WO1997042170A1

WO1997042170A1 - A process for the preparation of azetidinones

Info

Publication number: WO1997042170A1
Application number: PCT/EP1997/002328
Authority: WO
Inventors: Gianfranco Cainelli; Achille Umani Ronchi; Michele Contento; Paola Galletti; Daria Giacomini; Marco Da Col; Leone Dall'asta; Irene Resta
Original assignee: Biochimica Opos S.P.A.
Priority date: 1996-05-06
Filing date: 1997-05-02
Publication date: 1997-11-13
Also published as: ITMI960885A0; ITMI960885A1; IT1282956B1

Abstract

There is described the preparation of 4-acetoxy-3-acylaminoazetidin-2-ones through the introduction of an acetoxy group in the 4 position of a 3-(N-acyl-N-protected)aminoazetidin-2-one not subtituted in the 1 position and the removal of the N-protecting group of the amine in the 3 position. The synthesis may be stereoselective in the case of the preparation of 4-acetoxy-3-phenylacetamidoazetidin-2-one if, starting from a 3-aminoazetidinone, the acylation at the 3 position is carried out with penicillanacilase. The novel 1-propenylazetidinones are furthermore described.

Description

A process for the preparation of azetidinones The present invention relates to a process for the preparation of 4~acetoxy~3~ acylaminoazetidin-2-ones, particularly of 4~acetσxy-3~ phenylacetamidoazetidin-2-one, through novel intermediate compounds, as well as to the novel intermediates and to their preparation. The 4~acetoxy~3-phenylacetamidoazetidin~2~one, more particularly in the (3S,4S) form, is a known product whose preparation is disclosed in the literature only as taking place by demolition of Penicillin G. This compound is extremely interesting since it permits, through the conversion thereof into the corresponding thioamide, suitably protected, the preparation of thiazolinoazetidinone having the formula A:

through cyclization of the thioamide and the removal of the protecting group. Owing to the fact that the 4-acetoxy-3-phenylacetamidoazetidin-2~one is difficulty accessible and that the literature does not describe suitable methods for its preparation, the interest for the product has been limited to the scientific world only.

It has been now found that, through novel intermediates of easy preparation, the total synthesis of the 4~acetoxy~3-phenylacetamidoazetidin-2-one and more generally of 4~acetoxy~3-acylaminσazetidin-2-ones can be effected. More particularly it has been found that by means of a number of highly flexible derivatives of N-substituted 3-amino- l -propenylazetidin-2-ones the unblocking of the azetidinone is permitted through the detachment of the propenyl group in the presence of other protecting groups and the subsequent preparation of corresponding 4-acetoxy derivatives is made possible. There has been also found a simple way for the preparation of 3-amino- l - propenylazetidin-2-ones, which are the starting compounds for the introduction of the acetoxy group at the 4 position, by direct oxidation of the azetidinone nucleus.

As a matter of fact, as it has been found, in the presence of an amino group at the 3 position of the azetidin-2-one cycle the introduction of the acetoxy group at the position 4 can take place only if two conditions simultaneously exist: (a) the amino group is disubstituted, namely it is not directly bound to a hydrogen atom, and (b) the 1 -azetidinone nitrogen atom is not substituted. Thus the problem existed on one side of introducing a protective group in the 3 position, besides the phenylacetic group, and, on the other side, of making possible to free the nitrogen atom of the azetidinone cycle without influencing the protective group on the amine at the 3 position.

The selection of the propenyl group as the substituent at the nitrogen atom of the 3~aminoazetidin~2-one has solved the problem, thus rendering the 4- acetoxy-3~phenylacetamidoazetidin-2-one readily accessible and the preparation of the thiazolinoazetidinone of formula Λ more economically advantageous.

According to one of its aspects, the present invention is directed to novel N- substituted 3~amino~ l -propenylazetidin~2-ones of formula I

wherein Ri represents hydrogen or a N-protective group, R₂ represents an acyl group, or NR₁R₂ is a succinimido, maleimido or phthalimido group and propenyl indicates allyl, 1 -propen- 1 -yl or a mixture thereof. By the term "N-protective" there is meant, in the present invention, any one of the groups used in the chemistry of the β-lactam antibiotics in order to prevent that an amido group gives place to side reactions. The term N-protected, as referred to a product, relates to a product in which the amido group is substituted for by an N-protective group.

Within the scope of the present invention the N-protective group is stable under oxidising conditions, whereas it is readily removed by hydrolysis or reduction, particularly through catalytic hydrogenation. More particularly said protective group may be a silyl group, such as trimethylsilyl, triethylsilyl, t- butyldimethylsilyl, a benzyl group possibly substituted on the benzene ring, such as 4-methoxybenzyl, 4-nitrobenzyl, or an N-protective acyl group, such as benzyloxycarbonyl or t-butoxycarbonyl.

N-protective groups fulfilling the above indicated criteria are widely described by T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2 edition, 1991 , pag. 397-405.

The preferred N-protective group is benzyloxycarbonyl, also named

"carbobenzoxy" and often indicated by the abbreviation "CBZ".

The acyl group represented by R2 is any one of the acylating groups of the 6- aminopenicillanic or 7-aminocephalosporanic acid or, more generally of penicillins, cephalosporins and of monobactams.

The phenylacetyl group, characteristic of penicillin G, which permits the preparation of 4-acetoxy-3-phenylacetamidoazetidin-2-one and of the thiazolinazetidinone of formula A is the preferred acyl group, but R₂ may represent other acyl groups, for example a possibly N-protected α- aminophenylacetyl group, a possibly N-protected α-amino-(4~ hydroxy) phenylacetyl group, a phenoxyacetyl group, a cyanoacetyl group, a 2- or 3-thienylacetyl group, a 2- or 3-furylacetyl group, a 2-furylglioxyl group, a

2-(2-furyl)-2-methoxyiminoacetyl group, a 2-(2-aminothiazol-4-yl)-2- methoxyiminoacetyl group, a 2-(2-aminothiazol-4-yl)-2-( l -carboxy- 1 - methyletoxyimino) acetyl group, or a 2-(2-aminothiazol-4-yl)~2-

(carboxymetoxyimino)acetyl group.

When NR1R2 represents succinimido, maleimido or phthalimido, these groups may bear substituents. Preferably NR1R2 is unsubstituted phthalimido.

The N-substituted 3-amino- l -propenylazetidin-2-ones of formula I are synthesised according to two separate steps consisting in firstly preparing the 3- amino- 1 -propenylazetidin-2-one as free amine and then carrying out the suitable substitutions on the amino group. Thus, according to another of its aspects, the present mvention relates to a process for the preparation of 3-amino-l -propenylazetidin-2-one of formula II

propeny l (ID

wherein propenyl is allyl, 1 -propen-2-yl or a mixture thereof, characterised in that:

(a) an acid of formula III

N — CH .COOH

(III)

wherein NRiRv represents a possibly unsubstituted succinimido, maleimido or phthalimido group, in activated form or as a functional derivative, is treated with 1 ,3,5-triallylhexahydro-s-triazine of formula IV

CH .-,— CH =CH -

(IV)

CH ^,= CH — CH^ CH ,— CH =CH

(b) the resulting product of formula V

wherein NR1R2 is as above defined,:

(i) either is reacted with a primary amine or with hydrazine in hydro-alcoholic medium and the compound of formula II, in which propenyl is allyl, is isolated, or

(ii) undergoes a isomerization reaction of the allyl group into 1 -propen- l -yl group to obtain a compound of formula V

wherein NR₁R₂ is as above defined and then to the reaction with a primary amine or with hydrazine in hydro-alcoholic medium and the compound of formula II in which propenyl is the 1 -propen- 1 -yl is isolated,

(c) said compounds of formula II are isolated in form of free bases or of one of their salts.

The compounds of formulas V and V are novel and are encompassed by the formula I.

The acids of formula III used as the starting compounds are known and can be readily prepared according to known methods, for instance through the reaction of glycine with the proper anhydride. The phthaloylacetic acid is disclosed in J. Prakt. Chem. (2), 1883, 27, 418. The chloride thereof is described in J. Am. Chem. Soc, 1949, 21, 1859. As the functional derivatives of the acids of formula III the chloride is generally used, possibly prepared "in situ", but the free acid can be used as well, provided that it is properly activated for instance with dicyclohexylcarbodiimide or with benzotriazol- 1 -yloxytris (dimethylamino)phosphonium hexafluorophosphate

(BOP), or with a mixed anhydride or an active ester.

The 1 ,3,5-triallylhexahydro-s-triazine of formula IV is described in the literature in Arch. Chem. Pharm. , 2, 160 (1935) and can be also prepared from allylamine and formaldehyde according to the method described in J. Het.

Chem., 1971 , 8, 597-604.

The step (a) is effected in an anhydrous organic solvent such as dichloromethane, 1 ,1 ,1 -trichloroethane, preferably in an inert atmosphere and at a temperature of between -50°C. and -30°C. in the presence of a tertiary amine, preferably triethylamine. The triallylhexahydro-s-triazine IV is preferably used in form of a complex with boron trifluoride, formed in situ through the addition of boron trifluoride etherate.

For the step (b), which is directly carried out on the compound V, methylamine in hydro-alcoholic solution (water/ethanol) at room temperature is preferably used. The compound of formula II in which propenyl is the allyl group, is isolated according to conventional methods, by removing the by-products, for instance through filtration, and evaporating the solvent.

In the case of the compound of formula II in which propenyl is 1 -propen- l -yl, the product of formula V is previously isomerized to the compound V. This isomerization can be effected by heating a hydro-alcoholic solution of the compound V in the presence of RhCl₃. The conversion of the allyl radical into the 1 -propen- l -yl radical takes place with practically quantitative yield.

As for the compound V, also the compound V is likewise converted into the compound of formula II wherein propenyl is 1 -propen- 1 -yl.

The thus obtained compound of formula II can be readily acylated at the 3 position of the amine by reacting with a compound of formula VI

R₂-OH (VI) wherein R₂ represents an acyl group as above defined, so as to obtain a compound of formula I, in which Ri is hydrogen and R₂ is an acyl group, represented by the formula I'

wherein R2 and propenyl have the above meanings.

When, in the compound I', propenyl is the allyl group, it can be isomerized to

I -propen- 1 -yl, as previously illustrated.

If the reaction of the compound of formula II with the compound of formula VI, particularly when the latter is the phenylacetic acid, is effected in the presence of penicillinacilase, the configuration of the obtained product is (3S). Likewise, if the racemic compound of formula I', in which R2 is phenylacetyl, is hydrolysed with penicillinacilase, the isomer (3S) of the compound of formula

II is obtained, which can be acylated with the said compound VI to obtain the compound I' in the (3S) configuration.

Starting from the compound of formula I' it is possible to prepare the corresponding derivatives N-protected at the amido nitrogen through the reaction with a compound of formula VII

RVW (VII) wherein R'ι represents an N protective group as above defined and W is a leaving group.

When the protective group is benzyloxycarbonyl, it is introduced through the reaction with benzylchloroformiate and can be removed by catalytic hydrogenation. A compound of formula I" is thus obtained

R'I represents an N protective group as previously defined, R₂ represents an acyl group and propenyl can be allyl, 1 -propen- 1 -yl or a mixture thereof.

When in the compound I" propenyl is an allyl group, it can be isomerized to the

1 -propen- 1 -yl as previously illustrated.

The isomerization of the allyl group to 1 -propen- 1 -yl is another aspect of the present invention and is characterised by that a compound of formula Ia

(la)

wherein X represents an N-protective group which is stable under oxidising conditions, Y represents an acyl group, or NXY represents a succinimido, maleimido or phthalimido optionally substituted group, is refluxed with a hydro-alcoholic solution in the presence of RhCl₃ whereby a compound of formula lb

wherein X and Y are as above define, is isolated.

There is thus obtained a 3-aminoazetidin-2-one disubstituted at the amino group in the 3 position, fulfilling the necessary requirements for the introduction of an acetoxy group in the 4 position. Thus, according to another aspect of the invention, the present invention provides a process for the preparation of 4-acetoxy-3-aminoazetidin-2-ones disubstituted at the amino nitrogen of formula VIII

(VIII)

wherein X represents an N-protective group which is stable under oxidising conditions, Y represents an acyl group, or NXY represents a succinimido, maleimido or phthalimido optionally substituted group characterised in that: (a) a compound of formula lb

wherein X, Y and NXY are as above defined, is oxidised under conditions by which the β-lactam ring is not influenced; and (b) the thus obtained compound of formula IX

(IX)

is treated with a peracid in acetic acid in the presence of a metal catalyst, e.g.

RuCh or rutenium on carbon.

The step (a) is effected by preferably using as the oxidising agent potassium permanganate, but also other oxidising agents, by which the β-lactam ring is respected, can be used, such as for instance the Lemieux-von Rudloff reactant

(sodium metaperiodate- potassium permanganate).

The reaction with potassium permanganate is carried out at room temperature at a pH of 7 to 8; it occurs practically instantaneously and can be readily monitored through the disappearance of the violet colour characteristic of the permanganate.

The compound of formula IX is isolated after removal of the thus formed manganese dioxide, evaporation of the solvent and recovery of the residue.

The step (b) takes place by oxidation with a peracid in acetic acid and in the presence of a suitable catalyst, preferably Ru/C. As the peracid perbenzoic acid or preferably peracetic acid can be used, the oxidation being carried out at room temperature.

The compound of formula VIII is isolated by conventional methods in form of a mixture of cis and trans isomers, or as the pure trans isomer.

In this manner, through the introduction of the 1 -propen- 1 -yl protective group for the nitrogen atom at the position 1 of the azetidinone cycle, it is in particular possible to prepare 4-acetoxy-3-phenylacetamidoazetidin-2-one and, if the process is carried out under enzymatic acylating or hydrolytic conditions,

(3S,4S)-4-acctoxy-3-phenylacetamidoazetidin-2-one can be prepared, this compound being a key intermediate in the synthesis of the compound of formula A.

Thus a further feature of the present invention resides in a process for the preparation of 4-aceloxy-3-phenylacetamidoazetidin-2-one, characterised in that:

(a) 1 -propenyl- 3-aminoazetidin-2 -one of formula II

H₂N

0 p ropeny l (ID wherein propenyl is allyl, 1-propen-l -yl or a mixture thereof, is reacted with a functional derivative of the phenylacetic acid;

(b) an N-protective R'ι, stable under oxidising conditions, is introduced in the resulting compound of formula X,

in which propenyl is as above defined ; (c) the obtained compound of formula (XI)

after that the possible allyl group has been isomerized into a 1 -propen-l -yl group, at the end of either step (a) or (b), is reacted with potassium permanganate;

(d) the obtained product of formula XII

in which R'ι is as above defined, is subjected to a catalytic oxidation with a peracid in acetic acid; and

(e) the protective group R'ι of the thus obtained compound of formula XIII

is removed.

In the step (a) the phenylacetylchloride can be effectively used as the functional derivative, under the classic conditions of acylation used in the chemistry of the β-lactams. However any other functional derivative of the above described type can be used. More particularly an alkyl ester containing 1 to 3 carbon atoms, e.g. methyl phenylacetate, can be used and the reaction is carried out in the presence of penicillinacilase. In this case (3S)-3-phenylacetamido- l - propenylazetidin-2-one is selectively isolated.

By operating under these conditions and using 3-amino- 1 -( 1 -propen- 1 - yI)azetidin-2-one as the starting material (3S)-3~phenylacetamido- l -( l propen- l -yl)azetidin-2-one is obtained.

The step (a) can also be effected according to the standard acylation method, by using for example phenylacetylchloride as the acylating agent to obtain the racemic 3-phenylacetamido- l -propenylazetidιn-2-one; the latter product is hydrolysed in the presence of penicillinacilase or penicillinamidase thus leading to (3S)-3-phenylacetamido- l -propenylazetidin-2-one and this compound is used as the starting material for the synthesis of (3S,4S)-4-acetoxy-3- phenylacetamidoazetidin-2 -one .

As the preferred starting material there is thus used 3-amino- 1 -( 1 -propen- 1 - yl)azetidin-2-one or (3S)-3-amino- l -( l -propen- l -yl)azetidin-2-one.

At the end of the step (a) there is obtained-3-phenylacetamido- l - propenylazetidin-2-one, preferably 3-phenylacetamido- 1 -( 1 -propen- 1 - yl)azetidin-2-one, in racemic or (3S) form, which is subjected to the subsequent steps.

In the step (b) the protective group R'ι is introduced through the reaction with the compound of formula R'ι-W, wherein W represents a leaving group. Said protective group must be stable under oxidising conditions. The preferred protective group is the benzyloxycarbonyl group (CBZ) introduced through the reaction of 3-phenylacetamido- l -propenylazetidin-2- one with benzylchlσroformiate.

In the step (c) the oxidation is preferably carried out with potassium permanganate under the above indicated conditions, after a possible isomerization of the allyl group to 1 -propen- 1 -yl group. Under these conditions the 1 -propen-l -yl group is removed with an almost quantitative yield, preserving the R'ι group, particularly the benzyloxycarbonyl group.

In the step (d) the introduction of the acetoxy group in the 4 position is effected by catalytic oxidation, preferably by means of peracetic acid in acetic acid, in the presence of ruthenium on carbon, as above illustrated.

Lastly in the step (e) the N-protectivc group R'ι is removed by means of conventional methods. More particularly the benzyloxycarbonyl group is removed by catalytic hydrogenation.

According to a conventional method, in the step (a) 3-amino- 1 -( 1 -propen- 1 - yl)azetidin-2-one is used, and methyl phenylacetate is used as the functional derivative of the phenylacetic acid, the reaction being carried out in the presence of penicillinacilase and the (3S)-3-phenylacetamido- l -(l -propen- l - yl)azetidin-2-one is isolated; in the step (b) the protective group R'ι is the benzyloxycarbonyl group; in the step (d) the catalytic oxidation is carried out by means of peracetic acid in acetic acid in the presence of Ru/C and in the step

(e) the unblocking of the protective group R'ι is effected by catalytic hydrogenation and the (3S,4S)-4-acetoxy-3-phenylacetamidoazetidin-2-one is isolated.

Alternatively (3S) 3-amino- 1 -0 -propen- l -yl)azetidin-2-one is used as the starting material, it having been obtained by hydrolysis of racemic 3- phenylacetamido- 1 -(1 -propen- 1 -yl)azetidin-2-one in the presence of penicillinacilase or penicillinamidase, the synthesis being then carried out as above described, to isolate (3S,4S)-4-acetoxy-3-phenylacetamidoazetidin-2- one.

This product is readily converted into thiazolinazetidinone of formula (A) through protection by sililation, conversion into thioamide with an inorganic sulfide and cyclization.

The following examples illustrate the invention without however having to be construed as a limitation. EXAMPLE 1 l ~allyl-3-phthaloylaminoazetidin-2-one

Under inert atmosphere and at room temperature 2.07 g (10 mmoles) of 1 ,3,5- triallylhexahydro-s-triazine are dissolved in 80 mL of anhydrous methylene chloride and 3.68 mL (30 mmoles) of BF₃-Et₂0 are added and then stirring is maintained for 30 minutes (solution A). Separately, always under inert atmosphere, 6.7 g (30 mmoles) of 2-phthalimidoacetyl chloride are dissolved in

80 mL of anhydrous methylene chloride and the temperature is brought to -

40°C; a solution of 8.4 mL (60 mmoles) of triethylamine in 2 mL of dichloroethane is added dropwise. After 30 minutes stirring, the solution A, as above obtained, is slowly added at -40°C. After maintaining 1 hour at cool, the reaction mixture is treated with 40 mL of I N HCI, the temperature is permitted to raise up to about 20 °C. and then the mixture is extracted with methylene chloride. The organic phase is washed with an aqueous solution of 5% NaHC0₃, then dehydrated and concentrated under vacuum. The residue is taken up with methanol, filtered and dried under vacuum. Yield: 60%. M.p.: 87°C.

IR (nujol): 1759, 1 71 7.

'H-NMR (300 MHz, CDCb): 3.62 (dd, 1 H, J = 5.4 Hz); 3.7 (dd, I H, J = 2.9 Hz,

J = 5.4 Hz); 3.8-3.9 (dd, 1 H, J = 5.5 Hz, J = 1 5.7 Hz), 4.0-4.1 5 (dd, 1 H, J = 5.5

Hz, J = 1 5.7 Hz); 5.25-5.35 (m, 2H); 5.45 (m, I H), 5.8-6.0 (m, I H); 7.7 (m,

2H), 7.9 (m, 2H).

^,3C-NMR (300 MHz, CDClj): 166.9; 164.7;134.4- 131 .6- 123.7; 131 ; 1 18;

53.6; 45.5; 44.6.

By operating under the same conditions, but substituting 2 -succinimido- and 2- maleimidoacetyl chloride for the 2-phthalimidoacetyl chloride l -allyl-3- succinimidoazetidin-2-one and l -allyl-3-maleimidoazctidin-2-one are obtained.

EXAMPLE 2

1 -(1 -propen- l -yl)-3-phthalimidoazetidin-2-onc

10.24 g (40 mmoles) of l -allyl-3-phthalimidoazetidin-2-one are suspended in

90 mL of ethanol and 10 mL of water, 1 50 mg of RhCl₃-xH₂0 are added and the mixture is refluxed. After 30 minutes the reaction mixture is treated with water and ice, the precipitate is separated by filtration, the solid product is dissolved in methylene chloride, is decolored, is made anhydrous and is concentrated under vacuum. Quantitative yield. M.p.: 173°C. IR (nujol): 1775, 1745, 1720.

'H-NMR (300 MHz, CDC1₃): 1.74 (dd, 3H, J = 1.6 Hz, J = 7.1 Hz); 3.82 (m,

2H); 5.17 (m, 1H, J = 7 Hz); 5.5 (dd, 1 H, J = 3.2 Hz,J = 5.5 Hz); 6.66 (dd, IH,

J = 1.5 Hz,J = 14.2 Hz); 7.8 (m, 2H); 7.9 (m, 2H).

¹³C-NMR (300 MHz, CDC1₃): 166.7; 160.5; 134.3- 131.4- 123.5; 121.9; 108.5,

52.7; 45.1 ; 14.6.

EXAMPLE 3

1 -allyl-3-aminoazetidin-2-one

2.56 g ( 10 mmoles) of l -allyl-3-phthalimidoazetidin-2-one are suspended at

20°C: in 1 5 mL of ethanol and 10 mL of 33% ethanol solution of methylamine are added. A clear solution is obtained, which is maintained under stirring for

3 hours; the precipitate thus separated is removed by filtration. After concentration under vacuum of the filtrate, the solid residue is added with methylene chloride (few mL) and the mixture is filtered. After concentration of the new filtrate the desired product is obtained in form of a waxy solid. Yield:

80%

1R (CDC1₃): 3300, 1 750.

^■H-NMR (300 MHz , CDCI3): 1 .8 (bs, 2H); 2.98 (dd, 1 IΪJ = 2.3 Hz, J =5.6 Hz);

3.5 (dd, 1 H, J = 6 Hz); 3.8 (d, 2H, J = 6.1 Hz), 4.16 (m, I H); 5.1 -5.25 (m, 2H);

5.6-5.8 (m, I H)

^,3C-NMR (300 MHz, CDC1₃): 1 70; 131.4; 1 18.6; 59.6; 50; 44.

EXAMPLE 4

1 -( 1 -propen- 1 -yl)-3~aminoazetidin-2-one

2.56 g (10 mmoles) of 1 -(1 -propen- l -yl)-3-phthalimidoazetidin-2-one are suspended in 15 mL of ethanol and are supplemented with 10 mL of 33% ethanol solution of methylamine. The solution becomes clear. It is maintained under stirring and, after about 3 hours, phthalimido by-products are precipitated and removed by filtration. After concentration under vacuum of the solvent, the residue is added with methylene chloride (few mL), filtered and after concentration of the filtrate the desired product is obtained as a slightly yellow oil. Yield: 80%

IR (CDCls): 3300, 1750.

'H-NMR (300 MHz, CDC1₃): 1.67 (dd, 3H,J = 1.6 Hz, J = 6.8 Hz); 3.1 (dd, I H,

J = 2.2 Hz,J = 6.2 Hz); 3.54 (dd, 1H,J = 2 Hz, J = 5.8 Hz); 4.25 (m, I H); 5-5.1

(m, 1 H); 6.5 (d, 1HJ = 14.2 Hz). ¹³C-NMR (300 MHz, CDC1₃): 162; 122.2; 107.6; 65.83; 47.97; 24.3.

EXAMPLE 5

1 -(1 -propen- 1 -yl)-3-phenylacetamidoazetidin-2-one

1.26 g (10 mmoles) of 1 -(1 -propen- l -yl)-3-aminoazetidin-2-one are dissolved in 15 mL of acetone and 20 mL of water, wherein 20 mmoles of Na₂C0₃ have been dissolved. The mixture is cooled to 0°C. and dropwise added with a solution of 1.85 g (12 mmoles) of phenylacetylchloride in 5 mL of acetone. The mixture is maintained for 12 hours at room temperature, then the solvent is concentrated and the residue is taken with ethyl acetate. The organic phase is washed with a saturated water solution of NaCl, is dried and concentrated under vacuum. The residue is purified by flash chromatography eluting with a mixture cyclohexane/ethyl acetate = 6/4 v/v and the product is isolated in form of a white solid. Yield: 85%. M.p.: 102°C.

IR (CHC1₃): 3300, 1 752, 1655.

'H-NMR (300 MHz, CDC1₃): 1.68 (d, 3H, J = 6.6 Hz); 3.25 (dd, I H, J = 2.6 Hz;

J = 6.1 Hz); 3.56 (s, 2H); 3.65 (dd, I H, J = 6.5 Hz); 4.9 (m, I H); 5.06 (m, IH),

6.42 (dd, 1HJ = 1 .6 Hz, J = 14.22 Hz); 7.08 (d, 1 H, J = 7.4 1 Hz); 7.2-7.4 (m,

5H).

¹³C-NMR (300 MHz, CDC1₃): 1 71.45; 162.8; 134- 123; 121.8; 108.5; 55.24;

47.44-42.98; 14.56.

EXAMPLE 6

1 -( 1 -propen- 1 -yl)- 3- (S) -phenylacetamidoazetidin-2 -one

122 mg (0.5 mmoles) of 1 -( 1 -propen- 1 -yl)-3-phenylacetamidoazetidin-2-one, as obtained according to example 5, are hot dissolved in 1 mL of acetonitrile and added with 10 mL of phosphate buffer at pH 7.5. The pH is adjusted to 7.4 and to the well stirred solution 80 mg of penicillinacilase, previously washed with distilled water, are added. The pH, tending to decrease, is corrected by bringing it to the initial value by adding 0. I N NaOH; after adding 2.5 mL of this solution (corresponding to a 50% conversion) the enzyme is removed by filtration. After acidification with IN HCI down to pH 4, the aqueous phase is extracted with ethyl acetate, the organic phase is dried with sodium sulphate and concentrated under vacuum isolating the not hydrolysed starting product.

The aqueous filtrate is added with an equal volume of acetone and the solution is dropwise added with 310 mg (2 mmoles) of phenylacetylchloride, the temperature being maintained at 0°C. Upon the pH is brought to 8 by means of Na₂C0₃ the reaction is carried out for 1 hour, the acetone is removed by distillation, the remaining aqueous phase is brought to pH = 2 and is several times extracted with ethyl acetate. The product is purified by silica gel chromatography eluting with ethyl acetate. (OC]D = -23° (CH₃OH, c = 1 .5); ee

(chiral HPLC) = 82.

EXAMPLE 7

1 -( 1 -propen- l -yl)-3-(S)-phenylacetamidoazetidin-2-one

A solution of 126 mg (1 mmole) of 1 -(1 -propen- l -yl)-3- phenylacetamidoazetidin-2-one in 10 mL of phosphate buffer at pH 5.5 is supplemented with 225 mg (1.5 mmoles) of methyl phenylacetate and then

200 mg of penicillinacilase. After HPLC checking the enzyme is filtered, the filtrate is extracted with ethyl acetate, the organic phase is concentrated under vacuum and the desired product is obtained, which can be purified by flash chromatography (eluant: ethylacetate).

EXAMPLE 8 l -aIlyl-3-phenylacetamidoazetidin-2~one

1.26 g (10 mmoles) of l -allyl-3-aminoazetidin-2-one are dissolved in 15 mL of acetone and 20 mL of water, wherein 20 mmoles of Na₂C0₃ have been dissolved. After cooling to 0°C. the solution is dropwise added with a solution of

1.85 g (12 mmoles) of phenylacetylchloride in 5 mL of acetone. The mixture is maintained for 12 hours at room temperature and then the solvent is concentrated under vacuum. The residue is made acid and extracted with ethylacetate, the organic phase is washed with saturated aqueous solution of

NaCl, is dried and concentrated under vacuum. The desired product is obtained in form of a slightly yellow oil which is selfconverted into a waxy solid. Yield:

85%.

IR (neat): 3300, 1 758, 1654.

'H-NMR (300 MHz, CDCl₃): 3.18 (dd, IH, J = 2.4 Hz; J = 5.6 Hz); 3.48 (dd,

1 H, J = 5.2 Hz), 3.53 (s, 2H); 3.8 (d, 2H, J = 5.8 Hz); 4.82 (m, IH); 5.1 7-5.26

(m, 2H); 5.6-5.78 (m, I H); 7.03 (d, I H, J = 6.8 Hz); 7.35 (m, 5H).

¹³C-NMR (300 MHz, CDC1₃): 171.5; 166.7; 130.9; 134- 127; 1 18.7; 56.1 ;

47.9-44.4-43.0.

EXAMPLES 9 - 1 7

By operating as described in example 8, starting from l -allyl-3-aminoazetidin-

2-one and, respectively, from the chlorides of phenoxyacetic, cyanoacetic, 2- thienylacetic, 3-thienylacetic, 2-furylacetic, 3-furylacetic, 2 -furylglyoxylic, 2- (2-furyl)-2-methoxyiminoacetic acid, and the hydrochloride of 2-(2- aminothiazol-4-yl)-2-methoxyiminoacetylchloride, there are obtained: l -allyl-3-phenoxyacetamidoazetidin-2-one (example 9); l -allyl-3-(2-cyanoacetamido)azetidin-2-one (example 10); l -allyl-3-[2-(2-thienyl)acetamido]azetidin-2-one (example 1 1); l -allyl-3-[2-(3-thienyl)acetamido]azetidin-2-one (example 12); l -allyl-3-[2-(2-furyl)acetamido|azetidin-2-one (example 13); l -allyl-3-[2-(3-furyl)acetamido|azetidin-2-one (example 14); l -allyl-3-(2-furyl)glyoxylamidoazetidin-2-one (example 15); 1 -allyl-3-(2-(2-furyl)-2-methoxyiminoacetamido]azetidin-2-one (example 16); 1 -allyl- 3-[2- (2 -aminothiazol-4-yl)-2-methoxyiminoacetamido]azetidin-2-one (example 17). EXAMPLES 18 - 26

By operating as described in the example 5, starting from 1 -( 1 -propen- l -yl) - 3-aminoazetidin-2-one and respectively from the chlorides of phenoxyacetic, cyanoacetic, 2-thienylacetic, 3-thienylacetic, 2-furylacetic, 3-furylacetic, 2- furylglyoxylic, 2-(2-furyI)-2-methoxyiminoacetic acid, and the hydrochloride of 2~(2-aminσthiazol-4-yl)-2-methoxyiminoacetylchloride, there are obtained: 1 -0 -propen- l -yl)-3-phenoxyacetamidoazetidin-2-one (example 18); 1 -0 -propen- 1 -yl)-3-(2-cyanoacetamido)azetidin-2-one (example 19); 1 -0 -propen- l -yl)-3-|2- (2-thienyl)acetamido|azetidin-2-one (example 20); 1 -0 -propen- 1 -yl)-3-|2- (3-thienyl)acetamido)azetidin-2-one (example 21 ); 1 -0 -propen- l -yl)-3-|2-(2-furyl)acetamido]azetidin-2-one (example 22); 1 -0 -propen- 1 -yl)-3-|2- (3-furyl)acetamido]azetidin-2-one (example 23); 1 -0 -propen- l -yl)-3-(2-fιιryl)glyoxylamidoazetidin-2-one (example 24); 1 -0 -propen- l -yl)-3- |2- (2-furyl)-2-methoxyiminoacetamidolazetidin-2-one (example 25);

1 -0 -propen- l -yl)-3-[2- (2-aminothiazol-4-yl)-2- methoxyiminoacetamido]azetidin-2-one (example 26). EXAMPLE 27 l -aIlyl-3-(N-benzyloxycarbonyl-N-phenylacetyl)aminoazetidin-2-one A solution of 976 mg (4 mmoles) of l -allyl-3-phenylacetamidoazetidin-2-one in 40 mL of tetrahydrofuran is added at 20°C. with 6 mL of a IM solution of potassium t-butylate in tetrahydrofuran. After stirring for 40 minutes, the mixture is then dropwise added with 853 mg (5 mmoles) of benzyl chloroformiate dissolved in 2 mL of tetrahydrofuran. After 15 hours permanence at 20°C. the mixture is treated with ice and extracted with ethyl acetate. The organic phase is dried and concentrated under vacuum. The desired product is obtained in form of a white solid. Yield: 60%.

IR (CDCls): 1760, 1700.

'H-NMR (300 MHz, CDC1₃): 3.28 (dd, IH, J = 2.8 Hz;J = 5 Hz); 3.41 (dd, IH, J

= 5.8 Hz); 3.44-3.51 (dd, 1H, J = 6 Hz, J = 15.7 Hz); 3.71 -3.78 (dd, I H, J =

5.8 Hz, J = 15.2 Hz); 4.25 (s, 2H), 5. 1 -5.28 (m, 4H); 5.48-5.6 (m, I H); 5.68

(dd, IH, J = 2.5 Hz,J = 5.2 Hz); 7.2-7.5 (m, 10H).

^I3C-NMR (300 MHz, CDC1₃): 173.5; 166.1 ; 153; 131:3; 134- 127; 1 18.6; 69.7;

57.7; 45.6-44.4-44.0.

EXAMPLE 28

1 -0 -propen- 1 -yl)~3(N-benzyloχvcarbonvI-N-phenylacetyl)aminoazetidin-2- one

976 mg (4 mmoles) of l -( l -propen-l -yl)-3-phenylacetamidoazetidin-2-one are dissolved in 40 mL of tetrahydrofuran and added with a IM solution of potassium t-butylate in tetrahydrofuran. After 15 hours permanence at 20°C. the mixture is treated with ice and extracted with ethyl acetate. The organic phase is dehydrated and concentrated under vacuum. The desired product is obtained in form of a white solid. Yield: 60%.

IR (CDCI₃): 1 760, 1650.

'H-NMR (300 MHz, CDC1₃): 1.6 1 (dd, 3H, J = 6.8 Hz; J = 1.6 Hz); 3.36 (dd,

1 H,J = 3.0 Hz, J = 5.8 Hz); 3.57 (dd, I H, J = 5.8 Hz); 4.26 (s, 2H); 4.7-4.9 (m,

1H,J = 7 Hz); 5.2 (s, 2H), 5.75 (dd, I H, J = 3.2 Hz, J = 5.8 Hz); 6.36 (dd, 1 H,J

= 1.6 Hz,J = 14.22 Hz); 7.2-7.4 (m, 10H).

¹³C-NMR (300 MHz, CDC1₃): 1 73.5; 162.4; 152.8; 133- 127; 121.9; 107.2;

69.7; 57.1 ; 45.2-44.3- 14.6.

As an alternative to the potassium t-butylate sodium hydride can be used.

EXAMPLE 29

By operating as described in example 28, starting from 1 -( 1 -propen- l -yl) -3-

(S)-phenylacetamidoazetidin-2-one prepared as described in the example 6 or

7, there is obtained, by reaction with benzylchloroformiate in the presence of potassium t-butylate, 1 -0 -propen- 1 ~yl)-3~(S)-(N-benzyloxycarbonyl-N- phenylacetyl)aminoazetidin-2-one. [α]_D = -56.6° (CHCl₃, c = 0.5). EXAMPLE 30

3-(N-benzyloxycarbonyl-N-phenylacetyl)aminoazetidin-2-one

A solution of 3.38 g (10 mmoles) of l -(l -propen-l -yl)-3-(S)-(N- benzyloxycarbonyl-N-phenylacetyl)aminoazetidin-2-one, obtained as described in example 28, in 40 mL of acetone an 5 mL of phosphate buffer at pH 7.5 is dropwise added with a solution of 1.74 g ( 1 1 mmoles) of potassium permanganate in 5 mL of acetone and 5 mL of phosphate buffer at pH 7.5. The instantaneous conversion of potassium permanganate into manganese dioxide is waited for and then potassium permanganate is added up to persistent violet colour, the manganese dioxide is removed by filtration, the solution is evaporated for the removal of the acetone and the aqueous phase is extracted with methylene chloride. After drying and concentration the desired compound is isolated in form of an oil.

IR (neat): 1 760, 1 748, 1670.

•H-NMR (300 MHz, CDCl₃): 3.4 (dd, IH, J = 3.2 Hz, J = 5 Hz); 3.47 (dd, 1 H, J

= 5.4 Hz); 4.24 (s, 2H); 5.25 (dd, AB, 2H); 5.69 (dd, I H, J = 3.2 Hz, J = 5.5

Hz); 5.8 (b, I H), 7.21 -7.38 (m, 10H).

¹³C-NMR (300 MHz, CDC1₃): 1 73.6; 162; 153; 1 33- 127; 69.6; 59.7; 44.4-

42.1.

EXAMPLE 31

By operating as described in example 30, starting from 1 -0 -propen- l -yl)-3-

(S)-(N-benzyloxycarbonyl-N-phenylacetyl)aminoazetidin-2-one prepared according to example 29, there is obtained 3-(S)-(N-benzyloxycarbonyl-N- phenylacetyl)aminoazetidin-2-one. [α]_D = -33.2° (CHC1₃, c = 4.1 ).

EXAMPLE 32

3-(N-benzyloxycarbonyl-N-phenylacetyl)amino-4-acetoxyazetidin-2-one

A solution of 338 mg ( 1 mmole) of 3-(N-benzyloxycarbonyl-N- ρhenylacetyl)aminoazetidin-2-one in 1 mL of glacial acetic acid is added with 82 mg (1 mmole) of sodium acetate and 80 mg of 5% Ru/C (0.04 mmoles). The mixture is dropwise added, in 1 hour and at 15°C, with a solution of 0.46 mL (2.2 mmoles) of peracetic acid (32%) in acetic acid and 1 mL of ethyl acetate. During the peracid addition the development of gas is noticed. The mixture is maintained for 1 hour under stirring and, in the case if incomplete reaction, an equal amount of peracid is added. After 2 further hours the mixture is treated with water and extracted with 3 x 15 mL of methylene chloride. The organic phase is washed with a 10% aqueous solution of Na₂Sθ₃, dried with anhydrous

Na₂S0₄ and evaporated under reduced pressure. The residue (containing only the trans isomer) is purified by flash chromatography (eluant: cyclohexane/ethyl acetate = 1 / 1 v/v).

'H-NMR (300 MHz, CDC1₃): 2.06 (s, 3H), 4.26 (AB, 2H), 5.25 (s, 2H); 5.6 (s,

IH); 5.9 (s, I H); 6.42 (b, lH);7.2-7.5 (m, 10H).

'³C-NMR (300 MHz, CDC1₃): 1 73.7, 171 ; 163; 152; 133- 127; 78; 69.8; 65.6;

44.32; 20.66.

EXAMPLE 33

By operating according to example 32, starting from 3-(S)-(N- benzyloxycarbonyl-N-phenylacetyl)aminoazetidin-2-one prepared according to example 31 , there is obtained (3S,4S)-3-(N-benzyloxycarbonyl-N- phenylacetyl)amino-4-acetoxyazetidin-2-one.

EXAMPLE 34

3- phenylacetamido-4-acetoxyazetidin-2-one.

A solution of 0.396 g ( 1 mmole) of 3-(N-benzyloxycarbonyl-N- phenylacetyl)amino-4-acetoxyazetidin-2-one in 10 mL of tetrahydrofuran is added with 100 mg of 10% Pd/C and the resulting mixture is hydrogenated in

Parr equipmenl at 6.52- 10^-3 Pa up to the disappearance of the starting product.

After filtration, concentration and washing with methylene chloride the desired product is obtained with quantitative yield.

IR (CDC1₃): 3050, 2987, 1793, 1 750, 1680, 1260.

'H-NMR (300 MHz, CDCI3): 2. 1 1 (s, 3H); 3.62 (s, 2H), 4.63 (d, I H, J = 7.3

Hz), 5.82 (s, IH); 6.22 (d, 1 H,J = 7.2 Hz); 6.82 (bs, IH); 7.27 (m, 5H).

¹³C-NMR (300 MHz, CDCl₃): 171.9 ; 170.8; 164; 133- 127; 78.6; 63.8; 43.1 ;

20.7;

EXAMPLE 35

By operating as described in example 34, starting from (3S,4S)-3-(N- benzyloxycarbonyl-N-phenylacetyl)amino-4-acetoxyazetidin-2-one prepared according to example 33, there is obtained (3S,4S)-3-phenylacetamido-4- acetoxyazetidin-2-one.

EXAMPLE 36

3-phthalimido-4-acetoxyazetidin-2-one

(a) 2.56 g (10 mmoles) of l -( l -propen-l -yl)-3-phthalimidoazetidin-2-one, prepared according to example 2, are suspended in 40 mL of acetone and 40 mL of phosphate buffer at pH 7.5. Separately a solution is prepared of 1.740 g

(1 1 mmoles) of potassium permanganate in 5 mL of acetone and 5 mL of phosphate buffer at pH 7.5. This solution is dropwise added in 15 minutes to the previous suspension. After checking the disappearance of the starting product, the mixture is filtered, the filtrate is evaporated for the removal of the acetone and the residue aqueous phase is extracted with methylene chloride.

The organic phase is dried and concentrated under vacuum to give 3- phthalimidoazetidin-2-one in form of a white solid. Yield: 93%.

(b) A solution of 216 mg ( 1 mmole) of 3-phthalimidoazetidin-2-one in 3 mL of methylene chloride is added at 20°C. with 80 mg 5% Ru/C (0.04 mmoles), 82 mg (1 mmole) of sodium acetate and 1 mL of glacial acetic acid. The suspension is dropwise added within 1 hour with a solution of 0.46 mL (2.2 mmoles) of peracetic acid (32%) in acetic acid in 1 mL of ethyl acetate. The mixture is maintained for 1 hour under stirring and slowly added with an equal amount of peracid. After two further hours the mixture is treated with water and extracted with 3 x 1 5 mL of methylene chloride. The organic phase is washed with a 10% aqueous solution of Na₂S0₃, dehydrated with anhydrous Na₂S0₄ and evaporated under reduced pressure . The residue is purified by flash chromatography and the two diastereoisomers cis and trans are separated

(eluant: cyclohexane/ethylacetate = 6/4 v/v) - Rf 0.55 (trans); Rf 0.5 (cis).

There are obtained 1 5 1 mg (0.55 mmoles) of isomer trans and 26 mg (0.1 mmoles) of isomer ci.v Yield: 65% (85: 15 trans:cis).

Trans - M.r.: 197- 1 98 C.

IR (nujol): 3250, 1 790, 1 7-15, 1 7 10.

•H-NMR (300 MHz, CPC1₃): 2. 1 5 (s, 3H); 5.4 (d, 1 H, J = 1.5 Hz), 6.18 (d, 1 H, J

= 1.5 Hz), 6.75 (bs, 1 H ) , 7.S (m, 2H); 7.9 (m, 2H):

^,3C-NMR (300 MHz, d-DMSO) . 1 70.2; 166.7; 1 62.5; 1 35. 1 ; 131.1 ; 123.7;

76.6; 60.2; 20.6;

Cis

•H-NMR (300 MHz, CDC1₃): 2.05 (s, 3H); 5.57 (d. I H; j = 4 Hz); 6.05 (dd, I H,

J = 1.34 Hz; J = 4 Hz); 6.88 (bs, I H); 7.S5 (m, 4H).

EXAMPLE 37

O R,5R) 3-benzyl-4J-diaza-2-thiabicvclo[3.2.0|ept-3-en-6-one

(a) A solution of 5.24 g (20 mmoles) of (3S,4S)-3-phenylacetamido-4- acetoxyazetidin-2-one in 60 mL of anhydrous dichloromethane is added, at room temperature under inert atmosphere, with 4.9 g (40 mmoles) of 4- dimethylaminopyridine and 4.5 g (30 mmoles) of t-butyldimethylchlorosilane. After 16 hours of vigorous stirring there are added, at -50°C, 6.25 mL (50 mmoles) of N,N-dimethylaniline and 4.58 g (22 mmoles) of phosphorous pentachloride. The reaction mixture is stirred for 3 hours at -50°C, then hydrogen sulfide is bubbled thereinto for about 30 minutes. The temperature of the reaction mixture is left to raise to about 20°C, then it is treated with an aqueous solution of sodium bicarbonate. It is extracted with dichloromethane, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulphate and concentrated under vacuum. The thus obtained thioamide is purified by chromatography on a silica gel column (eluant: cyclohexane /ethyl acetate = 6/4 v/v). There is obtained pure (3S,4S)-4-acetoxy-3-phenylethanthioylamino- 1 -tert- butyldimethylsilylazetidin-2-one.

'H-NMR (300 MHz, CDC1₃): 0.25 (d, 6H); 0.98 (s, 9H); 2.14 (s, 3H); 4.1 (s, 2H), 5. 1 (d, I I I); 6.2 (s, I H); 7.3 (m, 511), 8.0 (d, I H).

(b) a solution of 0.16 g (0.4 mmoles) of the sililated thioamide obtained in the step (a) in 10 mL of toluene is added with 0.1 mL (0.4 mmoles) of triethylamine. The reaction mixture is refluxed for 1 hour, then brought to room temperature and maintained under vigorous stirring overnight. After addition of water the reaction mixture is extracted with ethyl acetate, dried with anhydrous sodium sulphate and concentrated under vacuum. The reaction raw product is purified by chromatography on silica gel (eluant: cyclohexane /ethyl acetate = 1 / 1 v/v) Yield: 98%) of the compound of formula A.

'H-NMR (300 MHz,. CDC1₃): 3.9 (q, 2H); 5.45 (d, I H); 6.0 (dd, I H); 6,69 (bs, s, 1 H); 7.3 (m, 5H).

Claims

CLAIMS 1. N-substituted 3-amino- 1 -propenylazetidin-2 -ones of formula I

wherem Ri represents hydrogen or a N-protective group, R₂ represents an acyl group, or NRιR₂ is a succinimido, maleimido or phthalimido group and propenyl indicates allyl, 1 -propen- 1 -yl or a mixture thereof.

2. 3-phenylacetamido- l -propenylazetidin-2 -one, wherein propenyl is allyl, 1 - propen- 1 -yl or a mixture thereof.

3. (3S)-3-phenylacetamido- 1 -0 -propen- 1 -yl)azetidin-2-one

4. 1 -allyl-3-phthaloylaminoazetidin-2-one

5. 3-phthaloylamino- 1 -0 -propen- 1 -yl)azetidin-2-one

6. 3-(N-benzyloxycarbonyl-N-phenylacetyl)- 1 -propenylaminoazetidin-2-σne, wherein propenyl is allyl, 1 -propen- 1 -yl or a mixture thereof.

7. N-substituted 3-amino- 1 -propenylazetidin-2-ones according to claim 1 , wherein Ri represents a silyl group, particularly trialkylsilyl, a benzyl group optionally substituted on the benzene ring, or an N- protective acyl group, such as benzyloxycarbonyl or t-butoxycarbonyl.

8. . N-substituted 3-amino- 1 -propenylazetidin-2-ones according to claim 1 , wherein R₂ is phenylacetyl.

9. A process for the preparation of 3-amino- 1 -propenylazetidin-2-one of formula II

wherein propenyl is allyl, l -propen-2-yl or a mixture thereof, characterised in that:

(a) an acid of formula III

wherein NRιR₂ represents a possibly substituted succinimido, maleimido or phthalimido group, in activated form or a functional derivative, is treated with 1 ,3,5-triallylhexahydro-s-triazine of formula IV

(b) the resulting product of formula V

wherein NRιR₂ is as above defined,:

(i) either is reacted with a primary amine or with hydrazine in hydro-alcoholic medium and the compound of formula II, in which propenyl is allyl, is isolated, or (ii) undergoes a isomerization reaction of the allyl group into 1 -propen- 1 -yl group to obtain a compound of formula V

wherein NRιR₂ is as above defined and then to the reaction with a primary amine or with hydrazine in hydro-alcoholic medium and the compound of formula II in which propenyl is the 1 -propen- 1 -yl is isolated, (c) said compounds of formula II are isolated in form of free bases or of one of their salts.

10. A process according to claim 9, wherein the isomerisation reaction is effected by refluxing in a hydro-alcoholic solution, preferably in aqueous ethanol, in presence of rhodium trichloride.

1 1 . A process according to claim 9, characterised in that a functional derivative of the phthaloylaminoacetic acid is used as the starting compound.

12. A process according to claim 1 1 , characterised in that said functional derivative is the chloride.

13. A process for the preparation of a compound of formula lb

wherein X represents an N-protective group which is stable under oxidising conditions, Y represents an acyl group, or NXY represents a succinimido, maleimido or phthalimido optionally substituted group, characterised in that a compound of formula Ia

\

CH₂— CH =CH₂ (la)

wherein X and Y are as above defined, is treated with a hydro-alcoholic solution under refluxing conditions in the presence of RhCl₃.

14 A process according to claim 13, wherein the isomerisation reaction is effected in hydro-alcoholic solution, preferably in aqueous ethanol.

15. A process for the preparation of 4-acetoxy-3-aminoazetidin-2-σnes disubstituted at the amino nitrogen of formula VIII

wherein X represents an N-protective group which is stable under oxidising conditions, Y represents an acyl group, or NXY represents a succinimido, maleimido or phthalimido optionally substituted group, characterised in that: (a) a compound of formula lb

is treated with a peracid in acetic acid in the presence of a metal catalyst, e.g. RuCl₃ or ruthenium on carbon.

16. A process according to claim 15, characterised in that 3-(N- benzyloxycarbonyl-N-phenylacetyI)amino- 1 -0 -propen- l -yl)azetidin-2-one is used as the starting compound.

17. A process according to claim 15, characterised in that in the step (b) the catalytic oxidation is effected by means of peracetic acid in acetic acid in the presence of ruthenium on carbon.

18. A process for Ihe preparation of 4-acetoxy-3-phenylacetamidoazetidin-2- onc, characterised in that:

(a) 1 -propenyl-3-aminoazctidin-2-one of formula II

wherein propenyl is allyl, 1 -propen- l -yl or a mixture thereof, is reacted with a functional derivative of the phenylacetic acid;

(b) an N-protective R'ι group, stable under oxidising conditions, is introduced in the resulting compound of formula X,

m which propenyl is as above defined , (c) the obtained compound of formula (XI)

after that the possible allyl group has been isomerized into a 1 -propen- l -yl group, at the end of either step (a) or (b), is reacted with potassium permanganate,

(d) the obtained product of formula XII

in which R'j is a N-protective group, is subjected to a catalytic oxidation with a peracid m acetic acid, and

(e) the protective group R'ι of the thus obtained compound of formula XIII

is removed

19 A process according to claim 18, characterised in that m the step (a) phenylacetylchloride is used as the functional derivative of the phenylacetic acid

20 A process according to claim 18, characterised in that in the step (a) as the functional derivative methyl phenyl acetate is used, and the reaction is carried out in the presence of penicillinacilase and the (3S)-3-phenylacetamιdσ-l - propenylazetιdιn-2-one is isolated

21 A process according to claim 18, characterised in that 3-amιno- l -( l - propen- l -yl)azetιdm-2-one is used as the starting compound and (3S)-3- phenylacetamido- 1 -0 propen- 1 -yl)azetιdm-2-one is isolated

22. A process according to claim 18, characterised in that in the step (b) benzyloxycarbonyl is the protective group RY

23. A process according to claim 18, characterised in that in the step (d) the catalytic oxidation is effected by means of peracetic acid in acetic acid in the presence of ruthenium on carbon.

24. A process according to claim 18, characterised in that in the step (b) the protective group R'ι is benzyloxycarbonyl, in the step (d) the catalytic oxidation is effected by means of peracetic acid in the presence of ruthenium on carbon and in the step (e) the removal of the protective group R'ι is effected by catalytic hydrogenation.

25. A process according to claim 18, characterised in that in the step(a) 3- amino- 1 -0 -propen- l -yl)azetidin-2-one is used as the starting compound, methyl phenylacetate is used as the functional derivative of phenylacetic acid, the reaction is carried out in the presence of penicillinacilase and (3S)-3- phenylacetamido- 1 -0 propen- l -yl)azetidin-2-one is isolated; benzyloxycarbonyl is the protective group R\ in the step (b); in the step (d) the catalytic oxidation is effected by means of peracetic acid in the presence of ruthenium on carbon and in the step (e) the removal of the protective group R'ι is effected by catalytic hydrogenation, (3S,4S) -3- phenylacetamido-4- acetoxyazetidin-2-one being then isolated.

26. A process according to claim 18, characterised in that in the step (a) (3S) 3- amino- l -( I -propen- l -yl)azetidin-2-one is used as the starting material, it having been obtained by hydrolysis of racemic 3-phenylacetamido- l -O - propen- 1 -yl)azetidin-2-one in the presence of penicillinacilase.