DE2046823A1 - New azetidinones (2) and processes for their preparation - Google Patents

Description

FARBWERKS HOECHST AKTIENGESELLSCHAFT formerly Master Luciur: & Brüning, Frankfurt / Main

Date: September 17, 1970 Dr.B / jk File number:. HOE? 0 / F 18O

New Azetidinones- (2) and Processes for Their Production-

The present invention relates to a method of manufacture of azetidinones- (2) of the general formula

9 ~ ( ^Y h ~ CH CT 2 η, _{| χ}

N - CQ ^K 4

^R l

R ₁ a) a hydrogen atom, a phenyl radical which can be substituted by alkyl groups, preferably with 1-4 carbon atoms, halogen, nitro, cyano, sulfamido, carbonamido, carboxylic acid ester, alkylsulfonyl or trifluoromethyl groups, a Cj- CjQ-alkyl radical, Cg-C ^ cycloalkyl-, Cg-Cg-cycloalkyl-C ^ -Cg-alkyl-, Cg-C ^ -haloalkyl-, C ₃ -C ₁₀ -haloalkenyl-, C ₁ -C ₃ -cyanoalkyl- , C ₁ -C ₃ -alkyl-Xt C ₂ -Cg-alkyl-, where X is oxygen or sulfur, a phenyl-O ^ -C ₃ -alkyl radical, where the phenyl radical can be substituted as indicated above, or

b) a carboxy-O ^ -Cg-alkyl-, C ₁ -Cg -alkoxycarbonyl-C - Cg-alkyl-, a formyl-Cj-Cg-alkyl- or a C ₁ -Cg-alkyl-carbonyl-Cj ^ -Cg-alkyl radical means

R ₂ a) a phenyl radical which can be substituted by alkyl groups, preferably with 1-4 carbon atoms, halogen, nitro, cyano, sulfamido, carbonamido, carboxylic acid ester, alkylsulfonyl or trifluoromethyl groups, a C 1 -C 6 alkyl radical , Cg-C ^ cycloalkyl,

./2 2098U / 16A9

Cj-Cg-cyano-alkyl-, C ₁ -C ₃ -alkyl-XC ^ -Cg-alkyl-, where X stands for oxygen or sulfur or a phenyl-C- ~ Co-alkyl radical, where the phenylvest is substituted as indicated can be *) means, or

if ix is zero, b) a formyl or carboxy Ir it t _f / or a formylcarbonyl-Ci-Cg-alkyl-, C - C _ß -alkoxy-carbonyl-C «-C ^ - alkyl- or a G- -Cg-alkyl-carbonyl-C ^ -C ^ -alkylroBt, where at least one of the radicals IL and K _? has the meaning given under b),

R _{3 is} a hydrogen atom or halogen atom, in particular a chlorine or bromine atom, a hydroxy, an azido or an acylamino group or a sulionyloxy group of the formula R-SOo-O-, in which R is an alkyl group, preferably with 1-4 carbon atoms, which can be substituted by halogen atoms or cyano groups, an aryl radical, especially a phenyl or naphthyl radical, which can be substituted by alkyl groups, preferably with 1-4 carbon atoms, alkoxy groups, preferably with 1-4 carbon atoms, halogen atoms, nitro, cyano, sulfonamido , Carboxylic acid ester, carbonamido, alkylsulfonyl or trifluoromethyl groups can be substituted,

R _{4 is} a hydrogen or a halogen atom, in particular a chlorine or bromine atom,

Y stands for -O- or -S- and
η means zero or 1,

in which one azetidinone (2) of the general formula

^ R ^{I3 [}

N - CO ³

*) or a renzhydryl or trityl radical

2098U / 1649

wherein R ₃ , R ₄ , Y and η have the meanings given above,

R ₅ a) has the same meaning as Ra), or

b) a C ₃ -C ₁₀ -alkenyl-, Cg-CQ-haloalkenyl-, 2'-furyl-CL-Cg-alkyl-, 2 '-thienyl-Cj-Cg-alkyl- or a phenyl - C ₁ - C ₃ alkyl radical, where the phenyl radical is substituted by electron supplying substituents, preferably hydroxyl, alkoxy and / or amino groups,

R ₆ a) has the same meaning; as R _{2 has} ^a ), or

b) a 2'-Fury 1-, 2'-hiienyl -, a β-phenylvinyl radical, it being possible for the phenyl radical to be substituted as indicated above, or a C ₃ -C _lo -alkenyl-, Cg-C - ^ - alkynyl -C ₃ -CjQ-haloalkeny 1-, C ₃ -C ^ -haloalkynyl-, 2'-furyl-C ₁ -C ₃ -alkyl-, 2'-thienyl-O ^ -C ^ alkyl- or a phenyl-C ^ -Cg-alkyl radical, where the phenyl radical is substituted by electron-donating substituents, preferably hydroxyl, alkoxy and / or amino groups,

where at least one of the radicals R 1 and R _{g has} the meaning given in each case under b), treated with ozone, and the compounds thus obtained are hydrolyzed or reduced.

The present invention also relates to new compounds the general formula

R ₂ -S-CH-C

ir-cc / ⁴

wherein R-, R ₃ and R _{4 have} the meanings given in claim 1 and

2098U / 1649

a) a phenyl radical which can be substituted by alkyl groups, preferably with 1-4 carbon atoms, halogen, nitro, cyano, sulfainido, carbonamido, carboxylic acid ester, alkylsulfonyl or trifluoromethyl groups, a C ₁ -C _in - Alkyl radical, C _r -C "-cycloalkyl ~, C ₃ -C ₆ -cycloalkyl-Cj-Cg-alkyl, C ₂ ~ C ₁₀ -halagenalkyl ~,

X stands for oxygen or sulfur, or a phenyl-C - C _Q ~ alkyl radical, where the phenyl radical can be substituted as indicated above, means ^ or

b) means a Forrayl-carbonyl-C - Cg-alkyl, C ₁ -Cg carbonyl-Cj-Cg-alkyl or a C ^ -Cg-alkyl-carbonylC - Cg-alkyl radical,

where at least one of the radicals R. and R _{2 has} the meaning given in each case under b).

The method of the present invention is described below at some typical examples explained by formula:

C ₆ H ₅ -CH = CH-CH-CHN ₃ ° 3 \ C-CH-CHN «I / ι

N-CO H N - CO

i I

^C 6 ^H 5. ^C 6 ^H 5

^ Cl O Cl

CH - C ^ _r , ± -ϊ HOOC-CH - C -C _rl

N-CO N CO

I.

CH ₂ COOH

*) or a benzhydryl or a trityl radical,

./4a

2098U / 1649

/ \ - CH-C <

N CO

OCH, \ ³

Cl ^C1

CH.

OCH ₃

CH ₂ = C-CH ₂ -S-CH - CH-N ₃

N - CO I
CH ₂ -C-CH ₂

^l 3

CH ₂ = C-CH ₂ -S-CH-CH-N

N-CO I CH ₂ = C-CH ₂

Cl

4a »'-

- c

N - CO

CELCOOH

Cl Cl

CH _Q -C-CH ₀ -S-CH 3 "2,!

O N CO

CH ₀ -C-CH ₀ -S-CH - CH-N ^d if 4 ι ι \

, CO

CO

N - CO

CH ₀ OC-CH,

HCsC-CH ₂ -S-CH - CH-OSO ₂ - /

N-CO ^C 6 ^H 5 3, O.

^N "CC-CH ₀ S-CH - CH-OSO ₀ ■ H '■ II ^ II *

O N-CO

^C 6 ^H 5

./5

2098U / 1649

Those compounds of the above-mentioned formulas I, II and III in which the radicals R ₁ to R _{fi have} the following meanings are of particular importance:

R ^ = phenyl, benzyl, hydrogen, carboxymethyl, acetonyl, Formylmethyl;

if η / zero,
Rn-Y = formyl, carboxy / methy lthi ο, acetonylthio, formylcarbo-

nylmethyl, phenyl;
R ^ - halogen, especially chlorine or bromine, hydrogen;

R - halogen, especially chlorine, bromine, hydrogen, hydroxy, Azide, phthalimido, alkyl and naphthylsulfonyl radicals or phenylsulfonyloxy radicals, where the phenyl or Naphthyl radical through 1-3 methyl groups or halogen atoms, in particular chlorine or bromine, can be substituted;

Rc * »phenyl, benzyl, hydrogen, furfuryl or alkenyl radicals, in particular 2-methyl-propen- (2) -yl, 2-chloro

propen (2) -yl or propen- (2) -yl;

when η is zero, R ₆ - phenyl, styryl, vinyl, furyl, /, methylthio or alkenylthio radicals, in particular 2-methyl-propen-£) -ylthio, 2,3-dimethyl-buten (2) -yl-thio or propargylthio ^ tritylthio.

The starting compounds used in the process according to the invention of the above formula II can be prepared in a manner known per se, for example by reaction of acid chlorides with the corresponding Schiff's see Base.

In the process according to the invention it was surprising that the sensitive ß-lactam ring is not attacked ·, moreover, it was very surprising that even when present easily oxidizable groups, such as sulphide sulfur, this is not oxidized to sulfoxide or sulfon, but that unsaturated systems are specifically oxidized.

• ./6

209814/1649

There are 2 oxidation equivalents per double bond for oxidation (Required to absorb 2 electrons ^. Triple bonds also consume 2 oxidation equivalents. Since ozone is an electrophilic reagent, double bonds, by electron-withdrawing groups, e.g. B. halogen, are substituted, somewhat slower than corresponding unsubstituted Double bonds are oxidized, but also *) run with sufficient speed, so that a selective Oxidation is possible in the presence of sulphidic sulfur.

The primary oxidation products (ozonides, peroxides) formed during oxidation do not need to be isolated, but rather they can be converted directly into the azetidinones described according to the invention by reductive or hydrolytic aftertreatment. of formula I are converted.

The oxidations can be carried out in aprotic, hydroxyl-free solvents, such as methylene chloride, ethylene chloride, acetone, ethyl acetate, tetrahydrofuran, dioxane, dimethylformamide, Acetonitrile, pyridine, toluene, chlorobenzene or containing hydroxyl groups Solvents such as lower alcohols ,, lower carboxylic acids or water are carried out. It is also possible and particularly advantageous with regard to dissolving power and work-up, in mixtures of the two groups of solvents to work.

The reaction is generally carried out at temperatures between -80 and +50 ⁰ C, but also to work at higher temperatures up to about 100 C is possible. In the presence of other easily oxidizable groups, such as sulphide sulfur, v (
worked.

fei, is preferably used at temperatures below -20 ° C,

Compounds that cause reductive cleavage of the primary oxyda-

+) d, h. 1 equivalent of ozone .

*) box them dio oxidation

2098 U / 1649

tion products cause are ^<r, known us the literature. Can be used, for. B, phosphines, such as triphenylphosphine, tributylphosphine, phosphites, such as triphenylphosphite, triethylphosphite, potassium iodide, dimethyl sulfide, catalytic hydrogen, lithium aluminum hydride, sodium sulfite, and sodium bisulfite.

A hydrolytic cleavage of the prairie oxidation products is achieved if the oxidation is carried out in the presence of hydroxyl-containing solvents. These can also be added at a later date; acidic (e.g. HLSO ₄ , H ₃ PO ₄ , BFo etherate) or basic catalysts (e.g. NaOH, CH ₃ COONa, pyridine, triethylamine) can also be added.

The acid halides formed in the oxidation of halogen-substituted double bonds are converted by the addition of alcohols and pyridine converted directly into the acid esters by adding water to the carboxylic acids.

The method according to the invention is valuable in terms of preparation. In particular the described 4-sulfur-substituted azetidinones- (2) with functional groups on sulfur and nitrogen are important starting compounds for the preparation of further Azetidinone- (2). So z. B. by ring closure with elimination of water azetidinones (2) with condensed Rings in position 1.4 · can be obtained. The compounds according to the invention also provide valuable bacteriostatic properties and bactericidal agents.

Example 1:

In a solution of 12.8 g (0.04 mol) of N-phenyl-SS-dichloro-4-styryl-azetidinone- (2) in 170 ml of methylene chloride, an ozone-oxygen stream (1 mmol Og / Min.). After 200 minutes, the calculated amount of 0.04 mol of O _{3 has been} taken up. After adding 10 ml of dimethyl sulfide, the

2098U / 1649 * ^{/ 8}

3.

The solution is left to stand for 20 hours at room temperature and then washed 2 times with saturated aqueous Hatriwibicarbouatlöfjuag. After evaporation of the tfethylenchlorids remain colorless crystals after recrystallization from chloroform at 120 - 121 ⁰ C melt. Yield 0.1 g (82 % of theory) of N-phenyl-3,3-diehlor-4-formyl-azetidinone- (2).
C ₁₀ II ₇ Cl ₂ NO ₂ . calculated: C 49.21 H 2.89 Cl 29.05 N 5.74%

(244.1) found: C 49.2 H 2.9 Cl 28.9 N 5.7 %.

With 2,4-dinitrophenylhydrasine in alcohol / sulfuric acid (RL Shriner, RC Fuson, DY Curtin, The Systematic Identification of Organic Compounds Wiley NY, 5th edition, p. 126), the 2,4-dinitrophenylhydrazone is formed quantitatively with a melting point of 234 - 235 ° C.
C ₁₆ H ₁₁ Cl ₂ N ₅ O ₅ calculated: C 45.30 H 2.61 Cl 12.72 N 16.51%

(424.2) found: C 45.5 H 2.8 Cl 16.8 N 16.5%

By acidification of the bicarbonate Wasehwässer colorless crystals are obtained which by reprecipitation from methanol: water (1 ß 1) at 119 - 120 ⁰ C melt. They are identical to benzoic acid in all properties.

After reducing the ozonated solution with triphenylphosphine, Potassium iodide, palladium / hydrogen or sodium dithionite are produced 4-Formylazetidinon- (2) in comparable yield.

Example 2:

5.8 g (0.02 mol) of trans-N-phenyl-3-azido-4-styryl-azetidinone ~ (2) in 80 ml of methylene chloride are ^{treated with ozone at -6O 0} C until the solution turns blue Indicates the end of the reaction.

After adding 5 ml of diethyl sulfide and working up as in Example 1 described, 2 g (80% of theory) benzene

./Θ 2098U / 1649

*O

acid and 3.0 g (69% of theory) trans-N ~ phenyl ~ 3-a?; ido-4-formyl-azetidin.one- (2) in the form of colorless crystals. Melting point 134-135 ° C (from chloroform) obtained. C ₁₀ II ₈ N ₄ O ₂ calculated: C 55.55 H 3.73 N 25.92 %

(216.2) found: C-55.4 H 3.6 N 26.0%

The 2,4 ~ dinitrophenylhydrazone melts at 210 ° C with decomposition.

^C 16 ^H 12 ^N 8 ° 5 calculated: C 48.49 H 3.05 N 28.28 %

(396.3) found: C 48.7 H 3.1 N 28.3%

Example 3;

2.7 g (0.009 mol) of trans-N-benzyl-3-azido-4-styryl-azetidinone- (2) are oxidized with ozone as described in Example 1. In addition to benzoic acid (82% of theory) the oily trans ~ N ~ benzyl-3-azido-4-forrayl-azetidinone- (2) obtained, which can be characterized as 2,4-dinitrophenylhydrazone can. Yellow crystals with a melting point of 158-160 ° C. are obtained here. The yield is 2.2 g (60% of theory).

C ₁₇ H ₁₄ N ₈ Og calcd: C 49.76 H 3.44 N 27.31% (410.4); found: Y 49.8 H 3.5 N 27.6%

Example 4 :

4.85 g (0.05 mol) of 4-Vinylazetidinon- (2) are treated in 200 ml of methanol at -6O ⁰ C until a permanent blue coloration with ozone. After adding 10 ml of dimethyl sulfide, the mixture is left at room temperature for 15 hours. To characterize the 4-formyl-azetidinone- (2) obtained in this way, a solution of 6 g (0.03 mol) of 2,4-dinitropheny! Hydrazine in Al-

209SU / 1649

Koliol / sulfuric acid (RL Shriner, RC Fuson, DY Curtin, The Systematic Identification of Organic Compounds, 5th edition, p. 237) was added. The precipitate (6 g) of 4-formyl azetidinone (2) 2 _f 4-dinitrophenyl hydrazone is reprecipitated from glacial acetic acid and then melts at 142 - 144 C.

C ₁₀ H ₉ N ₅ O ₅ calculated: C 43.02 H 3.25 N 25.08% (279.2). found: C 43.0 H 3.2 N 25.0 %

Example 5;

6 g (0.02 mol) of N-benzyl-3,3-dichloro-4- / ~ furyl- (2'27-azetidinone- (2)) in a mixture of 80 ml of methylene chloride and 5 ml of methanol at -50 C. with a stream of ozone and oxygen (1 mmol O "/ minute). After the uptake of 0.032 mol O ₃ , the solution is colored blue. 0.5 ml of concentrated hydrochloric acid is added and left at room temperature for 24 hours 3 χ extracted with saturated aqueous sodium bicarbonate solution, whereupon the bicarbonate solution is acidified with hydrochloric acid. 5 g of an acidic resin are extracted therefrom with methylene chloride, which is neutralized with potassium hydroxide in ethynol. For characterization of the N-benzyl-3,3-dichloro- 4-carboxy-azetidinone- (2) 5 g (0.021 mol) of p-chlorobenzylthiuronium chloride in 50 ml of hot 95 % ethanol are added to this solution (RL Shriner, RC Fuson, DY Curtin, The Systematic Identification of Organic Compounds, 5th Edition , P. 237) After 2 days, 5 g of colorless crystals with a melting point of 170 ⁰ C filtered off. The melting point remains unchanged after it has been precipitated from dioxane. The p-chlorobenzylthiuronium salt of N-benzyl-3,3-dichloro-4-carboxy-azetidinone (2) is obtained in a yield of 53% of theory.

./11

2098U / 1649

C ₁₉ H ₁₈ Cl ₃ N ₃ O ₃ S calc .: C 48.07 H 3.82 Cl 22.40 N 8.85 S 6.75 % (474.8) found: C 48.1 H 3, 9 Cl 22.3 N 8.9 S 7.0%

Example 6:

24 g (0.08 mol) of »-benzyl-3 _# 3-dichloro-4- / furyl- (2 ^l ) 7-azetidinone- (2) are treated with ozone in 300 ml of glacial acetic acid at + 20 ° C. After uptake of 0.156 mol 0 ,. the solution is colored blue. The glacial acetic acid is then removed in vacuo at a bath temperature of 20-30 ° C. To identify the 4-carboxy compound obtained, the residue is treated exhaustively with an ethereal diazomethane solution. The distillation gives 16.5 g of N-benzyl-3,3-dichloro-4-carboinethoxy-azetidinone- (2) in the form of a colorless oil with a boiling point of 148-150 ° C./0.01 Torr; the yield is 72 % of theory.

calculated C 50.02 H 3.85 Cl 24.61 N 4.86 % (288.1) found: C 50.3 H 3.7 Cl 24.4 N 5.0%

Example 7:

22.3 g (0.06 mol) of N-phenyl-3,3-dibromo-4- / Turyl- (2'27-azetidinone (2) are oxidized in 250 ml glacial acetic acid at +15 ⁰ C with ozone. After 6 hours, the solution is pale blue in color and around 0.095 mol of O _{3 has been} taken up.After work-up and treatment with diazomethane as in Example 6, the residue remaining after evaporation of the ether is deactivated over silica gel (0.05-0.2 mm, with 10% water) , 3 × 120 cm column) with benzene. In fractions 3-13 (100 ml each) 10 g (46 % of theory) of colorless crystals of N-phenyl-3,3-dibromo-4-carbomethoxy-azetidinone- (2) obtained which, after reprecipitation from benzene: isopropyl ether (1: 3), melt at 134-135 ° C.

./12

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NO ₃ calcd: C 36.39 H 2.50 Br 44.03 N 3.86 % (363.0) found: C 36.6 H 2.5 Br 44.1 N 4.0

Example 8;

11.8 g (0.04 mol) of N-furfuryl-3,3-dichloro-4-phenyl ~ azetidinone (2) are oxidized in 150 ml glacial acetic acid at +15 ⁰ C with ozone. After taking up 0.08 mol of O ₃ , the glacial acetic acid is removed in vacuo and, for the purpose of characterizing the compound obtained, is treated with diazomethane as in Example 7 and chromatographed on silica gel. Colorless crystals are obtained in fractions 2-10, which melt at 114 ° C. after reprecipitation from isopropyl ether. 3 g (26% of theory) of N-carbomethoxymethyl ~ 3,3-dichloro-4-phenyl-azetidinone- (2) are obtained

C ₁₂ H ₁₁ Cl ₂ NO ₃ calcd: C 50.02 H 3.85 Cl 24.61 N 4.86% (288.1) found: C 50.1 H 4.0 Cl 24.5 N 4.9 %

Example 9;

11.5 g (0.04 mol) of N-furfuryl-3,3-dichloro-4- / Turyl- (2 ^e) 7-azetidinone (2) with in 150 ml of glacial acetic acid at 20 ⁰ C for 8 hours Treated ozone, 0.14 moles of O _{3 are} consumed. To characterize the N-carboxymethyl-3,3-dichloro-4-carboxy-azetidinone- (2) obtained, it is reacted with diazomethane and then according to Example 7, but with ethyl acetate / cyclob / exane (2: 1) as the eluent Purified by chromatography N-carbomethoxyraethyl-SjS-dichloro ^ -carbomethoxy-azetidinone- (2) is obtained as a viscous oil which boils at 130-135 ° C./Q05 / Torr. The yield is 4.6 g (42 % of theory).

C ₈ H ₉ Cl ₂ NO ₅ calculated: C 35.58 H 3.36 Cl 26.26 N 5.19% (270.1) found: C 36.2 H 3.6 Cl 25.9 N 5.2 % .

2098 14/1649

Example 10;

7.6 g (0.02 mol) of trans-N-phenyl-S-phthalimido ^ V 2 ^r methyl-propen- (2 ') i7-yl ~ thio-azetidinone- (2) in 250 ml of methylol chloride are - 60 ° C treated with ozone (0.4 inMol Oo / minute). After taking up 0.02 mol of 0.1 (1 equivalent), 10 ral of dimethyl sulfide are added and the mixture is left at room temperature for 5 hours. The partially crystalline residue remaining after evaporation of the methylene chloride is digested with methanol, whereupon the methanol-insoluble crystals are recrystallized from chloroform: isopropyl ether (1: 2). 5 g (66% of theory) of trans-N-plienyl- W 3-phthalimldo-4-acetonylthio-azetidinone (2) with a melting point of 172-173 ° C. are obtained.

C ₂₀ H ₁₆ NO ₄ S calculated: C 63.15 H 4.24 N 7.36 S 8.43% (380.4) found: C 62.6 H 4.2 N 7.6 S 8.3 %

The corresponding 2,4-dinitrophenylhydrazone melts at 257 ° C, C ₂₆ H ₂₀ N ₆ O ₇ S calculated: C 55.71 H 3.60 N 14.99 S 5.72 % (560.6) found: C 55 , 4 H 3.8 N 15.2 S 5.9%

Example 11;

6.3 g (0.02 mole) of trans-N - / ^ ^{'t-methyl-propene} (2 ^t) 7-yl-3-phthalimido-4-methylthio-azetidinone (2) in a mixture of 200 ml Methylene chloride and 50 ml of methanol are oxidized with ozone as in Example 10 besc-Jirieben. Working up according to Example 10 gives trans-N-acetonyl-S-phthalimido ^ - methylthio-azetidinone- (2) in the form of colorless crystals with a melting point of 108-109 ° C. The yield is 4.6 g, corresponding to 72% of theory.

C _1K H _{n> l} N _o 0.S calculated: C 56.5 £

15 14 δ 4 (318.4) found: C 56 _t 8

H 4th , 44 N 8th, 80 S. 10 , 07 H 4th »6 N 8th, 8th S. 10 , 0

./14

209814/1649

/ Γ

Example 12;

25 g (0.07 mol) trans-N- / 2 "'- meth3 ^r l-propen- (2» 27-yl-3-

are in methylene chloride: methanol (5OO: 100 ml) at -60 ° C oxidized with ozone. After an uptake of 0.14 mol 0 «become 40 ml of dimethyl sulfide were added, followed by 5 hours at room temperature is left. After evaporation of the solvent, the crystalline residue is used to remove impurities Digested with methanol. The colorless crystals obtained are then washed several times with ice-cold methanol .

Yield 21 g (83% of theory) of trans-N-Acetony1-3-phthaiimido-4-acetonylthio-azetidinone- (2) of melting point 129 130 ° C. "/ i

C ₁₇ H ₁₆ N ₃ O ₅ S calcd: C 56.66 H 4.48 N 7.77 S 8.90% (360.4) found: C 56.8 H 4.5 N 7.9 S 8, 8th %.

The corresponding bis-2,4-dinitrophenylhydrazone melts at 240 ^° C.

^C 29 ^H 24 ^N 10 ° ll ^{S calculated:} C 48.34 H 3.36 N 19.44 S 4.45% (720.7) found t C 48.1 H 3.6 N 19.1 S 4, 8th %

Example 13; .

According to Example 12, 5.7 g (0.015 mol) of trans-N- / ~ 2 * -methylpropene- (2 ^f ) 7-yl-3-tosyloxy-4- / 2 ' ^I -methyl-propen- (2 ^f _) 7-yl-thio-azetidinone- (2) in methylene chloride; Methanol (200: 40 ml) is ^{oxidized at -6O 0} C with ozone. After treatment with dimethyl sulfide, working up and recrystallization from methanol, 3 g (52% of theory) of trans-N-acetonyl-3-tos'yloxy-4-acetonylthio-azetidinone- (2) in the form of colorless crystals with a melting point of 100-101 ° C.

./15 2098U / 1649

^S 2 calculated: C. Xi * .. H 4, 97 N 3 , 63 S. 20468 23 found : C. Λ H 4, 8th -N 3 , 2 S. CL AL _Q NO _r
16 19 6 49, 86 16.64 % (385.5) 49, 8th 16.7 %

Analogously, the oxidation of 24.2 g (0.06 mole) of trans-N - / ^ ^{"t-methyl-propene} (2 ^f) _7-yl-3- (p-chlorophenyl) -sulfonyloxy-4-A ^l -raethyl-propen- (2 ^l ) 7-yl ~ thio-axetidinone- (2) 21.2 g (88% of theory) of trans-N-acetonyl-S-ip-chlorophenylJ-sulfonyloxy-4 ~ acetonyl-thio ~ azetidinon- (2) of melting point 73-74 C (from methanol).

S ₂ Calculated: 44.39 H 3.97 Cl 8.74 N 3.45 found C S15,83% (405.9): C 44.0 H 3.8 Cl 8.9 N 3.5 S 15, 6%

Similarly, the oxidation of 25.7 g (0.059 mol) of trans-N- / 2 " ^l -Methyl-propen- (2 ^t 27 -yl-3- (3 ^f , 4'-dichlorophenyl) -sulfonyloxy ~ 4- / ^ '- methylpropen- (2 ^! ) 7 ~ yl-thio ~ azetidinone ~ (2) in a yield of 11.5 g (44% of theory) the trans-N-acetonyl-3 ~ (3 *, 4 '-dichlorphenyl) -sulfonyloxy-4-acetonylthioazetidinon- (2) of melting point 107-108 ⁰ C (from methanol).

^C 15 ^H 15 ^C1 2 ^NO 6 ^S 2 ^calculated : ^c 40.92 H 3.43 Cl 16.10 N 3.18 S14.57% (440.3) found: C 40.7 H 3.8 Cl 16, 4 N 3.3

Example 14:

5 g (0.02 mol) cis-N- / ~ 2'-methyl-propen- (257-yl-3-azido-4- / n2 ^l -methyl-propen- (2 *) 7-yl-thio- -azetidinone- (2) are oxidized with ozone in methylene chloride: methanol (200: 50 ml) at ~ 60 ° C. After taking up 0.04 mol of O ₃ Averden, 20 ml of (CHo) _n S are added After washing with water and stripping off the solvent, the oily residue is over silica gel (0.05-0.2 mm, deactivated with 10% water 2.5 × 110 cm column) with ethyl acetate to give cyclohexane (2: 1 ) chromatographed in the fractions

./16 2098U / 16A9

5 - 10 are 1.9 g (38% of theory) of a thin layer chromatographically uniform. Obtain oil, which according to IR and NMR spectrum of the cis-N-Acetonyl-S-azido ^ -acetonylthioazetidinone- (2) represents.

Example 15:

19 g (0.055 mol) of trans-N- / 2 ^{"t-chloro-propen} (2 ^t 27» yl - 3-phthalimido-4- / ~ 2 '-methyl-propen (2 *) -yl _7 thio-azetidinone-CS) are treated in methylene chloride: methanol (450: 100 ml) with a stream of ozone and oxygen (1 n ole, 0.1 / minute) at -60 ° C. After 135 minutes, 0.109 mol of O _{3 are} absorbed acidic reaction solution v / ith then with 40 ml of dimethyl sulfide and 40 ml of pyridine, heated to 20 ° C and allowed to stand for 5 hours at room temperature. the mixture is then worked-up with 2N HCl sodium bicarbonate and water. the residue remaining after evaporation of the solvent resinous residue is then dissolved in 60 ml of warm ethyl acetate After 3 hours , the colorless crystals which have separated out are filtered off with suction and washed twice with ethyl acetate.

This gives 14.7 g (71% of theory) of trans-N-Caxbomethoxymethyl-3-phthalimido ~ 4-acetonylthio-azetidinone (2) of melting point 127-128 ⁰ C.

₃ O ₆ S calculated: C 54.25 H 4.29 N 7.44 S 8.52%

(376.4) found : C 54.1 H 4.2 N 7.6 S 8.6 %

The 2,4-dinitrophenylhydrazone prepared accordingly for characterization melts at 194 ° C,

C ₂₃ H ₃₀ NgO ₉ S "calculated: C 49.64 H 3.62 N 15.10 S 5.76%

(556.5) found: C 50.0 H 3.6 N 14.8 S 6.1%

If the ozone oxidation after the ingestion of 1.2 equivalents of O ₃

'/ 17

209814/1649

terminated and the resin obtained after treatment with PyricUn / (CHO) ₀ S is chromatographed over silica gel with cyclohexane-ethyl acetate (1; 1), then in addition to the product described above (yield 10%> as the main product (Bo % yield) the trnns- N- / 2 ^{"l-chloro-propene} (2 * 27 ~ yl-3-phthalimido-4-Rcetonylthio-aaetidinon- (2) of melting point 140 - 141 ⁰ C to cool (after recrystallization from methanol).

C ₁₇ H ₁₅ ClN ₂ O ₄ S calcd .: C 53.90 H 3.99 Cl 9.36 N 7.40 S 8.46% (378.8) found: C 53.9 H 4.0 Cl 9.6 N 7.3 S 8.4 %

If the oxidation of 22.6 g (0.06 mol) of trans-N- / 2 * ^r -chloropropene- (2 ^l 27-yl ~ 3-phthaliraido-4 - / ^ ' ^f methyl-propen- (2 * y7 -yl thio-azetidinon ~ (2) carried out in the presence of ethanol and, after working up as above, the residue of the organic phase is recrystallized from ethanol, 13.5 g of colorless crystals of melting point 95-96 ° C. of trans-N-carboethoxymethyl are obtained -3-phthalimido-4-acetonylthio-azetidinone- (2) The yield is 58% of theory.

C ₁₈ H ₁₈ N ₂ O ₆ S calc .: C 55.38 H 4.65 N 7.18 S 8.21 % (390.4) found: C 55.8 H 4.8 N 7.5 S 8.1% If 7.5 g (0.02 mol) of trans-N- / 2 ' ^l -chloro-propen- (2 ' YT-yl- 3-phthalimido-4- / 2 '' - methyl-propen- (2 '_) 7-y 1-thio-azetidinone- (2) in 200 ml of acetone and 10 ml of water at -60 ° C with ozone and worked up as described above, so 6 g (82 % of theory) are colorless Crystals of trans-N-carboxymethyl-3-phthalimido-4-acetonylthio-azetidinone- (2) obtained, which after reprecipitation a
melt.

Falling over from glacial acetic acid at 185-190 ° C with decomposition

C ₁₆ H ₁₄ N ₃ OgS calcd: C 53.03 H 3.89 N 7.73 S 8.85 (362.4) found: C-53.3 H 3.7 N 7.7 S 8.6

Example 16 :

6 g (0.015 mol) trans-NA ^t -Chlor-propen- (2 ^t ) / - yl-3-tosyloxy-4- / 2f ^l -methyl-propen- (2 ^f ) _7-yl-thio-azetidinone- ( 2) are treated with ozone in methylene chloride: methanol (200: 40 ml). After uptake of 0.032 mole , a slight blue coloration occurs

2098U / 1649 * ^{/ 18th}

Solution on. It is mixed with 15 ml (CII) _o S and 15 ml pyridine and left at room temperature for 5 hours. After working up as in Example 15, the residue of the organic phase is chromatographed on silica gel (0.05-0.2 mm, deactivated with 10% water 2.5 × 110 cm column) with ethyl acetate: 'Cyclohexane (2: 1) chromatograph! location. In fractions 3-6, 4.5 g of thin-layer, chronographically uniform oil are obtained, which crystallizes with methanol. The melting point of the trans-N-carbomethoxyinethyl-S-tosyloxy ^ -acetonylthioazetidinone- (2) obtained in this way is 69 ° C. and the yield is 74 % of theory.

C ₁₆ H ₁₉ KO ₇ S ₂ calcd: C 47.87 H 4.77 N 3.49 S 15.97% (401.5) found: C 48.2 H 4.7 N 3.3 S 15.5 %

28.3 g (0.062 mol) of trans-N- / 2 "" - chloropropen- (2 ') 7-yl-3- (3', 4'-dichlorophenyl) -sulfonyloxy-4- / -2 · - methyl-propen- (2 ^) 7-yl "thio-azetidinon- (2) oxidized with ozone, then after chromatographic purification 20 g (71 % of theory) of a thin-layer chromatographically uniform resin are obtained, which according to IR and NMR Spectrum represents the trans-N-carbomethoxymethyl-3- (3 ', 4'-dichlorophenyl) -sulfonyloxy-4-acetonylthio-azetidinone- (2).

Example 17;

3 g (0.01 mol) of trans-N-propene- (2 ^t ) -yl-3-phthalimido-4-raethylthio-azetidinone- (2) are dissolved in methylene chloride: methanol (150: 20 ml) at -60 ° C oxidized with 1 equivalent of ozone. After adding 10 ml (CHg) ₂ S, the mixture is left at room temperature for 5 hours. According to thin-layer chromatography, the residue of the organic phase (3.5 g of oil) contains a reaction product which is not obtained in crystalline form. The oil is dissolved in 100 ml of warm ethanol and treated with 0.015 mol of 2,4-dinitrophenylhydrazine. The yellow crystals which precipitate out immediately are filtered off with suction after 2 hours and _{washed acid-free with C 3} H OH: ELO (1: 1).

209814/164 9 './19-

$ 0

Yield 3 g (62 % of theory) 2,4-Din ± trophenylhydrazone of trans-N-Formy! Methyl-3-phthalimido- 4-methylthio-azetidinone- (2) with a melting point of 199-2OO ° C (after recrystallization from glacial acetic acid ).

^C 20 ^H 16 ^N 6 ^C ) .-, p calculated: C. 49 , 58 H 3 , 33 N 17th , 35 S. 6th , 62 % (484.5) found : C. 49 , 7 H 3 , 3 N 17th , 2 S. 6th , 7 % example 18:

⁷ » ⁷ g (0.02 mol) of trans-N-phenyl-S-tosyloKy-4-propargylthioazetidinone- (2) are treated with ozone in 200 ml of methylene chloride at -60 ° C. After taking up 0.021 mol of O ₃ , the solution is colored blue. There are 20 ml (CHQ) ₀ S added, WO

^ is left for 5 hours at room temperature. After working up with water, the solvent is evaporated, the resinous residue is dissolved in 100 ml of warm alcohol and dinitrophenyl hydrazine reagent (RL Shriner, RC Fuson, DY Curtin, The Systematic Identification of Organic Compounds Wiley NY 5th edition, p. 126) containing 0.03 mol of 2,4-dinitrophenyl hydrazine was added. A red-colored precipitate immediately separates out, which is filtered off with suction and _{washed free of acid with alcohol: H 2} O (1: 1). Yield 8 g, melting point unsharp at 215-220 ° C, insoluble in boiling glacial acetic acid. The compound is reprecipitated by dissolving it in cold dimethyl sulfoxide and adding 10 parts by volume of glacial acetic acid. The melting point is then 228-230 ° C. According to the IR and NMR spectrum, that is

ψ bis-2,4-dinitrophenylhydrazone of trans-N-phenyl-3-tosyloxy-4τ · (2 ^f , 3 ^f -dioxo-propyl) thio-azetidinone- (2) before; the yield is 51% of theory. .

calculated: C. 47 , 75 H 3 , 23 N 16 , 17th S. 8th , 23 % found : C. 47 ,8th H 3 , 3 N 16 , 3 S. 8th , 2 %

(779.7)

Example 19:.

16.5 g (0.067 mol) of crude trans-N- / 2 "'-chloro-propen- (2 · _) 7-yl-3-hydroxy-4- / 2- ^f -methyl-propen-(2 '27 yl ~ thio-azetidinone (2) werdem in methylene chloride: methanol (220: 80 mL) ⁰ C 65-in with ozone After uptake of 0.135 I »5ol O ₃ be 40 ml.

2098U / 1649.

(CIL,) ,, S 40 and ail Py chloride in added followed by 4 hours left at room temperature "Eg, as shown in Example 15, the residue work up of the organic phase xxnd (5.5 g oil) as usual chromatography Ί ; (2.5 χ 100 era column, eluted with cyclohexane: ethyl acetate 1: 2). In fractions 10-16, 1.5 g of an oil which is uniform according to thin-layer chromatography and which, according to the CMR spectrum, is trans-N-carbomethoxy-methyl-3-hydroxy -4-acetonylthio-az: etidinone- (2) ■ is obtained.

Example 20;

⁸ * 6 S (0.02 mole) of trans-3- / ¥ '-Chlorphenyl7 - sulfonyloxy-4- / 2 "', 3 '-dimethyl-butene (2 ^t 27-yl-thio-N - / ^ " ^1- methyl-propen- (2» 27 yl-a2setidinone- (2) are oxidized with ozone in methylene chloride: methanol at -70 ° C. After the absorption of 0.043 mol of 0.1, 20 ml (CHo) oS are added, then is left at room temperature for 4 hours and the solution is washed with water. 4 g of colorless crystals with a melting point of 72-74 ° C. crystallize from the residue of the organic phase ^1- chlorophenyl) -sulfoii / i5xy-4-acetonyl-thio-azetidinone- (2) are identical to Example 13. The yield is 50 % of theory.

./21 2098U / 1649

Claims (2)

claims '. Process for the preparation of azetidinones. '! - (2) the general formula R ₉ - (Y) _n - CH - CC ^{3 2} IIR ₄ I, N-CO- *
I. ^R l wherein R ₁ a) a hydrogen atom, a phenyl radical which can be substituted by alkyl groups, preferably with 1-4 carbon atoms, halogen, nitro, cyano, sulfaraido, carbonamide, carboxylic acid ester, alkyl sulfonyl or trifluoromethyl groups , a Cj-CjQ-alkyl radical, Cg-C ^ cycloalkyl-, Cg-Cg-cycloalkyl-O, -C "-alkyl-, C ^ -C - ^ - haloalkyl-, C ₀ -C _n -.- haloalkenyl- , C ₁ -Co-cyanoalkyl-, C _n -C _Q -alkyl-X- XO Xo Cg-Cg-alkyl-, where X is oxygen or sulfur is a phenyl-C. -Co-alkyl radical, where the phenyl radical, as indicated above, may be substituted, or b) a carboxy-Qj-Cg-alkyl-, C.-Cg-alkoxycarbonyl-C | -C _fi -alkyl ~, a pormyl-Cj-Cg-alkyl- or a Cj-Cg-alkyl-carbonyl-Cj-Cg -alkyl radical means R «a) a phenyl radical which can be substituted by alkyl groups, preferably with 1-4 carbon atoms, halogen, nitro, cyano, sulfamido, carbonamido, carboxylic acid ester-f alkylsulfonyl or trifluorruethyl groups, an Oj-Cj ^ - Alkyl radical, C ₅ -C ₇ -CyCIoalkyl-, C ₃ -Cg -cycloalkyl-C ₁ -Cg -alky ^ -, C ₂ -C ₁₀ -Habgen- Χ »} X« J 4b Ό where X stands for oxygen or sulfur or a phenyl-C ₁ -Co-alkyl radical, the phenyl radical as above ./22 2 0 98U / 1649 indicated may be substituted f / means, or JTall-s η is zero, b) a formyl or carbo?: yl radical, / or a Forraylcarbonyl-C ^ -Cg -alkyl-, C-j-Cg -alkoxy-carbonyl-C. -Cgalkyl- or a C - Cg-AIl: yl-carbonyl-Cj-Cg-alkyl radical means, where at least one of the radicals R- and R «are each has the meaning given under b), Rq denotes a hydrogen atom or halogen atom, in particular a chlorine or bromine atom, a hydroxy, an azido or an acylamino group or a sulfonyloxy group of the formula R-SO ₂ -O-, in which R an alkyl group, preferably with 1-4 Carbon atoms which can be substituted by halogen atoms or cyano groups, an aryl radical, especially one .; Phenyl or naphthyl radical, which can be substituted by alkyl groups, preferably with 1-4 carbon atoms, alkaxy groups, preferably with 1-4 carbon atoms, halogen atoms, nitro, cyano, sulfonamido, carboxylic acid ester, carbonamido, alkylsulfonyl or trifluoromethyl groups, R ₄ denotes a hydrogen or a halogen atom, in particular a chlorine or bromine atom, Y stands for -0- or -S- and
η means zero or 1, characterized in that one azetidinone- (2) the general formula R _fi ~ (Y) - CH-C ^
^{6 n} I | ^X
N-CO
I. ^R 5 wherein R ₃ , R ₄ , Y and η have the meanings given above, *) or Giiien Benzhydryl- odci-Tritylrest, 2098U / 16A9 ', 20A6823 R ₅ a) has the same meaning as R a) or b) a C ₃ -Cj ₀ -alkenyl-, C ₃ -C ₁₀ ~ alkynyl-, alkenyl, 2 '-Fury 1-C ₁ -C ₃ -alkyl-, 2 • -ί.,!. ■ .. alkyl or a phenyl-C ₁ -C ₃ -alkyl radical, where the phenyli' est is substituted by electron-donating substituents, preferably hydroxyl, alkoxy and / or amino groups, means R_ a) has the same meaning as Rn a) or "; b) a 2'-furyl, 2'-thienyl, a β-phenylvinyl radical, where the phenyl radical can be substituted as indicated above, or a Cg-CjQ- Alkenyl, C ₃ ~ C ₁₀ -alkynyl-Cg-CjQ-haloalkenyl-, Cg-CjQ-haloalkynyl-, 2'-furyl-, Cj ^ -Cg-alkyl-, 2 »-thienyl-Cj-C ^ alkyl- or a phenyl-C ₁ -Cg-alkyl radical, where the phenyl radical is substituted by electron-donating substituents, preferably hydroxyl, alkoxy and / or amino groups, where at least one of the radicals R- and R _{ß has} the meaning given in each case under b), treated with ozone and the compounds thus obtained hydrolyzed or reduced. 2. Compounds of the general formula *1 wherein R ₁ , R ₂ »R ₃ and R _{4 have} the meanings given in claim 1 and at least one of the radicals R ₁ and has the meaning given in each case under b). 2098U / 16A9