeding as in Example 24, but using the sodium salt of 1,2,3-triazole-5-1iol, 2.2 g of the title compound were obtained.

Example 26 4-O'-1- (5-Methyl-1,3,4-thiadiazol-2-yl) -thioacetylthio-30 <-2075163 (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl azetidine-2 -one.

OCC ^ PNB M OCO2PNB N

; 2 g of the compound prepared in Example 24 was dissolved in 250 ml of dichloromethane and cooled to -78 ° C. A stream of ozonated oxygen was bubbled through the solution until a blue color was obtained. A few drops of PCOCH 2) were added to the solution and the temperature of the mixture was allowed to rise to room temperature. The mixture was evaporated to dryness to give 1.5 g of the title compound.

Example 27 * fi _ Γλ (λ nn o. _ J ί. · C.,.. Ι, · ϊ 7 _ 4.. · .---- i.... -T _ · 4- -wf .

_m OCO-PNB ι-N

OCO-PNB |, M 1 2 I II

COOCH3 cooch3

Starting from the compound prepared in Example 25 (1.6 g) and proceeding according to Example 26, 1.1 g of the title compound were obtained.

it 21 751 63

Example 28 4- [1- [1- (5-Methyl-1,3-thiadiazol-2-yl) -thioacetylthio] -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one.

Reaction (13) to (14).

OCO «jPNB, N— N λρλ pop! 1.5 g of the compound prepared in Example 25 was dissolved in a 1: 1 mixture of methanol and ethyl acetate. A few grams of silica gel were added and the mixture was kept at room temperature with vigorous stirring. After removal of the silica gel by filtration, the filtrate was evaporated to dryness to give an oil which was chromatographed on silica gel with dichloromethane: ethyl acetate (6: 2) to give 0.9 g of pure title compound.

Example 29 4H- [1- (1,2,3-Triazol-5-yl) -thioacetylthio-3c * - (1-p-nitrobenzyloxycarbonyloxyethyl) azetidin-2-one. Reaction (13) to (14).

OCCUPNB, -N ____ r-M

2 (f QCO2pnb f | tl

/ "Ί-SVN

I O H »O H

s? -Nv -> i-N

I OH

COOCH

Starting from 1.1 g of the compound prepared according to Example 27 and proceeding according to Example 28, 0.6 g of the title compound was obtained.

Example 30 4- [3 - [(S-Methyl-N, N-thiadiazol-2-yl) thioacetylthio] -3- (1-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-hydroxymethyl ) -azetidin-2-one Reaction (14) - (15).

0C02pnb »-} f oco2PNB II» - * jl 's ^ s ^ - CH., ------ S S - 1- S-L- ch3 Ε3Γ 4 JZJ »0

cT \ \ -OH

COOCH 2 COCH 3 0.9 g of the compound prepared in Example 28 was dissolved in 40 ml of benzene; 0.6 g of acetonyl glyoxylate was added and the resulting solution was refluxed for 3 hours. After evaporation of the solvent, the obtained crude oil was used for the next step without further purification.

Example 31 4- [1- (1,2,3-Triazol-5-yl) -7-thioacetylthio-3 - [(1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-hydroxymethyl)] - azetidine-2-one. Reaction (14) to (15).

OCÖjPNB N OCOjPNB (j ff

I — 1 S 'Γ ~ ι o H

/) - \ \ -Nv

0 H O

cooch2coch3

II

2> 3 75163 Starting from 0.6 g of the compound prepared in Example 29 and proceeding as in Example 30, 0.7 g of the title compound was obtained.

Example 32 - (5-Methyl-1,3,4-thiadiazol-2-yl] -thioacetylthio-30 - (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-chloromethyl) azetidine -2-one Reaction (15) - (16).

0CO2PNB n-N 0CO2PNB .N n / L_ / χ_ i ° ^ J_N ° O \ p OH O Γ C1 COOCH2COCH3 cooch2coch3

The crude oil obtained in Example 30 was dissolved in anhydrous tetrahydrofuran (30 ml) and cooled to 0 ° C. Pyridine and thionyl chloride were added in equimolar amounts to the solution until the starting material disappeared. After the insoluble matter was removed by filtration, the filtrate was used directly for the next step.

Example 33 - (1,2,3-Triazol-5-yl) -thioacetylthio-3- [1- (1-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-chloromethyl) -azetidine-2] -one. Reaction (15) to (16).

OCO.PNB | j-1) f ° 2PNB M

/ './'Χς O / "* S

2 V- ^ hf 5

i-N -I-N

O Y> «+ yci COOCH2COCH3 COOCH2COCH3 24 75163 Starting from 0.7 g of the compound prepared according to Example 3L and proceeding according to Example 30, a crude chlorine derivative was obtained. The product was used for the next step without further purification.

Example 34 4 - [- 1- (5-Methyl-1,3,4-thiadiazol-2-yl) -7-thioacetylthio-N- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1- triphenylphosphoranylidenemethyl] -azetidin-2-one Reaction (16) - (11].

OC00PMB MM

jOCOjPNB f “| Λ, sll Λ ·. ^ S ^ S "'sJ'CH3 __s C« 3 l N 0 ->} - \ / yci o x ^ pphj COOCH2COCH3 cooch2coch3

In Example 3 2 s 3 31 u Γ 3 3 k31 uotg li Dissolved in 20 g of 1: 3 3 n tetrahydrofuran; 700 mg of triphenylphosphine and 0.35 ml of pyridine were added and the resulting solution was kept at 70 ° C under nitrogen for a few hours. The title phosphorane was purified on silica gel eluting with dichloromethane: ethyl acetate (1: 1) to give 0.6 g of the title compound.

Example 35 4/3 - "1- (1,2,3-Triazol-5-yl) -7-thioacetylthio-30- (1- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyloxyethyl) -1- -triphenyl-phosphoranylidenemethyl) -azetidin-2-one Reaction (16) - (11).

25 751 63 oc ° 2pnB | j — n ocOjPnb | 1 '

S '^ S' '\ -C H

O 0 H - »J—» // - \ o Y pph3 cooch2coch3 cooch2coch3 Starting from the crude chloro derivative obtained in Example 33 and proceeding as described in Example 34, 0. 55 g of the title compound were obtained.

Example 36 (5R) -Acetonyl-2-Z '(5-methyl-1,3,4-thiadiazol-2-yl) -1-methyl-6 - [- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-penem] 3-carboxy tile. Reaction (11) to (1).

OCO-, ΡΝΒ N-N

r> ”* j? I λ / -XXc

"I = CC

0.6 g of the compound prepared in Example 34 was dissolved in 50 ml of toluene and refluxed under nitrogen for 3 hours. The title compound was purified by short column chromatography on silica gel eluting with dichloromethane / methylene chloride. -la (8: 2) to give 0.25 g of the title compound.

1. R.: 1,795.1750.1 720.

·. Example 37 (5R) -Acetonyl-2-[(1,2,3-triazol-5-yl) -thiomethyl] -6®- (1- [p-nitrobenzyloxycarbonyloxyethyl) -2-penem-3-carboxylate.

Reaction (11) to (1).

26 75163

r-N

.-N OCO-PNB II

~ .Q l: V

"'τ-r ^ Y i - * IHIa.' /" "vpsPPhj 0 cooch2coch3 COOCH2COCH3 Starting from 0.45 g of the compound prepared according to Example 35 and proceeding according to Example 36, 0.180 g of the title compound was obtained.

I.R. : 1,795.1,759.1,720.

Example 38 (5R) -Acetonyl-2 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl] -6 '- (1-hydroxyethyl) -2-penem-3- carboxylate. Reaction [1).

OCO PNB N — N OH N-N

J. il / 7 JI ij X "ch3 \ ^ SV ^ SS ^ OH3 O COOCH-COCH-, O __„ 2 3 C00CH2COCl3 0. 450 g of the compound prepared in Example 36 were dissolved in 25 ml of acetonitrile containing a few drops of ethanol and hydrogenated. 10% Pd on carbon (400 mg) The catalyst was removed by filtration and the filtrate was chromatographed on silica gel eluting with dichloromethane: ethyl acetate (7: 3) to give 0.18 g of the title compound.

1. R.: 3605.1 795, 1745.1 720.

Example 39 (5R) -Acetonyl-2-Z '(1,2,3-triazol-5-yl) -thiomethyl] -6 ° <- (1 - 11,775,163 hydroxyethyl) -2-penem-3-carboxylate . Reaction (1).

PCV »B J-J OH f | —ff

ΙΖΓΊ h -> □ _if H

o COOCH2COCH3 0 COOCH2COCH3 Starting from 0.380 g of the compound prepared according to Example 37 and proceeding according to Example 38, 0.12 g of the title compound was obtained.

I.R. : 361 0.1 795.1 750.1 720.

Example 40 (5R] -2H "(5-Methyl-1,3,4-thiadiazol-2-yl) -thiomethyl] -6 ° <- (1-hydroxyethyl) -2-penem-3-carboxylic acid. Reaction (1 ).

f f ~ t x n: s "s l ch> ws-Γ s AcH3 -1, -5 * J> -N- \ o COOCH2COCH3 o cooh

A solution of 0.200 g of the compound prepared according to Example 38 in acetonitrile (30 ml) containing a few more drops of water was cooled to 0 ° C; 5 ml of 0.1 N NaOH solution was added under nitrogen and the solution was stirred for 10 minutes. The alkaline mixture was extracted twice with methylene chloride, acidified with 10% aqueous citric acid and re-extracted twice with methylene chloride. The combined organic phases were dried over Na 2 SO 4 and evaporated to dryness to give 0.110 g of the title compound.

I.R. : 3500.1 795, 1665.

28 751 63

Example 41 (5R) -1- (1,2,3-Triazol-5-yl) -1H-methyl-ecu- (1-hydroxyethyl) -2-penem-3-carboxylic acid. Reaction (1).

jzO —s. nr T * / s \ sy-K- \

o COOCH2COCH3 O ^ COOH

Starting from 0.25 g of the compound prepared according to Example 39 and proceeding as described in Example 43, 0. 135 g of the title compound was obtained.

1. R.:3490,1795,1660.

ί, i

S

\ i j 1! i

Claims (5)

29 751 63 PATENT CLAIM A process for the preparation of novel penemicarboxylic acids or esters having antibacterial activity having the 5R configuration and having the general formula ✓CH-Z I (I) / -N \ o uOOR "" wherein R "'is hydroxy-lower alkyl, Z is triazolylthio, methylthiadiazolylthio or OCOR 4, where R 1 is lower alkyl and R "" is hydrogen or an in vivo hydrolysable ester group such as acetoxymethyl, and for the preparation of pharmaceutically acceptable salts of the compounds of formula, characterized in that RV_ (II > A compound of formula OODR wherein R is alkyl and R "'is as defined above is reacted with an acetylene derivative of formula X'C = CY wherein X' is a group of formula CH 2 Z 'wherein Z' is halogen, hydroxy , carbamoyloxy or a group of the formula OCOR1 where R 75 is lower alkyl and Y is hydrogen, lower alkyl, cyano or a group of the formula COOR or HC 2 Z ', wherein R and Z' are as defined above. to give a compound of general formula II II I (III) ° '' '-COOR wherein R, R "1, X' and Y have the same meaning as above, which compound is then isomerized under basic conditions to give the general formula □ 7 (IV ) 'COOR to a compound represented by the formula wherein R, R "', X 'and Y have the same meaning as above, wherein X', when otherwise, can be converted to an X group by a substitution reaction which X represents a compound represented by the formula CH 2 Z a group in which Z is as defined above, and then a) the compound of formula (IV) is reduced to a compound of general formula X 1 n (XIV) J-V 0, in which R "'and X are as defined above, are ozonated and hydrolyzing, which compound is then reacted with the appropriate glyoxylic acid ester represented by the formula CHOCOOR, wherein R "" has the same meaning as above, to give a compound of the general formula II 31 7 516 3% _s 5 ^ ητ'χ α (χν) ..... -_ ^ Ν ° Η 0 COOR "" wherein X, R »· and R" "have the same meaning as above, which compound is converted to the general formula R1-L · __S — ηρ- ^ Χ __M 0 (XVI) / N '~ r /' Ci D COOR "" to a chlorine compound represented by the formula X, R ", and RM" have the same meaning as above, which is converted to the phoforan represented by the general formula Q, .i _ J-IL 0 <XI) 6 ~ 'pph3 COOR "" wherein X , R "· and R" "have the same meaning as above, and are finally cyclized to a compound of general formula (I), or b) the compound of formula (IV) is selectively ozonated with R 11> - Γ-5 · ^ γχ (V) ff "0 to a compound of formula XY: oor in which n = 1 and X, Y, R and R" 1 have the same meaning as above, which compound is then reduced - to a compound of formula (V) in which n = 0 which compound is hydrolyzed by the general formula (0) r_ II "'; XH Y 32 751 63, wherein X, Y and R "'have the same meaning as above and n = 0, which compound is reacted with a suitable glyoxylic acid ester of the formula CHOCOOR" ", where RM" has the same meaning as above , to a compound of formula (0) is ir n O "9 I * '| Il (VII) J- \ 0 ^ Y C00R" "wherein X, Y, R"' and R "" have the same meaning as above and n = 0, which compound is converted to a chlorine derivative of the formula (°) n R · '1 v (VIII) ^ SA ^ N ^ pCl \ y CDQR "" wherein X, Y, R "1 and R" "have the same meaning as above and n = 0, which compound is converted into a phosphorane of the general formula (0) R \ _I ”1}" rPPh3v CQOR "”, in which R "', R" ", X and Y have the same meaning as above, Ph represents phenyl and n = 0, which compound is ozonated to give a compound represented by the general formula ^ (XI) JN A ^> PPh3 C00R ”” il 751 63 33, in which R "', R" ", X and Ph have the same meaning as above, which compound is finally cyclized of general formula (I) to the corresponding compound. 34 75163 A process for the preparation of a pure carboxylic acid or an ester with an antibacterial network, preferably with a 5R-configuration or a brittle allergy for RAJ _2 (I) / N-C00RM hydroxylgearkyl, Z is triazolylthio, methylthiaziazylthio or OCOR *, or R * is an alkyl group, and R '' '' is an in vivo hydrolysis ester group, acetoxymethyl is also used as a pharmaceutical compound. in the case of a compound having the same formula, the compound having the formula 0 or R / '1 di) tOQR in the form of a mixture of alkyl and R' '' the formula is X'C = CY is X 'and the group is an alkyl form CH, z is Z' is halogen, hydroxy, carbamyl or a group, the formula is OCOR », R is an alkyl, and Y is , en alkyl, cyano or group, the formula is COOR or HCjeZ ', colors R och Z' avser samma sak som ovan, colors er-hälle s en förening stem allmänna formel är 751 63 35 0 1 j ,. Β · '_s --- s * NJ l (III) O' -.COOR där R, R '' ', X', och Y avser samma sak som ovan, vilken fö-rening sedan i basiska förhällanden isomereras account en före -in the full length of the first formula 1 '/ X' II (IV) 'COOR i vilken formula R, R' '', X 'and Y avser samma sak som ovan, varvid X' dä det har en annan betydelse kan ändras account for the X-group of the group consisting of a substitution reaction, the X-group of the group is selected from the group consisting of CH * Z, for which the Z-group is selected from the group consisting of a) a) all of the formulas _r ^ s "T ^ x I (XIV) J · —V b 0 \ H i form the formula R '' 'and X aver decamma som ovan, ozonize-ras and hydrolysers, vilken förening sedan bringas att rea-Gera med en Ester av en warmplig g ^ Yoxylsyra visad av formeln CHOCOOR '' '' varvid R '*' 'avser decamma som ovan, och en förening rod allmänna formulel är 36 75163 nht> —r'T 0 (XV) —— - N —___ ^ \ λΌΗ ° TOOR ”” erhälles, i vilken formula X, R '' ', och R' '' 'avser detsa mma som ovan, vilken förening ändras account en klorförening enligt den allmänna formuleln H o J? - (XVI) o COOR "" i vilken formulas X, R '', och R '' '' avser decamma som ovan, vilken förening ändras till phosphorus, all of which may be of the form ^ —TTX} - ^ ° <XI) | prh3 COOR ”in formula X, R '' ', and R *' '' are selected from the group consisting of ozone compounds of formula (I) or (b) in the form of ozone compounds selective account in the case of all formulas (0) R "'Il \ _x II (V) sr N' ~~~ Fo 0 COOR 751 63 37 i vilken formula n = l och X, Y, R och R '' ' if a solid is formed, then the reduction of the sedan to the corresponding formula (V), n = 0, to the hydrolysis to the formation of the formula I (0) R · II S, ^ i to the formula X, Y, R and R '' 'are separated from the octane and n = 0, the first ring is reacted with an ester of an enriched glioxyl salt, the formula is CHOCOOR' '' 'for R' '' ' in the case of the formula (0) _ I _., I (VII) -γΜΙΗ Y COOR "" for X, Y, R '' 'and R' '*' avser decamma som ovan och n = 0, vilken förening ändras to clear, stem formula is (D) n R "· \ (VIII) COOR” ”