DE3248678A1 - NEW BICYCLIC COMPOUNDS AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

MpL Chero. DR. PETER W AGER Pl

8 monks β, Μι Telephone 223702

Today's Blcyolian Compounds and Processes for Theirs

Manufacture (III)

The invention relates to new bioyclic compounds and a process for their preparation. The new compounds correspond to the general formula (I)

SR »

COOQ *

(I)

wherein

X ¹ and Y ^{2 represent} a removable substituent which protects the carbony group, preferably a ketal group or its thio analogue,

. Uwe/· Alkyl group with 1-5 carbon atoms ^ substituted Benzy! Group, hydrogen or alkali metal

BATH ORIGINAL

ion means and

R "represents an optionally substituted hydrocarbon radical, preferably for) benzyl, 2-Aminoäthyl- or 2-Aoylaminoäthylgruppe, stands

The compounds of general formula (I) are new,

A.

effective * thienamycin analogs and can - with the exception of the compounds containing an alkyl group as substituents Q '- also for the production of thienamycin as ^ fe * β ^^ - ± rq can be used.

Thienamycin is an antibiotic with a broad spectrum of activity. It was first used microbiologically (US Pat. No. 3,950,357) and later also synthetically (DE-DS No. 2,751,597).

The aim of the invention was to work out a synthesis in the case of the azetide framework and the uC-hydroxyethyl side chain (or an easy to implement side chain) can be built up at the beginning of the synthesis and the The key compound obtained can then be worked up to thienamycin or its analogues.

It has now been found that when acylating one the amino group protected dialkylaminomalonates with diketene and reacting the acylated product with an alkali alcoholate and iodine one having an α-acetyl side chain Azetidinone of the general formula (XIII) is obtained, which is suitable as a key intermediate.

(COOZ) ₂

(XIII)

In the general formula (XIII), R stands for a removable substituent protecting the amide group, preferably for one or more times through methoxy

substituted benzyl group or optionally one or more times by methoxy-substituted phenyl group, and Z denotes an alkyl group having 1-5 carbon atoms.

The new jf of the general formula (XIIX) and their production are the subject of a further application. However, their production is also described in the example section of the present application.

It has also been found that it is expedient to react with thienamycin or its analogues the keto group in the do-C-acetyl side chain of the compound of the general formula (XIII) by a protective group which can be split off later, preferably a ketal group or its Thio analog, to protect. In particular, it is useful, with ethylene glycol or one of its thioanalogues ^, for the

game mercaptoethanol, an ethylene ketal respectively To introduce Hemithioketal-Sohutzgruppe. The on theee Way obtained compound of general formula (XII)

(XII)

wherein χ and Y together represent a group suitable for the temporary protection of the keto group, preferably for the

Ethylene ketal group or its thio analog, stand and the meaning of R as well as of Z is the same as above, is in pyridine or a similar solvent or but reacted with an alkali halide in aqueous dimethyl sulfoxide. In this way, the connections of the general formula (XI)

, 2

COOZ

(XI)

received, in c (he the meaning of R, Y, χ and Z die same as above.

The compounds of the general formula (ΣΙ) are mixtures of the cis and trans isomers. The isomers can chromatographically or based on differences in solubility separated from each other. The separated trans isomer general formula (2Ia)

(XIa)

is hydrolyzed, and the trans-carboxylic acid of the general formula (X) is obtained.

H ₃ C ~

COOH

(X)

O'

Voi-t he is in a hurry, however, to the entire Isomeijgemisoh hydrolyze, because the hydrolysis is selective (only the trans-läster hydrolyzes).

Then the trans-carboxylic acid of the general formula (X) is first treated with a carboxyl group activator, then reacted with diazomethane, and the compound of the general formula (IX) obtained in this way

COCHN,

(IX)

in the presence of water

subjected to the Wolff rearrangement (diazo-ketone rearrangement). This makes the azetidine acetic acids of the general formula (VIII)

Y ¹ Y ²

CH ₂ COOH

(VIII)

obtained, which can be reacted in various ways to give the compounds of general formula (I).

In the general formulas (S.) _f (IX) and (VIII), the meanings of χ, χ and R are the same as above.

One of the methods for the further implementation of the compounds of the general formula (VIII) is based on that one containing a phenyl group as a substituent R Compound of the general formula (VIII) nitrated and then reduced, the compounds of the general Formula (villa)

HC
^Ά 3

Y ¹
\

Y ²

CH ₂ COOH

(Villa)

J. 2 are obtained in which the meaning of χ and Y is the same as above and A for MIitro group, after the Reduction stands for) amino group. The connections of the general Formula (Villa) then become compounds of the general formula (VIIa) in a manner known per se

CHgCOOX

(VIIa)

esterified, where Z is a selectively removable esterified Group and the meaning of the other substituents

same as above. X is preferably an arylmethyl or diarylmethyl group. From the connections of the In general formula (VIIa), the amide group-protecting aminophenyl group is oxidatively converted into two with chromium trioxide in the presence of glacial acetic acid, split off, and the resulting compound of the general Formula (VI)

CH ₂ COOX

(VI)

is isolated.

Another method for the further implementation of the compounds of the general formula (VIII) is that one containing a phenyl or benzyl group which is monosubstituted or polysubstituted by methoxy as the substituent R Compound of the general formula (VIII) in a manner known per se to form esters of the general formula (VII)

ϊ ¹ Ϊ ²

-V-

■ CH ₂ COOX

(VII)

.N

1 2 converts, in which the meanings of Y, - Y and X are the same is as above and R is * phenyl or benzyl group which is monosubstituted or polysubstituted by methoxy. Well will the group R protecting the amide group is removed. If R stands for} dimethoxybenzyl group, this protective group is with

C ^ with a peroxydisulfate removed; R stands for methoxyphenyl group, they are split off with a cerium (IV) salt in the presence of an acid. The compound of the general formula (VI) obtained is isolated.

From any of the ways described obtained compounds of the general formula (VI) is then the esterifying group X - expediently by reduction, preferably by catalytic ^ hydrogenation - removed, and the resulting compound of the general formula (V)

CH ₂ COOH

(V)

12th
wherein the meaning of Y and Y is the same as is above, is activated on the carboxyl group and then with the salt of a Malonsäurehalbesters, preferably magnesium or potassium salt of a Alkylmalonatjis or in the benzyl-group-substituted Benzy lraalonat "ls _e implemented · The obtained compound of the general formula (IV)

CH ₂ COCH ₂ COOQ

(IV)

wherein the meaning of χ and χ is the same as above and Q for an alkyl group with 1-5 carbon atoms or a substituted benzyl group is in the presence of a tertiary amine reacted with sulfonic acid azide, wherein a compound of the general formula (III)

CH ₂ COCT ₂ COOQ

(III)

is obtained. This is in the presence of a rhodium salt cyolized, where a compound of the general formula (II)

H ₃ C -

Y ¹

v ~

(n)

COOQ

is obtained. In the general formulas (II) and (III), the meanings of Y, Y ^ and Q are the same as above. The compounds of the general formula (II) are the starting materials for the process according to the present invention Invention. .

Another method for the further implementation of the compounds of the general formula (VIII) is that as a substituent R one or more diiroh Compounds of the general formula (VIII) containing methoxy-substituted benzyl or phenyl groups on the carboxyl group activated, then with the salt of a malonic acid half-ester, preferably substituted with the magnesium or potassium salt of an alkyl malonate or one in the benzyl group Benzylmalonatj & s, reacts and the compound obtained "of the general formula (XIV)

Y ¹ Y ² \

HC
3

CH ₂ COCH COOQ

(XIV)

wherein the meaning of χ, ΊΓ and Q is the same as above and R 'stands for ^ one or more benzyl or phenyl group substituted by methoxy, reacted with a sulfonic acid azide in the presence of a tertiary amine. In the obtained compound of the general formula (XV)

Y ¹ Y ²

(XV)

the meaning of the substituents is the same as above.

If the substituent R contains a benzyl or phenyl group which is monosubstituted or polysubstituted by methoxy Compounds of the general formula (VIII) activated on the carboxyl group and then with an ester of Diazoacetic acid reacted, the compounds of the general formula (XV) are also formed.

Of the compounds of general formula (XV) obtained by any of the routes described, is then, in the manner already explained, the substituent R protecting the amide group is removed, and the compounds obtained of the general formula (III) become compounds of the general in the manner already described Formula (II) implemented.

The compounds of the general formulas (II) - (XV) are new compounds and racerates. Part of the connections of the general formula (XII) the subject of a separate earlier application (Hungarian patent application no. 2263 / 8O). The other compounds of the general formula (XII) and the compounds of the general formulas (XI) - (II) or (XIV) and (XV) are described in separate registrations made on the same day as the present application has been submitted.

When examining the possibilities for converting the compounds of general formula (II) into products of the general formula (I) it has been found that the latter can be obtained if the compounds of the general Formula (3D O-acylated and then with the appropriate Mercaptan converts. The substituted benzy group present in place of Q 'can, if desired are split off, and from the carboxylic acid obtained (Q '= H) the alkali salts can be formed.

The invention accordingly relates to new bicyclic

Compounds of the general formula (I), wherein

12th
Y and Y for a removable, the carboxyl group

protective substituents, preferably a ketal group or a thio analogue thereof, Q » tint denotes alkyl group with 1-5 carbon atoms ^ substituted benzyl group, hydrogen or> alkali metal ion and

R » ^{f stands} for an optionally substituted carbon hydrogen radical, preferably for a benzyl, 2-aminoethyl or 2-aoylaminoethyl group.

The invention also relates to a method for Preparation of the compounds of the general formula (I). According to the invention, these are obtained by adding compounds of the general formula (II) - in which the meaning

τ ο. ' <4.r * e

of YT and ι is the same as above and Q for'alkylenes group with 1-5 carbon atoms or for) substituted benzyl group - in the presence of a tertiary amine with a suitable O-acylating agent, preferably a sulfonyl or phosphoryl halide, and then with a mercaptan, preferably with benzyl mercaptan or Cysteamine or its N-acylated derivative, converts and those, a narrower group of the compounds of the general formula (I) forming compounds in which χ and Y and R '* have the same meaning as above and Q is identical to Q', isolated, or

of those having a closer circle of connections of the general formula (I) forming compounds in which the meanings of YT and Y are the same as above and

Around*
Q * stands for substituted benzyl group, the substituted benzyl group is removed reductively and the carboxylic acid obtained (Q '= H) converts to its alkali metal salt and the compound containing an alkali metal ion as substituent Q' is isolated.

/ lh

For the purposes of the invention, the compounds of the general formula (II) are first used in the presence of a tertiary amines with a Q-acylating agent. as O-acylating agents can be derivatives of carboxylic acids or preferably sulfonyl or phosphoryl halides be used Diphenylphosphoric acid chloride is particularly suitable

The O-aoylated compound of the general formula (II) is then with a mercaptan, preferably with benzyl meroaptan or cysteamine or its H-aoylated derivative implemented in the presence of a tertiary amine.

This implementation creates connections of the general Formula (I), the substituent Q 'is an alkyl group with 1-5 carbon atoms or a substituted benzyl group.

The substituted benzyl group is split off from the compounds of the general formula (I) containing a substituted benzyl group as substituent Q ^1. This can be done in a reductive way; Catalytic hydrogenation proved to be the most suitable. During the reduction, hydrogen-containing compounds of the general formula (I) are formed as substituents Q ', which compounds can be converted to alkali metal salts. In the first place, the sodium salt can be prepared in a simple manner by adding sodium carbonate or sodium hydrogen carbonate. The resulting compound of the general formula (I) containing an alkali metal ion, preferably a sodium ion, as substituent Q 'is isolated from the reaction mixture by extraction and / or evaporation. The compounds of the general formula (I) have pharmaceutical effects, primarily they inhibit ß-lactamase.

The invention is illustrated by the following examples explained in more detail, but is not limited to these examples.

W 1 * * ·

example 1

Athy 1- / 5- (formylaraino-ethylthio) -6- (2-methyl-1,3-dioxolan-2-y1) -7-oxo-1-azabioyolo D.2.0 Jhept-2-en-2-carboxylate 7

To the solution of 1.133 g (4.0 mmol) of ethyl- / 6- (2-methyl-1-1,3-dioxolan-2-yl) -3,7-dioxo-1-azabicy o Io [3.2.0 "I heptane-2-carboxylate7 in 10 ml of anhydrous acetonitrile are added at ⁰ ° C. within about 10 minutes with stirring, 0.61 ml (4.4 mmol) of triethylamine and 0.91 ml (4.4 mmol) of diphenylphosphoric acid chloride Stirring, a further 0.61 ml (4.4 mmol) of triethylamine and 0.46 g (4.4 mmol) of N-I ormyloysteamine are added at 0 ° C. The reaction mixture is stirred at 0 ° C. for one hour and then evaporated in vacuo The residue is dissolved in 20 ml of dichloromethane. The solution is extracted by shaking with 10 ml of 3% strength aqueous sodium hydrogen carbonate solution and then with 2 × 10 ml of water. The organic phase is dried over magnesium sulphate, filtered and the piltrate is evaporated. The residue (2.4 g) säulenchromatographisoh is worked up (adsorbent: Kieselgel 60, 0.063-0.200 0 mm; eluent: benzene: acetone 7: 3). 0.51 g (36%) of the above product will n received. ..

O '"

Melting point: 152-153 C (methanol-ether)

IR (KBr): 3400, 1790, 1700, 169Ο cm " ¹ .

¹ H-KMR (CDCl ₃ ): (51.35 t (3H), 1.45 s (2H), 2.82-3.65 m

(7H), 3.95-4.5 m (7H), 6.1 s (IH), 8.20 d (IH). ¹³ C-KMR (CDCl ₃ ): ^ 14.3, 23.4, 31.6, 38.6, 40.1, 52.0, 61.3,

. 65.2, 65.4, 67.2, 106.8, 145.0, 161.4,

161.7, 174.1.
Mass spectrum m / z: 370, 284, 242, 197, 87, 43.

The starting material was obtained in the following manner: Method I

a) 109.8 g (0.66 mol) of 2,4-dimethoxybenzaldehyde and 72 ml (0.66 mol) of benzylamine are stirred in 660 ml of methanol at room temperature for 20 minutes (from the initial Suspension becomes a clear solution). To the solution

13.2 g (0.33 mol) of sodium tetrahydroborate (III) are added in small portions with external cooling of ice water .

The course of the reaction is followed by thin film chromatography (Schiohts silica gel G according to Stahl, developer benzene: acetone - · 9 si). After completion of the reaction, the mixture is vacuum evaporated to dryness _t HHC the Rüokstand is mixed with 300 ml of water and extracted with 500 ml ether. The aqueous phase is twice more

n ■

extracted with 200 ml of ether each time. 'The combined essential Phases are dried over magnesium sulfate ^ filtered, and then 112 ml (0.66 mol) of diethyl bromomalonate and 93 ml (0.66 mol) of tert-ethylamine are added to the ethereal solution given. The reaction mixture is at room temperature Stirred for 2-3 days. The precipitated tristhylammonium

bromide is filtered off and washed with ether. Washing liquid and Piltrat are combined and evaporated.

It-

The residue is recrystallized from 150 ml of ethanol.

It

210 g of crude product are obtained, which is made from 400 ml of ethanol is recrystallized.

197 g (72 %) diethyl - ^ - benzyl-N- (2,4-dimethoxy ~ benzyl) -amino-malonate / are obtained, which melts at 62-63 ° C

It "" ■

(Ethanol).

IR (KBr) ι 1750/1725 cm " ¹ , d. '

b) 61.7 g (0.149 mole of) the method according to I a) obtained Diäthy1- ^ f-benzyl-N- (2,4-dimethoxy-benzy1) amino-malona t £ f in the presence of about 20 g Palladiuq ^ ktivkohle in ti

500 ral of ethanol hydrogenated at atmospheric pressure. The catalyst is filtered off and the Piltrat evaporated.

47.1 g (97 %) diethyl- (2,4-dimethoxy-benzylamino) -tjialonat / are obtained. If desired, this can be converted to hydrochloride. Melting point of the HCl salt 122-124X (EtOAo). '. .

IR (film) s 3250, 2900, 2850, 1730, 1720 cm " ¹ .

Elemental analysis for C ₁₆ H _{24 ClNO 6} (M β 361.82)

Regretted , % '. C. 53 11th H 6th , 69 Cl 9.80 N 3 , 87 found, % \ C. 52, 51 H 6th , 77 Cl 10.30 N 4th , 09

¹ H-NMR (CDCl3): £ 1.3 (t, 6H); 3.78 (a, 3H), 3.82 (s, 3H),

4.21 (q, 4H), 6.20 (s, 2H), 6.4-6.6 (m, 2H), + 7.3-7.55 (b, IH), 7.7 (D. ₁ s, IH),

0.) 39.6 g (0.122 mol) diethyl Z ^^ - dimethoxy-benzylamino) malonate 7 (Method I, example b) are mixed with 12.3 g (11.2 mlj 0.146 mol) of diketene in 80 ml of acetic acid cooked for half an hour. The glacial acetic acid is on the water bath distilled off in vacuo and the oily residue crystallized duroh trituration with 150 ml v / water. The product

is dissolved in 60 ml of ethyl acetate and recrystallized by adding petroleum ether. 29.6 g (60 %) diethyl- / N- (2,4-dimethoxy-ben2yl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxy'lat7 and / or its tautomers obtain. Melting point: IO6-IO7 ⁰ C.

Elemental analysis for C ₂₀ H ₂₇ NO ₈ (M = 409.43) calculated, % i C 58.67 H 6.65 N 3.42 found, % t C 58.79 H 6.33 N 3.34 .. IR (KBr): 3400, 2950, 2S50, 1730 / Ϊ740 Soh ^ i710 om ". ·

¹ H-NMR (CDCl ₃ ): cTl.l (t, 3H), 1.17 (t, 3H), 1.52 (s, iV3H),

2.8 '(<0.1H), 2.65 ( ^b , s, 2H) ,. 3.75 (s, 6H), 3.8-4.15 (m, 4H), 6.7 (*>, s, 2H), 6.25-6.45 m + 7.0-7.25 (m-, 3H).

d) 20.5 g (50 mmol) of the method I according to Example 0)

ti

produced product are i: i 50 ml of anhydrous ether suspended. Two dropping triohters are added to the suspension with vigorous stirring and external cooling with water at the same time quickly the solution of 3.45 g (150 mmol) of metallic sodium in 100 ml of anhydrous

Ethanol and the solution of 12.7 g (50 mmol) of iodine in 150 ml given anhydrous ether. 200 ml of saturated aqueous sodium chloride solution is added to the mixture while stirring given a prepared solution of 5 g of sodium hydrogen sulfite.

The mixture is poured into a soaking funnel and the precipitation of inorganic salts is prevented by adding 60 ml of water. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The oily office stand (18.5 g) is crystallized from 30 ml of 2-propanol. 10.9 g (54 ⁰ A) diethyl-ZJ-aoetyl-1- (2,4-dimethoxy-benzyl) -4-oxo-2,2-; azetidine-dicarboxylate7 are obtained, which melts at 84-85 G ( 2-propanol).

Elemental analysis for C ₂₀ H _{2 -NO 8} (M = 407.41),% :. C 58.96 H 6.19 H 3.44 found $ i C 58.99 H 6.04 N 3.57. ¹ H-NIiIR (CDCl) j S : 1.12 (t, 3H), 1.21 (t, 3H), 2.31 (s * 3H) -,

3.76 (s, 6H), 3.8-3.4 (m, 4H), 4.53 (d, IH), 4.63 (d, IH), 4.69 (s, '1H), 6.3-6.4 (m, 2H), + 7.07 (d, IH).

e) To the solution prepared with 500 ml of anhydrous dioxane of 179 g (0.484 mol) of diethyl-Z> acetyl-1- (2,4-dimethoxy-benzyl) -4-oxo-2,2-azetidine-dioarboxyla £ 7 ( Method I,

Il

Example d) and 107 ml (1.936 mol; 120 g) ethylene glycol are added dropwise with vigorous stirring and external ice water cooling 179 ml (1.452 Holj 206 g) boron trifluoride diethyl etherate. The reaction mixture is left to stand for one hour at room temperature with occasional stirring. The solution of 415 g (1.452 mol) of sodium carbonate decahydrate is slowly poured into the mixture with stirring and external ice-water cooling. One liter of ether and one liter of water are then added to the mixture and the phases are separated. The aqueous phase is extracted by shaking with 2 × 500 ml of diethyl ether. The ethereal phase is dried over magnesium sulfate. After filtering off the desiccant, it is evaporated. The residue is treated with 33.9 · g (0.58 mol) of sodium chloride, 17.4 ml (0.968 mole) of water and 220 ml DimethyIsulfoxyd added, and the mixture is stirred on the oil bath at 180 ⁰ C until completion of the reaction ( about 15 hours!

the reaction is followed by thin-layer chromatography, where as an adsorbent Kisselgel G according to Stahl, as a development

Il

ler a geraisoh of benzene and ethyl acetate in proportion 6: 4 is used). The reaction mixture is in 1100 ml Saturated aqueous saline solution poured in and then once with 1000 ml, then twice with 500 ml each Diethyl ether shaken out. The ethereal phase is clarified with activated charcoal and dried over magnesium sulfate and after filtering so "evaporated that still about

200 ml of ether remain. Then the solution is cooled with ice water. 59 g (35 %) of trans-ethyl-Zl- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) ~ 4-oxo-2-azetidine ~ carboxyla ^ are obtained . The product melts at 95 ° C

f) 0.5 g (1.2 mmol) of diethyl- £ i-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dioarboxylate / (prepared according to example d) of method I. ) are boiled in 3 ml of anhydrous tetrahydrofuran together with 0.53 g (3.6 mmol) of meroaptoethanol for 4 hours. Then 10 ml of water and 10 ml of chloroform are added to the reaction mixture. The organic phase is separated off, extracted with 5% strength aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and filtered. From the. Piltrate, the product is isolated by means of preparative thin-film chromatography (adsorbent: silica gel 60 ^ ₂ ^ A ^ 66 '^ ¹¹ * "wiokler: toluene and acetone in the ratio 8: 2). 0 | 30 g (53 %) diethyl-jQ> (2,4-diroethoxy-benzyl) -3- (2-methyl-1,3-oxathiolan-2-yl) -4-oxo-2,2-azetidine-dioarboxy-Ia ij. Are obtained.

¹ H-NMR (CDCl ₃ ): cT 0.8-1.55 (m, 6H), 1.72 + 1.77 (d, 3H),

2.9-3.4 (m, 2H), 3.75 (s, 6H), 4.0-5.0 (m, 9H), 6.4 (m, 2H) + 7.1 (d, IH).

g) To the suspension of 41.2 g (0.109 mol) of trans -A thy 1- ^ 1- (2,4-dimethoxy-benzyl) -3- (2-methy 1.-1,3-dioxolane-2 -yl) -4-oxo-2-azetidine-carboxylate 7 (manufactured according to

^324δδ78

Example e) of method I) in 50 ml of ethanol, the solution of 5.21 g (0.130 mol) of sodium hydroxide in 60 ml of water is added with stirring and external ice water cooling. The mixture is stirred until a clear solution is obtained (about 20 minutes). The solution is mixed with 100 ml of water and then extracted with 100 ml of ether. The aqueous phase is acidified to pH 1 with concentrated aqueous hydrochloric acid and then extracted with 100 ml and then twice with 50 ml of dichloromethane each time. The organic extracts are dried over magnesium sulfate, filtered and then evaporated. The oily residue is crystallized from a mixture of toluene and petroleum ether. 35 g (92 %) trans-1- (2,4-dimethoxy-benzyl) L3_ (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-acetldin-carboxylic acid are obtained. Melting point 117-118 ° C (toluene).

Blemental analysis for C ₁₇ H ₂₁ NO ₇ (M = 351.35)

Calcd, % t C 58.11 H 6.03 N 3.99 found, #i C 58.17 H 6.30 F 4.24.

IR (KBr): 3500-2500, 29ΟΟ, 1760, 1720 cm " ¹ .

¹ H-NMR (CDCl ₃ ): 6 1.39 (β, 3H), 3.50 (d, IH, J = 2.5 Hz),

3.77 '(β, -3H), 3.79 (s, 3H), 3.86 (d, IH, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4 .56 (d, 2H, J _m = 15 Hz), 6.44 (m, 2H) + 7.15 (d, IH, J = 10 Hz), 7.58 (b, _a , IH),

h) To the solution of 17.6 g (50 mmol) tranB-l- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-diozolan-2-yl) -4-oxo- 2-azetidine-carboxylic acid (prepared according to example g) of method I) in 150 ml of anhydrous tetrahydrofuran 7.3 ml of triethylamine given. Then the mixture is taking

Il *

Cooling with ice 5.0 ml (52.5 mmol) of ethyl (chiorfortsiat) was added, cooled to -15 ⁰ C and cooled for 20 minutes at this temperature. The triethylamine salt formed is filtered off at the same temperature under an argon atmosphere. The cold solution of

150 mmol of diazomethane are added to 230 ml of diethyl ether. The solution is stirred and the temperature is allowed to rise to room temperature. After two hours the mixture is evaporated to dryness. The brown, viscous Hasse is dissolved in 20 ml of benzene and purified by column chromatography (adsorbent: 150 g of silica gel 60, 0.063-0.200 mm, eluent: benzene and acetone in a ratio of 7: 2). 12.0 g (64 %) trans-4- (diazo-acetyl) -l- (2,4-dimethoxy-benzyl) 3- (2-methyl-1,3-dioxolan-2-yl) -2- azetidinone are obtained.

Elemental ^{analysis for G} ₁₈ ^H ₂₁ ^K 3 ° 6 ^ ^{M = 37} ^ i37) calculated, % i C 57.59 H 5.64
Found, %: C 57.78 H 5.39
IR (KBr): 2900, 2110, 1760 cm " ¹ .

i) The mixture of 2.25 g (6 mmol) trans-4- (Diazoaoetyl) -l- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -2-azetidinone, 100 ml of peroxide-free tetrahydrofuran and 50 ml of water are irradiated for about 4 hours in .einem Pyrex device with a removable high pressure mercury lamp (HPK 125) under an argon atmosphere. The solution is then concentrated to 50 ml in vacuo and diluted to 130 ml with water. 2.4 ml of 10% strength aqueous sodium hydroxide solution are added to the aqueous solution. The alkaline solution is extracted with 3 × 20 ml dichloromethane. The aqueous phase is then acidified to pH 2 with concentrated aqueous hydrochloric acid. The acidic solution is extracted with 3 × 20 ml of dichloromethane. The extract is dried over magnesium sulphate and, after filtration, evaporated to dryness. The residue is crystallized from ether. 1.82 g (83%) / trans-l - (2,4-dimethoxy-benzyl) -3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl7- acetic acid / melting point: 124 ⁰ C (etherJ7 are obtained.

Elemental analysis for C LJO. (M = '365.37)

Io dj (

Calculated,%: 0 59.17 H 6.34 N 3.83 found%: C 59.22 H 6.49 N 4.07.

IR (KBr): 3500-2300, 2900, 1730, 1700 cm " ¹ .

j) To the solution of 5.4-8 g (15 mmol) of ^ (2,4-dimethoxy-benzy1) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2 Acetidinyl / acetic acid (prepared according to example i) of method I) in 50 ral dichloromethane are added at room temperature with stirring, 3 _{tons of} O5 g (15.75 mmol) of diphenyldiazomethane. After the evolution of nitrogen has ceased, the excess diphenydiazomethane is decomposed with a few drops of acetic acid. The solution is evaporated to dryness and the residue (6.77 g) is dissolved in 84 ml of acetonitrile. ² ^ ^ ⁶ * "solution are 16.2O g (60 mmol) of potassium peroxydisulfate (K ₃ S ₃ Og), 21.60 g (120 mmol) of disodium hydrogen phosphate monohydrate (Na'pHPO. .H _? 0) and 54 ml of water The mixture is stirred vigorously for 4 hours, boiled up and finally cooled. The cold mixture is filtered and the two-phase filtrate is separated into its phases. The aqueous phase is extracted with 3 × 30 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and dried . nitriding evaporated the prepared with benzene solution of the Rückstandes.wird worked up by column chromatography (adsorbent Kieselgel 60 j, 0 .050 to .200 mm, KLutionsraittel: benzene and acetone in a ratio of 7: 2). 2.68 g (47%) of benzhydryl / • brans- / J (2-raethyl-l, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl7 ~ acetat7 are obtained. melting point: 130 ⁰ C (ethanol).

Elemental analysis for ° ₂ 2 ^H 23 ^N0 5 ^ ^M

calculated; #: "C 69.27 H 6.08 N 3.67 found, % i C 69.15 H 6.20 K 3.55. '

IR (-KBr): 3250, 2900, 176O, 1740 onf ¹ .

¹ H-NIvIR (CDCl ₃ ): ^ 1.39 s (3H), 2.63 dd (2H, j = 4.4 Hz)

and 2.89 dd (2H, J * 9.1 Hz), 3.97 m (5H), 6.12 s (IH), 6.9 s (IH), 7.28 s (10H),

k) The mixture of 3.80 g (10 tnMol) benzhydryl / trans ~ - ^] i- ⁽² - ^met hyl-l, 3-dioxolan-2-yl) - 4 ~ oxo-2-azetidinylT-aoetat /, 0.4 g trooked Palladiur activated charcoal with 8 % palladium content and 50 ml anhydrous ethanol is stirred under a hydrogen atmosphere. The uptake of hydrogen has ended after two hours. The catalyst will

ti

filtered off and washed with 10 ml of anhydrous ethanol. The piltrate combined with the washing liquid is evaporated on a water bath at 30-40 ° C. The residue will

Il

Washed with 3x20 ml ether and decanted. 2.02 g (94 %) / trans -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-acetic acid are obtained. Melting point; 126-129 C.

Elemental analysis calculated for CH ₁ NO (M = 215.20),%: N 6.51

found, % ·. N 6.34

IR (KBr): 3500-2300, 3350, 2900, 1730, 1700 cm " ¹ .

1) The mixture of 2.15 g (10 mmol) of trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-acetic acid _t 1.82 g (11 mmol) of 98% carbonyldi-imidazole and 60 ml of anhydrous tetrahydrofuran is stirred for 30 minutes. The solution is mixed with 1.58 g (11 mmol) of magnesium ethyl malonate and the reaction mixture is stirred at room temperature for 2 hours. The equipment is evaporated in a vacuum. The residue is stirred gently for a few minutes with 180 ml of dichloromethane and 180 ml of 0.5 η aqueous hydrochloric acid and the mixture is then separated into its phases. The aqueous phase is extracted by shaking with 3 × 30 ml of dichloromethane, and the combined organic phases are washed with 2 × 20 ml of 3% strength aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and, after filtering, evaporated to dryness. 2.02 g (71 i>) Ethyl - /? - Zt * rans-3- (2-raethyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-3-oxo-butanoate / will get"

ο ^w
Melting point: 65-68 C (ether).

IR (KBr): 3220, 1770, '1735, 1720 cm " ¹ .

¹ H-NMR; Jl, 28 t (3H), 1.42 s (3H), 2.77 dd and 3.10 dd (2H, J = 9.4 Hz and J = 3.6 Ha) »5.11 d (IH, J = 2.6 Hz), 3 * 75-4.35 m (7H), 6.13 s (IH).

m) To the solution of I ₈ 426 g (5.0 tnmol) ethyl- / 4- / trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7- 3-oxo-butanoate / (prepared according to Example 1) of method I) in 15 ml of anhydrous acetonitrile are added 0.69 ral (5.0 mmol) of triethylamine and 0.9.86 g (5.0 mmol) of tosyl azide while cooling with ice. The solution is stirred for 3 hours, its temperature rising to room temperature. Then the solution is evaporated to dryness * The residue is dissolved in benzene and worked up by column chromatography. (Adsorbent? 100 g silica gel 60, 0.063-0.200 mm, eluent: benzene and aoetone in a ratio of 7: 2).

1.12 g (72 %) ethyl Z2-diazo-4- _i / irans-3- (2-methy1-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-3-oxo-butanoate7 become obtain.

IR (film): 3250, 1750, 1710, 163Ο cm " ^{1. 1} H-NlR: £ 1.36 t (3H) ₁ 1.42 s (3H), 2.96 dd and 3.44 dd (2H, J = 9.4 Hz and J = 3.6 Hz), 3.75-4.15 m (5H), 4.33 q (2H), 6.08 s (Hl).

n) To the solution of 1.245 g (4.0 mmol) of ethyl- / 2-diazo-4- / trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2- azetidinyl7-3-oxo-butanoate / (prepared according to example m) of method I) in 10 nl benzene are added at the boiling point, a total of 0.03 g dirhodium tetraacetate ^ h ₂ (OAo) .. 2THP /. After the reaction has ended the reaction mixture is filtered through Celite and the piltrate is evaporated.

1.13 g (100 %) ethyl- / 6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-1-azabicyoloD.2.0] lheptane-2-carboxylate7 are obtained. The product melts at IO9 ⁰ C.

IR (KBr); 1750, 1735 whether " ¹ .

¹ H-NIR: S l'i30 (3H, J «7.4 Hz), 1.49 s (3H), 2.41 dd (IH, J _gem = 19.5 Hz, J _viQ - 7.5 Hz ), 2.9Q dd ^(1H » ^J according to" ¹⁹ » ^{5 Ez} > ^J vic" ⁷ '° ^Hz) » ³ · ^{43 d} (IH, J = 2.4 Hz), 3.97-4.20 m ( 5H), 4.24 q (2H,

J * 7.4 Hz) ', 4.63 t (IH, J = * 0.6 Hz).

Method II

a) A mixture of 24.6 g (0.2 mol) of 4-methoxyaniline and 23.9 g (17 ml, O ₁ I mol) of diethyl (bromomalonate) is stirred at room temperature for two days. The substance obtained is triturated with 100 ml of diethyl ether, the precipitated 4-methoxy-anisidine-hydrobromide is filtered off and washed on the filter with a little diethyl ether. The mother liquor is evaporated and the residue is crystallized by adding dilute acetic acid. 13.2 g (47%) * diethyl (4-methoxy-anilino) -malonate are obtained.

ο "
Melting point χ 64-65 C (ethanol).

Elemental analysis for C ₁ -H ₁ NO (M = 281.31) calculated, "%: C 59.77 H 6.81 N 4.99 found, % i G 59.99, H 6.97 N 5.25.

IR (KBr): 3300, 1775, 1725 cm " ¹ .

¹ H-NMR (CDCl3): <3 1.23 (t, 6H, J = 7.2 Hz), 3.67 (a, 3)

4.2 (q, 4H, J = 7.2 Hz), 4.62 (s, IH), 4.1-4.5 (η s, IH), 6.55 (2H) +6.73 ( 2H), (AA ¹ BB ', J = 9 Hz).

b) 11.2 g (0.04 mol) of the diethyl (4-methoxy-anilino) -malonate4s prepared according to Example a) of Method II are dissolved in 15 ml of glacial acetic acid together with 4 g (3.7 ml, 0.048 mol) Diketene boiled for half an hour. The solution is evaporated in vacuo. The oily residue is triturated with diethyl ether and filtered. 10.5 g (72 %) diethyl- ^ T- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidinedicarboxylate ^ and / or its tautorea are obtained. Melting point: 136-137 C (ethyl acetate) IR (KBr): 36ΟΟ-3ΟΟΟ, 1760, 1740, 1685 om " ¹ .

Elemental analysis for C ₁₈ H ₂₃ NO ₇ (M = 365.38)

calculated, % t 0 59.17 H. 6.39 N 3.83 found, % i C 58.98 H 6.90 N 4.04 «

¹ NMR (CDCl ₃ ): <f 1.07 (t, 3H, J = 7.2 Ha), 1.28 (t, 3H ₉ J = 7.2 Hz), 1.58 (s, 3H), 2.76 (s, 2H), 3.64 (s, 1H), 3.76 (s, 3H), 4.1 (q, 2H ₉ J - 7.2 Hz), 4.27 (q, 2H , J = 7.2 Hz), 6.7 (2H) + 7.0 (2H), (AA ', SB *, J = 9 Hz).

c) 9.1 g (0.025 mol) of diethyl- ^ U-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dioarboxyla ^ (prepared according to example b) of method II) are "suspended in 50 ml of anhydrous diethyl ether. At the same time with vigorous stirring and external ice water cooling Solution of 1.72 g of metallic sodium in 30 ml of water

Il

free ethanol and the solution of 6.35 g (0.025 mol) of iodine in 50 ml of anhydrous diethyl ether were added dropwise. The mixture is poured into 100 ml of saturated aqueous sodium chloride solution and then 2 g of lithium hydrogen sulfite and 2 ml of glacial acetic acid are added. The ethereal phase is separated off, the aqueous phase is shaken out with 3x50 ml of diethyl ether ^. Ιλμ { and the combined ethereal phases are dried over magnesium sulphate. After filtering, the solution is evaporated. The oily residue is crystallized by trituration with 2-propanol. 6.2 * g (68 %) diethyl-ZJ-aoetyll- (4-methoxyphenyl) -r4-oxo-2,2-azetidine dicarboxylate /

ο "are obtained. Melting point 70-71 C (ethanol).

Elemental analysis for C ₁₈ H ₂₁ NO ₇ (M = 363.38)

calculated, % '. C 59.50 H 5.82 N 3.85 x Found, % t C 59.04 H 5.84 N 4.08 IR (KBr): I76O, 1735, 1720 cm " ¹

¹ H-NMR (CDCl ₃ ) J ς 1.20 (t, 3H, J. 7.2 Hz), 1.22 (t, 3H,

J = 7.2 Hz), 2.33 (s, 3H), 3.7 (s, 3H), 4.17 (q, 2H, J = 7.2 Hz), 4.19 (q, 2H, J = 7.2 Hz), 4.7 (s, IH), 6.7 (2H) + 7.31 (2H), AA ', BB, j " _{s 9 Ez) m}

d) 6 g (0.0165 mol) diethyl- / β-aoetyl-1- (4-metho: jcyphenyl) -4-oxo-2,2-azetidine-dioarboxylate 7 (prepared according to example o) of method II) are in a mixture from 20 ml of anhydrous dioxane and 4.1 g (3.75 ml, 0.066

Mol) ethylene glycol dissolved. The solution is stirred and cooled externally with ice and added 7.1 g (6.3 ml, 0.05 Mol) boron trifluoride diethyl etherate added. The reaction mixture is stirred at room temperature for a further 2 hours. The pH of the solution is adjusted with aqueous sodium carbonate solution made alkaline, then 100 ml of water are added to the solution and 3 × 50 ml of diethyl ether are added extracted. The organic phase is dried over magnesium sulfate and evaporated after filtering. The oily one

ti

The residue is crystallized by trituration with ether. 6 g (89 %) diethyl - /! 5- (2-methyl-1,3-dioxolan-2-yl) -l- (4-methoxyphenyl) -4-oxo-2,2-asetidine-dicarboxylate / will get. Melting point: 82-83 C (ethanol).

Elemental analysis for C ₂₀ H ₃ HO (M = 407.43) calculated,%: C 58.96 H 6.18 Ii 3.44 "· ■ found, %: C 58.70 H 5.68 N 3.63 IR (KBr): 1740 cm " ¹ (wide)

¹ H-MHiR (CDCl3): -J 1.17 (t, 3H, J = 7.2 Hz), 1.26 (t, 3H,

J * = 7.2 Hz), 1.5 (s, 3H), 3.7 (s, 3H), 3.9 (m, 4H), 4.2 (m, 6H), 6.67 (2H ) + 7.34 (2H), (AA ¹ , BB ', J = 9 Hz).

e) 11 g (0.0245 mole) of diethyl _<ZJ- (2-methyl-l, 3-dioxolan-2-yl) -l ~ (4-methoxy-phenyl) -4-oxo-2,2-azetidindicarboxylat7 (prepared according to example d) of method II) are dissolved in 20 ml of dimethyl sulfoxide. 1.72 g (0.0295 mol) of sodium chloride and 0.9 ml (0.049 mol) of water are added to the solution and the mixture is stirred at 175 ° C. until the reaction, which is followed by dümisohiohtchromatographically (adsorbent: 'silica gel G after Steel, developer: benzene and ethyl acetate in a ratio of 6: 4), has expired «

After cooling, the reaction mixture is poured into 150 ml

Poured saturated aqueous sodium chloride solution and extracted with 3x50 ml diethyl ether. The organic Phase is dried over magnesium sulphate and evaporated after nitriding. The oily residue obtained

Il ·

(6 g) is dissolved in 25 ml of 96% ethanol. The solution is cooled from the outside with Biswasser and with a solution of 0.72 g (0.018 mol) of sodium hydroxide in 10 ml of water added »The mixture is stirred for half an hour, then diluted with 50 ml of water and with 2 x 25 ml of dichloromethane extracted. The aqueous phase is concentrated with aqueous hydrochloric acid acidified to pH 1 and then extracted with 3x25 ml dichloromethane. The organic phase is dried over magnesium sulfate and evaporated after filtering. The oily residue is made from benzene crystallized. 4 g (54%) trans -3- (2-Hethyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidine-carbonic acid will get.

Elemental analysis for C ₁ , 63 H _r N O ₆ ( M = 307.32) calculated, % i C 58 40 H 5 , 57 π 4.56 found, SS: C 58 5 , 80 4.66

IR (KBr): 3400-2700, 1750 om " ¹ (wide)

¹ H-ITOLR (CDCI): Jl, 5 (s, 3H), 3.7 (d, IH, J = 2.5 Hz),

3.76 (s, 3H), 4.0 (m, 4H), 4.38 (d, IH, J = 2.5 Hz), 6.82 (2H) + 7.26 (2H), AA ¹ EB *, J m 9.5 Hz), 9.2 (s, IH).

f) 3g (P, 01 mol) of the method according to example e) The compound produced by II is dissolved in 20 ml of anhydrous tetrahydrofuran. 1.11 g are added to the solution (1.56 ml, 0.011 mol) given anhydrous triethylamine. The solution is cooled to -15 ° C and, with constant stirring, 1.2 g (1.06 ml, 0.011 mol) of ethyl (chloroformate) offset. After 20 minutes it will be boiled out The salt was filtered off under a nitrogen atmosphere. 4.8 g (0.025 mol) are added to the piltrate at room temperature

Diazomethane, dissolved in diethyl ether, added. The reaction mixture is stirred for two hours, then the excess of the diazomethane is decomposed with acetic acid and the solution is evaporated in vacuo. The oily residue crystallizes. 3 g (90 %) of trans-4- (diaaoaoetyl) -3- (2-methy1-1,3-dioxolan-2-yl) -l- (4-raethoxyphenyl) -2-azetidinone are obtained. Melting point: 95-96 C (benzene / ether).

IR (KBr): 2200, 1760, 1640 cm "" ¹ .

¹ H-NMR (CDCl ₃ ): J 1.50 (s, 3H), 3.51 (d, IH, J = 2.6 Hz),

3.75 (s, 3H), 4.05 (m, 4H), 4.31 (d, IH, J = 2.6 Hz), 5.47 (s, IH), 6.85 (2H) + 7.30 (2H) (AA ¹ BB ', J = 9 Ba) ..

g) 3.3 g (0.01 mol) trans ~ 4- (diazpaoetyl) -3- (2-methy1-1,3-dioxolan-2-yl) -l- (4-uiethoxyphenyl) -2- azetidinone (prepared according to example f) of method II) are dissolved in a device of 50 ml of water and 100 ml of tetrahydrofuran. The solution is irradiated at room temperature under a nitrogen atmosphere in a photoreactor with a high pressure mercury lamp. The course of the reaction is followed by thin-layer chromatography (adsorbent: silica gel G according to Stahl, developer: benzene and acetone in a ratio of 7: 1). After the reaction is complete, the tetrahydrofuran is removed in vacuo. removed from the solution. The residue is made alkaline with 20% strength aqueous sodium hydroxide solution and extracted with 3 × 15 ml of dichloromethane. The aqueous phase is acidified to pH 1-2 with concentrated aqueous hydrochloric acid and then extracted by shaking with 3 × 20 ml of dichloromethane. The organic phase is dried over magnesium sulfate and, after filtration, evaporated. 1.6 g (50 %) ^ trans-3- (2-Hethyl-1,3-dioxolan-2-yl) -l- (4-raethoxyphenyl) -4-oxo-2-azetidinyi7-acetic acid are obtained .
IR (film): 3500-2500, 1760-1700 cm "" ¹ .

Elementary analysis for C ₁₆ H ₁ KOg (Id = 321.35) calculated, % -. C 59.80 H 5.96 H 4.36 found, #: 0 59.60 H 5.76 N 4.08.

h) 1.0 g (3.12 nmol) of the compound prepared according to Example g) of Method II is dissolved in 10 ml of dichloro-diethan. The solution of 0.53 g (3.12 mmol) of diphenyldiazomethane in 10 μl of dichloromethane is added dropwise to the solution at room temperature. After the evolution of gas has ceased, the solution is evaporated in vacuo. 1.45 g (98 %) benahydryl - /? Rans - /> (2-methyll, 3-dioxolan-2 ~ yl) -l- (4-methoxyphenyl) -4-oxo ~ 2-azetidinyl7-acetate / will get"

Elemental analysis for CH ₂ NO ₆ (1 = 487.55) calculated, #: C 71.44 H 5.99 N 2.87 found, g: C 71.13 H 6.21 Έ 2.93. ¹ H-HTiR (CDCl ₃ ): Jl, 35 (s, 3H), 2.7-3.1 (m, 2H), 3.38 (d, ". IH, J = 2.5 Hz), 3 , 72 (s, 3H), 3.8-4.1

(ü, 4H), 4.1-4.5 (m, IH), 6.85 (s, IH),

6.7-7.4 (ra, 14H).

i) 0.28 g (0.65 mmol) of the compound prepared according to Example h) of Method II are dissolved in 2 ml of acetone. _{The solution of 0.9 g (1.6 mol) cerium (IV) ammonium nitrate ^ Ce (HH /} ,) ₂ (N0.), Prepared with 2 ml of 5% strength aqueous sulfuric acid, is added dropwise to the solution at room temperature. given g7. After the addition, the reaction mixture is stirred for a further 2 hours and then carefully neutralized with 5% aqueous sodium hydrogen carbonate solution. The mixture is extracted with 3 × 4 ml of ethyl acetate. The organic phase is dried over magnesium sulfate and, after filtration, evaporated in vacuo. The oily residue is purified by means of preparative thin-layer chromatography. (Adsorbent: silica gel 60, 0.050-0.200 mtn, eluent: benzene and acetone in the ratio 7s2).

0.06 g (30 %) benzhydryl - /, trans- £> - (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -aoetate / are obtained # The physical data of the product correspond to those of the compound prepared according to example j) of method I.

The compound can be converted to the starting compound of Example 1 in the manner described in Examples k) -η) of Method I.

Method III

a) 38 g (0.152 mol) diethyhanilino malonate) (R. Blank: Ber, 3Jl, 1815 / Ϊ8987) are dissolved in 38 ml of glacial acetic acid with 15.3 g (13.9 ml, 0.182 mol) diketene for half an hour long cooked. The glacial acetic acid is distilled off in vacuo on a water bath. The oily residue is going through

IT

Trituration with ether crystallizes. 36.5 g (72 %) diethyl (N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dioarboxylate) and / or its tautomer

ο "obtained. Melting point: 98-99 C (ethyl acetate / petroleum ether)

Elementary analysis for C ₁ 88 L7 ^H i 21 NO ₆ (M = 335, 35) calculated, % i C 60, 83 H 6th , 31 N 4th , 18 found,? &: C 60, H 6th , 15 N 4th , 43.

IR (KBr): 3350, 2950, 176Ο, 1750 d, 1700 cm " ¹ .

¹ H-NMR (CDGl ₃ ): ^ 1.02 (t, .3H), 1.3 (t, 3H), 1.6 (s, 3H),

2.8 (s, 2H), 3.6 (b, s, IH), 4-4.45

(m, 4H), 7.2 (s, 5H).

b) 10.2 g (0.447 mol) of metallic sodium become

η
dissolved in 250 ml of anhydrous ethanol. First 50 g (0.149 mol) of diethyl (N-phenyl-3-hydroxy-3-methyl-5-OXO-2,2-pyrrolidine-dicarboxylate) (prepared according to Example a) of method III) are added to the solution and then while stirring vigorously the solution of 37.9 g (0.149 mol)

ti

Iodine given in 200 ml of anhydrous ether. after the Reaction is over, become the reaction mixture

8.5 ml (8.9 g, 0.149 mol) of glacial acetic acid, 200 ml of water and

»Ι
100 ml of ether given. The organic phase is removed

separates and the aqueous phase extracted with 100 ml of ether. The ethereal phases are combined, dried over magnesium sulfate and, after filtration, evaporated. The oily residue is recrystallized from 50 ml of 2-propanol. 31 g (62 %) diethyl (3-acetyl-1-phenyl-4-oxo-2,2-azetidine dicarboxylate) are obtained. Melting point: 55-56 ⁰ C (2-propanol)

Elemental analysis for C H_ NO ^
calculated, % '. C 61.25 H 5.75 K 4.20 found, % '. C-61.38. H 5.89 N 4.24. IR (KBr): 1770, 1740, 1720 cm " ¹

¹ H-MS (CDCl ₃ ): £ 1.12 (t, 6H), 2,: 3 (s, 3H), 4.25 (q, 4H),

4.75 (ff, '1H), 7.0-7.6 (m, 5H).

c) 28.5 g (0.085 mol) of diethyl (3-acetyl-1-phenyl-4-0X0-2,2-azetidine dicarboxylate) (prepared according to example b) of method III) are in the mixture of 90 ml dissolved anhydrous dioxane and 21 g (18.8 ml, 0.34 mol) anhydrous ethylene glycol. 36.5 g (31.5 ml, 0.255 mol) of boron trifluoride diethyl etherate are added dropwise from the outside to the solution while stirring and cooling with water. The solution is stirred at room temperature for two hours and then neutralized with saturated aqueous sodium carbonate solution. The neutral solution is diluted with 100 ml v / ater and then extracted with 3 × 50 ml diethyl ether. The organic phase is dried over magnesium sulfate and filtered. evaporated in vacuo. The oily residue crystallizes on trituration with ether. 28.5 g (90 %) diethyl-iJ-phenyl-3- (2-methyl-1 _e 3-dioxolan-2-yl) -4-axo-2,2-azetidin-dicarboxylate / are obtained. Melting point: 59-61 ⁰ O (gasoline).

Elemental analysis for CH NO- calcd,%: C 60.47 H 6.14 N-3.71 found, % i C 60.74 H 6.21 N 3.79.

IR (KBr): 1770, 1740 at " ¹ .

¹ H-NMR (CDCl ₃ ): J 1.18 (t, 3H, J - 7.2 Hz), 1.24 (t, 3H,

J = 7.2 Hz), 1.51 (s, 3H), 3.92 (m, 4H),

4.3 (m, 5H), 7.2 (m, 5H).

d) 28.5 g (0.075 mol) of diethyl £ "-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azetidine-dicarboxylate 7 (prepared according to example o) of method III) are added in a mixture of 44 ml of Diine thy lsulf oxy d, 5 »6 g '(0.1 Mol) sodium chloride and 3.05 ml (0.17 mol) water i> ei 175 C stirred until the reaction has ended. The course of the reaction is followed by thin layer chromatography. (Adsorbent: Kieaelgel G according to Stahl, developer: It

Benzene and ethyl acetate in a ratio of 6: 4). The solution is in 200 ml of saturated aqueous sodium chloride solution poured in and extracted with 3x150 ml of diethyl ether. The organic phase is dried over magnesium sulfate and evaporated after filtering. The oily residue (16.4 g) is dissolved in 100 ml of ethanol and the solution with ice-water cooling and constant stirring with the solution of 2.15 g (0.054 mol) of sodium hydroxide in 30 ml of water offset. The reaction mixture is stirred for 30 minutes, 150 ml of water are then added and the mixture is extracted with 3 × 20 ml of diethyl ether. The aqueous phase is concentrated with Aqueous hydrochloric acid strongly acidified (pH = 1) and extracted with 3x50 ml of dichloromethane. The organic Phase is dried over magnesium sulfate and evaporated after filtration. The oily residue crystallizes from benzene. 12 g (56%) trans-1-Pheny1-3- (2-methy1-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid will get. Melting point: 165 ° C (benzene).

Elemental analysis for C ₁₄ H ₁₅ NO ₁ . (M = 277.27) Calculated, %: 0 60.64 H 5.45 N 5.05 found % i C 60.64 H 5.72 N 4.99. IR (KBr): 3500-2700, 177O ₁ 1730 cm " ¹ .

¹ H-NtIR (CDCl ₃ ): cT 1.5 (s, 3H), 3.69 (d, IH ₉ J = 3 Hz),

4.0 (m, 4H), 4.4.2 (d, IH, J = 3 Hz), 7.3 (m, 5H) ₉ 7.55 (s, IH).

e) 13.8 g (0.05 Hol) according to example d) the Method III obtained trans-1-phenyl-3- (2 * -methy 1-1,3-dioxolan-2-yl) -4-oxo-2 = azetidine-carboxylic acid are dissolved in 100 ml of anhydrous tetrahydrofuran. 5.55 g (7.7 ml, 0.055 mol) of ethyl, (ohlorformiat) given. The mixture is 20 minutes long stirred, then the precipitated salt was filtered off under a nitrogen atmosphere and added to the Slltrat with stirring solution of 22.6 g (0.15 mol) prepared with diethyl ether Given diazomethane. After the evolution of gas has ceased, the excess of the diazomethane by adding Glacial acetic acid decomposed and the solution evaporated. The oily residue crystallizes on trituration with ether.

11.5 g (77 %) trans-4- (diazo-acetyl) -l-phenyl-3- (2-methyll, 3-dioxolan-2-yl) -2-azetidinone are obtained. Enamel

o ir - "

point: 96-97 C (benzene / ether).
IR (KBr). 215O, 1760, 1635 ota " ^1
1 H-HMR (CDCl): <y 1.50 (s, 3H), 3.5 (d, IH ₈ J »2.6 Hz),

3.50 (m, 4H), 4.34 (d, IH, J = 2.6 Hz),

5.45 (β, -IH), 7.25 (m, 5H).

f) 3.8 g (0.0126 mol) of the trans-4- (diazo-aoetyl) -l-phenyl-3- (2-methyl-1,3-dioxolane-2-, prepared according to Example e) of Method III yl) -2-azetidinones are dissolved in a mixture of 100 ml of tetrahydrofuran and 50 ml of water. The solution is irradiated at room temperature under a nitrogen atmosphere in a photoreactor with a high-pressure mercury lamp. The course of the reaction is followed by thin-layer chromatography (adsorbent? Silica gel G according to Stahl; benzene and acetone in a ratio of 7si). After the reaction is complete, the tetrahydrofuran is removed in vacuo. The residue is made alkaline with 20 foxgev aqueous sodium hydroxide solution and

extracted with 3x15 ml dichloromethane. The watery one The phase is acidified to pH 1-2 with concentrated aqueous hydrochloric acid and then with 3 × 20 ml of dichloromethane extracted. The organic phase is dried over magnesium sulfate and, after filtration, evaporated.

Il

The product crystallizes on trituration with ether. 1.8 g (50 fo) ^ trans-l-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-οχο-2-azetidiny! / - acetic acid are obtained.

ο ^w
Melting point: 128-129 G (ethanol).

Elemental analyzes for C ₁₅ H ₁₇ NO ₅ (M = 291.29) calculated, % i C 62.00 H 5.88 N 4.82 found, % t C 61.75 H 5.86 N 5.08.

IR (KBr): 1760, 1740 cm " ¹ .

¹ H-NMR (CDCl ₃ ): <£ 1.48 (s, 3H), 2.65 (dd, IH, J = 15 Hz,

^J vic ^{= 8 Hz) + 3 '12 (dd} » ^J gem ^{= 15 Ha} ' J _vic = 8 Hz), 3.47 (d, IH, J = 2.5 Hz),

3.98 (m, 4H), 4.4 (m, IH), 7.3 (m, 5H), 9.33 (sz, s, IH).

g) 0.81 ml of concentrated nitric acid (% β 1.5) are added dropwise to 3 ml of acetic anhydride with constant stirring on the ice water bath so that the temperature of the solution does not rise above + 5 ° C. The nitration mixture prepared in this way is added to the solution of 2.9 g (0.01 mol) of the ^ trans-1-Pheny1-3- (2-methy1- (2-methy1-) prepared in accordance with Example f) of Method III at -5 C with stirring 1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / acetic acid was added dropwise to 20 ml of anhydrous dichloromethane. The Gemisoh is stirred for one hour, then poured onto ice water and the phases are separated. The aqueous phase is extracted with 2 × 25 ml dichloroethane. The combined organic phases are dried over magnesium sulfate and, after filtration, evaporated in vacuo. The oily residue crystallizes on trituration with ether. 1.95 g (58 #) / trans -3- (2-methyl-1,3-dioxolan-2-yl) -1- (2-nitrophenyl) -4-oxo-2-azetidinyl7- "acetic acid

BATH ORIGINAL

* - 175-176 "- -." 3248678 Melting point s H 4.79
H 4.68 obtain. Elemental analysis for C ₁ "
calculated, % i C 53.57
found, % z C 53.31 ⁰ C (ethanol). M = 336.33)
N 8.33
H 8.21.

IR (KBr); 36OO-29OO, 1740, 154-0, 1340 ca " ¹ .

h) 0.336 g (1 mmol) of the method according to Example g) III prepared / trans-3- (2-] methyl-1,3-dioxolan-2-yl) -1- (2-nitrophenyl) -4-oxo-2-azetidiny! / - acetic acid are dissolved in 15 ml of methanol and hydrogenated in the presence of 0.05 g of palladium activated carbon under atmospheric pressure. The catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in 10 ml of dichloromethane

And much more «(

dissolved ^ 0.17 g (1 mmol) of diphenyl diazomethane were added to the solution and the mixture was stirred for 24 hours. Then the solution is evaporated. 0.4 g (90 %) Benzhydryl-Ztrans- ^ i- (2-aminophenyl) -3- (2-methyl ~ 1,3-dioxolan-2-yl) -4-oxo-: 2-azetidinyl7-acetate / will get. IR (KBr): 1740, 1720 cm " ¹
MS: m / z 472 ß ⁺ j.

i) 0.45 g (1 mmol). Benzhydryl- / trans- ^ 1- (2-aminophenyl) -3- (2-3iethyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / acetate7 (prepared according to Example h) of the method III) are dissolved in 2 ml of glacial acetic acid and the solution is treated at room temperature with a solution of 0.2 g (2 mmol) of chromium (VI) oxide (CrO) in a mixture of 2 ml of glacial acetic acid and 0.2 ml of water. The solution is stirred at room temperature for 3 hours, then poured into 10 ml of ethyl acetate and finally washed neutral with 5% aqueous sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate and, after filtration, evaporated in vacuo. The evaporation residue is purified by preparative thin-layer chromatography (adsorbent: silica gel 60 ^ 254 + 36O ¹ ^^ ϊ- ^ Ιβη benzene and acetone in a ratio of 7: 3).

0.09 g (30 %) of benahydryl- / trans- / J- (2-methyl '! Rl, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-aoetate / are obtained. The physical properties of the product are identical to those of the compound according to example j) of method I.

The compound can be based on the in examples k) - n) of Method I described manner to be converted to the starting compound of Example 1.

Method IV

a) To the solution of 0.730 g (2 mmol) of the ^ trans-1- (2,4-dimethoxy-benzyl) -3 ~ (2-methyl-1,3-dioxolane-2) prepared according to Example i) of method I -yl) -4-oxo-2-azetidinyl7-acetic acid in 10 ml of anhydrous tetrahydrofuran are given 0.364 g (2.2 mmol, 98%) of carbonyl-di-imidazole. The mixture is stirred for 20 minutes. 0.315 g (2.2 mmol) of the magnesia salt of monoethyl malonate are added to the solution. The Gemisoh is stirred for 2 hours and then evaporated. The residue is shaken out with 40 ml of dichloromethane and 40 ml of 0.5 η aqueous hydrochloric acid. The phases are separated from each other. The aqueous phase is extracted with 20 ml of dichloromethane. The combined organic phases are ausgesohüttelt with 2x10 ml 3 f & ger aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and, after filtration, evaporated. 0.41 g (47 %) ethyl- / trans-4- £ - (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetdinyl7 -3-oxo-butanoate / are obtained.

IR (film): 1750, 1740, 1720 at " ¹

¹ H-WMR (CDCl ₃ ): 6 1.26 (t, 3H), 1.39 (s, 3H), 2.2-3.3 (m,

5H), 3.65-4.45 (m, 14H), 6.25-6.6 and

7.05-7.25 (m, 3H)

b) 2.77 g (5.0 mmol) of ethyl- / fcrans-4- ^ T- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4- oxo-2-azetidinyl7-3-oxofbutanoate7 (produced according to example a) the

BATH ORIGINAL

Method IV) are dissolved in 15 oil anhydrous acetonitrile. 0.69 ml (5.0 mmol) of triethylamine and 0.986 g (5 * 0 mmol) of tosyl azide are added to the solution while cooling with ice. The solution is stirred for 3 hours, its temperature rising to room temperature. The solution is then evaporated to dryness and the residue is worked up by column chromatography (adsorbent t - silica gel 60, 0.063-0.2QQj elution agent benzene and acetone in a ratio of 7 t 3). 1.41 g (61 %) Athy l - // F-diazo-4-trans - ^ - (2,4-dimethoxy-bensy 1) -3- ( ^: 2-methyl-1,3-dioxolane-2 -3rl.} - 4-oxo-2-8zetidinyl / -3 ™ oxobutanoate / are obtained.
IR (film) * 2160, 1750, 1720, 1640 ecf ¹ .

c) To the solution of 2.340 g (5.0: .mJSol) of the compound prepared according to Example b) of Method IV in 30 ml of acetonitrile, 5.4 g (20 mmol) of potassium persulfate (K-SpOg), 7.2 g (40 mmol) disodium hydrogen phosphate monohydrate (Na ₂ HPO ₄₁ H ₂ O) and 18 ml of water. The mixture is boiled for 10 hours. The cooled reaction mixture is filtered and the two-phase filtrate is separated into its phases. The aqueous phase is extracted with 3 × 10 ml of ethyl acetate. The combined organic phases are dried with magnesium sulfate and, after filtration, evaporated. The residue is worked up by column chromatography (adsorbent - silica gel 60, 0.063-0.200 min, eluent: benzene and acetone in a ratio of 7-3). 0.56 g (36 _%) Ethyl-Zi'-diazo ^ -trans- ^> - (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidiny] L7-3- oxo-butanoate / are obtained. The physical constants of the product agree with those of the compound obtained according to example m) of method I. The product can be converted into the starting material of Example 1 according to example n) of method I.

Method v

To the prepared with 10 tal dichloromethane solution of 1.830 g (5.0 mmol) of the / trans-1- (2,4-dimethoxy-benzyl) -3- (2-methyl-l , 3-dioxolan-2-yl) -4-oxo-2-azetidiny "Q- acetic acid are added 1 drop of dimethylformamide and 0.37 ml (5.0 mmol) of thionyl chloride while stirring and cooling with ice Stirred for hours, then treated with 1.7 ml of ethyldiazoacetaf and stirred at room temperature for a further 24 hours 7: 2). 0.17 g (7.3 %) ethyl- / 2-diazo-4-trans- ^ T- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3 dioxolan-2-yl) -4-oxo-2-azetidiny ^ 7-3-oxobutanoate / are obtained. The IR spectrum of the product agrees with that of the compound according to example b) of method IV. The compound can be based on the im Example o) of method IV besc The described procedure can be converted to the starting compound of Example 1.

Method VI

a) 0.4 g (1.24 mmol) of the ^ trans-3- (2-methyl-1,3-dioxolan-2-yl) -l- (4-methoxyphenyl) prepared according to Example g) of Method II ) -4-oxo-2-azetidinyl / acetic acid are dissolved in 15 ml of anhydrous tetrahydrofuran. After adding 0.22 g (1.36 mmol) of carbonyldi-imidazole the reaction mixture is stirred at room temperature for about an hour. After the gas evolution has ended 0.196 g (1.36 mmol) of the magnesium salt of monoethyl malonate are added. The mixture is stirred for another hour and then evaporated. The residue is dissolved in 50 ml of dichloromethane and the solution is extracted with 25 ml of 2N aqueous hydrochloric acid, then the aqueous phase with 25 ml of dichloroethane. The combined organic phases are

rait 2x20 ml 5 pointer aqueous sodium carbonate solution washed. The organic phase is dried over magnesium sulfate and, after filtering, evaporated «O ₉ 3 g (62 $>) Ethyl- / trans-4 - ^ - (2-methyl-1,3-dioxolane-2-.yl) -l- (4-methoxyphenyl) -4-oxo-2-azetidinyl / -3-oxo- »butanoate / are obtained.

Elemental analysis for C ₂₀ H ₃₅ NO (M = 391 »425 calculated, $ &: ■ C 61.37 • H 6.44 I 3.58 found, %: C 61.20. H 6.59 ■ N 3.72 .IR (film): 1750cm " ¹ .

b) 0.5 g (1.44 mmol) of the compound obtained according to Example a) of Method VI are dissolved in 6 ml of anhydrous acetonitrile and the solution is, with external cooling and constant stirring, with 0.28 g (1.44 mmol) of p- Toluene sulfonic acid azide and 0.2 ml '(1.44 mol) of triethylamine were added. The reaction mixture is stirred at room temperature for 2 hours. The course of the reaction is followed by thin-layer chromatography (adsorbent: silica gel G according to Stahl, developer: benzene and acetone in a ratio of 7: 3). After the reaction has ended, the mixture is evaporated, the residue is dissolved in 40 ml of dichloromethane and the solution is washed free of acid first with 10 ml of 40% strength aqueous potassium hydroxide solution, then with 10 ml of water. The organic phase is dried over magnesium sulfate and, after filtration, evaporated. The residue is purified by means of preparative thin-film chromatography (adsorbent: silica gel 60 ^PI 254 + 366 'developer benzene and acetone in a ratio of 7: 3) * 0.25 g (36 $) ethyl- / 2-diazo-4- ^ rans-3 - (2-methyl-1,3-dioxolan-2-yl) -l- (4-m © thoxyphenyl) -4-oxo-2-azetidinyl7-3-oxo-butanoate / are obtained. Melting point: 131-132 C (ether).

IR (KBr): 2200, 1740, 1710, 1640 cm " ¹ .

Elementary analysis for C2OH23N3O7 (M = 417.41) found, % x C 57.55 H 5 * 55 N 10.07, $ s C 57.56 H 5.80 N 10.08.

0) 0.45 g (0.106 mmol) of the compound prepared according to example b) of method VI are in 4.5 ml Aoeton dissolved. The solution prepared with 4.5 ml of 5% aqueous sulfuric acid is added to the solution with stirring of 1.5 g (2.7 mmol) cerium (IV) ammonium nitrate added dropwise The reaction mixture is stirred for a further 5 minutes Then the yellow solution with 5 # aqueous sodium hydrogen carbonate solution neutralized and with 3x10 ml

Ethyl acetate extracted. The organic phase is over Magnesium sulfate dried and evaporated after filtering. The residue is on the previous one Example described way cleaned. 0.10 g (27 lbs) Ethyl- ^ 2-diazo-4- / trans-3- (2-methyl-1,3-dioxolan-2-yl) * 4-oxo-2-azetidinyl7-3-oxo-butanoate7 would be obtained; the IR spectrum of the product is identical to that of the compound according to example b) of method IV * The compound can be referred to in example n) of method I. Manner to be converted to the starting material of Example 1 ·

■ Example 2

M - 'j ■

Athy1- £ T- (benzylthio) -64 (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyolO | D.2.03hept-2-en-2-oarboxylate7

To the solution of 1.133 g (4.0 mmol) of ethyl - ^ - (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxQ-l-azabioyoloC3.2.03heptane, prepared with 10 ml of anhydrous acetonitrile -2-oarboxylat7 and 0.61 ml (4.4 mmol) of triethylamine are added at 0 ⁰ C under stirring within 10 minutes 0.91 ml (4.4 mmol) of diphenylphosphoryl chloride (PhgO-PCl). A further 0.61 ml (4.4 mmol) of triethylamine and 0.52 ml (4.4 mmol) of benzyl meroaptan are then added to the reaction mixture. The mixture is ^{stirred at 0 °} C. for one hour and then evaporated in vacuo. Of the

HO ■ \

The residue is shaken out in 50 ml of Siohlormetliaii jgel et and the solution first with 2x5% al 3% aqueous latrimalsydrogenoarhonatlösung, then with 3% 5 ml water. The organic phase is dried over magnesium sulphate and evaporated after filtration. The oily residue (1.0 g) is cleaned in a siulenütooraatograpliisoli (adsorbent: silica gel 60, "0.063-0.200; eluent benzol and acetone in a ratio of 7sl). 0" 90 g (58 %} of product are obtained (from Ether-teriatallizing® erection) · Sotaelzppnkt $ 109 ⁰ C

ZR (KBr) ί 1780 »1700 em" ¹ ·

¹ H-HJiR (CDCl ₃ ) s J 1.33 (t, -3H, J - 7.5 HaK 2-t87-3.3 ■ " in the _9th

2H), 3.35 (d, IH, j - 3 Ha) -, 3 ₉ 95-4_ _f 45

(η, 7H) _r 7.33 (a,

¹³ C-HISR (CDCl ₃ ) S 14.30, 23.35, 36.85, 40 _f 28, 51.94, 61.15, -

65.1β, 65.33, 67.15, 106.85, 124.4, 127.7, 128.69, 128.88, 136.42, 145.93, I6l, 32,

fVSp. . 173.91. -

) aaea «), '0 / at 389, 303, 261, 91, 87, 43.

Example 3

(p-Nitro-benzyl) - / 5 ^{> v} ( ^f öiB7lemino-ätb7lthio) H6 »| 2i * -sethyl-1,3-dioxolan» 2-yl) -7-oxo-l-aaabioyolo C3 # 2 «OJhept-

To the solution of 1.5.61 g (4 ₉ 0 mlol) (p-nitro-benzyl) - / 6- (2-meth3fl-1 _S! 3-dioxolan-2-yl) -3, prepared with 10 ml of anhydrous acetonitrile, 7-dio3Eo "l" asa-bi0yolo "D" 2 "OJheptan-2-oarboxyla £ 7 are under. Stirring at 0 ⁰ C 0.61 ml (4.4 mmol) and- Triäthylaniin danui innernalb of about 10 minutes O ₉ 91 ml (4.4 mmol) säureohlorid added. The Geioieoh nird at 0 ⁰ C stirred and treated with a further O., 6l nil (4.4 mmol) Eriäthylanain andhaving 0.46 g (4.4 mmol) of M-Pormyl-oyateamin "that · is ßemisoh nooli a long Stmide stirred and then evaporated in vacuo "The Huoketand is dissolved in 20 ml of dichloromethane" The solution is mixed with 10 ml of 3

aqueous sodium hydrogen carbonate solution and then extracted with 2x10 ml v / water. The organic phase is dried over magnesium sulfate and, after filtration, evaporated. The residue is worked up by column chromatography (adsorbent: silica gel 60,

0 0.063-0.200 mm; Eluent * Benzene and Aoeton im

Ratio 7: 3). 1.05 g (64 %) of product are obtained.

ο ^M
Melting point: 183 C (ether).

IR (KBr): 3330, 1750, I67O (v I68O.) CNT ^{1 1} H-NMR (CDCl + DMSO): J "1.43 (s, 3H), 2.85 to 3.45 (m, 6H) ,

3.58 (d, IH, J = 3 Hz), 4.0-4.3 (m, 5H), 5.24-5.51 (d, 2H, J ^ = 13.8 Hz), 7.68 + 8.20 (d, 4H, J ^ »11 Hz), 8.16 (s, IH).

The starting material of Example 3, the (p-nitrobenzyl ) - / £ - (2-methy1-1,3-dioxolan-2-yl) -3,7-dioxoazabicycloD.2.0Jheptane-2-carboxylate ^ can be prepared as follows will:

A) from Z ± rans-3- (3-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-acetic acid, their production in the example

1 has already been described (examples a) -k) of the method I; Examples a) -i) of method II + example k) of method I; Examples a) -c) of method III + example k) method I), or

B) from / trans-1- (2,4-dimethoxy-benzyl) -3- (2-raethyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidiny! / - acetic acid, the production of which was given in Example 1 (in Example i) of Method I), or

C) from / trans-3- (2-methyl-1,3-dioxolan-2-yl) -l- (4-methoxyphenyl) -4-oxo-2-azetidiny] j / acetic acid, the preparation of which was described in Example 1 (Example g) of Method II).

Method A) is illustrated by the following examples :

a) A Geraisoh made from 0.645 g (3.0 mlol) 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-acetic acid, 0.535 g (3.3 mmol) carbonyl -di-imidazole and 15 ml of anhydrous tetrahydrofuran is stirred at room temperature for 30 minutes. Then 0.825 g (3.3 mmol) of magnesium (p-nitrobenzyl) malonate are added and the mixture is stirred at tree temperature for a further two hours. Then, the Reaktionsgemisoh is Naoht allowed to stand ^ finally evaporated in Yakuum and the residue treated with 50 ml and 50 ml Diohlormethan O partitioned ₉ 5 η aqueous hydrochloric acid. The aqueous phase is extracted once more with 25 ml of dichloromethane. The combined organic phases are washed with 2 × 10 ml of 3% aqueous Fatriuraoarbonatlösung, then dried over magnesium sulfate and evaporated after filtration. 0.730 g (62.1 %) (p-nitro-benzyl) - / trans-4- ^ J- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-3- oxo-butanoate / are obtained.
IR (Ulm) j 3250, 1760, 1740, 1720 cm " ¹ .

b) 1.962 g (5.0 mmol) of the compound prepared according to Example a) are dissolved in 15 ml of anhydrous acetonitrile solved. 0.69 ml (5tO niBfol) triethylamine and 0.985 g (5.0 mmol) are added to the solution while cooling with ice. Tosylazide given. After 5 minutes a crystalline one falls Substance from. The mixture is nooh for 20 minutes

fun «. η

Stir ^ · then filter off the bottom bottom, washed with ether and ^ «οή. dried. 1.326 g (63.4 %) (p-nitrobenzyl ) - £ 2-diazo-4- / trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -3-oxo-butanoate / are obtained. Melting point j 163-164 ⁰ C.

IR (KBr): 3320, 2160, 1750, 1710, 1630 cm " ¹ .

¹ H NMRi S 1.41 (s, 3H), 2.98 dd and 3.44 dd (2H, J = 10 Hz and J = 4 Hz), 3.18 (d, IH, J = 2.4 Hz), 3.83-4.15 (m, 5H), 5.36 (s, 2H) _t 6.0 "(e, IH), 7.54 d and 8.26 d (4H, AB, J - 9 Hz).

o) 1.673 g (4.0 mmol) of the compound prepared according to Example b) suspended in 45 ml of anhydrous benzene. The suspension is stirred while boiling and 0.050 g dirhodium tetraaoetate (Hh ₂ ^ OAo / .. 2THP) is added in several fortions. After boiling for 10 hours, all the starting material has been converted. The mixture is cooled, the precipitated substance is dissolved in dichloromethane and the solution is filtered through Celite. The Ultrat is evaporated in vacuo and the residue is washed on the filter with ether. 1.32 g (84.6 %) (p-nitrobenzyl) - / 6 "- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-lazebioyoloE3.2.0-jheptane-2-carboxylate 7 are obtained Melting point: 167 ° C

IR (KBr): 1760, 1735 cm " ¹

¹ H-NMR: J 1.48 a (3H), 2.47 dd (IH, J _{according to} - 19 Hz, J _{v ± <j} «8 Hz), 2.92 dd (IH, J _{according to} - 19 Hz, J _yio «8 Hz), 3.46 d (IH, J - 2.4 Hz), 4.0-4.2 η (5H), 4.75 s (IH), 5.30 d (2H, J ^ - 14 Hz), 7.53 and 8.23 d (4H, J ^ ₈ χ = 9 Hz).

Method B) corresponds to method IV or V of Example 1, and method C) corresponds to Method VI of Example 1. In each case, (p-nitrobenzyl) - / 2-diazo-4-Zfrans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7 -3-oxo-butanoajt / obtained, its physical data are identical to those of the product obtained according to example b) of method A). From the obtained compound is in the manner described in Example o) of method A) the starting substance of the Example 3 produced.

Example 4

Sodium / 3- (formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7.oxo-1-azabioyolo [3,2.OJhept-2-en- 2-oarboxylaJi7

A suspension of 0.25 g of 10% palladium-activated carbon in 70 ml one in a ratio of 2: 1 ready

Teten mixture of dioxane and water is at room temperature For 20 minutes under a hydrogen atmosphere touched. The warm solution becomes iron to the suspension 0 »477 g (1.0 mmol) (p-nitrobenzyl) - / 3- (formylaininQ-ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-assabioyoloD.2.0 ] hept-2-en-2-carboxylate 7 (prepared according to Example 3) added to 30 ml of peroxide-free dioxane. The reaction mixture is under hydrogen for a further 3 hours stirred atmosphere, then treated with a solution of 0.084 g (1.0 mmol) of sodium hydrogen carbonate in a little water and finally filtered through Celite. From the Piltrate, the dioxane is filtered off in vacuo, and the aqueous residue is extracted with 3x10 ml Dlohlormetban. The aqueous phase is at room temperature in Evaporated in vacuo. The evaporation residue becomes cold

crystallized, washed on the filter with 6 ml of ethanol and then dried. 0.25 g (73 %) of product are obtained. Melting point ι 201 ⁰ C (decomposition)

IR (KBr): 3420, 1760, / 77Ο shoulder ?, 1690, 1610 cm ¹ H-NMR (DgO): ύ 1.42 s (3H), 2.7-3.6 m (6H), 3.65 d

(IH, j - 3 Ha), - 3.95-4.3 m (5H),

8.03 s (IH).

-1

Claims (14)

M. .J Process for the production of new bicyclic isoher Compounds of the general formula (I) (D COOQ * wherein Y and ι for a removable one, the Carbony! Group so-protecting substituents, preferably a ketal group or their hioanalogon, are, Q -e / "* e alkyl group with 1-5 carbon atoms ^ 'substituted benzy! group, hydrogen or t \ * \ alkali metal ion and R ″ for an optionally substituted hydrocarbon radical, preferably benzyl, 2-arainoethyl or 2-acylaminoethyl, characterized in that compounds of the general formula (II) (II) "" ^ COOQ - in which the meaning of ζ and Y ^ is the same as above and Q f ixt) alkyl group with 1-5 carbon atoms or is »substituted benzyl group - in the presence of a tertiary amine with a suitable O-aoylating agent, preferably a sulfonyl or phosphoryl halide, and then with a mercaptan, preferably with benzyl mercaptan or cysteamine or its N-acylated derivative, and those, a narrower group of compounds of the general formula (I) forming compounds in which t and "χ as well as R" have the same meaning as above _; and Q is identical to Q ' • ■ c «I · is, isolated, or of those compounds forming a narrower group of compounds of the general formula (I) in which the meanings of T " and ΊΓ have the same meaning (gfnß is as above and Q * is ^ substituted benzyl group, the substituted benzyl group is removed reductively and the carboxylic acid obtained (Q '= H) is converted to its alkali salt and the substituent Q' is an alkali metal ion containing compound isolated. 2. The method according to claim 1, characterized in that there is used as the 0-acylating agent diphenyl-phosphoric acid chloride. 3 · The method according to claim 1, characterized in that the N-aoylated derivative of cysteamine N-formyloysteamine used. 4. The method according to claim 1, characterized in that the substituted benzyl group located at the point of Q * is removed duroh catalytic hydrogenation · 5. The method according to claim 1, daduroh characterized in that the reaction to a salt with a. Alkali carbonate or bicarbonate makes. 6. The method according to claim 1 for the preparation of ethyl- / J- (formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabioyoloE3.2.0Jhept-2 -en-carboxylate7, daduroh characterized that one Athy1- / 6- (2-methyl-l, 3-dioxolan-2-yl) -3,7-dioxo-l-azabioyolo C3.2.OJheptan-2-oarboxylat / in the presence of a tertiary amine with a O-aoylating agent and then reacted with N-IOrmyloysteamin. 7. The method naoh claim 1 for the preparation of Ethyl- _i 5 * (benzylthio) -6- (2-methyl-l, 3-dioxolan-2-yl) -7-oxo-l-azabioycloD ^ .OJhept ^ -en- ^ -carboxylate /, daduroh η -
characterized in that ethyl- / 6- (2-m © thyl-l, 3-dioxolan-2-yl) -3 "7-dioxo-l-azabioyclo D. 2 .OJheptane-2-carboxylate / in the presence of a tertiary Amine reacts with an O-aoylating agent and then with benzyl meroaptan 8. The method according to claim 1 for the production of (p-Nitrobenzy1) - / 3- (for-my lamino-ätny lthio) -6- (2-metbyl-1,3-dioxolan-2-yl) -7-oxo-l-azabioyoloD.2.0Jhept-2- en-2-carboxy la t /, characterized, that one (p-Mitrobenzyl) - / 6- (2-methyl-1,3-dioxolan-2-y1) -3,7-dioxo-lazabioycloD «2.0Jheptane-2-Garboxylat / in the presence of a tertiary amine with an O-acylating agent and then with N-Porrayloysteamin. 9. Process according to Claim 1 for the preparation of sodium 2 [3- (formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo E3.2.0Jhept-2-en-2-carboxylate /, characterized in that (p-mitrobenzyl) - / 3- (formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-l-azabioyolo D.2.OJhept-2-en-2-carboxylate / reduced and the sodium salt is formed from the reduced product 10. Process for the preparation of compounds of the general formula (I) as active ingredients - in which the meaning of i ", Y, Q * and R" the same as in the generic term of claim 1 is - containing pharmaceutical preparations, characterized in that one according to Example 1 obtained active substance with carriers, extenders and / or auxiliary substances customary in the manufacture of pharmaceuticals mixed and formulated into pharmaceutical preparations. 11. Compounds of the general formula (I) _v l γ2 HH H ₃ O -V- ~ SR '» wherein Y and ΊΓ denote a removable substituent which protects the carboxyl group, preferably a ketal group or its thio analogue, Q χ IHT alkyl group having 1-5 carbon atoms?) Represents substituted benzyl group, hydrogen or ^ ih alkali metal ion and R "represents an optionally substituted hydrocarbon radical, preferably for) benzyl, 2-Aminoäthyl- or 2-Acylaminoäthy! Group stands. 12 · Ethyl- / 3- (formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyoloE3.2.0] hept-2-en-2-oarboxylate /. 13. Ethyl- / 3- (benzylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabioyoloE3.2.O3hept-2-en-2-oarboxylate /. 14. (p-Nitrobenzyl) - / 3- (formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabioyolo E3.2.0] hept-2-en-2-carboxylate /. 15 Sodium- / I- (formylamino-äthylthio) -6- (2-methy1-1,3-dioxolan-2-yl) -7-oxo-l-azabioyolo E3 * 2.O3hept-2-en- 2- oarboxylate7