New process for producing azetidinon derivatives

This invention relates to a novel process for the preparation of a 4-acyloxyazetidinone derivative of formula (I) wherein:

R³ represents a phenyl group

This compound is generally the corresponding 4acyl azetidinone derivative of formula (Π) - wherein R³ is prepared by oxidation by the known reaction, for example as described in Hanessian S. et al., J. Am. Chem. Soc. 107.1438.

The resulting compound of formula (I) is useful as an intermediate for the preparation of antimicrobial penem compounds (e.g., British Patent No. 2,111,496-B).

Organic peracids such as monoperphthalic acid or m-chloroperbenzoic acid are used for oxidation.

Although such reagents are only weakly acidic in themselves, they are converted to the corresponding relatively strong carboxylic acids by reduction. Therefore, organic peracids do not efficiently oxidize compounds which are particularly volatile under acidic conditions, such as the 4-acyl azetidinone derivative of formula (Π). the alcoholic function in an acidic medium must be protected by a stable protecting group: ism-butyldimethylsilyl is generally used for this purpose (Shiczaky M, Ishida N, Maruyama H, Hirahoka T, Tetrahedron 32, 2399 (1983)); Maruyama H, Shiozaky M, Hirahoka T, Bull Chem. Soc. Jpn. 5S, 3264 (1985); ChibaT.NakaiT, Chem. Lett. 651 (1985)]. The compounds introducing the above silyl group are alcohol. Due to the costly nature of the tetrabutylammonium chloride required for regeneration of the losine function, there is a serious disadvantage in the industrial preparation of the antibacterial compounds to be prepared from the intermediate (1).

Occasionally, potassium peroxy monosulfate is also used for the oxidation of ketones to ethers, but this compound, which is generally used in combination with acids such as KHSO4 and even sulfuric acid, is barely effective against compounds which are degradable under acidic conditions.

It is therefore an object of the present invention to provide a simple and inexpensive process for the oxidation of a 4-acyl-azeddinone derivative of formula (Π) to a 4-acyloxy-azetidinone derivative of formula (I); the process of the invention is also suitable for the oxidation of compounds having unprotected alcoholic function.

Many of the peracids described in the literature as oxidizing agents are not commercially available and must be prepared separately, which greatly increases the time and cost of such processes. Commercially available peracids are too costly for large-scale use or have pHs that can degrade the starting material. and the β-lactam ring of the products

It is a further object of the present invention that the process of the present invention does not cause corrosion and safety problems that are commonly encountered when using organic peracid solutions - that is, do not endanger the health of workers and allow the cost of safety equipment to be reduced.

These requirements are met by the preparation of the 4-acyloxyazetidinone derivative of formula (I) wherein R 3 is phenyl according to the present invention wherein the corresponding 4-acyl azetidinone derivative of formula (I) wherein R 3 is as defined above is organic or alkali metal or alkaline earth metal salts of inorganic pet acid ² is oxidized in a two-phase system.

The two-phase system

(a) an organic phase containing an acyl azetidinone of formula (Π) and an onium salt dissolved in a water immiscible medium; and

(b) it consists of an aqueous solution containing an alkaline or alkaline earth metal salt of organic or inorganic peracid.

In the 4-acyl azetidinone derivative of formula (Π) which can be oxidized by the process of the present invention, R3 is phenyl.

The starting material of formula (Π) is a known compound or may be prepared by methods known in the art, such as those described above or in the patents.

The novel process, which involves the use of alkali metal or alkaline earth metal salts of inorganic or organic peracids as oxidizing agents instead of peracids, can produce the azetidinone derivative in a shorter reaction time and / or at a lower cost than the known processes.

The formula (I) includes all optical isomeric forms (racemic or optically active) The preferred configuration of the azetidinone is 3R, 4S and the hydroxyl-bearing carbon atom of the chain, so that the final preferred stereochemistry of the penem compounds of formula (I) is [5R, 6S, (IR)].

The quaternary ammonium salt of formula (ΙΠ) can be used as the onium salt in the reaction, wherein M is N, A 'is an inorganic stable anion such as Cl' or SO 2, R ', R 1, R e and R 7 may be the same or different alkyl groups

Typical onium salts useful in the reaction include dimethyldioctadecyl (75%) + dihexadecyl (25%)] - ammonium chloride (sold under the tradename ARQUAD 2HT) and methyltrioctylammonium chloride (sold under the tradename ALIQUAT 336).

As a solvent, a water immiscible solvent such as ethyl acetate or chloroform may be used. The alkali metal or alkaline earth metal salts of any organic or organo-peracid acid may be used as the oxidation color in the reaction.

Potassium peroxy monosulphate and acid magnesium monoperoxyphthalate hexahydrate (sold under the tradename H48) are particularly preferred for stability and low price.

The reaction is carried out with vigorous stirring of the biphasic mixture at about 5-60 ° C, preferably between 15-45 ° C. The concentration of 4-acyl azetidinone (Π) in the organic phase is from about 2% to about 25% by weight. The concentration of peroxy compound in the aqueous phase may be from about 2 to about 5% by weight, and may be from about 1 to about 5 moles per mole of 4-acyl azeidinone. The acidity of the solution can be further controlled by dissolving the peroxy compound in a buffer solution, for example sodium phosphate solution at pH about 7, not in water. The reaction time is about 548 hours, depending on the conditions chosen. After completion of the reaction, the compound of formula (I) is isolated by conventional means

The following examples are intended to further illustrate the invention without limiting the scope thereof. The yields are those of pure yield which yield a single spot by thin layer chromatography (Merck F-254 silica gelmer ethyl acetate / heptane 9: 1 eluent; detection of spots at 254 nm under UV-2HU 200325 Β).

First example

Into a 50 ml beaker fitted with a thermometer, a reflux condenser and a magnetic stirrer was charged 440 mg of (3S, 4S) -4-benzoyl-3 - [(1R) -hydroxyethyl] -azetidin-2-one (2 millimoles) in ethyl acetate. acetate, 50 mg dimethyl [dioctadecyl (75%) + dihexadecyl (25%)] ammonium chloride (about 0.1 mmol), 14 mL & pH 6 sodium phosphate buffer and 1.7 gCAROAT2; the mixture contains 41.5% potassium peroxymonosulfate (4 millimoles) and KHSCU and K2SO4. The slurry was heated to 40 ° C with vigorous stirring and kept at this temperature for 9 hours. The lceta phase was separated, the organic layer was washed with saturated bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and evaporated. 310 A yellow solid was washed with pentane to give 273 mg (3S, 4S, 4-benzoyloxy-3 - [(1R) -hydroxy-ethyl] -azetidin-2-one, m.p. 149-151 '). C (crystallized from ethyl acetate / pentane), total reaction time: 14-15 hours, maximum mixed volume 19-20 ml, productivity: ~ 1 g / ohm / liter product

Γα] 4 = +101 {(χ = 1, μετανολ;

1 H NMR (CDCl 3, 300 MHz): δ 138 (3H, d), 3.11 (1H, broad), 339 (1H, dd, J = 1.1Hz), 7.17 (1H, broad), δ , 47,7162 and 8.05 (5H, mm);

Mass spectrum (CI isobutane): m / e = 235 (M +).

Second example

The procedure of Example 1 is repeated, but CAROAI * is replaced with 1.98 g of acidic magnesium monoperoxyphthalate hexahydrate (H-48; 4 mmol) in 20 ml of pH 64 sodium phosphate buffer and the reaction time is extended to 10 hours. .

264 mg (56%) of (3S, 4S) -4-benzoyloxy-3 - [(1R) -hydroxyethyl] azetidin-2-one are obtained. Total reaction time: 15-16 hours; maximum mixed volume 2526 ml; Productivity: -0.7 g / h / l product

Third example (Comparative)

440 g of (3S, 4S) -4-benzoyl-3 - [(1R) -hydroxyethyl] -azetidin-2-one (2 millimoles), 10 ml of chloroform are weighed into a 50 ml beaker fitted with a thermometer, a reflux condenser and a magnetic stirrer. and 133 g of 90% m-chloroperbenzoic acid (8 mmol) and the resulting solution were stirred at room temperature for 60 hours. The solution was washed successively with saturated aqueous sodium metabisulfite solution, sodium bicarbonate solution and sodium chloride solution, anhydrous potassium chloride. over drying, filtered and evaporated to give 180 mg (38%) of pure (3R, 4S) -4-benzoyloxy-3 ((1R) -hydroxyethyl) -azetidin-2-one.

Comparison between peracid-induced corrosion is best accomplished by showing the pH of solutions of said compounds. Unfortunately, the salts used in the process of the invention. (potassium monoperoxysulfate, or Caroar, and magnesium monoperoxyphthalate), such a comparison is not at all easy because it is impossible or at least very difficult to make an aqueous solution of the corresponding peracids (monoperoxysulfonic acid and monophthalic acid) without impurity. Both of these peracids are dibasic, the first dissociation construct (Ki) of which is significantly higher than the second (K2), so the Ki values ​​are much more responsible for the acidity of the compounds. non-peroxidated acid (in this case sulfuric and phallic acid) to Ki.

In view of the foregoing, the comparison between good acidity and the addition of an equimolar solution of sulfuric acid and phthalic acid is good for KOZ & illcSSCft IGuCOCgCS SZ CnilllCu Kft. The results of the comparative tests are as follows:

Compound Concentration pH

Caroat * 03mol (as KHSO5) 13

Sulfuric acid 03 mol 03

Magnesium monoperoxyphthalate 03 mol (as ArCCbH) 3.85

Phthalic acid_043 mol_245

In the best case scenario, which is Caroat¹¹The difference in pH is one unit, which is 10 times less acidity than that of the equimolar solution of sulfuric acid, so the above illustrates that the corrosion of the salts of the invention is significantly less than that of the acids.

4th EXAMPLE (Comparative) - Monoerphthalic Acid Aliquot 5 ml of water and 1.06 g (10 mmol of sodium carbonate) were added to a 1 ml two-necked flask equipped with a thermometer and a magnetic stirrer. After the carbonate salt is completely dissolved, the mixture is cooled to about 5 ° C and 1.26 ml of 30% hydrogen peroxide (12 mmol) are added in portions, keeping the temperature between 5 ° C and 10 ° C. Powdered phthalic anhydride (48 g, 10 mmol) was stirred at this temperature for half an hour, then ethyl acetate (63 ml) was added, and very carefully 30 ml of o-acetic acid cooled to 0 ° C was added very carefully. The two layers are shaken and separated; the aqueous layer was extracted with a small amount of ethyl acetate and the extract was combined with the organic layer which was then dried (2 x 4 mL of 40% ammonium sulphanilHSSBKCl / gsulfuric acid sulfate) for 16 hours. Yield 40% based on phthalic anhydride.

The stolen solution was placed in a flask with 440 mg (2mmol) 3S, 4S, 4-benzoyl-3 - [(1R) -hydroxyl] -azetidin-2-one for 18 hours at room temperature. The reaction is initially exothermic and the temperature rises to 40 ° C. At the end of the reaction, the reaction mixture containing a large amount of precipitated phthalic acid was removed by Ma Ztf f I - - -4- ΙιιγΙτι-ιύϊΑπ

Wash with carbonate solution until the washings are slightly alkaline and then wash with a little brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to room temperature. 334 mg (71%) of product are obtained.

The total reaction time required to carry out the reaction is 44-45 hours and up to about 19-20 mL volume. Based on this, the productivity of the reaction - which influences the host of the process3

-3HG 200325 Β - as follows: 0334 g / 44 hours x 0.0191 ~ 0.4 g product / hour / 1.