CS207656B2 - Method of preparation of 2-oxo-3-acylamino-4-mercap-toazetidins - Google Patents

Description

(54) A process for the preparation of 2-oxo-3-acylamino-4-mercaptoazetidines

The present invention relates to a process for the preparation of 2-oxo-3-acylamino-4-mercaptoazetidines of the formula I

R ¹ GONH SH

wherein R ¹ is benzyl or phenoxymethyl, p

R is a hydrogen atom or a group of formulas

Y

-CHR ³ -COX or -C = CH ₂ -Hal '

COX where R 6 is isopropenyl or a hydrogen atom,

X 1 is 1-morpholinyl, hydroxyl, methyl, dimethylamino, 1-piperidinyl, Hal 'is halogen,

X is p-nitrobenzyl, 2,2,2-trichloroethoxy group, a p-nitrobenzyloxy, benzyloxy, t-butoxy, difenylmethoxyskupina, characterized in that the thiazoline ring of compounds of formula II R ¹ (II) ^N \ ^Z ₂ OR

Wherein R and R are as defined above, cleaving with an acid such as perchloric acid, hydrochloric acid, sulfuric acid, phosphoric acid, oxelic acid, p-toluenesulfonic acid, trifluoroacetic acid and mercuric chloride in the presence of at least 1 molar equivalent of water in the solvent, such as dichloromethane, chloroform, acetone, benzene, ethyl acetate, dioxane, tetrahydrofuran, methanol or ethanol at -10 ° C to 70 ° C.

The compounds of formula II may be named as 7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-enes.

The starting material can be prepared, for example, from the corresponding penicillin-1-oxide esters by treatment with methylphosphites or by reaction of its products by conventional methods.

Decomposition of the azetidinothiazoline compound with aqueous acid is a novel general reaction for obtaining 4-mercapto-3-carboxy-acylamino-2-oxoazetidine derivatives according to the reaction scheme

Wherein R and R are as defined above.

It can also be carried out by reacting the thiazolinoazetidine of formula II with acid and water. The reaction of water is necessary to cleave the thiazoline ring to form a 4-mercapto- and 3-acylamino-azetidine ring. Preferred acids include mineral acids (e.g., hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hypochlorous acid), sulfonic acid (e.g. alkanesulfonic acid, arylsulfonic acid, arylalkylsulfonic acid, especially alpha-haloalkenesulfonic acid, alpha-halocarboxylic acid polycarboxylic acid, preferably acids with a dissociation constant of at least 0.01.

More specifically, these acids are strong acids such as perchloric acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid, fluoroboric acid, hydrochloric acid, hydrofluoric acid, hydrobromic acid, nitric acid, phosphoric acid, benzenesulfonic acid toluenesulfonic acid, bromobenzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like.

The reaction may be carried out in solvents which include hydrocarbons (pentane, hexane, benzene, toluene, etc.), halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, dichlorobenzene, etc.), esters (ethyl acetate, butyl acetate, methyl benzoate, etc.), ketones (acetone, cyclohexanone, benzophenone, etc.), ethers (diethyl ether, ethylene glycol, dimethyl ether, tetrahydrofuran, tetrahydropyran, dioxane, morpholine, anisole, etc.), alcohols (methanol, ethanol, ethylene glycol, benzyl alcohol, etc.), carboxylic acids (acetic acid) propionic acid and the like), bases (butylamine, triethylamine, pyridine, picoline, etc.), amides (dimethylformamide, dimethylacetamide, hexamethylphosphoramide etc.), nitriles (acetonitrile, benzonitrile, etc.), nitrated hydrocarbons, sulfoxides (dimethylsulfoxide etc.), water and mixtures thereof.

More preferred solvents are polar solvents capable of dissolving water and acid (e.g. ethers, ketones, alcohols, amides, sulfoxide, water), solvents capable of dissolving the starting material II (e.g. halogenated hydrocarbons, esters, ethers, ketones) and mixtures thereof.

If a strong acid is used, side reactions such as decomposition of the azetidinone ring can take place. The yield can be improved by selecting reaction conditions, such as concentration, temperature, reaction time, and the like. Generally, the reaction proceeds rapidly at room temperature, sometimes within 10 minutes to 1 hour, to give the desired compound in high yield.

The products are unstable to alkalis and oxidation. Therefore, the reactions and work-ups are carried out without subjecting the reaction mixture to these conditions.

Some starting compounds are prepared by the following procedures:

Preparation

To a solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -α- (1-hydroxyethylidene) acetate (504 mg) in tetrahydrofuran (8 mL) was added dropwise with ice-cooling methanesulfonyl chloride (0.13 mL) and triethylamine (0.23 mL). After three hours, the mixture was evaporated to leave a residue which was dissolved in methylene chloride, washed with water, dried over magnesium sulphate and evaporated. Purification of the residue by chromatography on silica gel containing 10% water (15 g) using benzene / ethyl acetate (5: 1) afforded p-nitrobenzyl-alpha-β-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3,2,0] hept-2-en-6-yl] - alpha - (1-methanesulfonyloxyethylidene) acetate (353 mg). Colorless foam.

I WANT ”1

The product does not contain a geometric isomer in alpha position. ^IR: max3 780 »1730 cm

NMR: δ ^CDCl 3 2.60, s, 3H, 3.18, s, 3H, 4.58 + 4.88, ABq, (14Hz), 2H, 5.24, s, 2H, 5.92 + + 6.08, ABq, (5HZ), 2H, 6.73-8.20, m, 9H.

Preparation 2

To a solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-ω-4-thia-2,6-diazabicyclo [3.2.1] hept-2-en-6-yl] -α- (1-hydroxyethylidene) acetate ( 940 mg) in dimethylformamide containing 10% tetrahydrofuran (5 mL) was added toluene-p-sulfonyl chloride (456 mg). After cooling to -70 ° C, the solution was treated with triethylamine (0.3 mL). The reaction mixture was allowed to warm slowly to room temperature, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue obtained is chromatographed on silica gel with 10% water using benzene and 5% ethyl acetate. There was thus obtained p-nitrobenzyl .alpha .- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.1] hept-2-en-6-yl] -. (sulfonyloxyethylidene) acetate (644 mg). IR: .in ^X ^ 3 1785 ', 1735 cm ^1st NMR: δ ^CDCl 3 2.45, s, 3H, 4.75 + 4.20, ABq, (14Hz), 2H, 5.15, s, 2H, 5.77, s, 2H, 8.30-6.60, m, 13H.

Preparation 3

To a solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonylethylidene) acetate (298 mg) in benzene (3 mL) was added folin plague (0.095 mL) at 7-10 ° C. After 130 minutes, the reaction mixture was filtered and the filtrate was poured into ice water and extracted with methylene chloride. The extract was washed with water, dried (MgSO4) and evaporated to give p-nitrobenzyl .alpha .- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.1] hept-2-en-6-yl]. .alpha .- (1-morpholinoethylidene) acetate (284 mg). Foam. Yield 97.1%.

The product is a mixture (about 1: 1) of the geometric isomers of the substituent at the alpha position.

IR: v 1,768, 1,685, 1,612, 1,623 om ^-1 . NMR: ⁸ ° ^DC1 3.90, s, 1H, 2.42, s, 1H,

3.17 - 3.43, m, 4H, 3.52 - 3.83, m, 4H, 4.87, s, 2H, 5.21, s, 2H, 5.58-6.00, m, 2H,

6.80-8.22, m, 9H.

Preparation 4

To a solution of 2,2,2-trichloroethyl-alpha- [β-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.1] hept-2-en-6-yl] -alpha- ( 1-Methanesulfonyloxyethylidene) acetate (1.52 g) in benzene (30 mL) was added at below 10 ° C with morpholine (0.48 mL). After stirring for 1 hour, the mixture was washed with water, dried and evaporated. Purification of the residue by silica gel chromatography affords 2,2,2-trichloroethyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6- yl-.alpha .- (1-morpholinoethylidene) acetate (0.76 g). Yield = 50%.

The product is a mixture of isomers of the substituent at the alpha position.

NMR: δ CDCl ₃ 1.88 + 2.42, s, 3H, 3.1-3.9, m, 8H, 4.73, ABq, (12Hz), 2H, 4.95, s,

2H, 5.7-6.2, m, 2H, 6.8-7-5, m, 5H.

Preparation 5

To a stirred solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3,2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) acetate (500 mg) in tetrahydrofuran (20 mL) was added dropwise methyl chloroformate (200 mg) and triethylamine (216 mg) under ice-cooling. After one hour, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] - alpha - (1-methoxycarbonyloxyethylidene) acetate (546 mg). Foam. Yield: 97% ·

The product is a mixture (about 2: 1) of the geometric isomers in the alpha position.

^LCV max ^{13 1783} · ^{'732> 1642} i ^{1 6.2> 1600 cm' 1} · ^{10111: CDCl3 8} '· ^{95 »s' H> 2.47 's'}

2H, 3.68, s, 1H, 3.80, s, 2H, 4.54 + 4.86, ABq, (14Hz), 4 / 3H, 4.86, s, 2 / 3H, 5.25, s, 3H,

5.73-6.03, m, 2H, 6.70-8.16, m, 9H.

Preparation 6

To a solution of 2,2,2-trichloroethyl alpha- [3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo [3.2.0] hept-2-en-6-yl] -alpha- ( 1-hydroxyethylidene) acetate (450 mg) in methylene chloride (7 mL) was added at -25 ° C methanesulfonyl chloride (0.093 mL) and triethylamine (0.48 mL) and the mixture was held at this temperature for 40 minutes. To the resulting solution of 2,2,2-trichloroethyl .alpha .- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha. (1-methanesulfonyloxyethylidene) acetate was added dropwise with morpholine (0.112 mL) and the mixture was stirred for 1.3 hours. The reaction mixture was washed with water, dried and the residue was purified by chromatography on silica gel with 10% water to give 2,2,2-trichloroethyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3,2,0] hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate (205 mg).

The product is a mixture (about 1: 1.6) of the geometric isomers in the alpha position.

NMR 8CDC1 ₃ 1.67, s, +2.35, p, [3H], 2.83 to 4.00, m, 8H, 2.31, s, 2H, 4.45 + 4.88, q, (12Hz), 4.47 + 4.83, q, ( 12Hz), [2H], 5.60-6.12, m, 2H, 7.22, s, +7.23, s, [5H].

Preparation 7

To a stirred solution of p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) Methylsulfonyl chloride (0.18 mL) and triethylamine (0.31 mL) were added under ice-cooling with ice-cooling (680 mg) in tetrahydrofuran (15 mL) and the reaction mixture was stirred for one hour. The precipitated crystals were filtered off and the filtrate was evaporated, purification of the residue (800 mg) by chromatography on silica gel with 10% water (25 g) gave p-nitrobenzyl alpha- [3-benzyl-7] eluted fractions eluted with benzene and ethyl acetate (2: 1). oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate (609 mg). Yield 76.6%.

The product does not contain a geometric isomer in alpha position.

^{lC: v} max ^{l3 1,784} > ^1,728 ' ^1,700 ' ^{1,614 cm 1} · ™ ^{R; 8GDC1} 3 2.58, s, 3H, 3.00, s, 3H, 3.79, s, 2H, 5.18, s, 2H, 5.85 + 6.00, ABq, (5Hz), 2H, 7.22, s, + 8.23, m, 9H.

Preparation8

To a solution of p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) of acetate (609 mg) in methylene chloride (3 mL) at -15 ° C was added morpholine (0.2 mL) and the mixture was stirred at this temperature for 50 min. The reaction mixture was poured into ice water and extracted with methylene chloride. The extract was washed with water, dried and evaporated. Purification of the resulting foam (569 mg) was chromatographed on silica gel (25 g) to obtain p-nitrobenzyl alpha- [β-benzyl-7-oxo-4-thia-2,6-] from the fractions eluted with 2: 1 benzene / ethyl acetate. diazabicyclo [1,2.0] hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate (452 mg). Yield 75.5%. Foam.

The product does not contain geometric isomers in alpha position.

IR: in CHCl3 _{,? 78)} , ₆₉₅ ?, ₆₁₅ ? -1, _CDCl ? _{2? 37 ?} S _{? 3H? 3?? 3? 73? 8H?}

3.86, s, 2H, 5.20, s, 3H, 5.73 + 5.88, ABq, (5Hz), 2H, 7.15-8.28, m, 9H.

These products are also new and correspond to the following formula III

R ¹

I ^ ^c \ (III)

NS ——N ^x c = ct

I cox

Kde 'wherein R ¹ is as defined above, ϊ' is a carbon acyloxy group containing up to 12 carbon atoms, a disubstituted amino group having 2 to 20 carbon atoms or an aromatic or aliphatic sulfonyl group having 1 to 20 carbon atoms and X is a hydroxy or carboxyl protecting group.

The present invention is illustrated by the following examples.

Example 1

To a solution of 3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-ene (200 mg) in a mixture of methylene chloride (6 mL) and acetone (8 mL) was added A 30% aqueous solution of perchloric acid (1.0 mL) was added and the mixture was stirred at room temperature for 40 minutes. After dilution with excess water, the reaction mixture was extracted with methylene chloride. The extract was washed with water, dried over sodium sulfate and concentrated. As a residue, a white crystalline 4beta-mercapto-3p-phenoxyacetamido-2-oxo-azetidine, mp 137-138 ° C. [A] J ³ + 3,0 +38,0 ° [c = 0.261, CHC1 _3, and C-OH (4: 1)].

IR: 3290, 3200, 2562, 1757, 1658, 1549 cm ^- '. NMR: 6 ^ -DMSO _3>?> Br s, 1H, 4.58, s, 2H, 5.00, br s, 1H, 5.32, dd, (9, 5 Hz) 1H, 6.80 - 7 , 43, m, 6H.

Example 2

To a solution of the R ³ alpha- [3-substituted (R ¹ ) -7-oxo-4-thia-2,6-diazabicyclo [3.2.1] hept-2-en-6-yl] -alpha-substituted ester ( R ² ) -acetic acid (5) in the solvent is added acid and the mixture is stirred at the indicated temperature for the indicated time. The reaction mixture was diluted with water and extracted with methylene chloride. The extract was washed with water, dried over sodium sulfate to give the desired (R ³ ) alpha- [4-mercapto-3-substituted amino (R 1 -CONH) -2-oxoazetidin-1-yl] -alpha-substituted (R ² ) ester acetic acid.

Table I gives the reaction conditions and Table II gives the physical constants of the product.

Table I shows the crude product yield by weight. The products are almost pure according to thin layer chromatography and NMR spectra. Some of them were purified by crystallization.

ι φ

O

Ο γΜ

W

Ρ, Μ '>> Φ ί> * 3 b £) a

α> ο

Λ} β

Φ

CX φ

Η

Μ · Μ Ο Μ Μ- β Ο Μ Ο ο Κ Ο Ο cs γΜ ο <Χ « οί Ο rM rM • Η ο ω Γ * Ί ο Ο ο rM and ΕΜ ® Η ο ο ® and Φ ο ! *> Μ γΜ 00 ιχ \ ο and ο ο ο C0 Ο CC >> and ο ο "to ο · » and «* ο * ♦ » Ο · * Ο r. ο m ο Μ · ο σι τ- CM - οί w- bunch Μ- σΊ Ο σΊ r- ο ο μ · Μ · Μ νο Μ- Ο US Μ- ο ΓΜ ου Μ · Μ IfS ΙΓΊ

Ό> Φ

Ρ

ΧΟ

Ο

CX

Ν

Ο ϊ?

ο ο

R CM rM Ο σΊ Ί ® ® Ο Ο ο

ο

ΓΜ CM rM ο m CM® ® Ο Ο

Ο ο

CM CM rM 'Ο ΟΊ

ΓΜ ® ® Ο Ο

Ο

Ο

ΓΜ ΓΜ γΜ

Ο m ΓΜ ® ® Ο ο ο

ο ο

Μ-Ο ® σ 'νο® Ο Ο

Ο

CMO γΜ ο σΊ

CM® ® ο ο ο

ο

ΓΜ ΓΜ Η m

ΓΜ ® ® Ο Ο

Ο ο

ΓΜ tCM

ΓΜ

ΓΜ ΓΜ ΓΜ ΓΜ ΓΜ ΓΜ ΓΜ Ο Ο Ο Ο Ο Ο Ο and and and and and and and Μ · Μ ” Μ- Μ- Μ Μ ” Μ- σΊ and and and ι and and and Η _ζ - Ό V0 VO νθ νο Sat νθ Ο Η Ο Ο Ο Ο ο ο Ο Ο Η ΓΜ <Μ ΓΜ ΓΜ ΓΜ ΓΜ ΓΜ ΓΜ ® ® and and and and and and ΡΊ Ο Ο ο ο ο ο ο ο

οί γμ ®

Ο 0 = 0

AND

σΊ σ-ι ΡΊ ΡΊ m L J ΓΜ® ΓΜ® cm a ου® WHAT • 2 σΊ® ΡΊ ® and ο and ο and ο and ο <M AND and o and o 0 * 0 0 = 0 ο «ο 0 = 0 1 0-0 0-0 1 ί ί 1 o - O II II

CM CM OM CM CM OJ CM OM and and and and and and and and O O O O O O O O O O O O O O O O and 1 and Q 1 1 ISI 4 1

β

X »β

ΕΜ φ

ϋ

Μ β

φ. ® Ο ι

χυ ρ #> φ νο

X)

©) © © and Φ ο «Ό

ΙΑ 'Φ ©

Ρ

Ο ι-Ι

Ο.

φ

Ε- »ρ

• ϋ md

Ρ χη ο

λ (4 (

W λ μ Χ ~ 04 / 33 33 Μ Ν W 04 · νο X) 33 σ \ © 33 Β © 04 / Ο - Ο β > m ω 1 ' Μ ΙΑ • ο ·Α · >> «. IAV0 (Α’Φ 43 Ρ and - λ • 1 □ β ομ 33 • 04 'Φγπ Χθ © «Οο 33- + ο- 44 Ρ C- w Η 04 / ο · β ω ΙΑ β ο ω · σ \ νο Ο β • a ♦ a 33Α 33 Μ ί> ο 'C-33' ΙΑΟ Xfr Λ χΰ 44 - Ο Μ— 33 Ν Μ- Β «04 Μ 33 SΑ S - ο 31 a > β - irst- • 04 Χ4 · <Μ 04 33 * ωο © 44 ΙΑ33 * * ΟΊ00 νο · r9 © • v- C0 ο Μ | 04 ΙΛ η β what ω ι ιι ΟΟΟ • 1 Μ Φ ^ βη υ 04 0 ~ 04 04 > ϋ Ρ Ό ^ ΟΟ'- ' ΙΑ · - * β cm rn · 04 V0 • · • Η - οΌΟ 33 ία ΟΊ * · 04 γΗ C4lA · · 33 33 <->. ·> Ο 33 - 04 ΙΓ \ Κ · ΡΙ • · <μ r- Β -O13J ο 3331 Β 1 σ \ ο 0 \ Χ ^ ν— 0D <- if \ —'04 Μ

Μ W

©ΑΟΠ σ \ οο · γ—, • © L — 'Φ y LZJ

04 * -04 θ ’- 'Ολ - σ * * · ©

Ο

and Χθ νο C- VO σ » φ Μ • Μ · > 0- - C*" 0- Ο Ο Ο Ο ο t— ΙΑ Ο- C- Η Η rd Η β Ο Ο Ο Ο ο 31 31 33 31 <Ρ γΗ ft ft ο οο * ΙΑ β c-m ΟΟ 04 ΙΑΟ> Ο · ο · ο · ο σ » ΐΑσ \ V0 04 νθ - m ο ΓΊ - οο ο 0Ί Ο β ΓΟ IAVO ΙΑ ΙΑ ΙΑΙΑ

Ο

Ο

04 ι-9

Θ θ '<<& «&

and ο 53 θ’— É9 ο

β

Ρ ο

Ή

Β ©

ρ

Ο γΗ

00Α 00 - Tt * tΙΑ 04 c \ i σ> -ΦνΟ

ΙΑ · Φ ου σ \ ΦνΟ

ο

0) & 9

© β

χυ

ο.

CL 04 / OJ Φ Ο O 04 / CM 04 / Ρ and and Ο Ο Ο φ φ & and and φ and and Φ m φ φ • Γί VO VO 31 4— \ 31 and O O V0 ΟΊ νβ vo 04 / 04 / Ο 31 Ο ο Β and and 04 / Ο 04 / 04 / ΟΊ O O W 31 and • « 1 1 ο ο Ο ο Ρ

and ο

> 9 β Π H χ χσ AND > m 0 O she ω k X ^ 1 C4 « XJ and o 04 / z ^ and o © 04 / 0—0 and X 1 0 * 0 « II 1 O- O 1

§ δ

¢ 9

Ο β

Ό cm 2C ίβ Ο Ο - Ο I onsi na

BOKO 0-0 0-0

II II

•3 • 3 φ «« χυ

aT ¹ 04 / and Ol and 1 04 / O O O and O O O O 1 t si lá σ \ O CM

© β

Μ &

and and and O O O O O O and and and 34 P9 04 /

5

Μ

3>

Ε- »> ο 3 © ο β Η · Η ω β

Μ for Ν Μ « C- Ό · ΌΚ O cu and Κ) -Ο LTSr- ITS co oo <0 > W- σ · ITsz — a t- 1 ti <Μ a « * 03 «» it ti > » 01 ο < ITS'- ' and · tor— μ ο «- 00 • 0 cua Φ it Χ5 C tTs * ITs • m what - C-- ο Φ * οο ea and what 00 w it Ό) μ ”Φ I n and * Μ W ο + e. m cua ÍH ti 00 O -M-CU (0 cu ο ο aa * O «Ř— ea · - 00 w ► Μ SOSO M •*and ea ITsC- OJ + trsm W T * * cu Ν Μ what · * * a cua m ea ti 00 a M M-irs z — Os CCS X) o cu and · —'Π oj a * · Λ4 ~ a Ό ·> * _ ·· φ and * Φ Φ (\ J 00 X ~ a Ό r— TJ CM - a πΗ h + o O trs t bunch * of —ae— 0) Φ ITS - and- e- O CUOO OO w Ή μ (MlA O •C- * 1 - £ j * 2 X) ti * 1 Ό (Ts ea • φ-φ and • Η CU LfS O SO oo bunch of cu m O o— s CS w ea and - aso • a eax} r4 aa m cu cuas «- cuirs - ο r- what <- Z — and ·. WITH > * · M QSz ^ a oa e. ea ο axis and Φ CO v- Φ kw » '-'CM Os and (Ό e— tC it Ό what WHAT Φ · *> Ot- what about O CM o bunch IT \ trsm t-lCSe- · Pi * - cu CsJ « OOCP'S * 3 AND and * M CM § cu ics · " CU CM I > - ^ r-

my bunch m CD * t-CM C- «- OS C — cm Feeling" C- ΙΤ » SO t-bunch - e- - - - - - _E ea ea xt m O Φ o m O oo Ό OS LTS OS C0O if \ C- m irsso bunch Sat t-SO irsso cu »- o K and φ o s cu - cu what c · * - lasso IfS O oo > oucu e ~ • ’φ o - e- M- • e »[» Φ t- xtso Φί- > O ΓΟ »~ TO m · - m me ~

μ Φ X0 ti ► Φ Cu O Φ Φ Φ ti rH μ ti ti • XV O X » XV XV & 4 (X «X rH X cu

CD cu CM O O O and and and φ m φ and For and and SO m SO Sat O and O O cu O CU cu and and and m O O O O and 1 1 1 1

m and m M ti me and o cua and o * 3 CM 0—0 and 0-0 o «o > and II 1 II 1 O XJ Φ J3 O IX | 1 CU and sT af t cu M H 8 8 8 and O r— and 43 43 and and and and and and Φ -M rH ti AND » Φ X) XI X) ti Φ Φ O ti rM • H 6- » ω ti φ tfs SO r-

In reactions Nos. 3 and 6, the desired compounds are obtained in low yield along with a large amount of starting material and by-products.

Example 3

To a solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha-isopropenyl acetate (200 mg) in tetrahydrofuran (5 ml) oxalic acid (200 mg) and water (0.5 ml) were added and the mixture was stirred at room temperature for three hours. The chromatogram of the reaction mixture shows the presence of p-nitrobenzyl alpha- [4-mercapto-3-phenoxyacetamido-2-oxo-azetidin-1-yl] -alpha-isopropenylacetate and the starting material.

Example 4

Following the procedure of Example 2, the following compounds were prepared:

(1) 4-mercapto-3-thienylacetamido-2-oxo-1-acetylazetidine from 6-acetyl-3-thienylmethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2 (2) 4-mercapto-3-benzamido-2-oxo-1-trifluoroacetylazetidine from 6-trifluoroacetyl-3-phenyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] (3) 4-mercapto-3-acetamido-2-oxo-1-methylazetidine from 3,6-dimethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-ene (4) 4-mercapto-3- (alpha-phenyl-alpha-chloroacetamido) -2-oxo-1-carbethoxycarbonylazetidine from 6-carbethoxycarbonyl-3-phenylchloromethyl-7-oxo-4-thia- 2,6-diazabicyclo [3.2.0] hept-2-ene, (S) alpha - [4-mercapto-3-formamido-2-oxoazetidin-1-yl] - alpha -isopropylidene acetic acid from alpha - [ 7-Oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -α-isopropylidene acetic acid and (6) 4-mercapto-3-benzylthiocarbonylamino-2- oxo-1-p-toluenesulfonylazetidine from 3-benzyl-thio-6-p-toluenesulfonyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-ene.

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of 2-oxo-3-acylamino-4-mercaptoazetidines of the general formula I R ¹ CONH SH (I) ^X R ² where R is benzyl or phenoxymethyl, is a hydrogen atom or a group of formulas Y -CHR ³ -COX or -G = G-CH ₂ -Hal 'COX wherein r 3 is isopropenyl or a hydrogen atom, Y is 1-morpholinyl, hydroxyl, methyl, dimethylamino, 1-piperidinyl, Hal 'is a halogen atom X is p-nitrobenzyl, 2,2,2-trichloroethoxy, p-nitrobenzyloxy, benzyloxy, tert-butoxy, diphenylmethoxy, characterized in that the thiazoline ring of the compounds of formula IX (II) where R and R are as defined above, cleave with an acid such as perchloric acid, hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, p-toluenesulfonic acid, trifluoroacetic acid and mercuric chloride in the presence of at least 1 molecular equivalents of water in a solvent such as dichloromethane, chloroform, acetone, benzene, ethyl acetate, dioxane, tetrahydrofuran, methanol, or ethanol at -10 ° C to 70 ° C. 2. A process according to claim 1, wherein the acid is an acid with a dissociation constant of at least 0.01. 3. The process according to claim 1, wherein the reaction is carried out at a temperature of from 10 to 50 [deg.] C.