DE3006273A1 - CONNECTIONS WITH BETA LACTAM DEVICES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM - Google Patents

Description

HOFFMANN · EITjLÜ <& PARTNEiR 3 Ö ö 6 2 7

PATEN TAN WALTE

DR. ING. E. HOFfMANN (1930 ^ 976) < DIPL.-f NG. W.EtTLE DR. RER. NAT. K. HOFFMANN ETf PL.-ING. W. LEHN

DIFL.-ING. K. FOCHSLE - DR. RER. NAT. B. HANSEN ARABELLASTRASSE 4 (STERNHAUS) ■ D-SOOO MÖNCHEN 81 · TELEFON (089) 9Π087. TELEX 05-2? ΊΤ9 (PATHEf

33 073 ü / wa

- 12 -

FARMITALIA CARLO ERBA SpA , MILAN / ITALY

Compounds with ß-lactam skeleton, method too their manufacture and pharmaceutical preparations containing them

The invention relates to compounds with a β-lactam structure, processes for their preparation and those containing them pharmaceutical preparations.

In particular, the invention relates to penem carboxylic acids the general formula

Ö & 003 6/0 713

COOR

, (D

where η = zero or 1, R ¹¹ "signifies hydrogen, lower alkyl, acetonyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl or benzhydryl or represents a radical, which is subject to a metabolic activation "in vivo" and has useful pharmacokinetic properties, e.g. acetoxymethyl, pivaloyloxymethyl, phthalidyl or a group of the formula -CH-OCOOC ₂ H ₅ or -CH ₂ KHCOR ¹ "",

CH ₃

where R "" ^{1 is} alkyl having 1 to 5 carbon atoms, cycloalkyl or aryl; Z is hydrogen, halogen, hydroxy, amino, carbamoyloxy, mercapto or a pyridinium group or a group of the formula OR ¹ , OCOR ¹ , NHCOR 'or SR ", where R ¹ and R" are each lower alkyl, aryl or a heterocyclic ring are each optionally substituted; and R " ^{1 is} hydrogen, lower alkyl, lower alkoxy, cycloalkyl or hydroxyalkyl, preferably hydroxy-lower alkyl, where the alcoholic function of the hydroxyalkyl group is free or protected and the protective group is preferably p-nitrobenzyloxycarbonyl or dimethyl-tert .butylsilyl is. The substitution of the 6-position has the c6-configuration like the ß-configuration. The o ^ configuration is to be preferred.

Examples of radicals for R "" of which are known is that they undergo inetabolic activation "in vivo" and useful pharmacokinetic properties

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are acetoxymethoxy, pivaloyloxymethyl and phthalidyl as well as groups of the formulas -CH.OCOOC ₀ H ₁ - and -CH ₀ NHCOR ¹¹ "'.

CH ₃

When R ¹ and R "are heterocycles, they are preferably 5- or 6-membered heterocyclic rings, such as 5-methy1-1 _/ 3,4-thiadiazol-2-yl, 1-methyltetrazol-5-yl, 1,2, 3-Triazol-5-yl or pyrazinyl. Examples of R " ¹ are methyl, ethyl, methoxy, 1-hydroxyethyl and 1- (p-nitrobenzyloxycarbonyloxy) ethyl.

These compounds have a broad spectrum of antibacterial activity and also inhibit ß-lactamase Effectiveness. It should be noted that the stereochemistry at the C (- atom of the compounds according to the invention as well as those of all intermediate products formed in the course of their manufacture is the same as with naturally occurring penicillins and cephalosporins.

Pharmaceutically acceptable salts of penem carboxylic acids of the general formula (I), such as sodium, potassium, benzathine, procaine and the like. Salts usually with penicillins and Cephalosporins are formed also fall within the scope of the present invention.

The invention also relates to methods of manufacture of compounds of general formula (I), the intermediates obtained thereby and pharmaceutically acceptable ones Compositions containing these compounds in admixture with conventional carriers for oral and parenteral administration contain.

The following scheme shows the preparation of compounds of general formula (I) according to the present invention Invention.

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R " ¹

V- ^ V

Ή "ϊ ο-

(VI)

(Q)

R-

R "·

ο ·

■ Ν

O COOR

(XIII)

'COOR "" CVII)

H (XIV)

0-3 670713

E " ¹ \

pl

O
PPh-,

«J

COOR ""

16 (VII)

(O)

COOR

(VIII)

(IX)

¹ —V R ¹

R ¹

R ¹

(XIV)

COOR ¹

(XV)

COOR ""

(XVI)

COOR "

Ph.

COOR ¹

(XI)

(I) (XI)

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When R " ^{1 is} hydrogen, compounds of general formula (II) are prepared starting from (5R) -6-aminopenicillanic acid, ie 6-APA, according to the known general method of Cignarella et al., Journal of Organic Chemistry, 27 , 2668, and Evrard et al., Nature 201 , 1124.

i When R " ^{1 is} lower alkyl, cycloalkyl or hydroxyalkyl, the group R"'can be modified according to the method of Di Ninno et al. , Journal of Organic Chemistry A2_, 2960 (1977).

When R " ^{1 is} lower alkoxy, the group R"'can be modified according to the method of Hauser et al., Helv.Chem.Acta 5_0_, 1327 (1967) and Giddings et al., Tetrahedron Letters V1_, 995 (1978) , starting from 6-APA in the 6 position.

On the other hand, compounds of the formula (II) in which R " ^{1 is} H can be converted into compounds of the general formula (II) in which R"'is lower alkyl, cycloalkyl or hydroxyl, the substituent using a strong base is introduced into the 6-position, as illustrated in the following examples.

Compounds of the formula (II) in which R " ^{1 is} lower alkyl, cycloalkyl or hydroxyalkyl can also be prepared starting from a suitable ester of penicillanic acid S-oxide, as explained in the following examples 6 is stereospecifically directed to the 6a derivatives.

The ester of penicillanic acid S-oxide (II) (R is alkyl and R "'has the above meaning) can be mixed in an inert solvent such as benzene or toluene, usually at a temperature of 70 to 140 ° C., with a suitable acetylene derivative general formula X ¹ C = CY, where X ^{1 is} a group of the formula CH_Z ', where Z ^{1 is} hydrogen, halogen, hydroxy, amino, carbamoyloxy Gder is a group of the formula OR ¹ , OCOR ¹ or NHCOR ¹ , and Y is hydrogen, lower alkyl, cyano or a group of the formula COOR or CII ₉ Z ¹ , where R and Z ^{1 have} the meaning given above, has been heated.

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If X 'has another meaning, it can be converted into a group X by known substitution reactions, where X represents a group of the formula CH ₃ Z in which Z has the meaning given above.

The inclusion compound (III) can be isomerized to the compound (IV) with a base, which can be of two different types Species can be converted into the final compound (I). According to the first type, the compound (IV) can be attached to the isopropenyl double bond be selectively ozonated, the compound (V) (n = 1) being obtained, which can be treated with suitable reducing agents, like phosphorus tribromide or sodium iodide in acetyl chloride, to the compound (V) (n = zero) can be reduced, which then under mild basic conditions or on Silica gel is hydrolyzed to compound (VI) (n = zero). With condensation with a suitable ester of glyoxylic acid the compound (VII) (n = zero) obtained with a chlorinating agent such as thionyl chloride and pyridine in the . Chlorine derivative (VIII) (n = zero) and then into the phosphorane (IX) (n = zero) can be converted.

In addition, the same sequence of reactions is also starting carried out by the unexpected compound (VI) (n = 1), which is stable when Y is not a strong leaving group represents. In the case of compounds (IX) (n = zero), the compound can be used as the phosphonium salt under acidic conditions selectively ozonized / ground, the compound (XI) being obtained, which can be obtained in a simple manner by heating in an inert Solvent, such as toluene, is cyclized at a temperature of 50 to 140 C to give compound (I).

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

According to the τ. In a third way, the compound (IV) can be reduced under the usual conditions to the compound (XII), which is ozonated at both double bonds, the compound (XIII) and, after hydrolysis, the compound (XIV) -

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BATH ORIGINAL

will hold. According to the same method as described above, the glyoxylation of the compound (XIV) yields the compound (XV), the "into the chloro derivative (XVI) and then ± n Δππ phosphorane (XI) can be converted, which is a common intermediate for both Represents types of procedure.

If R " ^{1 is} hydroxyalkyl, the reaction sequence is preferably carried out with protection of the alcoholic function.

Compounds of general formula (I) wherein R "'is hydrogen can be obtained by hydrolysis or hydrogenolysis of the corresponding esterified compounds. Compounds of general formula (I) in which η = 1 are easily prepared starting from compounds of general formula (I) in which η = zero, according to the well-known oxidation processes. Advantageously, peracids can be used; m-chloroperbenzoic acid and peracetic acid are preferred.

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

Furthermore, the following are within the scope of the invention listed intermediates, which are particularly preferred. These are:

A compound of the general formula

COOR "

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wherein Ph is phenyl, R " ¹ and R""have the meaning given in claim 1, X represents a group of the formula CH ₂ Z, where Z has the meaning given in claim 1, Y is hydrogen, alkyl with 1 to 5 C- Atoms, CN or COOR, where R has the meaning given in claim 6, or CH_Z, where Z has the meaning given in claim 1, - and η = 1 or zero.

A compound of the general formula

, (XIV)

wherein X and R " ^{1 have} the above meaning.

A compound of the general formula

, (VI)

where R ¹ ", X and Y have the above meaning and η = 1 or zero.

A compound of the general formula

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COOR

wherein R " ¹ , R, X and Y have the above meanings. A compound of the general formula

^RM 'H "

H COOR

where R "', R, X and Y have the above meanings.

A number of in vitro experiments were performed to determine the efficacies of (5R) -acetoxymethyl-2-acetoxymethyl-2-penem-3-carboxylate (Laboratory code FCE / 20077 / B40 / 341), (5R) -acetoxymethyl-2 - [(i-methyl-IH-tetrazol-5-yl) -thiomethyl] -2-penem-3-carboxylate (Connection A) and two reference connections to compare. Table I below shows the results of the above experiments with regard to MIC (minimum heating concentration).

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BATH ORIGINAL

- ysfb -

• Table I: MIC µg / ml

tribe FCE / 20077 / B40 / 341 Connection A Ampicillin Cefoxitin Staphylococcus
anreos 209P i5 _r 39 0.39 £ 0.19 0.73 Staphylococcus
aureus 153 1.56 0.78 ί, 56 0.78 Staphylococcus
aureus PV2 0.39 0.78 <0.19 0.78, Staphylococcus aureus
Smith ATCC 13709 $ 0.19 0.39 £ 0.19 0.78 Streptococcus pyo-
genes ATCC 12384 3.12 0.78 3.12 1.56 Escherichia coil B 1.56 0.78 0.39 1.56 Escherichia coli V14 1.56 0.78 1.56 3.12 Escherichia coli V23 3.12 0.78 3.12 12.5 Enterobacter sp. V19 12.5 > 100 > 100 12.5 Klebsiella pneumoniae
ATCC 10031 3.12 50 0.78 Klebsiella sp. R2 25th - "50 12.5 Proteus vulgaris V15 3 _r 12 6.25 1.56 0.78 .Proteus mirabilis
V15 0.39 0.78 £ 0.19 0.78 Proteus mirabilis 525 3.12 0.78 0.39 1.56 Shigella flexneri 0.39 0.39 ^ 0.19 0.78 Pseudornonas aerugi-
nosa 3.12 0.39 25th 6.25 Salmonella typhi-
inurium 1.56 0.78 0.78 3.12 Salmonella panamae F15 1.56 0.78 0.78 1.56 Salironella Saint
Paul F20 1.56 0.78 0.78 3.12 Salmonella derby F14 3.12 0.78 0.78 3.12 Salmonella Montevideo
F16 3.12 0.78 0.78
1 3.12

The following examples are intended to explain the present invention in more detail without, however, being restricted thereto target.

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BATH ORIGINAL

- ar -

Example 1: 4ß-vinylthio- (1,2-diacetoxymethyl) -1-

(1-methoxycarbonyl - ^ - methyl - ^ - propeny1) -azetidin-2-one-S-oxide

COOCH

OCOCH, OCOCH,

"COOCH-

A solution of 2.0 g of methylpenicillanate S-oxide and 2.8 g of butynediol diacetate in 40 ml of toluene was refluxed for 24 hours heated. The title compound could be purified by column chromatography on silica gel be, eluting with 96: 4 dichloromethane-ethyl acetate, ■ 1.4 g of 4β-vinylthio- (1,2-diacetoxymethyl) -1 - (1 methoxycarbonyl-2-methyl-2-propenyl) -azetidine-2 -on-S-oxide obtain.

NMR (CDCl-.): 2.03 δ (s, CH - C-), 2.15 and 2.20 δ (two s, .2 CH ₃ CO), 2.88 δ (dd, Jgem = 14 Hz, Jvic cis = 4 Hz, C-3-Ηα), 3.38 6 (dd, Jgem = 14 Hz, Jvic trans = 2 Hz, C-3-Hß), 3.83 '(s, CH-O ), 4.88 δ (Jvic = 6 Hz, CH ₉ -C =), 4.92 δ (broad s,

³ (ή) ι π

CH ₂ -C =), 4.93-5.33 δ (m, = CH ₂

-NC
\ /

and CH), 5.32 δ (dd,

COO

Jvic = 4 and 2 Hz, C-4-H), 6.47 δ (t, Jvic = 6 Hz, = CC (H ₂ )).

Example 2: 4β-Vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one-S-oxide

COCI COCH

COOCH-

COOCH.

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BATH ORIGINAL

1.7 g of 4β-vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide were dissolved in 80 tons of dichloromethane. 0.5 ml of triethylamine were added and the solution was left to stand for a few hours at room temperature. After evaporation of the solvent, the compound named in the title was obtained in pure quantitative yield. NMR (CDCl ₃ ): 2.13 (9H) and 2.32 (3H) δ (two s, 2 CH ₃ CO and 2 CH ₃ -C =), 2.92 δ (dd, Jgem = 15 Hz, Jvic eis = 5 Hz, C-3-Ηα), 3.38 δ (dd, Jgem = 15 Hz, Jvic trans = 2.5 Hz, C-3-Hß), 3.82 δ (s, CH ₃ O) , 4.88 6 (d, Jvic = 6.5 Hz, CH ₃ -C =), 4.92 (s, CH ₂ -C =), 5.15 δ (dd, Jvic = 5 and 2.5 Hz , C-4-H), * * 6.50 δ (t, Jvic = 6.5 Hz, = C- (H ₂ )).

Example 3: 4β-Vinylthio- (1,2-diacetoxymethyl) -1-methoxyoxaloyl-azetidin-2-one-S-oxide

COCH-COCH.

COOCH,

OCOCH, COCIL

COOCH

2.0 g of 4β-vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-i-propenyl) -azetidin-2-one-S-oxide were dissolved in 150 ml of dichloromethane and after cooling at -78 C a stream of ozone in oxygen was bubbled through until a pale blue color appeared. The solution was brought to room temperature with an aqueous Na ₇ S _? Oj solution shaken and poured over Na ₃ SO. dried. The organic phase obtained gave 1.4 g of the title compound after evaporation of the solvent in vacuo.

NMR (CDCi ₃ ): 2.05 and 2.08 δ (two s, 2 CH ₃ CO), 3.03 δ (dd,: Jgem = 17 H2, Jvic cis = 5.5 Hz, C-3-1Ia ), 3.50 δ (dd, Jgem = 17 Hz, Jvic trans = 3 Hz, C-3-Hβ), 3.90 δ (s, CH ₃ O), 4.82 δ

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BATH ORIGINAL

(d, Jvic = 6.5 Hz, CH ₀ -C =), 4.90 δ {s, CH-C =), 5.32 δ (dd,

(H)

-Jvic = 5. _Γ 5 and 3 Ez _f CAH) ₁ 6, Al δ (t _r Jvic ■ - 6.5 Hz, = CC (H ₂ )).

IR (CH ₂ Cl ₂ ): 1830 cm " ¹ β-lactam C = O
1750 cm " ¹ ester C = O
1715 cm " ¹ amide C = O.

Example 4: 4β-vinylthio- (1,2-diacetoxymethyl) -1-methoxyoxaloyl-azetidin-2-one

O
Il

rf * Y ^ oCOCH ₃ ργ

on ο] = ^u

^C00CH 3 COOCH ₃

A solution of 1.4 g of 4ß-vinylthio- (1,2-diacetoxymethyl) -1-methoxy-oxaloyl-azetidin-2-one-S-oxide in 10 ml of anhydrous dimethylformamide was ^{cooled to w} 25 ° C. and 0 , 9 ml of phosphorus tribromoxd was added. After 10 min the mixture was diluted with ethyl acetate and washed twice with a saturated NaIICO ^ solution. After drying over Na ₀ SO.

O £ * * "X

and evaporation of the solvent gave 0.9 g of those mentioned in the title Connection received.

NMR (CDCl ₃ ): 2.07 δ (s, 2 CII ₃ CO), 3.17 δ (dd, Jgem = 19 Hz, Jvic trans = 3.5 Hz, C-3 Hβ), 3.65 δ (dd, Jgem = 19 Hz, Jvic eis = 5 Hz, C-3-Ηα), 3.90 δ (s, CH ₃ O), 4.73 δ (d, Jvic = 6.5 Hz, CH ₂ - C =), 4.88 δ (broad s, CH ₂ -C =), 5.52 δ (dd, Jvic = 5 un <i ⁿ 3.5 Hz, C-4-H), 6.25 δ ( t, Jvic = 6.5 Hz, = CC (H ₂ )).
H ·

IR (CIICl.,): 1815 cm β-lactam C = O

- -1

174 5 cm ester C = O

1710 cm " ¹ amide * C = O

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BATH

Example azetidin-2-one

• 56

5: 4ß-vinylthio (1,2-diacetoxymethyl) -

<f

-N

> 0

COOCH.

OCOC H

OCOCH

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

NMR (CDCl ₇ ): 2.25 δ (s, 2 CH-.CO), 2.98 δ (dd, Jgem = 15Hz, Jvic trans = 2 Hz, C-3-Hβ), 3.48 δ (dd , Jgem = 15 Hz, Jvic eis = 4.5 Hz, C-3-Ηα), 4.78 δ (d, Jvic = 7 Hz, CH ₉ -C =), 4.87 δ

'(H) "(s, CH ₂ -C =), 5.03 δ (dd, Jvic = 4.5 and 2 Hz, C-4-H), 6.02 δ (t, Jvic = 7 Hz, = CC (H ₂ )), 7.13 δ (broad s, NH).

IR (CHCl ₃ ): 1770 cm

-1 -1

β-lactam C = O

174 0 cm ester C = O.

Example 6: 4β-Vinylthio- (1,2-diacetoxymethyl) -azetidin-2-one-S-oxide

r-r *

GOOCH.

OCOCH. OCOCH.

OCOCH, OCOCH *

0.800 g of 4β-vinylthio {1 _f 2-diacetoxymethy 1) .- 1-ethoxyoxaloyl-azetidin-2-one-S-oxide were dissolved in 80 ml of methanol

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- -25 -

and a few grams of silica gel was added with stirring. After 1 hour the silica gel was filtered off and 0.5 g of 4β-vinylthio- (1,2-diacetoxymethyl) -azetidin-2-one-S-oxide were obtained after evaporation of the solvent.

NMR (CDCl ₃ ): 2.13 δ (s, 2 CH ₃ CO), 3.0-3.3 δ (m, 2 protons at C-3), 4.70 δ (m, C-4-H ), 4.88 δ (d, Jvic = 6 Hz,

4.93 δ (s, CH ₂ -C =), 6.53 δ (t, Jvic = 6 Hz, = CC (H ₂ )), 7.23 δ (s, NH). '

IR (CHCl ₃ ): 1790 cm

" ¹
" ¹

β-lactam C = O

1745 cm- ¹ ester C = O.

Example 7: 4β-Acetylglycolylthio-1-acetoxymethy1-oxyoxaloyl-azetidin-2-one

OCOCH, OCOCH.

COOCH ₂ OCOCh ₃

OCOCH.

COOCh ₂ OCOCH ₃

0.8 g of 4β-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxycarbonyl-2-methyl-i-propenyl) -azetidin-2-one were dissolved in 80 ml of dichloromethane, cooled to -78 ° C. and a stream of ozone in oxygen was bubbled through until a blue color appeared. After shaking with an aqueous Na 1 SO _{4 solution, the solution was dried over Na 3} SO 4, yielding 0.45 g of the compound named in the title. NMR (CDCl.): 2.10 and 2.13 δ (two s, 2 CH-CO), 3.20 δ (dd, Jgem - 17 Hz, Jvic trans = 3.5 Hz, C-3-Hßj, 3.77 δ (dd, Jgem = 17 Hz, Jvic eis = 5.5 Hz, C-3-Ηα), 4.73 δ (s, -CO-CH ₂ -OCO-), 5.73 δ (dd , Jvic = 5.5 and 3.5 Hz * C-4-H), 5.87 δ (s, COO-CH ₂ -OCO).

Example 8: 4β-Acetylglycolylthio-azetidin-2-one

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BATH ORIGINAL

OCOCH ₃ , f Ύ "" OCOCH ^

O ™ "" Τ «O ^J

-NV ^ ₀ ^ _N.

O 'Γ O ~ h

COOCH.

0.6 g of 4β-acetylglycolylthio-1r-methoxyoxaloyl-azetidine-2-οη was dissolved in 100 ml of methanol and a few g of silica gel were added with stirring. After 1 h the silica gel was filtered off and the resulting solution gave, after evaporation of the solvent, 0 _f 35 g of the compound named in the title.

NMR (CDCl): 2.20 δ (s, CH CO), 3.03 δ (dd, Jgem = 16 Hz, Jvic trans = 2.5 Hz, C-3-Hβ), 3.50 δ (dd, Jgem = 16 Hz, Jvic eis = 4.5 Hz, C-3-Ηα), 4 ₇ 77 δ (s, -CO-CH ₂ -OCO-), 5.32 δ (dd, Jvic = 4.5 and 2.5 Hz, C-4-H), 6.40 6 (broad s, NH).

Example 9: 4β-Vinylthio- (1,2-diacetoxymethyl) -1 - (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one

OCOCH ₃ j f ^{> v} »fj ^ ^N OCOCH ₃

.. ^ OCOCH ₃ - O 0 ^ 0C0 _CH 3

COOCH ₂ OCOCh ₃

0.7 g acetoxymethyl glyoxylate (freshly made by Ozonolysis of diacetoxymethyl fumarate) was dissolved in 30 ml of benzene and the resulting solution was purified by means of a Dean-Stark method Held at reflux for 20 min.

After cooling to 50 to 60 ° C, 0.7 g of 4ß-vinylthio (1,2-diacetoxymethyl) azetidin-2-one, dissolved in 10 ml of benzene, added and the resulting solution was refluxed for 2 h. The compound named in the title was obtained in almost quantitative yield and could be used as a crude mixture for the next stage uses v / ground. It was a pure sample

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BATH ORIGINAL

for analytical purposes by preparative thin layer chromatography obtain.

NMR (CDCl ₃ ): 2.07 δ (s, 3 CH ₃ CO), 2.37 S JrId, ilgem = 1 Hz, Jvic trans = 2 Hz, C-3 Hβ), 3.40 6 (dd, Jgem = 18 Hz, Jvic eis = 4 Hz, C-3-Ηα), 4.70 6 (d, Jvic = 6 Hz, CH ₀ -C =), 4.77 δ (s,

I (H) CH ₀ -C =), 5.0-5.4 δ (m, C-4-H and -N-CH-COO-), 5.77 δ (s,

¹ '■ O (H)

-COO-CH ₀ -OCO-), 6.12 δ (t, Jvic = 6 Hz, = CC (H ₀ )). δ H

Example 10: 4β-Vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxycarbony1-1-chloromethyl) -azetidin-2-one

COOCh ₂ OCOCH ₃ COOCH OCOCH ₃

0.6 g of 4β-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxy- "methyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one, dissolved in 15 ml of tetrahydrofuran, were cooled to 0 C; 0.115 g of pyridine and 0.104 ml of thionyl chloride were added and the mixture was stirred for 10 minutes, the insoluble matter was filtered off ¹ and the solution was evaporated in vacuo at room temperature to give the titled compound in high yield and a sample was taken for analytical purposes Purified preparative thin-layer chromatography, but the crude mixture could be used for the next step without purification.

NMR (CDCl ₃ ): 2.14 δ (s, 3 CH ₃ CO), 3.10 δ (dd, Jgem = 15.5 Hz, Jvic trans = 2 Hz, C-3 Hβ), 3.55 δ (dd, Jgem = 15.5 Hz, Jvic eis = 5 Hz, C-3-Ηα), 4.77 δ (d, Jvic = 6.5 Hz, CH ₀ -C =), 4.83 δ

(H) (s, CH ₂ -C =), 5.4-5.9 δ (m, C-4-H and -N-CHCl-COO-), 5.88 δ "

(s, -COO-CII ₂ -OCO-), 6.13 δ. (t, Jvic = 6.5 Hz, = CC ('h ₂ ))

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Example 11: 4β-vinylthio- (1,2-diacetoxymethyl) -1- (1st acetoxymethyloxycarbonyl-i-triphenylphosphoranylidenemethyl) azetidin-2-one

OCOCH ₃ OCOCH-,

^ PPh ₃

COCH

o ^ - ^N >

COOCH OCOCH ₃

A solution of 0.430 g of 4ß-vinylthio (1,2-diacetoxymethyl) -1- (i-acetoxymethyloxycarbonyl-i-chloromethyl) -azetidin-2-one in 5 ml of tetrahydrofuran and 5 ml of dioxane with a content of 0.520 g of tripheny! phosphine and 0.08 ml of pyridine were stirred at 50 ° C. overnight. The resulting phosphorane was purified by column chromatography on silica gel, eluting with 70:30 dichloromethane-ethyl acetate; 0.400 g of the compound mentioned in the title were obtained. NMR (CDCl ₃ ): 2.05 δ (s, 3 CH ₃ CO), 4.70 δ (d, Jvic = 6.5 Hz,

CH ₀ -C =), 4.73 δ (s, CH ₀ -C =), 5.77 δ (s, -COO-CH ₀ -OCO-), ² (H) ^Z '^

5.90 δ (t, Jvic = 6.5 Hz, = CC (H _O)), 7.1 to 8.0 δ (m, 3 0 H. _1).

Example 12: 4β-Acetylglycolylthio-1- (1-acetoxymethyloxycarbonyl-1-tripheny Iphosphoranylidenemethy I) -azetidin-2-one

OCOCH OCOCi

COCH

0 T = PPh ₃

COOCILOCOCII.

030036/0713

0.7 g of 4β-vinylthio- (1 ^ -diacetoxymethyD-i- (1-acetoxy-inethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one were dissolved in 40 ml of dichloromethane and, after cooling to -20 ° C., were 50 ml of a 10% solution of trifluoroacetic acid in dichloromethane were added. After a few minutes, a stream of ozone in oxygen was bubbled through at -20 ° C. until a slight blue coloration appeared. At this point the reaction was terminated and a few drops of trimethyl phosphite were added organic solution was washed with a saturated NaHCO ₃ solution and _{dried over Na 3} SO _{4 to} give 0.550 g of the title compound, NMR (CDCl ₃ ): 2.10 and 2.15 δ (two d, 2 CH ₃ CO) ₇ 4.72 δ (s, -CO-CH ₂ -OCO-), 5.64 δ (s, -COO-CH ₂ -OCO), 7.1 to 8.0 δ (m, ο Π TI \

Example 13: (5R) -Acetoxymethyl ^ -acetoxymethyl ^ -

penem-3-carboxylate

■ ^ - OCOCH ₃ ^ I f Tf ^ ₀ COCH

~ ^Nvs j = pph,

COOCh ₂ OCOCH ₃

0.7 g of 4β-acetylglycolylthio-1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one were dissolved in 30 ml of dry toluene and refluxed for 2 h heated. The reaction mixture, which consisted of the compound named in the title and triphenylphosphine oxide, was purified by short column chromatography on silica gel, eluting with 97: 3 dichloromethane-ethyl acetate; there were 0.250 g of acetoxymethyl-2-acetoxymethyl-2-penein-3-carboxylate obtain.

NMR (CDCl ₃ ): 2.11 and 2.13 δ (two s, 2 CII ₃ CO), 3.49 δ (dd, ■ Jgem = 16.5 Hz, Jvic trans = 2 Hz ₇ C-6-IIβ ), 3.86 δ "(dd, Jgem = 16.5 Hz, Jvic eis = 3.8 Hz, C-6-Ηα), 5.12 and 5.45 δ (two d,

030036/0713

BATH

. 35.

Jgein = / 15.5 Hz, = C-CH ₂ ), 5.68 δ (dd, Jvic = 3.8 tmd 2 Hz, C-5-H), 5.87 δ (s, -COO-CH ₂ -OCO-).
IR <CHC1 ₃ ) -: 1800 era " ¹ fi-Lactam C = O

1750-1725 cm " ¹ ester C = O.

UV (AtOH): λ 325 rim.

^λ max

MS: m / e 315.04108 (M) calculated for C ₁₃ H ₁₃ NO ₇ S 315.04127.

Example 14: 4β-Vinylthio- (1,2-diacetoxymethyl) -1- (1-p-nitrobenzyloxycarbonyl-i-hydroxymethyl) -azetidin-2-one

The title compound was obtained according to the procedure described in Example 9 using p-nitrobenzyl glyoxylate freshly prepared by ozonolysis of p-nitrobenzyl fumarate. .NMR (CDCl ₃ ): 2.1 δ (s, "6H), 2.8-3.7 δ (m, 2H), 4.7-4.9 δ (m, 5H), 5.1 - 5.6 δ (m, 2H), 5.2 δ (m, 1H), 6.1 δ (m, 1H), 7.5-8.3 δ (m, 4H). '

Example 15: 4ß-Vinylthio- (1,2-diacetoxymethyl) - (1 -p-nitrobenzyloxycarbonyl-1-chloromethyl) ~

The connection named in the title was named after "the in

Example 10 prepared method described.

0 3 0036/0713

3Ü06273

NMR (CDCl ₃ ): 2, -1 δ (s, 6H), 2.8-3.7 6 (m, 2H), 4.7 -4.9 δ (m, 4 H) ₇ 5.2 - 5.4 δ (m, 1H), 5.4 δ (m, 2H), 6.1-6.3 S (jn, 2H), 7.5-8.4 δ (m, 4H).

Example 16: 4ß-Vinylthio- (1,2-diacetoxymethyl) -1 - (1 p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one

¹ X

■ N \ _ ^ cl ^ /

j, "^ y-Cl

o I

COOCIL

OAc OAc

, nT

OAc

: - {0) " ^Ν ° 2

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

Example 17: 4β-Acetylglycolylthio-1- (1-p-nitrobenzyloxycarbonyl-1-tripheny! Phosphoranylidenemethyl) -azetidin-2-one

OAc

COOCH

NO,

The compound named in the title was named after the in

Example 12 prepared method described.

Example 18: (5R) ~ p-nitrobenzyl-2-acetoxyr.iethyl-2-penem-3-carboxylate

030036/0713

BATH ORIGINAL

22 -

The title compound was prepared according to the procedure described in Example 13. NMR (CDCl ₃ ): 3.75 δ (1H, dd, J = 2.3 Hz, 16.8 Hz, Η-6α), 3.87 (1H, dd, J = 3.6 Hz, 16.8 Hz, H-6β), 5.14 δ (1H, d, J = 15.8, = C-CH "0-), 5.50 δ (1H, d, J = 15.8 Hz, = C- CH "O), 5.71 <T (1H, dd, J = 2.3 Hz, 3.6 Hz, H-5).

[a] _D + 8T

(c = 1.2 in CHCl ₃ ).

-1

IR (CHCl ₃ ): 1800 (β-lactam), 1750 and 1720 cm UV (EtOH): 265 (£ 11000) and 322 (fc 7000) nm. MS: m / e 378 (M ⁺ ).
Mp 122-123 ° C.

"Example
acid

1 9: (5R) ■ ^ -Acetoxymethyl - ^ - penem-O-carbGn-

r— S

. f

Y N-

200 mg of (5R) -p-nitrobenzyl ^ -acetoxymethyl - ^ - penem-S-carboxylate, prepared as described in Example 18, were dissolved in 12 ml of ethyl acetate. 8 ml of a 0.2 M NaIICO solution and 400 mg of 10 % Pd / C were added and the resulting two-phase mixture was shaken under hydrogen for 60 minutes.

030036/0713

BATH ORIGINAL

/ - 23 -

After filtering the catalyst, the aqueous phase was acidified with 20 ml of 5% aqueous citric acid and extracted three times with methylene chloride. The organic layers were dried over Na ₇ SO. dried and evaporated, leaving 60 mg

the compound mentioned in the title were obtained. U): 1790 (β-lactam), 1735 and 1700 cm " ¹ .

UV (ÄtGH): 300 µm.

Example 20: 4β- (1-Hydroxymethyl) vinylthio-1- (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide

O Il

_N Λ

H COOCH

O ti

H% OOCH.

4 g of methyl penicillanate S-oxide were dissolved in 15 ml of toluene and refluxed with 15 ml of propargyl alcohol for 8 h. After evaporation in vacuo, the residue was purified by short column chromatography on silica gel, eluting with dichloromethane-ethyl acetate (1: 1). 2.8 g of the compound mentioned in the title were obtained. <■ NMR (CDCl ₃ ): 1.96 δ (broad s, 3H, C-CH ₃ ), 2.91 and 3.35 δ (dd, 2H, J = 2 Hz, 5 Hz, 15 Hz, CO- CH ₂ -CH-S), 3.78 6 (s, 3H, COOCH ₃ ), 4.36 6 (broad s, 2H, CH ₂ OH), 4.90-5.25 6 (m, 3H, CH -COOCH ₃ -CC = CH ₂ ), 5.356 (m, 1H, CH ₂ -CH-S), 5.88 6 (s, 211, CH ₃ = OS).

Example 21: 4β- (1-Hydroxymethyl) vinylthio-1- (1- 'methoxycarbonyl-2-methyl-i-propenyl) -azetidin-2-one-S-oxide

'O

COOCH

030036/0713

^COOCIi

3.0 g of 4β- (1-hydroxymethyl) ~ vinylthio-1- (1-niethoxyearbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide were dissolved in 100 ml of dichloromethane and left to stand for a few hours at room temperature After evaporation of the solvent, the residue consisted of the pure compound named in the title, which had been obtained in quantitative yield, NMR (CDCl ₃ ): 2.08 δ (s, 3H ₇ I-CH ₃ ), 2.18 (s, 3H, ^ -CH ₃ ), 2.7 3.6 (m, J = 2 Hz, 5 Hz, 16 Hz, CO-CH ₂ -CH-S), 3.78 (s, 3H, COOCH ₃ ), 4.35 (s, 2H, CH ₂ OH), 5.32 (m, 1H, CH-S), 5.90 (broad s, 2H, = CH ₂ ),

Example 22: 4- (1-Bromomethyl) vinylthio-1- (1-methoxycarbonyl-2-methyl-1-propenyl) azoetidin-2-one

COOCH ₃ COOCH ₃

1.8 g of 4β- (1-hydroxymethyl) vinylthio-1- (1-methoxycarbo- ■ nyl-2-methyl-1-propenyl) -azetidin-2-one-S-oxide were dissolved in 40 ml of dimethylformamide and dissolved -20 C cooled. 0.7 ml of pyridine and 3.0 ml of PBr ₃ were added and the mixture was stirred for 15 minutes. Ethyl acetate was added and the organic layer was _{shaken with a saturated NaHCO 3} solution, washed with water and then _{dried over Na 3} SO ₄ , 1.6 g of the title compound being obtained after evaporation of the solvent.
NMR (CDCl.): 2.04 δ (s, 3H, = "" ^CH 3), 2.24 δ (s, 3H, ^^),

0 ³

Il
3.24 δ (dd, J = 2.8, 5.16 Hz, 2H, C-CH ₂ -CH), 3.75 (s, 3H, OCH ₃ ), 4.02 (s, 2H, CH ₂ Br), 5.24 (broad s, 1H, = CH), 5.37 δ- (dd, J = 2.8 Hz, 5 Hz, 1H, CH ₂ -CH-S), 5.60 (broad s , 111, = CH).

03Ü036 / Q713

• 3 *.

Example 23: 4β- [1- {1-Methyl-1H-tetrazol-5-y I) -thiomethyl] -vinylthio] -1 - (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one - _- "

COOCH ₃

1.4 g of 4- (1-bromomethyl) vinylthio-1- (1-methoxycarbony1-2-methyl-1-propenyl) -azetidin-2-one were dissolved in 25 ml of tetrahydrofuran and cooled to 0 ° C. 0.8 g of 1-methyl-5-thioltetrazole sodium salt was added and the mixture was stirred at room temperature for 3 hours. After filtering off the insoluble matter, the mixture was diluted with ethyl acetate, washed with water, _{dried over Na 3} SO ₄ and evaporated. The residue consisted of 2.0 g of the pure compound named in the title.

I I

-NMR (CDCl ₃ ): 2.00 δ (s, 3H, S = C-CH ₃ ), 2.22 δ (ε, 3H, = C-CH_ ₃ ), 2.70-3.806 (m, 2H, J. = 2 Hz, 5 Hz, 15 Hz, CO-CH ₂ -CH-S), 3.72 δ (s, 3H, COOCH ₃ ), 3.95 δ (s, 3H, N-CH ₃ ), 4, 10 δ (s, 2H, CH ₃ -S), 5.18 δ (broad s, 1H, SC = CH), 5.36 δ (m, 1H, CH ₂ -CH-S), j 5.57 δ (broad s, 1H, SC = OH).

Example.' 24: '4β- (1-Methyl-iH-tetrazol-5-yl) -thioacetyl-thio-i-methoxyoxaloyl-azetidin-2-one

N-N

N \
Γ ⁰

0 l

CII.

COOCH,

030036/0713

- / 3Ί5 -

1.8 g of 4β- [1- (1-methyl-1H-tetrazol-5-yl) -thiomethyl] -vinylthio-1- (• l-methoxycarbonyl-2-methyl-i-propenyl) -azetidin-2-one were dissolved in 200 ml dichloroethane and cooled to -78.degree. A stream of ozonated oxygen was bubbled through the solution until it turned blue. A few drops P (OCH-) were added, the mixture was brought to room temperature

• J J

brought door and evaporated, leaving 1.3 g of those mentioned in the title Connection were obtained.

NMR (CDCl ₃ ): 2.9-3.7 δ (m, 2H, COCH ₂ CHS), 3.85 δ (s, 3H, COO-CH ₃ ), 3.98 (s, 3H, N-CH _3), 4.35 (s, 2H, CH ₂ S), 5.75 (m, 1H, CH ₂ CHS).

Example 25: 4β- (i-Methyl-iH-tetrazol-5-yl) -thio _r acetyl-thio-azetidin-2-one

N-

-N

COOCH,

I.

N N

O '

CH ₃

1.2 g of 4ß- (1-methyl-1II-tetrazol-5-yl) -thioacetyl-

thio-1-methoxyoxaloyl-azetidin-2-one v / urden in a 1: 1 mixture Ethyl acetate-methanol dissolved and a few g of silicate were added with vigorous stirring. After 1 hour, the insoluble ^ The substance was filtered off and the solution was evaporated in vacuo.

.The compound mentioned in the title crystallized from methanol • ethyl ether. Yield 0.6g.

Example 26: 4β- (1-Methyl-1H-tetrazol-5-yl) -thioacetylthio-1- (1-acetoxymethyloxycarbony1-1-hydroxymethyl) -azetidin-2-one

030036/0713

? n1

CH-

η - • 39 -

N \ ^ OH

COOCH ^ OCOCH.

N N

ο 1

CH-

1.5 g 4ß- (1-methyl ~ 1H-tetra _z ol-5-yl) -thioacetylthio-azetidin-2-one (freshly prepared by ozonolysis of Diacetoxymethylfumarat) in 50 ml of benzene with 1.2 g Acetoxymethylglyoxylat at reflux held. The reaction was over after 3 hours. The crude oil obtained after evaporation of the solvent could be used for the next stage without further purification. A sample was purified by thin layer chromatography for spectroscopic data. NMR (CDCl ₃ ): 2.05 δ (s, 3H), 2.7-3.8 (m, 2H), 3.95 δ {s, 3H), 4.30 δ (S ₁ 2H), 5 , 40 δ (s, 1H), 5.50 δ (m, 1H), 5.80 δ (s, 2H).

Example 27: 4β- (1-Methyl-iH-tetrazol-5-yl) -thio-.acetylthio-1- (1-acetoxymothyloxycarbony 1-1-chlorinethy 1) azetidin-2-one

N-

CH-

COOCH ₂ OCOCh

COOCH ₂ OCOCh ₃

The oil obtained according to the preceding example, which is obtained from crude 4ß- (1-methyl-1H-tetrazol-5-yl) -thioacetyl thio-1- (1-acetoxymethyloxycarbonyl-i-hydroxymethyl) -azetidin-2-one was dissolved in 20 ml of anhydrous tetrahydrofuran and at 0 C with equimolar parts of pyridine and thionyl chloride treated until all of the starting material

030036/0713

BATH ORIGINAL

- 2ΤΒ -

was gone. After filtering off the insoluble matter, the filtrate was used immediately for the next step.

Example 28: 4β- (1-Methyl ~ iH-tetrazol-5-yl) -thio -acetyl-thio-1- (1-acetoxymethyloxycarbonyl-1-triphenyl-

phosphoranylidenemethyl) azetidin-2-one

. O

<f

CH.

COOCh ₂ OCOCH ₃

O>

PPh ₃ ^w "3

To the solution containing the crude 4ß- (1-methyl-1H-tetrazol-5-yl) -thioacetylthio-1- (1 -acetoxymethyloxycarbonyl-1 chlorine thy 1) -azetidin-2-one, 800 rag triphenyl _phosphine and 0.4 ml of pyridine were added and the resulting Mixture heated to 60 to 70 ° C. for a few hours. The phosphorane was purified on silica gel, using dichloromethane-ethyl acetate (1: 1) was eluted.

Example 29: (5R) -Acetoxymethyl-2 - [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] -2-penem-3-carboxylate

<f

-N

I.
CH.

COOCH ₂ OCOCIi ₃

• ^ ^H 3 COOCH ₂ OCOCh ₃

0.500 g of 4- (1-methyl-1H-tetrazol-5-yl) -thiomcthylacetylthio-1- (1-acetoxymethyloxycarbonyl-i-triphenylphosphoranylidenemethyl) -azetidin-2-one were dissolved in 30 ml of toluene and

030036/0713

BATH ORIGINAL

Heated to 100 ° C. for 2 h. _{The title compound was purified from PPh 3} O by short column chromatography on silica gel, eluting with didhlorinethane ethyl acetate (8t 2) :

NMR (CDCl.,): 2.15 δ (s, 3H, COCH,.), 3.30-4.036 (ItI, J = 4 Hz, 2 Hz, -CH "- (6), 3.97 δ (s, 3H, -NCH-), 4.566 (d, J = 14 Hz, 1H, HCH-S), 4.84 δ (d, J = 14 Hz, 111, HCH-S), 5.656 (dd, J = 4 Hz, 2 Hz, 1H, H-5a), 5.88 δ (s, 2H, COOCH O).

Example 30: (5R) -2- (i-Methyl-IH-tetrazol-5-yl) -thiomethyl-2-penem-3-carboxylic acid

The title compound was obtained according to the procedure described in Example 19. The (5R) -p -nitrorbenzoyl-2- (1-methyl-iH-tetrazol-5-yl) -thiomethyl-1-penem-S-carboxylate was obtained by a procedure similar to that described in the previous examples. IR (CHCl ₃ ): 1800 (β-lactam), 1750 and 1720. Example 31: Methyl 6a- (1'-hydroxyethyl) penicillanate S-oxide

OH

CH

J ^H = S

^ ^G I ⁵

if '■' COOCH ₃

"'COOCH.

030036/0713

BATH ORIGINAL

ti ■ 30Ό6273 • WjL-

A solution of 2.3 g of methylpenicillinate S-oxide in 50 ml of anhydrous tetrahydrofuran was cooled to -78.degree. Lithium diisopropylamide (freshly prepared from 5 ml of diisopropylamine and 20 ml of a 1.6M BuLi-hexane solution), dissolved in anhydrous tetrahydrofuran, was added and the mixture was left to stand at -78 ° C. for 10 minutes. 5 ml of acetaldehyde was gradually added and the whole was stirred for 15 minutes. The reaction mixture was then _{quenched with a saturated aqueous NH 4} Cl solution, extracted with ethyl acetate, washed twice with water and dried over Na_SO. dried. After evaporation of the solvent, the residue was briefly purified by column chromatography on silica, eluting with dichloromethane-ethyl acetate (1: 1). Yield 1.5g. The compound named in the title consisted of a 2: 3 mixture of epimers on the hydroxyl group bearing the carbon atom, based on

on NMR, with the new C, .- C ₀ bond because of the stereospecificο-ο

did the reaction under the conditions used only in the

is α-position. :

NMR (CDCl ₃ ): 1.27 δ (s, 3H, 0.-CH ₃ ), 1.406 (d, 3H, J = 5.7 Hz, CH ₃ -CHOH) major isomer, 1.48 6 (d, 3H , J = 5.7 Hz, CH ₃ -CHOH) lower isomer, 1.70 δ (s, 3H, B-CH ₃ ), 3.4 - 3.8 δ (m, 111, .H- 6), 3.80 δ (s, 3H, COOCH_), 4.1-4.7 δ (m, 111, .CIIOH), 4.50 δ (s, 1H, H-3), 4.98 δ (d, J = 1.9 Hz, 1H, H-5) minor isomer, 5.05 δ (d, J = 1.9 Hz, 1H, H-5) major isomer.

Example 32: Methyl 6- (1-hydroxyethyl) -3-penicillanate

OH

^ N-

COOCH ₃ ■ O * COOCH ₃

To a solution of 2.2 g of Kcthylpenicillanat in 30 ml anhydrous tetrahydrofuran became a slight excess

030036/0713

BATH ORIGINAL

added to lithium diisopropylamide at -78 ° C under nitrogen. An excess of acetaldehyde was added dropwise, the mixture was stirred for 5 minutes, quenched with a trace of acetic acid, poured into water and extracted with methylene chloride. The over Na ₃ SO. Organic layers dried and evaporated in vacuo gave 0.8 g of the title compound.

Example 33: Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate .

'COOCH-

OCO ₂ PNB

H COOCIL

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

Example 34: Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicilianat-S-oxide

OCO ₂ PNB

COOCIL

COOCIL.

030036/0713

1.8 g of methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate were dissolved in 50 ml of methylene chloride 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 3} SO ₄ and evaporated. 1.4 g of the expected sulfoxide were obtained.

Example 35: 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethy1) -1- (i-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide

OCO ₉ PNB Il

_H COOCH ₃

OCO ₂ PNB

COCH. OCOCH.

COOCH.

A solution of 2.0 g of methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate-S-oxide and 2.4 g of butynediol • diacetate in 50 ml of toluene was refluxed for 24 h. The inclusion compound was then purified by column chromatography, eluting with 9: 1 dichloromethane-ethyl acetate became. 1.1 g of the compound mentioned in the title were obtained. ■ '

Example 36: 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethy1) -1 - (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one-S-oxide . _

OCO ₂ PNB \\
S.

OCOCH, OCOCH.

OCO ₂ PNB

OCOCII ₃

COOCH.

030036/0713

BATH ORIGINAL

■ Its-

1.3 g of 4ß-vinylthio (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (methoxycarbonyl - ^ - methyl - ^ - propenyl) -azetidin-2-one-S-oxide were dissolved in 80 ml of dichloromethane. 0.3 ml of triethylamine were added and the mixture at 2 h Left to stand at room temperature. The pure compound named in the title became more quantitative on evaporation of the solvent Yield obtained.

Example 37: 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one-S-oxide

OCO ₂ PNB jJ

COOCH-

OCOCH, OCOCH.

COOCIL

OCOCIL OCOCIL

A solution of 1.1 g of 4ß-vinylthio- (1,2-diacecoxymethyl) 3- (1-p-nitrobenzyloxycarbonyloxyethyl) -i (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one-S- oxide in 100 ml dichloromethane was cooled to -78C. Ozone in oxygen was bubbled through until it turned blue. The solution was shaken with an aqueous Na ₂ S ₂ O solution and dried _{over Na 3} SO _4. After evaporation, 0.5 g of the compound named in the title was obtained.

Example 38: 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one

0.

OCO ₂ PNB

COOCH

OCO ₂ PNB

OCOCH ₃ OCOCII.,

030036/0713

OCOCII. OCOCH.

COOCH.

BATH ORIGINAL

A solution of 0.8 g of 4β-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one in 15 ml of anhydrous dimethylformamide was on -_20 -C - cool and 0.6 ml of phosphorus tribromide was added. The reaction mixture was diluted with ethyl acetate after 10 min and washed twice with a NaHCOo solution. The ones about Na_SO. dried and evaporated organic phase gave 0.4 g of the reduced compound.

Example 39: 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one

OCO ₂ PNB

OCO ₂ PNB

OCOCH. OCOCH.

OCOCH.

ococh:

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

Example 40: 4β-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one

OCO ₂ PNB

OCO ₂ PNB

OCOCH, OCOCH.

'OCOCH. OCOCH.

COOCII OCOCH ₃

030036/0713

BAD ORIC

0.6 g of 4ß-vinylthio (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidia-2-one, dissolved in 30 ml of benzene. and 0.6 g Acetoxyi.iethylglyoxylat (freshly made by Ozonolysis of diacetoxymethyl fumarate) were refluxed. The reaction was over after 2 hours. The condensation product could be used for the next stage without further purification will.

Example 41: 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one

OCO ₂ PNB

-N

_oir ^ OCOCH ₃

COOCh ₂ OCOCH ₃

OCO ₀ PNB

OCOCH, OCOCIL

N \ - € l

COOCh ₂ OCOCH ₃

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

Example 42: 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenem «thy1) -azetidin-2-one

030036/0713

• 4 *

OCO ₂ PNB

"OCOCH, OCOCH-

COOCh ₂ OCOCH ₃

OCO ₂ PNB

COOCH ₂ OCOCh ₃

A solution of U, 760 g of 4β-vinylthio (1,2-diacetoxymethyl) -3- (1-p-nitrobenzoyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one in 10 ml of tetrahydrofuran and 10 ml of dioxane was mixed with 2 equivalents Triphenylphosphine and 1.1 equivalents of pyridine were stirred at 50 ° C. overnight. The phosphorane was determined by column chromatography Purified on silica gel using 70:30 dichloromethane-ethyl acetate was eluted. 0.480 g of the compound mentioned in the title were obtained.

Example 43: 4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one

OCO ₂ PNB

OCOCH.

COOCH OCOCH ₃

OCO ₂ PNB

OCOCH.

_{0 <} Η-Νγ _ΐ44ΐ3

COOCIi ₂ OCOCII ₃

0.45 g of 4β-vinylthio (1,2-diacetoxymethyl) -3- (1-pnitrobenzyloxycarbonyloxyethyl) -1 - (Acetoxymethyloxycarbonyl-, i-triphenylphosphoranylidenemethyl) -azGtidin-2-one were in 50 ml dichloroethane dissolved and cooled to -20 ° C. 30 ml one Solution of trifluoroacetic acid in dichloromethane were added,

030036/0713

BATH ORIGINAL

After a few minutes, ozone in oxygen was bubbled through until a light blue color appeared. The reaction was stopped and a few drops of trimethyl phosphite were added. The organic phase was washed with saturated NaHCO solution and dried _{over Na 3} SO _4. 0.260 g of the compound mentioned in the title were obtained.

Example 44: 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -acetiuin-2-one

OCOCH. OCOCH-,

COOCIL

OCO ₂ PNB

■ OCOCH ₃ OCOCH ₃

COOCH.

1.5 g of vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-i-propenyl) azetidin ~ 2 ~ one-5 - oxide were in 10 ml of anhydrous dimethylformamide dissolved and cooled to -20 ° C. 0.8 ml of phosphorus tribromide were added, the mixture was stirred for 10 min, diluted with ethyl acetate and _{washed twice with saturated NaHCO 3} solution. The over Na ₃ SO. dried and evaporated organic layer gave 1.1 g of the title compound.

Example 45: 4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -i-methoxyoxalyl-azeLidin-2-one

OCO ₂ PNB

COOCH.

OCO ₂ PNB

OC OCII. OCOCII.

COOCIL

OCOCH-

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BATH ORIGINAL

1.4 g of 4β-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one in 120 ml of dichloromethane were cooled to -78 ° C. Ozone in oxygen was bubbled through until it turned blue. The solution was _{shaken with aqueous Na 0} S ₀ O ₁ solution and poured over Na ₃ SO. dried. On evaporation, 0.8 g of the title compound was obtained.

Example 46: 4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one

OCO ^ PNB

OCO ₂ PNB

OCOCH.

-N

COOCH.

OCOCH.

0.800 g of 4ß-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -i-methoxyoxalyl-azetidin-2-one- were in 50 ml Methanol was dissolved and a few grams of silica gel was added. The mixture was left to stand for 60 min at room temperature, the insoluble material was filtered off and the filtrate, after evaporation, gave 0.300 g of the compound named in the title.

Example 47: 4β-Acetylglycolylthio-3- (1-p-nicrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-i-hydroxymethyl) -azetidin-2-one

OCO ₂ PNB

OCOCII

OCO ₂ PNB C) COCH S. J
0 ¹ 0
Ν-γΟΗ ₂ OCOCK ₃ COOCII

030036/0713

/ 0.5 g 4ß-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1 -acetoxymethyloxycarbony.1-1 -hydroxymethyl) azetidin-2-one and 0.5 g of acetoxymethylglyoxylate in 30 ml of benzene were refluxed until the reaction was complete (2 h). The compound obtained, mentioned in the title, could without further Cleaning can be used for the next stage.

Example 48: 4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbony1-1-chloromethyl) -azetidin-2-one

OCO ₂ PNB · ^0C0 2 ^PNB

OCOCH ₃ '\ ~ \ T ^0C0CH 3

COOCH ₂ OCOCh ₃

0.35 g of 4ß-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbony1-1-hydroxymethyl) -azetidin-2-one were in 10 .ml anhydrous tetrahydrofuran dissolved at 0 C. 1.1 equivalents of pyridine and 1.1 equivalents of thionyl chloride were added. The mixture was added Stirred for 10 minutes. The precipitate was filtered and the After evaporation, the filtrate gave the compound named in the title in quantitative yield. The crude product was made as such used for the next stage.

Example 49: 4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbony1-1-tripheny1-phosphoranylidenemethyl) -azetidin-2-one

030036/0713

st)

• 3βί ·

OCO _n PNB 'OCO ₂ PNB

OCOCH. ^^ ^

^X 3

cooch ₂ ococh_

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

Example 50: (5R) -Acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) - ^ - acetoxymethyl ^ -penem-S-carboxylate

OCO.PNB OCO ₂ PNB

^ 0COCH ₃ ^ \ f rf "" 0COCH ₃

-Nv-S-PPh ₃

COOCH ₂ OCOCIL

0.210 g of 4β-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonylüxyäLhyl) -1 - (1-aceloxymechyloxycdrboiiyl-i -Lriphenyiphosphoranylidenmethyl) -azetidin-2-one were dissolved in 7 ml of toluene and the solution was refluxed for 2 h. Purification by brief column chromatography, eluting with 95: 5 dichloromethane-ethyl acetate, gave 0.050 g of the title compound. ,

030038/071 3

BATH

Example 51: (5R) -acetoxymethyl-δ- (! -Hydroxy !; 2-acetoxymethyl-2-penem-3-carboxylate

Tf-

OCO ₂ PNB

OCOCH.

COOCH ₂ OCOCh ₃

OCOCH.

COOCh ₂ OCOCH ₃

0.060 g of SR-acetoxymethyl-edp-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-peneIn-3-carboxylate were _{poured into a mixture of water, ethanol and K 2} HPO ₄ and hydrogenolyzed with 10% Pd / C. Rapid purification by column chromatography on silica gel gave 0.015 g of the title compound.

When working as in the previous examples, but using 5-methyl-2-thiol-1,3,4-thiadiazole, 5-thiol-1,2,3-triazole or thiolpyrazine instead of 1-methyl-5-thioltetrazole were (5R) -2 - [(5'-methyl-1 ', 3', 4'-thiadiazol-2'-yl) -thiomethyl] -2-penem-3-carboxylic acid, (5R) -2-

■ [(1 ', 2', 3'-Triazol-5-yl) -thiomethyl] -2-penem-3-carboxylic acid, (5R) -2- (Pyrazinyl) -thiomethyl ^ -penem-S-carboxylic acid, (5R) -6- (1'-hydroxyethyl) -2 - [(5 "-methyl-1", 3 ", 4" - thiadiazol-2 "-yl) -thiomethyl] -2-penem-3-carboxylic acid, (5R) -6- (1'-Hydroxy3thyI) -2- [ (1 ", 2", 3 "-triazol-5" -yl) -thiomethyl] -2-penem-3-carboxylic acid- and (5R) -6- (1'-hydroxyethyl) -2- (pyrazinyl) -thiomethyl ^ -penem-S-carboxylic acid obtain.

When working as described above, but under

Reduce methyl 6- (1'-hydroxyethyl) -3-penicillanate according to the well-known procedure, the corresponding

6-ethyl derivatives obtained.

030036/0713

BATH ORIGINAL

Claims (22)

PAT ENlΑΛWALTE DR. ING. E. HOFFMANN (1930-1976) DIPL.-ING. W. EITLE. D R. RER. NAT. K. HOFFMANN. Dl PL.-ING. W. LEHN DIPL.-1NG. K.FOCHSLE DR. RER. NAT. B. HANSEN ARABELLASTRASSE 4 (STERN HAUS) D-8000 MO NCH EN 81 TELEPHONE (089) 911087. TELEX 05-29619 (PATH E) - 33 073 u / wa FARMITALIA CARLO ERBA SpA, MILAN / ITALY Compounds with ß-lactam skeleton, processes for their production and pharmaceutical preparations containing them Patent claims: Compounds with a ß-lactam structure of the general formula R "· -N , (D COOR ¹ where η 0 or 1, R "" denotes hydrogen, lower alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl or benzhydryl or represents a radical which "in vivo "is subject to metabolic activation and has useful pharmacokinetic properties, Z represents hydrogen, halogen, hydroxy, amino, carbamoyloxy, mercapto, a pyridinium group or a group of the formula OR ', OCOR', NHCOR 'or SR", where R' and R " are in each case lower alkyl, aryl or a heterocyclic ring, which are in each case optionally substituted, and R " ¹ denotes hydrogen, lower-alkyl, lower-alkoxy, cycloalkyl or hydroxyalkyl, the alcoholic function of the hydroxyalkyl group being free or protected . 0 3 0 C 3 Π / 0 7 1 3 BATH ORIGINAL 2. 'Compounds according to claim 1, characterized in that that the remainder that is subject to metabolic activation "in vivo" and has useful pharmacokinetic properties, an acetoxymethyl, pivaloyloxymethyl or phthalidyl group or a group of the formula -CH-OCOOC ₂ H ₅ or -CH ₂ NHCOR "" ¹ CH ₃ where R "" ¹ denotes alkyl having 1 to 5 carbon atoms, cycloalkyl or aryl. 3. Compounds according to claim T or 2, characterized in that the heterocyclic ring is a 5-methyl-1,3,4-thiadiazol-2-yl, i-methyl-tetrazol-5-yl-, 1, 2,3 ~ triazol-5-yl- or pyrazinyl group. 4. Compounds according to any one of claims 1 to 3, characterized in that R " ^{1 is} methyl, ethyl, methoxy, 1-hydroxyethyl, 1- (p-nitrobenzyloxycarbonyloxy) ethyl or 1- (Dimethyltert.butylsilyloxy) ethyl. 5. Compounds according to any one of claims 1 to 4, characterized . characterized that R "'is 1-hydroxyethyl. 030036/0713 BATH ORIGINAL 6. (5R) -Z-acetoxymethyl - ^ - penem-S-carboxylic acid. 7. (5R) ~ 2 ~ acetoxymethyl-6-ethyl-2-penem-3-carboxylic acid. 8. (5R) -2-acetoxymethyl-6- (1'-hydroxyethyl) -2-penem-3-carboxylic acid. 9. 5 (R) -2 - [(1'-methyl-1'-H-tetrazol-5'-yl) -thiomethyl] -2-penem-3-carboxylic acid. 10. (5R) -2 - [(1'-Methyl-1'-H-tetrazol-5'-yl) -thiomethyl] - __ e-ethyl ^ -penem-S-carboxylic acid. 11. (5R) -6-Π'-hydroxyethyl] -2 - [(1 "-methyl-1" -H-tetrazol-5 "-yl) -thiomethyl] -2-penem-3-carboxylic acid. 12. (5R) -2 - [(5'-methyl-1 ', 3', 4'-thiadiazol-2'-yl) -thiomethyl] ^ -penem-S-carboxylic acid. 13. (5R) -2 - [. (5'-Methyl-1 ', 3 ¹ , 4'-thiadiazol-2'-yl) -thiomethyl] -6-ethyl-2-penem-3-carboxylic acid. 14. (5R) -6-Π'-Hydroxyethyl] -2 - [(5 "-methyl-1", 3 ", 4" -thiadiazol-2 "-yl) -thioraethyl] -2-penem-3-carboxylic acid . 15. (5R) -2 - [(1 ', 2 ", 3' -triazol-5 '-yl) -thiomethyl] -2-penem-3-carboxylic acid. 16. (5R) -2 - [(i ', 2', S'-Triazole-S'-yD-thiomethylJ-G-ethyl-2-penem-3-carboxylic acid. 17. (5R) -6- [1'-hydroxyethyl] -2 - [(1 ", 2", 3 " yl) -thiomethyl] ^ -penem-S-carboxylic acid. 18. iSR) -6- ϊ 1 '-Hydi-uxyätiiyi] -2-1 (pyrazinyl; -thiomethyl] 2-penem-3-carboxylic acid. 19. (5R) -2- (pyrazinyl) -thiomethyl-1-penem-S-carboxylic acid. 20. (5R) -2 - [(pyrazinyl) thiomethyl] -6-ethyl-2-penem-3-carboxylic acid. 030036/0713 -A- 21. A method for the preparation of compounds according to claim 1, characterized in that a compound of general formula COOR wherein R denotes alkyl and R ", 'has the meaning given in claim 1, with an" acetylene derivative of the formula X ¹ CS CY wherein X ^{1 represents} a group of the formula CH “2 ': in which Z' 030036/0713 BATH ORIGINAL Halogen, hydrogen, hydroxy, amino, carbaraoyloxy or a group of the formula OR ¹ , OCOR ', NHCOR' and Y is hydrogen, lower alkyl, cyano or a group of the formula COOR or CH ₃ Z ¹ , where R and Z ' have the above meaning to a connection of the general formula , (HD wherein R, R " ¹ , X ¹ and Y have the above meanings, which then under basic conditions to a compound of the general formula , (IV) 0OR wherein R, R " ¹ , X ^f and Y have the above meaning is isomerized, where X ¹ , if it has a different meaning, by a Represents a group of the formula CH ₂ Z, in which Z has the meaning given above, and then a) the compound of the formula (IV) to a compound of all; common formula 030036/0713 BATH ORIGINAL , (XIV) wherein R " ¹ and X have the above meaning, is reduced, ozonized and hydrolyzed, which is then treated with a suitable ester of glyoxylic acid of the formula CHOCOOR "", wherein R "" has the above meaning to a compound of the general formula he , (XV) COOR "" wherein X, R " ¹ and R""have the above meaning, which compound is converted into the chlorine derivative of the general formula R "' \ ^ ^S Y ^X , (XVI) COOR "" wherein X, R " ¹ and R""have the above meaning, which is converted into the phosphorane of the general formula 030036/0713 R ¹ -ν COOR " ¹ , (XI) wherein X, R " ¹ and R""have the above meaning, is converted, which is finally cyclized to a compound of the general formula (I), or b) the compound of the formula (IV) to form a compound of general formula R " COOR where η = 1 and X, Y, R and R " ^{1 have} the meaning given above, is selectively ozonized, which is then reduced to a compound (V), where η = zero, which is reduced to a compound the general formula (O) R ¹ , (VI) II where X, Y and R " ^{1 have} the above meaning and η = zero, is hydrolyzed, which is hydrolyzed with a suitable ester of glyoxylic acid of the formula 03003-6 / 07T3 BATH ORIGINAL CHOCOOR "", wherein R "" has the above meaning to a compound of the general formula R ¹ " (O) COOR ¹ , (VII) wherein X ₇ Y, R " ¹ and R""have the above meaning and η = zero, which is converted into the chlorine derivative of the general formula (0) JJI , (VIII) COOR " wherein X, Y, R ¹¹¹ and R " ^{11 have} the above meaning and η = zero, is converted, which is converted into the phosphorane of the general formula _._ (9) 0 ' , (IX) COOR "" where R "', R" ¹ !, X and Y have the above meanings, Ph phenyl 030036/0713 BAD ORlGiA _ g represents and η = zero, which is converted to a Compound of the general formula -N O PPh ₃ COOR "" , (XI) wherein R " ¹ , R"", X and Ph have the above meaning, is ozonated, which is finally cyclized to a compound of the general formula (I), or c) the compound of the formula (IV) selectively to give a compound of the general formula COOR where η = 1 and X, Y, R and R ^{'11 have} the above meaning, is ozonated, which then gives a compound of the general formula (0) R ¹ , (VI) wherein X, Y and R " ^{1 have} the above meaning and η = 1, is hydrolyzed, which is hydrolyzed with a suitable ester of the glyoxylic acid dor formula 030036/0 713 _ iBAD ORfGINAL wherein R "" has the above meaning to a compound of the general formula (O) η
S ^ ^ X COOR ¹ , (VII) where X, Y, R "'and R" "have the above meaning and η = 1 is, which is converted into the chlorine derivative of the general formula (0) , (VIII) COOR "" wherein X, Y, R " ¹ and R""have the above meaning and η = zero, which is converted into the phosphorane of the general formula , (ix) in which R " ¹ , R"", X and Y have the above meaning, Ph is phenyl and η = 1, is converted, which is then reduced to a compound of the general formula (IX) in which η = zero, which to -a compound of the general formula 030036/0713 B A Γ "\ ΛΓ" * Ι / * \ ΙΚ I A I ⁰ , (XI) COOR "" wherein R " ¹ , R""/ X and Ph are as defined above, is ozonized, polygamy is finally cyclized to a compound of the general formula (T). 22. A pharmaceutical composition, characterized in that it contains a compound according to claim 1 or a pharmaceutical an acceptable salt thereof in admixture with a pharmaceutically acceptable "diluent or carrier. 030036/0713 BATH ORIGINAL