Preparation of azetidinones

(42) Date of commencement of the patent: 15.12.1990 (45) Date of issue: 25. 7.1991 (30) Priority:

15.10.1986 IT 22003/86 claims. (56) Documents:

EP-A2 / A3-0181831

EP-Al-0180252 GB-PS-2144419 (54) PROCESS FOR PREPARING AZETIDINONES (57) A process for preparing 4-acyloxyazetidinones of general formula (I) wherein R and R ₂Is hydrogen or a protecting group and R is -JC-alkyl or aryl, by oxidation of 4-acylazetidinones of the general formula (II) wherein R p R 2 and R -j have the above meaning, in a two-phase system, the

a) an organic phase containing a 4-acylazetidinone (II) and a 0nium salt dissolved in a water-immiscible medium and

b) an aqueous solution comprising an alkali or alkaline earth metal salt of an organic or inorganic peracid.

4-acyloxyazetidinones (I) are useful intermediates in the synthesis of antibacterial compounds.

(51) Int. Cl.⁵ : C07D 205/08 (73)

Patentee:

FARMITALIA CARLO ERBA SPA 1-20159 MILAN (IT).

(72) Inventor:

RICCI MARCO NOVARA (IT). ALTAMURA MARIA NOVARA (IT). BIANCHI DANIELE MILAN (IT). CABRI WALTER LIMBIATE (IT). GATTI NORBERTO GALLIATE (IT).

/ CH_X /^OCR3

CH-CH

II

Z^CR3 n® eeraeas

AT 392 965 B, (I)

4-Acyloxyazetidinone of the general formula fi

".Λ" / "³ i i

N where R j and R₂ Represent hydrogen or protecting groups of the alcohol and amide functions, and R₃ C 1-1 alkyl or aryl, are usually prepared by oxidation of the corresponding 4-acylazetidinones of the general formula

<img file="AT392965B_D0001.tif" />

0R 0

I ¹ II

CH. / CR

TH-CH^{Z ϋ} (ID

Where R j, R₂ and Rβ have the above meaning, prepared; this reaction is known, see, for. BS

Hanessian et al., JACS 107, p. 1438.

The resulting compounds of formula (I) are useful intermediates in the preparation of antibacterial compounds called penems, such as e.g. As described in GB-PS 2111496-B.

The above oxidation is treated with organic peracids such. As monoperphthalic or m-chloroperbenzoic acid performed.

However, such reagents, although only slightly acidic in nature, by virtue of their reduction, yield the corresponding carboxylic acids with characteristic, relatively high acidity constants. Accordingly, with the organic peracids as such, it is not possible to obtain satisfactory results in the oxidation of compounds which are particularly unstable under acidic conditions, such as the 4-acylazetidinones (II) in which Rj is hydrogen. The alcohol function must therefore be protected with a group with good stability in an acid environment; For this purpose, the tert-butyldimethylsilyl group is usually used (see M. Shiozaky, N. Ishida, H. Maruyama, T. Hirahoka, Tetrahedron 1983, 39. 2399; H. Maruyama, M. Shiozaky, T. Hirahoka, Bull. Chem. Soc. Jpn. 1985, 58. 3264; T. Chiha,

T. Nakai, Chem. Lett. 1985, 651). However, because of the high cost of the above-mentioned silyl group and tetrabutylammonium chloride, which must be used for later recovery of alcohol function, this step of protection presents a serious drawback in the industrial production of antibacterial compounds to be prepared from the intermediate of formula (I).

Also, potassium peroxymonosulfate has sometimes been used in the oxidation of ketones to ethers, but this compound, which is usually used in admixture with acids such as KHSO4 or even sulfuric acid, is hardly effective against starting compounds that are unstable under acidic conditions.

The aim of the present invention is therefore to provide a simple and inexpensive process for oxidizing 4-acyloxyazetidinones (Π) to 4-acyloxyazetidinones (I), which process can be applied to starting compounds having an unprotected alcohol function. κ

Another object of the invention is the provision of a method that does not require corrosion and

Raises the safety issues that are commonly encountered when using organic peracid solutions.

It has now been found that these and other objects are achieved by a process for preparing 4Acyloxyazetidinones d the general formula

-2AT392965B

<img file="AT392965B_D0002.tif" />

(1) wherein Rj is hydrogen or a protecting group of the alcohol function, R₂ Represents hydrogen or a protecting group of the amidic NH group and Rβ is Cj.jg-alkyl or aryl, which is characterized in that the corresponding 4-acylazetidinones of the general formula

0R

II

<img file="AT392965B_D0003.tif" />

CR, (Π) where R j, R₂ and Rβ have the above meaning, in a two-phase system, that

a) an organic phase containing a 4-acylazetidinone (Π) and an onium salt dissolved in a water-immiscible medium and

b) an aqueous solution comprising an alkali or alkaline earth metal salt of an organic or inorganic peracid oxidized

EP-A1-0 180 252 describes a process for the preparation of 4-acyloxyazetidinones by oxidative decarboxylation of a carboxylic acid compound. However, the starting compound is other than the one used in the present invention, and in the three methods disclosed, lead tetraacetate or cerium ammonium nitrate is used as the oxidizing agent. wherein lead tetraacetate is used, when the nitrogen atom of the ring is protected and cerium ammonium nitrate is used, when the 1-hydroxyethyl group is protected in position 3 this means that the oxidizing agents used in the processes of this patent can not be used with completely unprotected starting compounds.

In contrast, in the process according to the invention, oxidizing agents can be used both in protected and unprotected starting compounds.

Also GB-PS 2,144,419 discloses a carboxylic acid as starting compound which is oxidatively decarboxylated with cerium ammonium nitrate, wherein the 1-hydroxyethyl group in position 3 is also protected ie silylated is.

EP-A2 / A3-0 181 831 describes in Example 7 c) the oxidation using magnesium monoperphthalate hexahydrate in a homogeneous phase. The method of the invention, in contrast, employs a two-phase system, which offers the following advantages

Magnesium monoperphthalate hexahydrate is soluble in water and sparingly soluble in organic solvents; therefore, a two-phase system in which magnesium monoperphthalate hexahydrate is dissolved in water allows a drastic reduction in the volume of solvent used. The possibility of using potassium monoperoxysulphate is all the more important as it is completely insoluble in organic solvents and therefore can not be used in the process of EP-A2 / A3-0 181 831.

Furthermore, in the emulsion system described in the process of EP-A2 / A3-0 181 831, both the starting compound and the product are exposed to acidic (magnesium monoperphthalate) or nucleophilic (ethanol) reagents capable of reacting with the β-lactam ring. In contrast, the two-phase system used according to the invention makes it possible to protect the β-lactam ring from such attacks by avoiding the use of ethanol and leaving the acid salts dissolved in the aqueous phase.

Examples of 4-acylazetidinones (II) which can be oxidized according to the invention are those in which R j is hydrogen or silyl (for example trimethylsilyl or else tert-butyldimethylsilyl) R₂ Is hydrogen, optionally substituted benzyl (e.g., p-methoxybenzyl) or optionally substituted phenyl (e.g., p-methoxyphenyl), and Rβ is phenyl or alkyl (e.g., methyl)

The starting materials da formula (Π) are known compounds oda can after in da literature, such as

-3AT392965B the above cited references.

The general formula (1) includes all optical forms (racemic or optically active). The preferred configurations are 3R, 4R for azetidinone and R for the carbon atom in the hydroxy-bearing chain so that the penem compounds resulting from the compounds of formula (I) have the preferred end stereochemistry [5R, 6S, (1R) J.

In the reaction, as the onium salt, a quaternary ammonium or phosphonium salt of the general formula (R4, R5, Rg, R₇) M + Y, (ΙΠ) wherein M represents a nitrogen or phosphorus atom, Y represents an inorganic stable anion such as Cf or HSO4, and R4, R5, Rg and R7 which may be the same or different hydrocarbyl groups having a total of about 10 up to 70 C atoms are used.

Examples of onium salts which can be advantageously used in the reaction are dimethyl [dioctadecyl (75%) + dihexadecyl (25%)] ammonium chloride (as ARQUAD 2HT on the market) and methyltrioctylammonium chloride (as ALIQUAT 336 on the market).

As the solvent, a water-immiscible solvent such as ethyl acetate or "chloroform can be used. As the oxidizing agent, in the reaction, any alkali or alkaline earth metal salt of an organic or inorganic peracid can be used.

However, in view of their stability and high availability at moderate prices, potassium peroxymonosulfate and acidic magnesium monoperoxyphthalate hexahydrate, available on the market as H-48, are particularly attractive.

The reaction is carried out by vigorously stirring the biphasic mixture at temperatures of about 5 to 60 ° C, preferably 15 to 45 ° C. The concentration of 4-acylazetidinone (Π) in the organic phase may be about 2 to 25% by weight. On the other hand, the concentration of the peroxy compound in the aqueous phase may be about 2 to 15% by weight, its proportion being about 1 to 5 moles per mole of 4-acylazetidinone (Π). The onium salt is used in proportions of about 0, The acidity of the solution can be further controlled by not dissolving the peroxy compound in water, but adding it in a buffer solution, such as sodium chloride. B. a sodium phosphate solution having a pH of about 7. The reaction time can be about 5 to 48 hours, depending on the conditions chosen, and at the end of this period, 4-acyloxyazetidinone (I) is isolated by conventional methods

The following examples are intended to further illustrate the invention, but are not intended to be limited thereto (yields refer to products exhibiting a single stain in layer chromatography using silica gel layers Merck F-254 and ethyl acetate / heptane 9/1 as the eluent; by irradiation with UV light at 254 nm).

Example 1:

Into a 50 ml two-necked flask equipped with thermometer, reflux condenser and magnetic stirrer were added 440 mg (2 mmol) of (3S, 4S) -4-benzoyl-3 - [(1R) -hydroxyethyl] -azetidin-2-one, 3 , 5 ml of ethyl acetate 50 mg (about 0.1 mmol) of dimethyl [dioctadecyl (75%) + dihexadecyl (25%)] - ammonium chloride, 14 ml NaPhosphatpuffer at pH 6.6 and 1.47 g CAROAT®, (Degussa , Frankfurt, FRG) containing a mixture

41.5% potassium peroxymonosulfate (4 mmol) and KHSO4 and K2SO4 were introduced. The mixture was heated to 40 ° C. with vigorous stirring and kept at this temperature for 9 hours. At the end of this period, the two phases were separated and the organic phase was washed with saturated bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and evaporated to give 310 mg of a yellowish solid, which after washing with pentane 273 mg (3R, 4R). 4-Benzoyloxy-3 - [(1R) -hydroxyethyl] -azetidin-2-one gave (yield 58%), m.p. 149-151 ° C (crystals of ethyl acetate / pentane), [a] p = + 101 ° (c = 1, methanol); 1H-NMR (CDC1₃, 300 MHz): δ = 1.38 (3H, d), 3.11 (1H, br), 3.39 (1H, dd, J = 1.1 and 64 Hz), 4.28 (1H, m ), 6.11 (1H, d, J = 1.1 Hz), 7.17 (1H, br), 7.47, 7.62 and 8.05 (5H, mmm); MS (CI isobutane): m / e = 235 (M +).

Example 2:

Example 1 was repeated, with CAROAT acidified by 1.98 g (4 mmol)

Magnesium monoperoxyphthalate (H-48) was replaced, 20 ml of Na phosphate buffer was used at pH 6.6 and the reaction time was extended to 10 h. There were thus obtained 264 mg of (3R, 4R) -4-benzoyloxy-3 - [(1R) -hydroxyethyl] -azetidm-2-one (yield 56%).

-4AT392 965B

Example 3;

(Comparative Example): Into a 50 ml two-necked flask equipped with thermometer, reflux condenser and magnetic stirrer were added 440 mg (2 mmol) of (3S, 4S) -4-benzoyl-3 - [(1R) -hydroxyethyl] -azetidine 2-one, 10 ml of chloroform and 1.53 g (8 mmol) of 90% m-chloroperbenzoic introduced and stirred the resulting mixture for 60 h at room temperature. At the end of this time, the solution was washed with saturated aqueous solutions of sodium metabisulfite, sodium bicarbonate and sodium chloride, dried over anhydrous calcium chloride, filtered and evaporated. There were thus obtained 180 mg of pure (3R, 4R) -4-benzoyloxy-3 [(1R) -hydroxyethyl] azetidin-2-one (yield 38%).