DK159448B - METHOD OF ANALOGUE FOR PREPARING PENEMCARBOXYLIC ACIDS OR ESTERS THEREOF - Google Patents

Description

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DK 159448 B

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The present invention relates to an analogous process for the preparation of novel penem carboxylic acids or esters thereof having a 5R configuration and of the general formula 5R "<" ^ CH2Z "JN-u COOR" 10 where R "" is hydrogen, lower alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitro-phenyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl or phthalidyl or a group of the formula -CH-0C00CoHc or -CHo-NHCO 'CH3 Z is carbamoyloxy, a pyridinium group or a group of the formula OCOR' or SR ", where R 'is lower alkyl and R" is 5- methyl-1,3,4-thiadiazol-2-yl, 1-methyl -tetrazol-5-yl, 1,2,3-triazol-5-yl or pyrazinyl, and R "'is 1-hydroxyethyl, 1- (p-nitrobenzyloxycarbonyloxy) ethyl or 1- (dimethyl tert) butylsilyloxy) ethyl, or a pharmaceutically acceptable salt thereof, which is characterized by the characterizing part of claim 1.

In the compounds of formula I, the substituent at the 6-position can be in both α and β configuration, with the α configuration being preferred.

Compounds which are closely related to the compounds of formula I and which are antibacterially active are known from EP 636, DE 2,819,655 and US 4,155,912.

The compounds of formula I also have a broad spectrum of antibacterial activity but, in contrast to the known compounds, exhibit β-lactamase inhibitory activity and therefore have a good action against bacteria that form β-lactamases.

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It is noted that the stereochemistry at the C C atom in the compounds produced by the process of the invention, as well as in all intermediates formed in their preparation, is the same as in naturally occurring penicillins and cephalosporins.

Pharmaceutically acceptable salts of penem carboxylic acids of formula I such as sodium, potassium, benzathine, procaine and the like salts commonly formed with penicillins and cephalosporins can also be prepared by the process of the invention.

The compounds can be used in pharmaceutically acceptable compositions containing the compounds mixed with conventional carriers for oral and parenteral administration.

The following diagram illustrates the preparation of the compounds of formula I by the process of the invention.

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3

0 S * O

1 $ i! IN

CAJ \ γ * γ_R "\ i“ V · ',

, COOR H # ^ '' COOR T

; (II) COOR

(III), * (IV) / \ Y_RS- | ^ S \ j-x I »J-k ^ S o ^ yk \

/ \ (V) COOR COOR

'gr \ (XII) ^ / V ------ 1_ \ f N' / 1 * o ir '·' - ° if C00Rin \

U H COOR H (y) n V

R \ _fsy ^ x RS_f ^ sVx N \ 0 ^ ~ Νγ0 °

, CQOR

'(VI)' 'Λ. (XIII)

* in I

arrow in H R1 "\ _ '" i_f ^ Yx y— ^ K o ^ ~ n \ h ° COOR "" (VID (XIV) v Ί'

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4 (VII) (XIV) (O) I n R \ _

-1KSV2KY J N ^ -OH

COOR "" COOR "" (VIII) (XV) O '' R "'- 1 x R" \

ΙνγννΓί WT

"J— COOR" "COOR" "(X) ^ / (IX) (XVI) β /. \ / y ...

R "'r"' ~ R "'γ_ ^ 5 · γ'χ \ _ \ ____ ί ^ 5χ ^ χ

o -> I <- N I

J N \ _ —N— \ J * —N \ _ CT J = PPh3 ^ COOR "" 0 ^ | = PPh3 COOR "" 'COOR' "(XI) \ I) (XI)}

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When R "is lower hydroxyalkyl, the group R" may be introduced by that of Di Ninno et al. disclosed in the Journal of Organic Chemistry 42, 2960 (1977).

On the other hand, compounds of formula II, wherein R R is hydrogen can be transferred to compounds of formula II wherein R "is lower hydroxyalkyl, with the substituent being introduced at the 6-position using a strong base, thus as shown in the following examples.

Compounds of formula II wherein R R is lower hydroxy-10 alkyl can also be prepared by starting from a suitable ester of the penicillanic acid S-oxide, as illustrated in the following examples. The substituent at the 6-position is directed stereospecifically on the 6a derivatives.

The ester of penicillanic acid S-oxide (II) (R is alkyl and R 5 has the above meaning) can be heated in an inert solvent such as benzene or toluene, usually at a temperature of 70-140 ° C, with a suitable acetylene derivative of formula X'C = CY, wherein X1 is a group of formula d ^ Z ', Z' being hydroxy, amino, carbamoyloxy or a group of formula OCOR ', and Y is hydrogen, lower alkyl, cyano or a group of the formula COOR or CJ 2 Z ', where R and Z' have the meanings given above, when X 'has a different meaning, it can be transferred to a group X of known X where X is a group of the formula CH ^ Z, where Z has the meaning given above.

Compound III can be isomerized with a base to Compound IV which can be transferred in two different ways to final Compound I. In the first method, Compound IV can be selectively ozonized by the isopropenyl double bond, yielding Compound V (n = 1) which can be reduced by suitable reducing agents such as phosphorus tribromide or sodium iodide in acetyl chloride to compound V (n = 0), which can then be hydrolyzed to compound VI (n = 0) under mild basic conditions or on silica gel. By condensation with a suitable ester of glyoxylic acid, the compound VII (n = 0) is obtained, which with a chlorinating agent such as thionyl chloride and pyridine

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can be transferred to the chlorine derivative (VIII) (n = 0) and then to the phosphorane IX (n = 0).

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

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

According to the second method, compound IV can be reduced under conventional conditions to compound XII, ozonized by both double bonds to give compound XIII and after hydrolysis compound XIV. According to the same method as described above, glyoxylation of the compound XIV gives the compound XV, which can be transferred to the chlorine derivative XVI and then to the phosphorane XI, which is a common intermediate in both methods.

When R "is hydroxyalkyl, the reaction sequence preferably occurs under the protection of the alcoholic function.

Compounds of formula I wherein R "" is hydrogen can be obtained by hydrolysis or hydrogenolysis of the "corresponding esterified compounds.

The following Table A shows how the choice of substituents affects the activity against bacteria. Thus, it is clear that the penem derivatives of the present invention are very active against the organism Escherichia coli TEM, a gram-negative strain that forms a particular β-lactamase enzyme which activates the tested compound described in DE 2,819,655. 35 US-4,155,912 and EP 636.

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TABLE A

R S X

v-1 Y (111)

N_L COOH

5 # -

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1) (5R, 6S) -2-acetoxymethyl-6- [1 (R) hydroxyethyl] -2-penem-3-carboxylic acid (III, R = CH3CHOH, X = CH3COOCH2 present invention).

2) (5R, 6S) -2 [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] -6- - [1 (R) -hydroxyethyl] -2-penem-3-carboxylic acid

N-N

(III, R = CH-CHCH, X = || \ -S-CH9, the present invention.

3) (5R, 6S) -2-carbamoyloxymethyl-6 [1 (R) hydroxyethyl] -2- -penem-3-carboxylic acid (III, R = CH 3 CHOH, X = EL , the present invention).

4) (5R, 6S) -2-methyl-2-penem-3-carboxylic acid.

(Ill, R = Η, X = CH 3, DE 2,819,655 Example 5; US 4,155,912 Example 5 and EP 636 Example 6).

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TABLE I; MIC Mg / ml

Tribe The present invention

12 3 4 5 a) Staphylococcus aureus Smith 0.04 0.01 0.04 1 b) "" 39/2 * 0.03 0.015 0.03 4 c) Diplococcus pneumoniae ATCC6301 0.04 0.006 0.015 0.5 d) Streptococcus pyogenes C 203 0.04 0.015 0.03 0.5 e) "faecalis ATCC6057 2.8 5.7 2 128 10 f) Escherichia coli 1507 0.5 0.17 0.5 16 g)" "TEM * 0 , 0.17 0.5> 128 h) Klebsiella aerogenes 1082 E * 1.4 0.35 0.7 128 i) "1522 E 0.5 0.25 0.5 16 j) Enterobacter cloacae P99 * 5 , 7 2.8 2.8 32

15 J

k) "" 1321 E 0.5 0.35 0.5 16 _ 1) Salmonella typhi Watson 0.5 0.125 0.5 16 m) Proteus vulgaris X 20 1 0.125 1> 128 η) "mirabilis ATCC 9921 1 0.125 2 8 o) Clostridium perfringens 2886A 0.5 0.25 0.25 p) Bacteroides fragilis ISM 75/42 0.7 0.25 0.5 ae and o: Gram-positive bacteria; fn and p: Gram-negative bacteria; O and p: anaerobic bacteria; * B-lactamase generators.

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The following examples serve to further elucidate the process of the invention.

Example 1 Methyl 6α- (11-hydroxyethyl) -penicillanate-S-oxide OH

c J H? IN

I-ch, <\ U-yiN-I - \ [6 | 5 2

10 -N - L · J-N-M

0 // COOCH- 07 4 / ^ cooCH, J H 3

A solution of 2.3 g of methylpenicillaninate S-oxide in 50 ml of anhydrous tetrahydrofuran is cooled to -78 ° C. Add lithium diisopropylamide (freshly prepared from 5 ml of di-isopropylamine and 20 ml of a 1.6 molar BuLi-hexane solution) dissolved in anhydrous tetrahydrofuran and the mixture is allowed to stand at -78 ° C for 10 minutes. 5 ml of acetaldehyde is added gradually and the mixture is stirred for 15 minutes. Then, the reaction mixture is diluted with a saturated aqueous NH 2 Cl solution, extracted with ethyl acetate, washed twice with water and dried over Na 2 SO 4. After evaporation of the solvent, the residue is briefly purified by column chromatography on silica gel eluting with dichloromethane / ethyl acetate (1: 1). Yield 1.5 g. The title compound consists of a 2: 3 mixture of epimers at the hydroxyl group carrying the carbonator with respect to NMR, the new Cg-Cg bond due to the stereospecificity of the reaction. under the conditions used are only in the α position.

NMR (CDClg): δ 1.27 (s, 3H, α-CHg), 1.40 (d, 3H, J = 5.7 Hz, CH3-CHOH) main isomer, 1.48 (d, 3H, J = 5.7 Hz, CH 3 -CHOH) only slightly isomer, 1.70 (s, 3H, 0-CH 3), 3.4-3.8 (m, 1H, H-6), 3.80 (s, 3H, C00CH3), 4.1-4.7 (m, 1H, CHOH), 4.50 (s, 1H, H-3), 4.98 (d, J = 1.9 Hz, 1H, H- 5), only slightly isomer, 5.05 (d, J = 1.9 Hz, 1H, H-5) main isomer.

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Example 2

Methyl 6- (1-hydroxyethyl) -3-penicillanate Off Off rOr ° N N cooch 3> N

To a solution of 2.2 g of methylpenicillanate in 30 ml of anhydrous tetrahydrofuran is added a small excess of lithium diisopropylamide at -78 ° C under nitrogen. An excess of acetaldehyde is added dropwise, the mixture is stirred for 5 minutes, cooled suddenly with traces of acetic acid, poured into water and extracted with methylene chloride. The organic layers are dried over Na 2 SO 4 and evaporated in vacuo to give 0.8 g of the title compound.

Example 3

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

OH 0C02PNB

25 µl-N__7V-J-0 H cooch3 h cooch3 1.2 g of methyl 6- (1-hydroxyethyl) -3-penicillanate are dissolved in 40 ml of tetrahydrofuran, cooled to -78 ° C and treated with 1 equivalent of butyllithium . 1.2 equivalents of p-nitrobenzyl-oxycarbonyl chloride are added to the mixture thus obtained. After 30 minutes at -78 ° C, the reaction mixture is left for 60 minutes at room temperature, poured into water and extracted with methylene chloride. After drying over ~ Na 2 SO 4 and evaporation, 1.4 g of the title compound are obtained.

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Example 4

Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate-S-oxide oco2pnb oco2pnb \ '- N - h, ^ N j * a if ^ COOCH-0 τΛ' COOCH,.

10 µg 1.8 g of Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate is dissolved in 50 ml of methylene chloride and treated at 0 ° C with 1.5 equivalent of m-chlorobenzoic acid. The organic phase is shaken with saturated NaHCO 3 solution, extracted, dried over Na 2 SO 4 and evaporated. 1.4 g of the expected sulfoxide are obtained.

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

25 0C02PNB II ° C02PNBU

Vι V _> 1 — N H JlV / OCOCHj '0 H' COOCH3 O ^ H 'COOCH3 30

A solution of 2.0 g of methyl 6- (1-p-nitrobenzyl-oxycarbonyloxyethyl) -3-penicillanate S-oxide and 2.4 g of butin diol diacetate in 50 ml of toluene is refluxed for 24 hours. The compound is then purified by column chromatography eluting with 9: 1 dichloromethane / ethyl acetate. 1.1 g of the title compound are obtained.

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Example 6 43-Vinylthio- (1/2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonylethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidine-2-one-S-oxide 5 O 0 oco2pnb Jj oco2pnb ii> X _- ^ sY ^ ococh3 Αγγ8 Y ^ JCOCHj 10 JI1 \ L ^ 0CO0CH3 'oJ-N ^^ OCOCH3 ° IT "C00CH3 COOCH3 1.3 g ) -3- (1-p-15-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide is dissolved in 80 ml of dichloromethane. 3 ml of triethylamine and the mixture is left at room temperature for 2 hours, after evaporation of the solvent the pure compound as mentioned in the title is obtained in quantitative yield.

Example 7 48-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one-S-oxide 0 ° COCOPNPN || oco2pnb | j oJ_Ny \ .L.OCOCH3 3 COOCH3 - COOCH3

A solution of 1.1 g of 4 (3-vinylthio- (1,2-diacetoxy-methyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxy-carbonyl-2-methyl-1-propenyl) - azetidine-2-one S-oxide in 100 ml of dichloromethane is cooled to -78 ° C. Ozone in oxygen is blown through until blue coloration occurs.

Bl No. 586

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with an aqueous Na2 SO2 solution and dried over Na2 SO4. After evaporation, 0.5 g of the title compound is obtained.

Example 8 43-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one o 10 'OCO2PNB | oco2pnbJ x-ococh3 —ζS v''yj ^ ococH3. never OCOCH, * No. OCOCH-

NyU 3 ^ 3 15 cooch3 COOCHj

A solution of 0.8 g of 43 "vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one in 15 ml of anhydrous dimethylformamide is cooled to 20 ° C and 0.6 ml of phosphorus tribromide is added. After 10 minutes, the reaction mixture is diluted with ethyl acetate and washed twice with a NaHCO 3 solution. The organic phase is dried over Na 2 SO 4 and evaporated to give 0.4 g of the reduced compound.

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Example 9 43-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarboxyloxyethyl) -azetidin-2-one oco2pnb and 2pnb AV "Y ^ OCOCH3 _ -Nv ^ 3 ϋ I oh 35 COOCH3 bi ·, '<hm

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1.2 g of 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one is dissolved in methanol and 2 g of silica gel is added to the solution. After 60 minutes, the insoluble material is filtered off and the organic phase is evaporated. Short column chromatography gives 0.4 g of the title compound.

Example 10 43-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonylloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one

0COoPNB

oco2pnb X S

15 A_i ^ S "^ Y ^ VOCOCHq —f ° c0? H3: 1 I nnnrn * I» I ^ OCOCH, 1_n ^ i ^ OCOCH3 # -Ν> γθ ^ 3

</ Η ° I

COOCH2OCOCH3 20 g of 43-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one dissolved in 30 ml of benzene and 0.6 g of acetoxymethylglyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate) is kept at reflux. The reaction is completed after 2 hours. The condensation product can be used for the next step without further purification. ~ —----

Example 11 43-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyl-oxyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one oko2pnb oco2pnb / Np- '^ 1 ^ vOCOCH3 A f' ^ f | NOCOCH3 35 ----- ^ U - OCOCH- * I_M} l ___ OCOCH- • k 3 4 Ν \ ν € ΐ ^ 3 <fror COOCH2OCOCH3 COOCH2OCOCH3

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0.5 g of 4β-vinylthio- (1,2-diacetoxymethyl) -3- (1β-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one is dissolved in 12 ml of anhydrous tetrahydrofuran and cooled to 0 ° C. 1.1 equivalents of pyridine and 1.1 asq valent thionyl chloride are added. The mixture is stirred for 10 minutes. The insoluble material is filtered off and the solution is evaporated at room temperature to give the title compound in almost quantitative yield. The product can be used for the next step without further 10 cleaning.

Example 12 4β-νΐηγ1ί3ιϊο- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one ocg 2 - | ^ S "'Y' ^ OCOCHj _" 'Trp ^ COCHj 20 oJ— NyC! ^ 0 «^ * J — Nv ^ pp ^ OCOCHs COOCH2OCOCH3 COOCH2OCOCH3

A solution of 0.760 g of 43-vinylthio- (1,2-diacetoxy-methyl) -3- (1-p-nitrobenzoyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one 10 ml of tetrahydrofuran and 10 ml of dioxane are stirred with 2 equivalents of triphenylphosphine and 1.1 equivalent of pyridine overnight at 50 ° C. The phosphorane is purified by column chromatography on silica gel eluting with 70:30 dichloromethane / ethyl acetate. 0.480 g of the title compound is obtained.

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Example 13 43-Acetylyocoylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -azetidin-2-one

0C0oPNB OCO PNB

c. i ώ g y.

. ^^ ococh3 ococh3 J_N ^ fh ^ 0C0CH3 ~ * J-Νγρ ^ 10. COOCH2OCOCH3 COOCH2OCOCH3 0.45 g of 43-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (acetoxymethyloxycarbonyl-1-triphenylphosphoranylidene methyl) -azetidin-2-one is dissolved in 15 ml. dichloromethane and cooled to -20 ° C. 30 ml of a solution of trifluoroacetic acid in dichloromethane are added.

After a few minutes, ozone in oxygen is blown through until a slight blue stain occurs. The reaction is quenched and a few drops of trimethyl phosphite are added.

The organic phase is washed with saturated NaHCO 3 solution and dried over Na 2 SO 4. 0.260 g of the title compound is obtained.

Example 14 43-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one

O OCO0PNB

oco2pnb 11, 2 30 i ^^ OCOCH ^ f 0C ° CH3

Liy. 35 - 1.5 g of vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-pro-cyclone) penyl) -azetidine-a-one S-oxide is dissolved in 10 ml of anhydrous dimethyl acid.

* «6tK

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formamide and cool to -20 ° C. Phosphorus tribromide 0.8 ml is added, the mixture is stirred for 10 minutes, diluted with ethyl acetate and washed twice with saturated NaHCO 3 solution. The organic layer is dried over Na 2 SO 4 and evaporated to give 1.1 g of the title compound.

Example 15 43-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxalyl-azetidin-2-one 10 COCO2PNB · OCO2PNB, - ^ OCOCH, ^> Υ5Ύ ^ 0 (: 0 (: Η3NN ^ JCOO °) 1.4 g of 43-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-20-propenyl) ) -acetidin-2-one in 120 ml of dichloromethane is cooled to -78 ° C. Ozone is blown in oxygen until a blue stain occurs. The solution is shaken with aqueous Na2S2O4 solution and dried over 11 SO2. 0.8 g of the title compound are obtained.

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Example 16 43-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one OCO "PNB? C02PNB ^ ^ o oococe3 _ Y Y Y <36 35

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Dissolve 0.800 g of 43-acetylglycolylthio-3- (1-p-nirobenzyloxy-carbonyloxyethyl) -1-methoxyoxalyl-azetidin-2-one in 50 ml of methanol and add a few g of silica gel. The mixture is allowed to stand for 60 minutes at room temperature, the insoluble material is filtered off and, after evaporation, the filtrate gives 0.300 g of the title compound.

Example 17 43-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -10-1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one oco2pnb oco2pnb ^ ococh3) -1% NCOCH3 0.5 g of 43-acetylglycolylthio-3- (1-p-nitrobenzyloxy-carbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl-acetyl) -acetidine 2-one and 0.5 g of acetoxymethylglyoxylate in 30 ml of benzene are kept at reflux until the reaction is complete (2 hours). The compound obtained is the one mentioned in the heading and can be used for the next step without further purification.

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Example 18 43-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-aethoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one oco2pnb ° co2pnb 'Ίί "~' 0CO0 '' OCOCH,

'O -f' o J

C00CHo0C0CH-

2 3 COOCH OCOCHL

35 ....... 2. 3 I r ·· 566

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0.35 g of 4β-acetylglycolylthio-3- (1-p-nitrobenzyl-oxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxy-methyl) -azetidin-2-one is dissolved in 10 ml of anhydrous tetrahydrofuran at 0 ° C. 1.1 equivalents of pyridine and 1.1 equivalents of thionyl chloride are added. The mixture is stirred for 10 minutes. The precipitate is filtered off and the filtrate gives, after evaporation, the title compound in quantitative yield. The raw product can be used as it is for the next step.

Example 19 4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidene methyl) -azetidin-2-one OGO ^ PMB OCC ^ PNB, A COOCH2OCOCH3 COOCH2OCOCH3 0.400 g of 43-acetylglycolylthio-3- (1-nitrobenzyloxy-carbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-2-chloromethyl) dissolve in 20 ml of a 1: 1 mixture of tetrahydrofuran and dioxane. 2 equivalents of triphenylphosphine and 1.1 equivalent of pyridine are added and the mixture is stirred overnight at 50 ° C. The title compound is purified by column chromatography on silica gel eluting with 70:30 dichloromethane / ethyl acetate. 0.280 g of the phosphorus is obtained.

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Example 20 (5R) -Acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2 '-acetoxymethyl-2-penem-3-carboxylate 5' '' oco2pnb oco2pnb ^ 'X ^ N | - OCOCH3 _f ^^^ OCOCi ^ i Nv-s-PPh ,, -N-. . ci in '0 COOCH 2 OCOCH 3 7 ml of two caps and the solution is kept at reflux for 2 hours.

Purification by short column chromatography eluting with 95: 5 dichloromethane / ethyl acetate gives 0.050 g of the title compound.

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Example 21 (5R) -Acetoxymethyl-5- (1-hydroxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate

• 0C02PNB - OH

f 3 COCH 3 _Y 2 OCOCH 2 iNL} -N-O COOCH 2 OCOCH 3 CO 2 CHOCOC 3 30 '· 560 g of 5R-acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate is poured into a mixture of water, ethanol and K 2 HPO 4 and hydrogenolysed with 10% palladium on charcoal. A rapid purification by column chromatography on silica gel gives 0.015 g of the title compound.

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Proceeding as in the previous examples, but instead of 1-methyl-5-thiotetrazole, 5-methyl-2-thiol-1,3,4-thiadiazole, 5-thiol-1,2,3-triazole are used. or thio-pyrazine is obtained (5R) -6- (11-hydroxyethyl) -2 - [(5 "-methyl-1", 3 ", 4" -5-thiadiazol-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) -6-6- (1'-hydroxyethyl) -2- (pyrazinyl) -thiomethyl-2-penem-3-carboxylic acid.

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Example 22 4β- (1-Hydroxymethyl) -vinylthio-3a- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -1- (1-methoxycarbonyl-2-ethyl-2-propenyl) -azetidine-2-one-S-oxide (reaction II-III) 5 0C0 PNB 0 Γ 2 5? ·? C02pnb ii

A AA

- »YES Λ 10. / \ 0 yy H COOCS3 / COOCH3.

A solution of 2.6 g of methyl 6- (1-p-nitrobenzyloxy-carbonyloxyethyl) -3-penicillinate S-oxide and 8 ml of propargyl alcohol in 20 ml of toluene is refluxed under nitrogen for 40 hours.

After evaporation of the solvent, the residual compound is purified by chromatography on a silica gel column eluting with dichloromethane / ethyl acetate in a ratio of 9: 1 to give 2.0 g of the title compound.

Example 23 4β- (1-Hydroxymethyl) -vinylthio-3α- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidine-25-2-one-S oxide (reaction III-IV) oco2pnb o "oco2pnb °

/ ^ S'Y ^ 'OH A-, OH

J-7N. * N

2.0 g of 4β- (1-hydroxymethyl) -vinylthio-3α- (1-p-nitro-benzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidine-2-one S-oxide dissolved in 50 ml of dichloromethane is left at room temperature in the presence of a few drops of triethylamine for 12 hours. After evaporation of the solvent, the pure compound mentioned in the title is obtained in quantitative yield.

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Example 24 4β- (1-Bromomethyl) -vinylthio-3α- (1β-nitrobenzyloxycarbonyloxy-ethyl) -1 "(1-methoxycarbonyl-2-methyl-1-propenyl) -azetidine-2 -one (Reaction IV-XII) oco2? nb ^ oco2pnb Χ .__ χν "0Η λ" τ- ^ '10' COOCH ^ COOCH3 3 Dissolve 2.0 g of the compound of Example 23 in 50 ml of dimethylformamide. At -20 ° C, 0.7 ml of pyridine and 3.2 ml of PBr3 are added and the reaction mixture is stirred for 15 minutes, ethyl acetate is added to the mixture and the organic phase is shaken with a NaHCO 4 saturated solution, washed with water and finally dried over Na 2 SO 4 · After evaporation of the solvent, 1.7 g of the title compound is obtained.

20

Example 25 4β- [1- (5-Methyl-1-3,4-thiadiazol-2-yl) -thiomethyl] -vinylthio-3α- (1-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1 -propenyl) -acetidin-2-one 25

oco2pnb oco2pnb N — N

). X-S_ ^ CH3 I in J_IV X- 30 J N f cooch3 cooch3 1.8 g of the compound of Example 24 are dissolved in 30 ml of tetrahydrofuran. The resulting solution is cooled to 0 ° C, 1.1 g of 5-methyl-1,3,4-thiadiazole-2-thiol sodium salt is added and the mixture is stirred for 4 hours. After filtering off insoluble substances, dilute 0 24

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the residual solution with ethyl acetate, washed with water, dried over Na 2 SO 4 and evaporated. 2 g of the title compound are obtained.

Example 26 43 ~ [1- (1,2,3-Triazol-5-yl) -thiomethyl] -vinylthio-3 (x- (1-p-nitro-benzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2- methyl-l-propenyl) azetidin-2-one

OCO_PNB OCO-PNB f— N

10 A. A ^ s-AJ

] -} *. H1 H

0 ^ Ϋ ~ ^ 0 ^ “V" COOCH- COOCH3 15 * w

Starting from 2.5 g of the compound prepared in Example 24 and in the others proceeding as described in Example 25 but using 1,2,3-triazole-5-thio sodium salt, 2.2 g of the mentioned in the title.

20

Example 27 43- [1- (5-Methyl-1,3,4-thiadiazol-2-yl)] -thioacetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxy-oxaloyl-azetidin-2-one

oco2pnb «n oco2pnb N — N

2 g of the compound of Example 25 are dissolved in 250 ml of dichloromethane and cooled to -78 ° C. An ozonized oxygen stream is bubbled through solution until a blue color is obtained. A few drops of P (OCH 2) 2 are added to the solution and the temperature of the mixture is allowed to rise to room temperature. The mixture is evaporated to give 1.5 g of the title compound

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Example 28 4β- [1- (1,2,3-Triazol-5-yl)] - thioacetylthio-3α- (1-p-nitrobenzyl-oxycarbonyloxyethyl) -1-methoxy-oxaloyl-azetidin-2-one (Reaction XII -XIII) 5

_m OCO-PNB -N

OCO-PNB h fj, 2 I tf I_N · J X Nn // Nr = o 10 O I 0 'cooch3 cooch3

Starting from 1.6 g of the compound of Example 26 and otherwise proceeding as described in Example 27, 1.1 g of the title compound is obtained.

Example 29 4β- [1- (5-Methyl-1,3,4-thiadiazol-2-yl)] -thioacetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one (Reaction XIII-XIV ) pC02PUB, NN 0C02PNB „Ά ·. ·,

• I

COOCH 3 1.5 g of the compound of Example 27 are dissolved in a mixture of methanol and ethyl acetate in a ratio of 1: 1. A few g of silica gel is added and the mixture is kept at room temperature with vigorous stirring. After filtration of the silica gel, the filtrate is evaporated to give an oil which is chromatographed on silica gel with 8: 2 dichloromethane / ethyl acetate to give 0.9 g of the pure compound mentioned above.

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Example 30 4β- [1- (1,2,3-Triazol-5-yl)] - thioacetylthio-3α- (1-p-nitrobenzyl-oxycarbonyloxyethyl) -azetidin-2-one (Reaction XIII-XIV) 5, - cf m. | -I | / "^ fsy" S-VN_ ^ sr ^ s ^

1 O H * I o H

A-N L-N

0 ^ \

1 OH

COOCH3

Starting from 1/1 g of the compound prepared in Example 28 and otherwise proceeding as described in Example 29, 0.6 g of the title compound is obtained.

15

Example 31 43- [1- (5-Methyl-1,3,4-thiadiazol-2-yl)] - thioacetylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-hydroxymethyl) -acetidin-2-one (Reaction XIV-XV) OCO2PNB - N- OCO2PNB || N

I \ I *> J

L-A A> J-n °

i ° X V H 0 '' 'y'OH

COOCH 2 COCH 3 0.9 g of the compound of Example 29 is dissolved in 40 ml of benzene, 0.6 g of acetonylglyoxylate is added, and the resulting solution is refluxed for 3 hours. After evaporation of the solvent, the crude oil is used for the next step without further purification.

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Example 32 4β- [1- (1,2 yl-Triazol-5-yl)] - thioacetylthio-3α- (1-p-nitrobenzyl-oxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-hydroxymethyl) -azetidine 2-on 5 (Reaction XIV-XV) 0CO2pnb '| j ff ri ^ 10 0 H o "- η x 1 ° H CGOCH

Starting from 0.6 g of the compound prepared in Example 30 and otherwise proceeding as described in Example 31, 0.7 g of the title compound is obtained.

Example 33 4β- [1- (5-Methyl-1,3,4-thiadiazol-2-yl)] - thloacetylthio-3α- (1-p-20-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1- chloromethyl) -acetidin-2-one (Reaction XV-XVI)

0C02PNB N-N. OCO-PNB JN-N

, il l | I 2. i il

^ ch3 / V

25 1 o -Ί i O

i-N 1_N

O Y ^ OH oX | * ^ C1 COGCH2COCH3 cooch2coch3

The crude oil prepared in Example 31 is dissolved in 30 ml of anhydrous tetrahydrofuran and cooled to 0 ° C. Equimolar amounts of pyridine and thionyl chloride are added to the solution until the starting material disappears. After filtration of insoluble material, the filtrate is used immediately for the next step.

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Example 34 4g- [1- (1,2,3-Triazol-5-yl)] -thloacetylthio-3a (1-nitrobenzyl-oxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-chloromethyl) -azetidine-2 -on 5 (Reaction XV-XVI) -N OCO-PNB f cf 10 I o HI 0

X_N in -N

07 O * OH OY ^ 1 * COOCH-COCH-, COOCH2COCH3 2 3 15 Starting from 0.7 g of the compound of Example 32 and otherwise proceeding as described in Example 31, the crude chlorine derivative is obtained . The product is used for the next step without further purification.

Example 35 4β- [1- (5-Methyl-1,3,4-thiadiazol-2-yl) 3-thioacetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1- triphenylphosphoranylidene methyl) -azetidin-2-one (Reaction XVI-XI) OCO.PNB wN OC02PNB - «J Γ H i Γ \ 's-sJ-cn3 ^ CH3

J_Η 0 ->) _N

30 r / 'V'-Cl cr V ^ PPh., I i cooch2coch3 cooch2coch3

The crude product prepared in Example 33 is dissolved in 20 ml of tetrahydrofuran, 700 mg of triphenylphosphine and 0.35 ml of pyridine are added, and the resulting solution is heated under nitrogen at 70 ° C for a few hours. The title phosphorus was purified on silica gel eluting with dichloromethane / ethyl acetate (1: 1) and obtained in a yield of 0.6 g.

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Example 36 - ["E1" (1'2 / 3-Triazol-5-yl)] - thioacetylthio-3- (1-p-nitrobenzyl-Q.xYcar®-nyloxyethyl) -1- (1-acetonyloxycarbonyloxyethyl-1-tri -E (enylphosphoranylidene methyl) -azetidine-2-one 5 (Reaction XVI-XVI I) 0CO2PNB j N OCO-PNB jj ^ λ. XJ. k TJ i · '-rzfl 1

10 Λ \ J-N

o XJ-C1 q / \ ^ pph3 I COOCH2COCH3 COOCH2COCH3

Starting from the crude chlorine derivative prepared in Example 34 and otherwise proceeding as described in Example 35, 0.55 g of the title compound is obtained.

Example 37 (5R) -Acetonyl-2 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl] -20-6a- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-penem-3- carboxylate (Reaction XI-I)

OCCUPNB N N

I 2 I I oco2pnb .n— »

S CH l U JJ

j Γ o -> 1-N 1 Γ [| 0.6 g of the compound of Example 35 is dissolved in 50 ml of toluene and refluxed under nitrogen for 3 hours. The title compound is purified by short column chromatography on silica gel eluting with dichloromethane / ethyl acetate in a ratio of 8: 2. 0.25 g of the title compound is obtained.

IR: 1795, 1750, 1720 cm -1.

0 30

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Example 38 (5R) -Acetonyl ~ 2- [(1 / 2,3-triazol-5-yl) thyl] -6 et- (ip-nitrobenzyloxy carbonyloxy e thy 11 -2-penem-3-oη) ^ οχγΐ at (Reaction XI-I) 5 oco2pnb oco2pnb 1-¾ Y______? _Y \ tj ° h ^ tir Y “Q ^ V- PPh, 'i'- \ 10 1 3 0 C00CH-C0CH-cooch2coch3 zj

Starting from 0.45 g of the compound prepared in Example 36 and otherwise proceeding as described in Example 37, 0.180 g of the title compound is obtained.

IR: 1795, 1750, 1720 cm -1.

Example 39 (5R) -acetonyl-2 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl] -20 - (1-hydroxyethyl) -2-penem-3-carboxylate (Reaction I )

r "'.π. X

0,450 g of the compound prepared in Example 37 is dissolved in 25 ml of acetonitrile containing a few drops of ethanol and hydrogenated over 400 mg of 10% Pd on carbon. The catalyst is removed by filtration and the filtrate is chromatographed on silica gel eluting with dichloromethane / ethyl acetate in a 7: 3 ratio to give 0.18 g of the title compound.

IR: 3605, 1795, 1745, 1720 cm -1.

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Example 40 (5R) -Acetonyl-2 - [(1,2,3-triazol-5-yl) -thiomethyl] -6a- (1-hydroxyethyl) -2-penem-3-carboxylate (Reaction I) pco2pnb . 17-¾ T Π J ^ Å * .J = Ml 'X COOCHoCOCH o COOCH-COCH ·.

10 o ί λ 2 3

Starting from 0.380 g of the compound prepared in Example 38 and otherwise proceeding as in Example 39, 0.12 g of the title compound is obtained.

IR: 3610, 1795, 1750, 1720 cm ”1.

Example 41 (5R) -2 [(5-Methyl-1,3,4-thiadiazol-2-yl) -thiomethyl] -62- (1-hydroxyethyl) -2-penem-3-carboxylic acid (Reaction I ) f π τ ri

\ _ / s * S s CH '"v AS / nsA

'3 xv ch.

i-i i ^ 'i-r I 3 25 _N __ ^ -z? 1_ft

QX COOCH2COCH-3 o COOH

A solution of 0.200 g of the compound of Example 39 in 30 ml of acetonitrile containing a few drops of water is cooled to 0 ° C and 5 ml of 0.1N NaOH solution is added under nitrogen, and the solution is stirred for 10 minutes. minutes. The alkaline mixture is extracted twice with methylene chloride, acidified with a 10% aqueous citric acid solution and extracted twice again with methylene chloride. The 35 combined organic phases are dried over Na 2 SO 4 and evaporated to give 0.110 g of the title compound.

IR: 3500, 1795, 1665 cm -1.

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Example 42 (5R) -2 - [(1,2,3-Triazol-5-yl) -thiomethyl] -6a- (1-hydroxyethyl) -2-penem-3-carboxylic acid (Reaction 1) 5 'H Π jr π I — i I Ί— Y k

—K «—Y

10 o COOCH2COCH3 O ^ COOH

Starting from 0.25 g of the compound prepared in Example 40 and otherwise proceeding as described in Example 41, 0.135 g of the title compound is obtained.

IR: 3490, 1795, 1660 cm ”1.

Example 43 4β- (1-Carbamoyloxymethyl) -vinylthio-3a- (1-p-nitrobenzyloxycarbonylloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one-S oxide (Reaction IV-V) OCO-PNB OC0-PN3! CO₂CH i COOCH3 2.2 g of the compound 30 of Example 23 are dissolved in 30 ml of acetonitrile and cooled at 0 ° C. ° C. Then 0.8 ml of chlorosulphonyl isocyanate is added under nitrogen and the mixture is stirred for 2 hours. The reaction mixture is poured into a saturated NaHCO 3 solution, stirred for a few minutes, and then extracted with ethyl acetate. After drying over Na 2 SO 4, evaporation of the solvent gives 1.5 g of the title compound.

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Example 44 4β- (1-Carbamoyloxymethyl) -vinylthio-3- (1-p-nitrobenzyloxycarbonylloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one (Reaction IV-XII)

OCO-PNB n 0C0oPNB

.2 γ I 2 y ^ QCONH2 / OCOm2 ~~ \ t «- ^ '] i 10 // - 0 VCOOCH3 0 COOCHj

Starting from 1.7 g of the compound prepared in Example 43 and otherwise proceeding as described in Example 24, 1.4 g of the title compound is obtained.

Example 45 4β- (1-Carbamoyloxy) -acetylthio-3α- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -1-methoxyoxaloyl-azetidin-2-one (Reaction XII-XIII) OCO 2 NB in 2 R / OCONH > -oconh2 i-2 _li JN 0 25 ^ o ^ -> 0 C00CH3 COOCH3

Starting from 2.2 g of the compound of Example 44 and otherwise proceeding as described in Example 27, 1.4 g of the title compound is obtained.

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Example 46 4β- (1-Carbamoyloxy) -acetylthio-300- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -azetidin-2-one (Reaction XIII-XIV) oco2pnb. oco2pnb

S '^ S ^ / ^ 0C0NHo I

'i-11 2 A_ * I O _. \ ^ if OCONH ,. Λν_. '· ·

I. ° H

COOCH 3

Starting from 1/4 g of the compound of Example 45 and otherwise proceeding as described in Example 29, 0.9 g of the title compound is obtained.

Example 47 4β- (1-Carbamoyloxy) -acetylthio-3a- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -1- (1-acetonyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one (Reaction XIV-XV) oco2 ? nb oco2pnb

L Λ / ^ OCONH

25 A_ ^ S ^ / N3CONH2 V_XSV 2 I i 0 ^ · l 0 0Mh * • COOCH2COCH3 30 Starting from 0.9 g of the compound of Example 46 and 0.6 g of acetonylglyoxylate and otherwise proceeding as described in Example 31, the crude carbinolamide is obtained.

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Example 48 43- (1-Carbamoyloxyl-acetylthio-Ba- (1-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-chloromethyl) -azetidin-2-one (Reaction XV-XVI) oco2pnb oco2pnb OCONHj 'you ° ->' IZj. «F Ύ · ° Η y yci 1 ° COOCHjCOCIIj cooch2coch3

Starting from the crude product prepared in Example 47 and otherwise proceeding as described in Example 33, the crude chlorine derivative is obtained.

15

Example 49 4β- (1-Carbamoyloxy) -acetylthio-3α- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -1- (1-acetonyloxycarbonyl-1-triphenylphosphoranylidene-methyl-1) -azetidin-2-one (Reaction XVI- XI)

0C0-PN3 OCO-PNB

f 1 I 2 ^ X-OCONH2 ^ S QCONK2 N 0 ^] j 0 25 N '| = pph3 COOCH2COCH3 cooch2coch3

Starting from the crude product prepared in Example 48 and otherwise proceeding as described in Example 35, 0.40 g of the phosphorane is obtained.

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Example 50 (5R) -Acetonyl-2-carbamoyloxymethyl-6a- (1-p-nitrobenzyloxycarbonyl-yloxyethyl) -2-penem-3-carboxylate (Reaction XI-I)

5 0CO0PNB

1 Δ Qco2pnb 'vi ^ // ^ 0C0NH2 y / ^' 0C0m2 0 0 -> '' i 1 'll s— \. J— »- \ o p PPh3 0 V COOCH ^ CCa ^ 10 COOCH2COCH3

Starting from 0.4 g of the compound of Example 49 and otherwise proceeding as described in Example 37, 0.11 g of the title compound is obtained.

Example 51 (5R) -Acetonyl-2-carbamoyloxymethyl-6a- (1-hydroxyethyl) -2-penem-3-carboxylate (Reaction I)

C002PN3 OH

A, oc ° nh2 ocohh2 1 · T -> 1 · ii _N_J] _N_! I

25 ^ Ά Oy ^ COOCHoCOCH

o COOCH-COCH-. 2 I 2 3 i

Starting from 0.35 g of the compound of Example 50 and otherwise proceeding as described in Example 39, 0.11 g of the title compound is obtained.

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Example 52 (5R) -2 (Carhamoyloxymethyl) -6α- (1-Hydraxyethyl) -2β-penem-3-carboxylic acid (Reaction I)

OH PH

A. _ .S ^ / ^ OCONH., 'X ^ S ^ if / AXOCOM2

io 0 ^ \: ooch2coch3 ^ C00H

Starting from 0.11 g of the compound prepared in Example 51 and otherwise proceeding as described in Example 41, 0.060 g of the title compound is obtained.

IR: 3400-3500, 1795, 1700-1650 cm -1.

Example 53 (a) 43-Acetylglycolylthio-3- [1-p-nitrobenzyloxycarbonyloxyethyl] -1- [1-acetonyloxycarbonyl-1-hydroxymethyl3-azetidin-2-one (Reaction XIV-XV)

- OC02PNB

OCO PNB _I

I \ __ OCOCHj \ -j ^ S OCOCHj 1 °

26 0 J

^ ° 1 '0 H COOCH2COCH3

A solution of 1.04 g of 43-acetylglycolylthio-3- [1- [nitrobenzyloxycarbonyloxyethyl] -azetidin-2-one, prepared as Example 30, and 1.8 g of acetonylglyoxylate in 20 ml of benzene are refluxed for 4 hours. Evaporation of the solvent gives the crude compound mentioned in the heading which is used for the next step without further purification.

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(b) 4β-Acetylglycolylthio-3α- [1-p-nitrobenzyloxycarbonyloxyethyl] -1- [1-acetonyloxycarbonyl-1-chloromethyl] -azetidin-2-one oco2pnb '| co2pnb \ -ococh3 f ° cocn310 - * ° -N ^ OH ^ O 1 ° 1

, n COOCH-COCH, I

10 cooch2coch3

The crude carbinolamide obtained in step (a) is dissolved in 20 ml of anhydrous tetrahydrofuran and cooled to 0 ° C. Equimolar amounts of pyridine and thionyl chloride are added until all of the starting material has disappeared. The precipitate is filtered off and evaporation of the filtrate gives the title crude compound used in the next step without further purification.

(c) 4ft-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl] -1- [acetonyloxycarbonyl-1-triphenylphosphoranylidenemethyl] - 20-acetylidin-2-one (Reaction XVI-XI) · qqq IL - (- "S ^ S / ^ OCOCH," - \ (^ ° coch3 I 'i 1 0 - * J— «25 o * -V ^ C1 0 YPPh3 ^ COOCH2COCH3 COOCH2COCH3

The crude chlorine derivative is dissolved in 100 ml of methylene chloride. 1.5 g of triphenylphosphine and 10 g of silica gel are added and the solvent is evaporated in vacuo. The solid is left at room temperature overnight, poured into a column chromatograph and eluted with 1: 1 methylene / ethyl acetate to give 1.5 g of the title compound.

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(d) (5R) -Acetonyl-6a- [1-p-nitrobenzyloxycarbonyloxyethyl] -2-a-cetoxymethyl-2-penem-3-carboxylate (Reaction XI-I)

OCO „PNB QCO-PNB

I 2 I 2

5 -1, c> ·. -S "v. / V

1.5 g of 43-acetylglycolylthio-3- [1-p-nitrobenzyloxycarbonylloxyethyl] -1- [1-yl] ococH 2 - r, - \ - J - »- ^ SY = pph3 o COOCH2COCn3 acetonyloxycarbonyl-1-triphenylphosphoranyl-ideninethyl] -azetidin-2-one is dissolved in 50 ml of toluene and refluxed for three hours. Evaporation of the solvent gives an oil which is purified by short silica gel column chromatography, eluting with dichloromethane / ethyl acetate in a 9: 1 ratio. 0.51 g of the title compound is obtained.

Erythro PMR (CDCl3): 1.46 (d, J = 6.5 Hz, 3H, CH3CH), 2.07 (S, 3H, OCOCH3), 2.16 (s, 3H, COO3), 4.02 ( dd, J = 2.0, 4.0 Hz, 1H, H-6), 4.73 (s, 2H, CH 2 CO), 5.0-5.3 (m, 1H, CHO), 5.12, 5.38 (dd, J = 15.5 Hz, 2H, CH 2 OCO), 5.22 (s, 2H, COCEL₂Ph), 7.4- 8.5 (m, 4H, PhNCL ·).

IR (CHCl 3): 1725 cm C = 0 unsaturated esters, ketones, J -1 1750 cm C = 0 esters 1800 cm 2 C = 0 β-lactam 30 Threo PMR (CDC13): 1.45 (d, J = 6.0 Hz, 3H, CH 3 CH), 2.08 (s, 3H, COCH 3), 2.19 (s, 3H, COCH 3), 3.96 (dd, J = 2.0, 7.0 Hz, 1H , H-6), 4.77 (s, 2H, O 2 CO), 5.0-5.4 (m, 1H, CHO), 5.13, 5.42 (d, J = 16.0 Hz, CH2OCO), 5.25 (s, 2H, CH2Ph), 5.66 (d, J = 2.0 Hz, 1H, H-5) 7.4- 8.5 (m, 4H, PhNO

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40 0 _! IR (CHCl 3): 1725 cm C = 0 unsaturated esters, ketones, 3-1 1750 cm C = 0 esters 1800 cm 3 = 0 β-lactam Example 54 (5R) -Acetonyl-6 α- [1-hydroxyethyl ] -2-Acetoxymethyl-2-penem-3-carboxylate (Reaction I)

OH

OCOPNB

V-OCOCH3 - i-f OCOCH3 -> __n-L4-N

(y ^ COOCH2COCH3 · O COOCH2COCH

0.51 g (5R) -acetonyl-6a- [1-p-nitrobenzyloxycarbonyl-oxyethyl] -2-acetoxymethyl-2-penem-3-carboxylate, prepared as in Example 53, is dissolved in 60 ml of acetonitrile / 95%. s ethanol in a 1: 1 ratio. 0.46 g of 10% Pd / C is added and the mixture is stirred under hydrogen atmosphere for one hour. After filtration 20 of the catalyst, the filtrate is evaporated and the title compound is purified by column chromatography on silica gel eluting with dichloromethane / ethyl acetate in an 8: 2 ratio to give 0.20 g of pure product.

Erythro PMR (CDCl3): 1.38 (d, J = 6.5 Hz, 3H, CH3CH), 2.09 (s, 3H, OCOO3), 2.20 (s, 3H, COCH3), 3.86 (dd , J = 2.0, 4.0 Hz, 1H, H-6), 4.22 (dq, 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, O 2 OCO) 5.58 (d, J = 2.0 Hz, 1H, H-5)

Threo PMR (CDCl3): 1.32 (d, J = 6.5 Hz, 3H, CH-jCH), 2.10 (s, 3H, OCOCH3), 2.20 (s, 3H, COCH3), 3.06 (bs, 1H, OH), 3.74 (dd, J = 2.0, 7.0 Hz, 1H, H-6) 4.23 (m, 1H, CHOH),

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4.77 (s, 2H, CH 2 CO), 5.12, 5.38 (d, J = 16.0 Hz, 2H, OCO) 5.63 (d, J = 2.0 Hz, 1H, H 5).

Example 55 (5R) -2-Acetoxymethyl-6a- (1-hydroxyethyl) -2-penem-3-carboxylate sodium salt (Reaction I)

| H OH

'' '/ \ S'VY / ^ Ss ^ OCOCH- - ^ OCOCH3 -j j 3. n_k ^; _k: _iv V \ y X COONa 0 COOCH..COCH, ϋ 15 *. Λ 0.21 g (5R) -acetonyl-6a- [1-hydroxyethyl] -2-acetoxymethyl-2-penem-3-carboxylate, prepared as in Example 54, is dissolved in 30 ml of acetonitrile and 3 ml of water. The reaction mixture is cooled at 0 ° C under nitrogen and 7.4 ml 20 of a 0.1 N aqueous NaOH solution is slowly added over 30 minutes. After evaporation of acetonitrile in vacuo, the residue is extracted twice with cold ethyl acetate. A C g g reverse phase chromatography (elution with water) of the evaporated aqueous phase gives 0.054 g of the pure compound mentioned in the title.

Erythro PMR (D 2 O) 1.34 (d, J = 6.3 Hz, 3H, CH 2 CH), 80 °: 2.14 (s, 3H, OCOCH 3), 4.01 (m, 1H, H-6 ) 4.22 (m, 1H, CHOH), 5.10, 5.44 (d, J = 14.0 Hz, 2H, CH 2 OCO), 5.63 (d, J = 1.0 Hz, 1H, H-5) UV (95 Vs ethanol): max 262 nm (6 2000), 308 nm (6 2520).

[α] D = 128 (C = 0.92, H 2 O).

Threo 35 PMR (D 2 O): 1.31 (d, J = 6.5 Hz, 3H, CH 2 CH), 2.19 (s, 3H, OCOCH 3), 3.92 (dd, J = 1.5, 7, 0 Hz, 1H, H-6),

ISLAND

42

DK 159448 B

4.21 (m, 1H, CHOH), 5.10, 5.44 (d, J = 14.0 Hz, 2H, CH 2 OCO), 5.67 (d, J = 1.5 Hz, 1H, H 5).

U.V (95% ethanol): - max 262 nm (S 3410, 308 nm 5 (6 4340).

Example 56

Sodium (5R, 6S) -6- [1 (R) hydroxyethyl] -2 - [(Ι-methyl-1,2,3,4-tetrazole-5-yl) thiomethyl] -penem-3- Carboxylate 10 Starting from 2.5 g of the compound of Example 24 and otherwise proceeding as described in Examples 25, 27, 29, 31, 33, 35, 37 and 39 but using 1-methyl 1,2,3,4-tetrazole-5-thiol sodium salt instead of 5-methyl-1,3,4-thiadiazole-2-thiol sodium salt and using the resulting compound as described in Example 55, obtains 0 , 13 g of the title compound.

O.V. (H 2 O) * max: 315 nm NMR (D 2 O) δ ppm: 1.28 (3H, d, J = 6.3 Hz), 3.87 (1H, dd, J = 1.4, and 6.3 Hz) , 4.10 (3H, s), 4.19 (1H, m), 4.40 (2H, AE3, J = 16.0 Hz, internal line separation = 13 Hz), 5.59 (1H, d, J = 1.4 Hz).

25 30 35

Claims (3)

43 DK 159448 B PATENT CLAIM. An analogous process for the preparation of penem carboxylic acids or esters thereof having 5R configuration and of the general formula 5R "S" CH2Z γ YYJ - NX XCOOR "" 10 wherein R "" is hydrogen, lower alkyl, 2.2 , 2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitro-phenyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl or phthalidyl or a group of the formula -CH-OCOOC2H5 or CH3 -CH2 -NHCOOR "" wherein R 1, n 'is alkyl of 1 to 5 carbon atoms, Z is carbamoyloxy, a pyridinium group or a group of the formula OCOR' or SR ", wherein R 'is lower alkyl and R" 20 is 5-methyl -1,3,4-thiadiazol-2-yl, 1-methyl-tetrazol-5-yl, 1,2,3-triazol-5-yl or pyrazinyl, and R ”is 1-hydroxyethyl, 1- (p -nitrobenzyloxycarbonyloxy) -ethyl or 1- (dimethyl-tert-butylsilyloxy) -ethyl, or a pharmaceutically acceptable salt thereof, characterized in that a compound of the formula 0 JN-II 30 + COOR wherein R is alkyl and R "has the meaning given to formula I g is reacted with an acetylene derivative of formula X'C = CY where X 'is a group of formula CE ^ Z' wherein Z 'is halogen, hydrogen, hydroxy, amino, carbamoyloxy or a group of formula OR', OCOR ', NHCOR ', and Y is hydrogen, lower alkyl, cyano or a group of the formula COOR or C2 Z1, wherein R and Z' have the above meanings, to form a compound of formula 0 5 II RT __> Sv χ, III y-N \ il 0> 0 γ H * '' COOR 10 wherein R, R ", X1 and Y have the above-mentioned meaning, which compounds are then isomerized under basic conditions to a compound of formula 15 pH I y-1> s''vx ', I IV </ - * νΛγ 20. COOR wherein R, R "1, X 1 and Y have the meanings set forth above, where X 1, when it has a different meaning, can be transferred by means of a substitution reaction to X, which is a group of the formula CH 2 Z wherein Z has the meaning given above, after which a) the compound of formula IV is reduced to a compound of formula Wherein R "and X have the meaning set forth above, and are ozonized and hydrolyzed, which compounds then with a suitable ester of glyoxylic acid of the formula: R'V \ XIV J-V 0 O H No. 6B6 35 O 45 DK 159448 B CHOCOOR "" wherein R "has the meaning given above is reacted to form a compound of the formula 10 R "'W'V ^ N \ ^ v0Ii COOR "" wherein X, R "1 and R", M have the meanings set forth above, which compound is transferred to the chlorine derivative of the formula 20 R "1 \ xysv-x I xvi. -Cl COOR "" where X, R "and R" have the above meanings, which compound is converted to a phosphorane having the formula: Formula 30 of "N> Ph3 COOR" ir 606 35 O 46 DK 159448 B where X , R "1 and R" have the above meanings, which compound is finally cyclized to a compound of formula I, or b) the compound of formula IV is selectively ozonized to a compound of formula (0) E "<1 \ xxrx v 10 Ns> ° Y C00R where n is 1 and X, Y, R and R "1 have the above meanings, which compound is then reduced to a compound V, where n = 0, which compound is hydrolyzed to a compound having the formula (°) n I! Ύ _!> x VI J - v CT H * wherein X, Y and R "have the meanings set forth above, and n = 0 which is reacted with a suitable ester of glyoxyl acid of the formula CHOCOOR" "wherein R" has the above meaning to form a compound of the formula <°> n R \ _i> sV'x VI1 35 s Νγ '% COOR "" No. 606 O wherein X, Y, R' "and R" "have and n = 0, which compound is transferred to a chlorine derivative of the formula 5 K "In WVX In wine X y COOR" "10 where Y, Y, R" and R "have the meanings given above and n = 0 which compound is converted to a phosphorane of formula (O) | fn. R "'" Λ) = CX 0. j = PPh ^ Y COOR "" wherein R "1, R" ", X and Y have the meanings set forth above, the pH is phenyl and n = 0, which phosphoran is ozonized to a compound of the formula 25 r" 1 f-rr Cf] = PPh 3 COOR "" Where R ", R", X and pH have the meanings given above, which compound is finally cyclized to a compound of formula I, or c) a compound of formula IV is selectively ozonated to a compound of formula # 636 Wherein n = 1 and X, Y, R and R "1 have the above meanings, which compound is hydrolyzed to a compound of formula 10.. wherein X, Y and R "1 have the above meanings and n = 1, which compound is reacted with a suitable ester of glyoxyl acid of the formula CHOCOOR "" where R "" has the meaning given above, to a compound of the formula Tn 25 n ", II yrr / ~ ιγιΝ COOR" "30 wherein X, Y, R" 1 and R "" have the meanings given above and n = 1, which compound is transferred to a chlorine derivative of formula 31 ° (°> n II R "'II COOR" "where X, Y, R" and R "" have the above and n = 0, which chloro derivative is converted to a phosphorane of formula 10 (0) II n R "1 X \ Vs IX Y is COOR "" where R "1, R" ", X and Y are as defined above, pH is phenyl and n = 1, which phosphorane is then reduced to a compound of formula IX where n = 0, which compound ozonized to a compound of formula R ° XI Cf j = PPh3 COOR "" where R ", R", X and pH have the meanings set forth above, which compound is finally cyclized to form a compound of formula I. Process according to claim 1, characterized in that R "'is 1-hydroxyethyl. 35 No. SO6 50 DK 159443B Process according to claim 1, characterized in that the compound prepared is (5R) -2-acetoxymethyl-6- (1'-hydroxyethyl) -2-penem-3-carboxylic acid, (5R) --6- [ 1 * -hydroxyethyl] -2- [(1 "-methyl-1" - H-tetrazol-5 "- yl) -5-thiomethyl] -2-penem-3-carboxylic acid, (5R) -6- [ 1'-hydroxyethyl] -2 - [(5 "-methyl-1", 3 ", 4" -thiadiazol-2 "-yl) -thiomethyl] -2-penem-3-carboxylic acid or (5R) -6- [1'-hydroxyethyl] -2 - [(1 ", 2", 3 "-triazol-5" -yl) -thiomethyl] -2-penem-3-carboxylic acid, which lacks physical or biological data for this compound. 10.