METHOD FOR SYNTHESIS OF THE SUBSTITUTED AZETIDINONES AND INTERMEDIATES

FOR THEIR SYNTHESIS

Field of the invention

The present invention refers to the method of the synthesis of substituted azetidinones of formula 1. In particular, the invention refers to the method of synthesis of (3R,4S)-1 -(4- fluorophenyl)-3-[(3'S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4 -(4-hydroxyphenyl)azetidin-2-one (2).

1

Background of the invention

Azetidinones of formula 1 constitute a class of the compounds exhibiting a hypercholersterolemic action that are used in a prevention of arteriosclerosis. Ezetimibe (2), (3R,4S)-1 -(4-fluorophenyl)-3-[(3'S)-3-(4-fluorophenyl)-3-hydroxypropy l]-4-(4- hydroxyphenyl)azetidin-2-on, a representative of this group of the biologically active compounds, is a selective inhibitor of cholesterol and phytosterols absorption in the small intestine.

Ezetimibe is an active ingredient of the ZETIA therapeutic, produced by Merck/Schering-Plough Pharmaceuticals. Ezetimibe was approved by United States Food and Drug Administration (US FDA) as a drug for patients with high level of cholesterol.

In contrast to other drugs of a hypolipemic action, for example statins, which inhibit biosynthesis of cholesterol in a liver (endogenous cholesterol), ezetimibe reduces a level of a blood cholesterol through the inhibition of its absorption in the small intestine (exogenous cholesterol). On the molecular level, the target of the ezetimibes' action of is sterols carrier, Niemann-Pick C1 -Like 1 (NPC1 L1 ) protein, which is responsible for the absorption of cholesterol and phytosterols in the small intestine. Ezetimibe binds with a brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. A different area of action of various classes of hypolipemic therapeutics allows their use in the combined therapy, which allows enhance of the therapy effectiveness. For example, ezetimibe is used in the combination with statins (Vytorin ^® , Inezy ^® ).

US RE37,721 discloses stereoselective process of producing ezetimibe (2) (Scheme 1 ).

In the method disclosed in the patent No US RE 37,721 and presented in the Scheme 1 , the key structural element - four-membered azetidinone ring is synthesized by TiCI ₄ catalyzed stereocontrolled condensation of the corresponding imine with amide bearing chiral oxazolidinone auxiliary. A necessity of the use of chiral auxiliary is the major drawback of the method of synthesis of ezetimibe disclosed in the patent US RE 37,721 due to the low process economy and necessity of the isolation of the product of the chiral auxiliary conversion or/and its regeneration. Additionally, the disclosed method for producing of ezetimibe is labor-consuming and comprises series of synthetic steps. For these reasons, there is demand for more effective methods of producing ezetimibe.

Other methods of producing of ezetimibe are disclosed in the following patent specifications US 5739321 , US 5856473, US 6207822, WO 2008/061238 and WO 2010/097350 A1 .

In the patent No US 5739321 , a key β-lactam ring in ezetimibe molecule (2) is formed by the reaction of non-racemic γ-lactone with imine, that leads to the formation of azetidinone having 1 ,2-diol functionality in the side chain (Scheme 2). Oxidative cleavage of diol provides corresponding aldehyde, which is subsequently submitted to condensation with enol silyl ether. Hydrogenation of double bond, with subsequent asymmetric reduction reaction of the ketone group and debenzylation leads to the target product 2. Scheme 2

In the patent specification US 5856473 discloses the side chain transformations that lead to the formation of ezetimibe 2; wherein suitable propenyl derivative is submitted to oxidation into ketone, which is subsequently submitted to asymmetric reduction (Scheme 3).

On the other hand, in the patent No US 6207822, a method for producing of ezetimibe 2 by the reaction of fluorobenzoylbutyric acid with pivaloyl chloride, and subsequent acylation leading to the formation of the product having chiral auxiliary, is disclosed (Scheme 4). The reduction reaction of the ketone functional group in the presence of chiral catalyst provides chiral alcohol, which is subsequently submitted to the reaction with imine and silylation reagent to afford the substituted β-aminoamide. Its cyclization and deprotection of hydroxyl groups lead to ezetimibe.

WO 2008/061238 discloses the method for producing of the β-lactam ring of ezetimibe by the reaction of imine with chiral 6-aryl-6-lactone that leads to the formation of azetidinone with side chain, identical as that in ezetimibe (Scheme 5).

WO 2010/097350 A1 discloses the method for producing of the azetidinone ring by the

Cu(l) catalyzed reaction of nitrone with chiral acetylene derivatived from L-glyceraldehyde

(Scheme 6). Removal of the isopropylidene protection from the side chain of the obtained azetidinone leads to the formation of diol, which is an epimer of diol disclosed in US 5739321 .

Oxidative cleavage of diol, combined with epimerization leads to the aldehyde derivative of azetidinone being an identical with the compound disclosed in the patent No US 5739321 and used as a precursor of 2.

Scheme 6

Publications (I . Panfil, M . Chmielewski, Tetrahedron, 1985, 41, 4713, I . Panfil, M. Chmielewski, C. Betzecki, Heterocycles, 1986, 24, 1609, I. Panfil, C. Betzecki, M. Chmielewski: J. Carbohydr. Chem., 1987, 6, 463 and I . Panfil, C. Betzecki, Z. Urbai czyk-Lipkowska, M. Chmielewski Tetrahedron, 1991 , 47, 10087) describe a process, wherein under the thermal non-catalytic conditions, diaryl- or alkylaryl- nitrones are reacted with α,β-unsaturated sugar lactones (6-0-acetyl-4-deoxy-D, L-glycero, 4,6-di-O-acetyl-D-e/yiftro and 4,6-di-O-acetyl-D- threo) to form mixtures of bicyclic products. One of them was converted into β-lactam compound having phenyl substituent at the nitrogen atom, p-anisyl substituent at C-4 and polyol substituent at C-3 atom of azetidinone ring.

Summary of the invention

The subject of the invention is method of synthesis of the substituted azetidinones of formula 1

wherein R ¹ , R ² and R ³ are independently any substituent selected from the group consisting of: (a) hydrogen atom; (b) halogen atom;

(c) substituent -OR ⁴ ; wherein R ⁴ is hydrogen atom, C^-alkyl, aryl, heteroaryl, C ₂ .s-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ _7-cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl;

(d) -C(=0)R ⁵ ; wherein R ⁵ is C _-6 -alkyl, aryl, heteroaryl, C ₃ . ₇ -cycloalkyl;

(e) Ci _-6 -alkyl, aryl, heteroaryl, biaryl;

(f) additionally R ¹ can be a substituent of -OR ⁶ type, wherein R ⁶ is monosaccharide (including protected monosaccharide), disaccharide (including protected disaccharide) or oligosaccharide (including protected oligosaccharide).

characterized in that, it consists of the following steps of:

(a) 1 ,3-dipolar cycloaddition reaction of nitrone of formula 4 with the lactone of formula 3 to afford the bicyclic isoxazolidine of formula 5;

(b) N-O bond cleavage in the isoxazolidine of formula 5 leading to aminoalcohol of formula 6;

wherein R ¹ , R ² , R ³ are as defined above;

(b) remova a compound of formula 6 leading to lactone 7;

wherein R ¹ , R ² , R ³ are as defined above;

(c) rearrangement reaction to afford a compound with 2-azetidinone ring of formula 7;

wherein R ¹ , R ² , R ³ are as defined above; (d) inversion of the configuration in the side chain of the compound of formula 7 to afford the compound of formula 1 ;

wherein R ¹ , R ² , R ³ are as defined above;

(e) optionally, when substituents R ¹ , R ² and R ³ are substituents of -OR ⁴ type (wherein R ⁴ is Ci_6-alkyl _> aryl, heteroaryl, C ₂ -6-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ . ₇ -cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), additionally deprotection reaction is performed, that leads to the formation of the free -OH group.

Preferably, the compound 5 is synthesized by Lewis acid catalyzed or thermally induced 1 ,3-dipolar cycloaddition reaction of the nitrone 4 to the lactone 3, in the presence of additive and optionally in a solvent.

Preferably, in the method according to the invention, where in the N-0 bond cleavage reaction in the isoxazolidine of formula 5 to obtain aminoalcohol of formula 6 is performed in the presence of trimethylsilyl chloride/potassium iodide mixtures.

Preferably, the compound of formula 6 is submitted to the water elimination reaction leading to the compound of formula 9, in which the double bond is subsequently reduced to afford the saturated lactone of formula 7.

Preferably, the compound of formula 6 is submitted to the deoxygenation reaction to obtain the lactone of formula 7.

Preferably, the compound of formula 7 is submitted to the rearrangement reaction to obtain 2-azetidinone 8, wherein this reaction is performed in the presence of a base and optionally in a solvent.

Preferably, the stereogenic center in the side chain of compound of formula 8 is epimerized be a nucleophilic substitution reaction, followed eventually by a hydrolysis, to afford the compound of 1 .

Next subject of the invention is a method of synthesis of the substituted azetidinones of formula 1 , wherein R ¹ , R ² , R ³ are as defined above; characterized in that, it consists of the following steps of:

(a) 1 ,3-dipolar cycloaddition reaction of nitrone of formula 4 with lactone of formula 3 to afford the bicyclic isoxazolidine of formula 5;

wherein R > 1 , □ R∑ , ο R3 are as defined above;

(b) cleavage of the N-O bond in the isoxazolidine of formula 5 leading to the aminoalcohol of formula 6;

wherein R ¹ , R ² , R ³ are as defined above;

(c) remova the compound of formula 6 affording the lactone 7;

wherein R ¹ , R ² , R ³ are as defined above;

(d) inversion of the configuration in the side chain of the compound of formula 7 resulting in formation of alcohol 14

wherein R ¹ , R ² , R ³ are as defined above;

(e) rearrangement leading to the formation of 2-azetidinone of 1 ;

11

wherein R ¹ , R ² , R ³ are as defined above;

(f) optionally, when R ¹ , R ² and R ³ are substituents of -OR ⁴ type (wherein R ⁴ is C^-alky!, aryl, heteroaryl, C ₂ -6-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ . ₇ -cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), additionally performing deprotection reaction, that leads to the free hydroxyl group formation.

Preferably, in the method according to the invention, wherein compound 7 is hydrolyzed to the compound 15,

wherein R ¹ , R ² , R ³ are as defined above

which is subjected to lactonization with the inversion of configuration, in the presence of azo compound and phosphine, to afford the lactone 14.

Preferably, in the presence of a base and optionally in a solvent, the compound of formula 14 is submitted to the rearrangement reaction to obtain the 2-azetidinone of formula 1.

Next subject of the invention is a method of synthesis of the substituted azetidinones of formula 1 , wherein R ¹ , R ² , R ³ are as defined above; characterized in that, it consists of the following steps of:

(a) 1 ,3-dipolar cycloaddition reaction of nitrone of formula 4 with lactone of formula 3 to afford the bicyclic isoxazolidine of formula 5;

wherein R ¹ , R ² , R ³ are as defined above;

(b) an inversion of absolute configuration in the lactone moiety of compound 5 leading to the lactone 16;

wherein R ¹ , R ² , R ³ are as defined above;

(c) cleavage of the N-O bond in the isoxazolidine 16 leading to the aminoalcohol of formula 17;

wherein R ¹ , R ² , R ³ are as defined above;

(d) removal of the OH group in compound 17 affording the lactone 14 formation;

(e) rearrangement leading to the formation of 2-azetidinone of 1 ;

wherein R ¹ , R ² , R ³ are as defined above;

(f) optionally, when R ¹ , R ² and R ³ are substituents of -OR ⁴ type (wherein R ⁴ is C^-alkyl, aryl, heteroaryl, C ₂ -6-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ . ₇ -cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trial kylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), additionally deprotection reaction is performed, that leads to the free hydroxyl group formation.

Preferably, in the method according to the invention, compound 5 is hydrolyzed to the compound 18,

wherein R ¹ , R ² , R ³ are as defined above;

which is subjected to lactonization with the inversion of configuration, in the presence of azo compound and phosphine, to afford the lactone 16;

Preferably, the cleavage of the N-0 bond in the compound 16 to obtain the aminoalcohol of formula 17 is performed in the presence of tnmethylsilyl chloride/potassium iodide mixtures.

Preferably, the compound of formula 17 is submitted to the deoxygenation reaction to obtain the lactone of formula 14. Preferably, compound 17 is submitted to water elimination step leading to unsaturated lactone of formula 45, in which the double bond is subsequently reduced to afford the saturated lacto

The next subject of the invention is a method of synthesis of non-racemic lactone of formula 3

(1 ) chiral metal complex catalyzed [4+2] cycloaddition reaction of aldehyde of formula 20 to the diene 21 , wherein R ³ is as defined above, to afford enone of formula 22;

(2) reduction of the enone of formula 22 to the alcohol of formula 23, wherein R ³ is as defined above;

(3) transformation of compound 23 into the lactone 3.

Preferably, compound 23 is rearranged into the acetal 24, which is subsequently oxidized to the lactone 3.

Preferably, compound 23 is oxidized with rearrangement to the hydroperoxide 25, which is subsequently dehydratated to the lactone 3.

Preferably, the method according to the invention is used in the synthesis of (3f?,4S)-1 - (4-fluorophenyl)-3-[(3'S)-3-(4-fluorophenyl)-3-hydroxypropyl ]-4-(4-hydroxyphenyl)azetidin-2-one (2)

as a result of the transformation of isoxazolidine 26:

obtained via Lewis acid catalyzed or thermally induced 1 ,3-dipolar cycloaddition between the nitrone 27

and the lactone 28

28

Preferably, starting with 4-fluorobenzaldehyde and the diene 21 non-racemic lactone 28 is obtained.

Thus, the present invention refers to the method for producing substituted azetidinones of the formula 1

wherein R ¹ , R ² and R ³ are independently any substituent selected from the group consisting of

(a) hydrogen atom;

(b) halogen atom;

(c) substituent -OR ⁴ ; wherein R ⁴ is hydrogen atom, C _-6 -alkyl, aryl, heteroaryl, C ₂ -s-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ . ₇ -cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl;

(d) -C(=0)R ⁵ ; wherein R ⁵ is C _-6 -alkyl, aryl, heteroaryl, C ₃ . ₇ -cycloalkyl;

(e) C^e-alkyl, aryl, heteroaryl, biaryl;

(f) additionally R ¹ can be a substituent of -OR ⁶ type, wherein R ⁶ is monosaccharide (including protected monosaccharide), disaccharide (including protected disaccharide) or oligosaccharide (including protected oligosaccharide).

characterized in that, it consists of the following steps of:

Lewis acid catalyzed or thermally induced, 1 ,3-dipolar cycloaddition reaction of nitrone of formula 4 with lactone of formula 3 to afford bicyclic isoxazolidine of the formula 5;

wherein R ¹ , R ² , R ³ are as defined above;

N-0 bond cleavage at the isoxazolidine moiety;

cyclization reaction leading to the formation of azetidin-2-one ring;

inversion of the configuration at selected stereogenic centers,

optionally, deprotection reactions of the corresponding functional groups;

wherein the sequence of aforementioned steps can be changed.

Present invention discloses three alternative routes consisting aforementioned steps but in different order.

Preferably, the method according to the invention, hereinafter referred as the route„A" comprises the following steps:

- N-O bond cleavage in the isoxazolidine of formula 5 leading to aminoalcohol of formula

6;

wherein R ¹ , R ² , R ³ are as defined above;

removal of OH group in compound of formula 6 leading to the lactone 7;

wherein R ¹ , R ² , R ³ are as defined above;

- rearrangement of the six membered ring lactone into the four one of 2-azetidinone ring formula 7;

wherein R ¹ , R ² , R ³ are as defined above; - inversion of the configuration in the side chain of the compound of formula 8 to afford the compound of formula 1 ;

wherein R ¹ , R ² , R ³ are as defined above;

- optionally, when substituents R ¹ , R ² and R ³ are substituents of -OR ⁴ type (wherein R ⁴ are C _-6 -alkyl, aryl, heteroaryl, C ₂ -6-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ . ₇ -cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), additionally deprotection reaction is performed, that leads to the formation of the free -OH group.

Preferably, the method according to the present invention, hereinafter referred as the route„B", consists of the following steps:

- N-O bond cleavage in isoxazolidine of formula 5 leading to aminoalcohol of formula 6;

wherein R ¹ , R ² , R ³ are as defined above;

- removal of the OH group in compound of formula 6 to obtain lactone 7;

wherein R ¹ , R ² , R ³ are as defined above;

- epimerization of the stereogenic center in the lactone ring of the compound of formula 7 leading to the compound of formula 14;

wherein R ¹ , R ² , R ³ are as defined above;

rearrangement of the six membered ring into a four one of 2-azetidinone of formula 1 ;

11

wherein R ¹ , R ² , R ³ are as defined above;

- optionally, when R ¹ , R ² and R ³ are substituents-OR ⁴ type (wherein R ⁴ is C^-alkyl, aryl, heteroaryl, C ₂ -6-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ . ₇ -cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), additionally deprotection reaction is performed, that leads to the free hydroxyl group formation.

Preferably, the method according to the present invention, hereinafter referred as the route„C" consists of the following steps:

- epimerization of the stereogenic center in the lactone ring of the compound of formula 5 leading to the la

wherein R ¹ , R ² , R ³ are as defined above;

- N-O bond cleavage in the compound 16 to afford aminoalcohol of formula 17;

wherein R ¹ , R ² , R ³ are as defined above;

- removal of the OH group in the compound 17 to obtain lactone of formula 14;

wherein R ¹ , R ² , R ³ are as defined above;

- rearrangement reaction leading to 2-azetidinone of formula 1 ;

11

wherein R ¹ , R ² , R ³ are as defined above;

- optionally, when R ¹ , R ² and R ³ are substituents of -OR ⁴ type (wherein R ⁴ is C^-alkyl, aryl, heteroaryl, C ₂ -6-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ . ₇ -cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), additionally deprotection reaction is performed, that leads to the free hydroxyl group formation.

Present invention discloses also the method of synthesis non-racemic lactone of formula

3

3

wherein R ³ is as defined above;

Preferably, method of synthesis of lactone of formula 3 consists the following steps:

(1 ) chiral metal complex catalyzed [4+2] cycloaddition reaction of aldehyde of formula 20 with the diene 21 , wherein R ³ is as defined above, to afford the enone of formula 22;

(2) reduction of enone of formula 22 to the alcohol of formula 23, wherein R ³ is as defined above;

(3) the rearrangement reaction of the alcohol of formula 22 to acetal of formula 24, wherein R ³ is as defined above;

(4) an oxidation of the compound of formula 24 to the lactone of formula 3, wherein R ³ is as defined above.

Preferably, the method according to the present invention is used in the synthesis of (3R,4S)-1 -(4-fluorophenyl)-3-[(3'S)-3-(4-fluorophenyl)-3-hydroxypropy l]-4-(4- hydroxyphenyl)azetidin-2-one (2)

as a result of transformation of isoxazolidine 26:

which is obtained through the Lewis acid catalyzed or thermally induced 1 ,3-dipolar cycloaddition between the nitrone 27

and the lactone 28

28

Preferably, non-racemic lactone 28 is obtained starting with 4-fluorobenzaldehyde and the diene

Detailed description of the invention

The present invention relates to a method for producing the compounds of formula 1 :

wherein

R ¹ , R ² and R ³ are independently any substituent selected from the group consisting of:

(a) hydrogen atom;

(b) halogen atom;

(c) substituent -OR ⁴ ; wherein R ⁴ is hydrogen atom, C _{1 -6} -alkyl, aryl, heteroaryl, C ₂ -s-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ . ₇ -cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl; (d) substituent -C(=0)R ⁵ ; wherein R ⁵ is C^-alkyl, aryl, heteroaryl, C ₃ . ₇ -cycloalkyl;

(e) Ci-e-alkyl, aryl, heteroaryl, biaryl;

(f) additionally R ¹ can be a substituent of a -OR ⁶ type, wherein R ⁶ is monosaccharide (including protected monosaccharide), disaccharide (including protected disaccharide) or oligosaccharide (including protected oligosaccharide).

In particular, the method according to the invention is applied in the synthesis of (3R,4S)-1 -(4-fluorophenyl)-3-[(3'S)-3-(4-fluorophenyl)-3-hydroxypropy l]-4-(4- hydroxyphenyl)azetidin-2-one (ezetimibe, 2).

According to the invention, azetidinone of formula 1 is obtained through the transformation of the bicyclic compoun 29:

wherein R ¹ , R ² and R ³ are as defined above;

obtained by thermally induced or Lewis acid catalyzed 1 ,3-dipolar cycloaddition reaction of nitrone of formula 4:

4

wherein R ¹ and R ² are as defined above;

with α, β-unsaturated lactone of formula 30:

30

wherein R ³ is as defined above.

In particular, the present invention refers to the method of producing of non-racemic lactone of formula 3: wherein R ³ is as defined above.

The present invention discloses a method of transformation of a compound of formula 5

into azetidinone of formula 1 . The present invention discloses three methods of transformation of isoxazolidine of formula 5 into azetidinone of formula 1. Each of the disclosed in the present invention routes of transformation of the compound of formula 5 to a compound of formula 1 comprises: (1) a cleavage of N-0 bond in a compound of formula 5, (2) rearrangement leading to the formation of a azetidin-2-one ring, (3) inversion of the configuration at selected stereogenic centers and optionally (4) deprotection of functional groups.

Disclosed in the present invention methods of transformation of the compounds of formula 5 to the compounds of formula 1 differ in order of performing aforementioned steps.

In particular, the present invention discloses the method for producing of ezetimibe (2):

as a result of transformation of isoxazolidine 26:

obtained through the Lewis acid catalyzed or thermally induced 1 ,3-dipolar cycloaddition between the nitrone 27

and the lactone 28

28

In accordance with the above, the present invention discloses the method for producing the compounds of formula 1 : wherein R ¹ , R ² and R ³ are as defined above. The method for producing the compounds of formula 1 according to the invention, hereinafter referred to as the route„A" is presented in the Scheme 7:

Scheme 7 R ¹

1

According to the reaction sequence presented in the Scheme 7, the method of synthesis of azetidinones 1 using route„A" comprises the following steps:

(a) Lewis acid catalyzed or thermally induced 1 ,3-dipolar cycloaddition reaction of nitrone of formula 4 to the lactone of formula 3 resulting in bicyclic isoxazolidine of formula 5 formation;

(b) cleavage of N-O bond in isoxazolidine of formula 5 leading to the aminoalcohol of formula 6 formation;

(c) removal of the OH group in compound of formula 6 affording the lactone 7 formation;

(d) rearrangement leading to the formation of 2-azetidinone of formula 8;

(e) inversion of the configuration in the side chain of the compound of formula 8 resulting in formation of alcohol of formula 1 ;

(f) optionally, when R ¹ , R ² and R ³ are substituents of -OR ⁴ type (wherein R ⁴ is C^- alkyl, aryl, heteroaryl, C ₂ .6-alkenyl, C ₂ .6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ _7-cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl) there is used additional step of deprotection resulting in free -OH group formation.

Nitrone 4 is produced by using of the known method accordging to the state of art of the organic synthesis, by reacting hydroxylamine of formula 31 :

31

wherein R ² is as defined above;

with the aldehyde compound of formula 32

32

wherein R ¹ is as defined above.

Alternatively, nitrone of formula 4 is synthesized by an oxidation of the corresponding amines of formula 33 or an oxidation of the corresponding imine of formula 34: wherein R ¹ and R ² are as defined above.

According to method disclosed in the present invention, the non-racemic, , β- unsaturated lactone of formula 3 is obtained through the reaction sequence presented in the Scheme 8:

Scheme 8

3 24

According to the invention, in the presence of a chiral metal complex, optionally additives, optionally a solvent, the aldehyde 20, wherein R ³ is as defined above, reacts with the diene 21 , to afford the compound 22 with high enantiomeric excess.

The method for producing of the diene 21 is known (Y. Yamashita, S. Saito, H. Ishitanti, S. Kobayashi J. Am. Chem. Soc. 2003, 25, 3793-3798) and is based on the reaction of (£)-4- metoxy-3-buten-2-one with silylating agent in the presence of a base. Preferably, in the reaction of the compound 20 with the diene 21 , from 1 to 10 equivalents of the diene 21 is used with respect to the aldehyde 20; more preferably 1 .5 equivalents of diene 21 with respect to the aldehyde 20 is used.

Preferably, in the reaction of the compound 20 with the diene 21 , as a chiral catalyst, complex of metal salt with chiral ligand is used. Preferably, as a metal salt is selected from the group consisting of salts of titanium, molybdenum, cobalt, chromium, nickel, tin, copper, scandium, indium, iridium; more preferred is when the metal compound is salt of chromium, scandium, titanium.

Preferably, as a chiral ligand, mono-, di-, tri- or four-coordination compounds having nitrogenic, oxygenic, phosphorous or sulfuric donor centers (or their combinations) are used. Preferably chiral ligand is selected from the group consisting of: BINOL type ligands, TADDOL type ligands, BINAP type ligands, PyBOX type ligands, TOX type ligands, Josiphos type ligands, PHOX type ligands, salen type ligands and bisoxazoline type ligands. Particularly preferred is when as the chiral ligand salen is used.

Preferably, a ready-to-use chiral complex of metal or generated in situ (through mixing of metal salt and chiral ligand) is used in the reaction.

Preferably, from 0.005 to 3 equivalents of the chiral metal complex with respect to the aldehyde 20 is used; more preferably 0.02 equivalent of the chiral metal complex with respect to the aldehyde 20 is used.

Preferably, in the reaction of the compound 20 with the diene 21 , the solvent is selected from the group encompassing aliphatic ethers; more preferably the solvent is selected from the group comprising of diethyl ether, methyl-ferf-butyl ether, tetrahydrofuran, and dioxane.

Preferably, in the reaction of the compound 20 with the diene 21 , molecular sieves are used as an additive; it is particularly preferred when, as an additive, molecular sieves 4 A are used.

Preferably, the reaction of the compound 20 with the diene 21 is performed at the temperature range from -78 °C to 100 °C. Particularly preferred is when reaction is performed at the temperature range from -40 °C to -20 °C.

According to the method disclosed in the present invention, the enone of formula 22 is reduced to the alcohol 23 in the presence of reducing agent, optionally activating agent, optionally in a solvent.

Preferably, for the reduction reaction of the enone 21 to the alcohol 23, a reducing agent is selected from the group encompassing: alkaline aluminumhydrides (and theirs derivatives), alkaline borohydrides (and theirs derivatives), alane (aluminum hydride, AIH ₃ and its derivatives), borane (and its derivatives). More preferably, sodium borohydride is used as a reducing agent. Typically, at the most 3 equivalents of reducing agent with respect to substrate 22 are used; most preferably, 1.5 equivalent of reducing agent is used. Preferably, for a reduction reaction of the enone 22 to the alcohol 23, an activating agent, selected from the group comprising lanthanides salts, is used. Preferably, cerium (III) salts are used as an activating agent. Typically, from 1 to 3 equivalents of an activating agent, with respect to the substrate 22, are used; most preferably, 1.5 equivalent of the activating agent is used.

Preferably, the reduction reaction of the enone 22 to the alcohol 23 is performed in alcoholic solvent or alcoholic-aqueous solvents or in aliphatic ethers. More preferably, the reaction is performed in methanol, ethanol or 2-propanol.

Preferably, the reduction reaction of the enone 22 to the alcohol 23 is performed at the temperature range from -78 °C to 80 °C. Particularly preferred is when the reduction is performed at the temperature range from -30 °C to 30 °C.

According to the method disclosed in current invention, the alcohol of general formula 23 is rearranged to acetal of general formula 24, in the presence of an acidic promoter, optionally in a solvent.

Preferably, the transformation of the alcohol 23 to the compound 24 is performed in the presence of Lewis acid selected from the group consisting of: BF ₃ Et ₂ 0, SnCI ₄ , l ₂ , FeCI ₃ , TMSOTf. Particularly preferred is when BF ₃ Et ₂ 0 is used as the Lewis acid. Typically, from 0.1 to 3 equivalents of the Lewis acid with respect to the substrate 23; more preferably, 0.1 equivalent of the Lewis acid is used.

Preferably, the transformation of the alcohol 23 to the compound 24 is performed in the presence of a protic acid selected from the group consisting of: inorganic acids, aliphatic carboxylic acids, aromatic carboxylic acids, aliphatic sulfonic acids, and aromatic sulfonic acids (including organic acids immobilized on a polymeric resin - acidic ion exchangers). More preferred when p-toluenesulfonic acid is used as an acidic promoter. Typically, from 0,1 to 1 equivalent of an acidic promoter is used with respect to the substrate 23. Preferably, 0,1 equivalent of an acidic promoter is used. It is particularly preferred when an acidic ion exchanger of DOWEX type or an acidic zeoilte are used as an acidic promotor.

Preferably, for the transformation of the alcohol 23 to the compound 24, aliphatic alcohols are used as a solvent. More preferably, the reaction is performed in methanol or ethanol.

Preferably, the transformation of the alcohol 23 to the compound 24 is performed at the temperature range from -20 °C to 60 °C. It is particularly preferred when the reaction is performed at the temperature range from 10 °C to 30 °C.

According to the method disclosed in the present invention, the acetal 24 is oxidized to the lactone 3, in the presence of oxidizing agent, optionally in a solvent.

Preferably, an oxidation of the compound 24 to the lactone 3 is performed in the presence of an oxidizing agent selected from the group encompassing: chromium (VI) derivatives, manganese (IV) derivatives and manganese (VII) derivatives, alkaline hypochlorites in the presence of TEMPO, ruthenium compounds in the presence of co-oxidizing agent (e.g. sodium periodate). It is particularly preferred when as an oxidizing agent there are used chromium (VI) derivatives. Typically, from 1 to 10 equivalents of the oxidizing agent with respect to the substrate 24 with 2 equivalents of the oxidizing agent being preferred.

Preferably, an oxidation of the compound 24 to the lactone 3 is performed in a solvent selected from the group encompassing: aliphatic ketones and carboxylic acids esters. Particularly preferably, the oxidation is performed in acetone.

Preferably, an oxidation of the compound 24 to the lactone 3 is performed at the temperature range from -30 °C to 60 °C. More preferably, the temperature range is from -10 °C to 10°C.

According to the method disclosed in the present invention, compound of formula 23 is alternatively converted into the lactone of formula 3 according to the Scheme 9. For this purpose, the compound of formula 22 is converted into the hydroperoxide of formula 25, which is directly submitted to the reaction leading to the formation of the lactone 3.

Scheme 9

23 25

According to the method disclosed in the present invention, the compound 23 is converted into the hydroperoxide 25 in the presence of an oxidizing agent, metal compound, optionally in a solvent.

Preferably, an aqueous solution of hydrogen peroxide is used as an oxidizing agent. Typically, the aqueous solution of hydrogen peroxide of a concentration from 5 to 90% is used, and the most preferably, of a concentration of 50%.

Preferably, the metal compound is selected from the group comprising tungsten, molybdenum or vanadium compounds, and particularly preferably, molybdenum trioxide is used. Typically, the metal compound is used in amount from 0.1 to 5 equivalents, and particularly preferably, 0.1 equivalent of the metal compound with respect to the compound 23 is used.

Preferably, an ether solution of hydrogen peroxide is used as an oxidizing agent. Typically, saturated ethyl ether solution of hydrogen peroxide is used.

Preferably, the acid catalyst is selected from non oxidizing acids such as sulfuric acid, alkyl, or aryl sulfonic acids, perchloric acid, Lewis acids such as boron trifluoride, and particularly preferably, sulfuric acid is used. Typically, the acid is used in amount from 0.1 to 5 equivalents, and particularly preferably, 0.1 equivalent of the acid with respect to the compound 23 is used. According to the method disclosed in the present invention, the hydroperoxide 25 is converted into the lactone 3 by treatment with an activating agent, base, optionally in a solvent.

Preferably, an activating agent is selected from the group comprising carboxylic acids anhydrides and acid chlorides of carboxylic acids. In particular, an activating agent is selected from the group encompassing acetic anhydride, propionic anhydride, benzoic anhydride, acetyl chloride, benzoyl chloride.

The transformation of compound 25 into the lactone 3 is performed in the presence of base selected from the group involving tertiary aliphatic amines and aromatic amines.

Particularly preferably, pyridine or 2,6-lutidine are used as a base.

Scheme 10

Alternatively, the lactone 3 is produced from the epoxide 35 according to the Scheme 10. Opening of the epoxide ring in 35 and carboxylation of the acetylene 36 provides the acid 37. Selective reduction of triple bond leads to olefin 38 that as a result of lactonization leads to the lactone 3 formation.

Scheme 11

39 3

Optionally, unsaturated lactone of formula 3 is produced from lactone of formula 39 according to the Scheme 1 1. Synthesis of the lactone 39 are disclosed by WO 2004/99132 A2, WO 2006/102674 A2 and WO 2008/61238 A2.

In the presence of a base and an electrophilic reagent, compound 39 is converted into derivative which treated with an oxidizing agent leads to the unsaturated lactone 3. As base, non-nucleophilic compounds selected from the group comprising: dialkyl amides (e.g. LDA), alkaline bis(trialkylsilyl)amides (e.g. KHMDS), sodium amide, alkaline alcoholates (e.g. M3uOK) are used; preferably, lithium diisopropylamide (LDA) is used as a base. Preferably, as an electrophilic reagent, sulfur and selenium compounds are used. Particularly preferably,: PhSeX, PhSeCN, PhSeSePh, PhSSPh, and PhSX (where X is halogen) are used as the electrophilic compounds. Preferably, an oxidizing agent is selected from the group comprising: hydrogen peroxide, organic peroxyacids (e.g. m-chloroperoxybenzoic acid), hydroperoxides (e.g. t-butyl hydroperoxide or cumene hydroperoxide), and salts of inorganic peroxyacids (e.g. alkaline periodates, alkaline peroxycarbonates, alkaline peroxysulfates). The reactions presented in the Scheme 11 are performed following known methods according to the organic synthesis art.

Non-racemic lactone 3 can be also obtained using the reaction sequence presented in the Scheme 12. The lactone 3 is synthesized from the alcohol 40 through acylation with acryloyi chloride (product 41) and a metathesis reaction. Non-racemic alcohol 40 can be produced directly through an asymmetric allylation of aldehyde 20 or asymmetric reduction of the carbonyl group in the compound 42.

Scheme 12

42

According to the method disclosed in the present invention, nitrone of formula 4,

4

wherein R ¹ and R ² are as defined above;

reacts with lactone 3, wherein R ³ is as defined above;

in the presence of metal salt, optionally additives, optionally in a solvent, to afford the compound of formula 5 with high diastereoselectivity.

Preferably, in the reaction of nitrone of formula 4 with the lactone of formula 3, from 1 to 10 equivalents of nitrone 4 with respect to the lactone 3 are used with 1.5 equivalent being preferred The metal salt is selected from the group encompassing: lanthanides salts, actinides salts, scandium salts, magnesium salts, transition metals salts (e.g. copper, iron, zinc, indium, iridium, yttrium). It is particularly preferred, that scandium salt selected from the group comprising: Sc(OTf)3, Sc(OAc) ₃ , and scandium halides is used. Typically, from 0.05 to 3 equivalents of metal salt with respect to the lactone 3 is applied; with 0.1 equivalent of metal salt being preferred. The solvent for the reaction is selected from the group consisting of aromatic hydrocarbons, haloalkanes, aliphatic nitriles, and aliphatic ethers. In particular, the solvent selected from the group comprising chloroform, methylene chloride, toluene, xylene, acetonitrile, tetrahydrofuran is used. Preferably, the reaction of nitrone of formula 4 with the lactone of formula 3 is performed in the presence of an additive selected from the group encompassing: molecular sieves, acidic clays (e.g. montmorillonite), anhydrous transition metals salts (e.g. anhydrous copper (II) sulfate), anhydrous salts of the main groups metals. In particular, molecular sieves 4A are used as The reaction is performed at the temperature range from -78 °C to 100 °C with the range from -40 °C to 40 °C being preferred. The resulting product of formula 5 is obtained with high diastereoselectivity.

Reaction of nitrone of formula 4 with the lactone of formula 3 can be also thermally induced without using Lewis acid. Thermally induced process leads to the diastereoisomeric isoxazolidines mixtures (including the compound of formula 5) in a ratio of 1 :1 . The reaction is performed at the temperature range from 40 °C to 180 °C with the range of 80-1 10 °C being preferred.

According to the method disclosed in the present invention, at the step (b) of route "A", compound 5 is submitted to the N-0 bond cleavage to result aminoalcohol 6.

The N-0 bond cleavage in the compound 5 is performed in the presence of reagent selected from the group comprising: zinc with protic acid, molybdenum compounds, sodium borohydride with transition metal salt (e.g. copper, nickel, and cobalt), palladium on activated carbon, Raney nickel. It is particularly preferred that cleavage of N-0 bond in 5 is performed by treatment with TMSCI/KI mixture. The reaction is performed in a solvent selected from the group encompassing aliphatic ethers, aliphatic nitriles, aliphatic alcohols, carboxylic acids esters with the acetonitrile being preferred. The cleavage is performed at the temperature range from - 50 °C to 60 °C with the range from 10 °C to 30 °C.

According to the method disclosed in the present invention, at the step (c) of route "A", free hydroxyl group in the compound of formula 6 is removed to afford aminolactone 7.

In the process of invention compound 6 is submitted to water elimination step leading to unsaturated lactone of formula 9, which is subsequently reduced to afford the lactone 7 according to the Scheme 13. Scheme 13

For such purpose, free hydroxyl group in the compound 6 is converted into a leaving group, and then treated with a base. The alcohol 6 is treated with a reagent selected from the group consisting of alkyl sulfonyl chlorides, aryl sulfonyl chlorides, carboxylic acids anhydrides (including trihaloacetic anhydride), carboxylic acid chlorides (acyl chlorides), trial kylsily I chlorides, alkylarylsilyl chlorides, triarylsilyl chlorides in the presence of an organic base selected from the group comprising tertiary alkyl amines (linear and cyclic), alkylaryl and aryl and heteroaromatic amines (e.g. imidazole, pyridine and its derivatives), amidines (DBU and its derivatives), or inorganic base selected from the group encompassing alkaline metal hydroxides, alkaline metal hydrogen carbonates, alkaline metal carbonates. The elimination is performed in a solvent selected from the group comprising chlorinated hydrocarbons (e.g. CH ₂ CI ₂ , CHCI ₃ ), aliphatic hydrocarbons, aromatic hydrocarbons, aliphatic ethers, with methylene chloride being preferred, at the temperature range from -50 °C to 100 °C, with the range from 0 °C to 25 °C being preferred.

In another process of the invention, water elimination step may be performed by treatment of the compound 6 with organic acid, selected from the group comprising aliphatic carboxylic acids, aliphatic sulfonic acids, aryl sulfonic acids (including acids immobilized on a polymeric resin - acidic ion exchangers), or with mineral acid selected from the group comprising hydrochloric acid, sulfuric acid, phosphoric acid. The elimination under acidic conditions is performed in a solvent selected from the group comprising aliphatic ethers, aliphatic hydrocarbons, aliphatic nitriles, and the most preferably, from the group consisting of diethyl ether, methyl-terf-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran. The elimination under acidic conditions is performed at the temperature from 0 °C to 100 °C, with the range of from 20 °C to 80 °C being preferred.

In another process of the invention, water elimination step may be performed by treatment of the compound 6 with azodicarboxylate in the presence of phosphine, optionally in a solvent. Preferably azodicarboxylate belongs to the group consisting of diethyl azodicarboxylate, di-/ ^' so-propyl azodicarboxylate, dibenzyl azodicarboxylate, di-te/ -butyl azodicarboxylate. Preferably, di-/so-propyl azodicarboxylate is used. Preferably, from 1 to 5 equivalents of azo compound is used with respect to the starting alcohol, and with 1-1.5 equivalent being preferred. Reaction is performed in the presence of phosphine selected from the group comprising linear or cyclic trialkylphosphines, dialkylarylphosphines, alkyldiarylphosphines, and triarylphosphines. Preferably, triphenylphosphine is used. Typically, from 1 to 5 equivalents of phosphine is used with respect to the starting alcohol 6, with 1 -1 .5 equivalent being preferred. The solvents which can be employed at this step include aliphatic ethers and haloalkanes; tetrahydrofuran is the most preferred. The reaction is performed at temperature range from -78 °C to 100 °C, with the range from 0 °C to 20 °C being preferred.

In alternative process of the invention, water elimination step may be performed by treatment of the compound 6 with a dehydrating agent, optionally in a solvent. As a dehydrating agent Burgess reagent (Et ₃ N-S0 ₂ -NH-COOMe) or Martin reagent (Ph ₂ S[0(CF ₃ ) ₂ Ph] ₂ ) can be used with Burgess reagent being preferred. A dehydrating reagent is used in the amount of 1 to 5 equivalents with respect to the starting alcohol 6, with 1 -1.5 equivalent being preferred. The reaction may be performed a solvent such as aromatic hydrocarbon or haloalkane. Preferably, the reaction is performed in toluene. The reactions are performed at the temperature range from 20 °C to 150 °C, with the range of from 40 °C to 100 °C being preferred.

According to the method disclosed in the present invention the double bond in the compound of formula 9 is reduced by treatment with a reducing agent, providing the lactone 7 with a high diastereoselectivity. A reducing agent is selected from the group involving alkaline aluminiumhydrides (and theirs derivatives), alkaline borohydrides (and theirs derivatives), borane (and its derivatives), alane (aluminium hydride and its derivatives). It is most preferred when a reducing agent is selected from the group encompassing lithium tri-sec-butyl borohydride (L-Selectride ^® ), potassium tri-sec-butyl borohydride (K-Selectide ^® ), sodium tri-sec- butyl borohydride (Na-Selectride ^® ). Typically, a reducing agent is used in amount from 1 to 5 equivalents with the 1 .5 equivalent being preferred. Typical suitable solvents are aliphatic ethers, haloalkanes, aliphatic and aromatic hydrocarbons. The most preferred solvents diethyl ether and methylene chloride. The reaction is performed at the temperature range from -78 °C to 20 °C, with the temperature -78 °C being preferred.

In alternative process of the invention, the double bond in the compound of formula 9 may be reduced by hydrogenation in the presence of catalyst and optionally in a solvent.

The reduction may be performed in the presence of either heterogeneous or homogenous catalyst. The heterogeneous catalyst is selected from the group involving platinum, Pt0 ₂ , palladium, Pd(OH) ₂ , ruthenium, rhodium including any form of the listed catalysts supported on any material (e.g. charcoal, asbestos, aluminum oxide, silica gel etc.). Typically, the catalyst is used in the amount of 0.001 to 5 equivalents with respect to compound 9, with the 0.001 to 0.1 equivalent being preferred. The homogenous catalyst is selected from the group involving salts and complexes of palladium, ruthenium, rhodium, iridium and platinum. Typically, catalyst is used in the amount of 0.001 to 5 equivalents with respect to compound 9, with the 0.001 to 0.1 equivalent being preferred. Typically suitable solvents for hydrogenation of lactone 9 are alcohols (e.g. MeOH, EtOH), aliphatic ethers (e.g. t-BuOMe), esters (e.g. AcOEt), aliphatic hydrocarbons (e.g. cyclohexane, hexane), aromatic hydrocarbons (e.g. toluene) and water. As a hydrogenating agent gasous hydrogen is used. The hydrogen atmosphere is present at 1 to 100 bar, with 1 -5 bar being preferred. The hydrogenation is performed at the temperature at the range from 0 °C to 100 °C, with the range from 20 °C to 50 °C being prefered. Alterativelly, other hydrogen-donors, selected from the group involving ammonium formate, secondary aliphatic alcohols (e.g. i-PrOH), diminine (HN=NH), linear or branched alkenes (e.g. cyclohexene, cyclohexadiene), Hantsch ester and its derivatives, may be applied.

In alternative process of the invention, compound of formula 6 is deoxygenated to afford aminolactone 7. For this purpose, the compound 6 is converted into thio-oxoester of formula 10, which is subsequently submitted to the Barton-McCombie deoxygenation reaction, leading to the lactone 7 according to the Scheme 14.

Scheme 14

According to the present invention, thio-oxoester 10 is synthesized from alcohol 6 by treatment with the compound 11 ,

s

11

wherein: X is SR, imidazolyl, OAr, OR; wherein Ar is any aromatic or heteroaromatic ring; R is any linear or branched Ci_ _s -alkyl substituent; and Y is halogen, imidazolyl;

in the presence of a base, optionally in a solvent. Preferably, Λ/,/V -thiocarbonyldiimidazole is used. The method of the synthesis of the tio-oxoesters method is well known process according to the organic synthesis art.

Alternatively, xanthogenate 10 (wherein X = SR) is obtained in the reaction of the alcohol 6 with the carbon disulfide, in the presence of a base, and then treated with alkyl halide, optionally in a solvent.

According to the present invention, thio-oxoester 10 is converted into the compound 7 in the reaction with an organotin compound of formula R ₃ SnH, wherein R: Ci_ ₆ alkyl, aryl; in the presence of a radical reaction initiator, optionally in a solvent. Typical suitable organotin compounds are trialkyltin hydrides with /7-Bu ₃ SnH being preferred. Reaction is conducted in the presence of a radical reaction initiator. Typically suitable initiators are azobisalkyl carbonitrile compounds, with the 2,2'-azobisisobutyl nitrile or 1 , 1 -azobis(cyclohexanecarbonitrile) being preferred. Optionally, as a free-radical reaction initiator acyl peroxides may be used; in particular, benzoyl peroxide may be applied. The procedure of a tio-oxoester group removal is well known procedure consistent with the organic synthesis art.

Optionally, in order to obtain lactone 7, thio-oxoester 10 is submitted to the reaction with a compound of formula R ₂ SiH ₂ or R ₃ SiH (wherein R = C^alkyl, aryl, halogen), in the presence of a radical reaction initiator, optionally in a solvent. In this case, the combination of Et ₃ B/0 ₂ is used as a free-radical reaction initiator. According to another method, the thio-oxoester 10 is converted into lactone 7 in the presence of a radical reaction initiator (e.g. lauroyl peroxide) in 2- propanol. The reaction procedure is generally known and consistent with the organic synthesis art.

In the alternative process of the invention, the compound of formula 6 is transformed into aminolactone 7 through the conversion of 6 sulfonyl ester of formula 43,

wherein G is linear or branched C^-alky!, trihaloalkyl (e.g. trifluoromethyl), aryl;

and subsequent reduction according to the Scheme 15. The methods of the synthesis of sulfonyl ester of formula 43 are well known according to the organic synthesis art.

Scheme 15

43

According to the present invention, the sulfonate 43 is submitted to reduction to lactone 7 by treatment with a reducing agent, optionally in a solvent. The reducing agents which may be employed include alkaline aluminiumhydrides (and their derivatives), alkaline borohydrides (and their derivatives), borane (and its derivatives), alane (aluminium hydride and its derivatives). Among them sodium borohydride is as the reducing agent of choice. The suitable solvents for reduction reaction are ethers, aliphatic hydrocarbons, and aromatic hydrocarbons. Preferably, as the solvent, a compound selected from the group comprising: diethyl ether, tetrahydrofuran, fe/if-butyl methyl ether is used.

According to the method disclosed in the present invention, at the step (d) of route "A", compound of formula 7 is submitted to the rearrangement step in the presence of a base, optionally a solvent, to afford azetidinone 8.

The base required for rearrangement step is selected from the group involving alkyl or aryl organomagnesium compounds (e.g. i-BuMgCI), alkyl or aryl organolithium compounds (e.g. f-BuLi), dialkyl amides (e.g. LDA, LiTMP), bis(trialkylsilyl)amides (e.g. KHMDS), sodium amide, alkaline alcoholates (e.g. i-BuOK). The i-BuMgCI is the most preferred base for conversion of the compound 7 into the azetidinone 8. Typically, from 1 to 5 equivalents of the base with the respect to the amine 7 is used, with the 2 equivalents being preferred. The rearrangement reaction is performed at the temperature range from -50 °C to 40 °C, with the range from 0 °C to 20°C being preferred. The suitable solvents for the rearrangement step are aliphatic ether, diethyl ether as the solvent of choice.

According to the method disclosed in the present invention, at the step (e) of route "A", the stereogenic center present in the side chain compound of formula 8 is epimerized in the presence of azo compound, phosphine, nucleophilic reagent, optionally in a solvent, leading to the azetidinone 1.

The azo compound belongs to the group encompassing diethyl azodicarboxylate, di- so- propyl azodicarboxylate, dibenzyl azodicarboxylate, di-ferf-butyl azodicarboxylate, 1 , 1 '- azobis(/V,A/-dimethylformamide), 1 , 1 '-(azodicarbonyl)dipiperidine. Preferably, di-/ ^' so-propyl azodicarboxylate is used. Typically, from 1 to 5 equivalents of azo compound with respect to the starting alcohol are used; with 1 -1 .5 equivalent being preferred. The required phosphine is selected from the group involving linear or cyclic trialkylphosphine, dialkylarylphosphine, alkyldiarylphosphine and triarylphosphine. Preferably, triphenylphosphine is used. Typically, from 1 to 5 equivalents of phosphine are used with respect to the starting alcohol 8, with 1 -1 .5 equivalent being preferred. Optionally, instead of the azo compound and phosphine, cyanomethylenetrialkyl phosphates are used in the reaction. The suitable solvents for the reactions are linear or cyclic aliphatic ethers, with tetrahydrofuran being preferred. The reaction is performed at the temperature range from -40 °C to 40 °C, and the most preferably, in the range of from -10 °C to 20 °C. The nucleophilic reagent required in the epimerization reaction of the azetidinone 8 is selected from the group which consists of aliphatic carboxylic acid (or suitable salt thereof), aryl carboxylic acid (or suitable salt thereof). Typically, from 1 to 5 equivalents of nucleophilic reagent are used with respect to the starting alcohol 8, with 1 -1 .5 equivalent being preferred. The 2-azetidinone 1 derivative, which is formed initially during the epimerization step, is directly hydrolyzed (without isolation) according to the organic synthesis art, leading to the azetidinone formula 1.

Scheme 16

In alternative process of the invention, the inversion of configuration in the side chain of the compound 8 can be also performed using the reaction sequence presented in the Scheme 16. For this purpose, the compound of formula 8 is converted into the sulfonyl ester of formula

12, wherein G is linear or branched C^-alkyl, trihaloalkyl (e.g. trifluoromethyl), aryl; which is subsequently submitted to the reaction with a nucleophilic reagent to form the ester of formula

13, wherein R is hydrogen, alkyl or aryl substituent. The synthesis of sulfonyl ester of formula 12 is well known and can be performed easily according to the organic synthesis art. The resulting compound 12 with nucleophilic reagent provides ester of formula 13, which after hydrolysis provides 2-azetidinone of formula 1 . The hydrolysis of ester of formula 13 is performed using known methods according to the organic synthesis art.

Optionally, when R ¹ , R ² and R ³ in a compound of the formula 1 are substituents of -OR ⁴ type, wherein R ⁴ is Ci _-6 -alkyl, aryl, heteroaryl, C ₂ -6-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ _ ₇ - cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), the additional step is deprotection reaction leading to the free -OH groups formation. Deprotection of functional groups is performed according to the organic synthesis art methods described in the literature (Theodora W. Greene and Pether G. M. Wuts, Protective Groups in Organic Synthesis, second edition, 1991 , John Wiley & Sons, Inc.).

According to the method disclosed in the present invention, azetidinones of formula 1 are obtained, by changing the sequence of the reactions presented in the Scheme 7.

According to the invention, the method for producing the compounds of formula 1 , hereinafter referred as the route„B" consists of the following steps:

(a) Lewis acid catalyzed or thermally induced 1 ,3-dipolar cycloaddition reaction of nitrone of formula 4 to the lactone 3 resulting in the bicyclic isoxazolidine 5 formation;

(b) cleavage of N-O bond in isoxazolidine of formula 5 leading to the aminoalcohol of formula 6 formation;

(c) removal of the OH group in compound of formula 6 affording the lactone 7 formation;

(d) inversion of the configuration in the side chain of the compound of formula 7 resulting in formation of alcohol 14;

(e) rearrangement leading to the formation of 2-azetidinone of 1 ;

(f) optionally, when R ¹ , R ² and R ³ are substituents of -OR ⁴ type (wherein R ⁴ is C^- alkyl, aryl, heteroaryl, C ₂ .6-alkenyl, C ₂ .6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ . ₇ -cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl) there is used additional step of deprotection resulting in free -OH group formation. Schemat 17

According to the method disclosed in the present invention, lactone of formula 7 is hydrolyzed to the hydroxyacid 15, which is subsequently submitted to the cyclization with the inversion of the configuration to afford the lactone 14.

According to the method disclosed in present invention, the lactone of formula 7 is hydrolized in the presence of a base, optionally a solvent. The suitable base for the hydrolysis is selected from the group containing alkaline hydroxides, alkaline hydrogen carbonates, and alkaline carbonates. The most preferably, lithium hydroxide, sodium hydroxide, potassium hydroxide are used as a base. The hydrolysis is performed in a solvent selected from the group comprising: water, Ci _-6 aliphatic alcohols, aliphatic ethers and the mixtures of these solvents. The most preferably, the hydrolysis is performed in tetrahydrofuran. The hydrolysis is performed at the temperature range from -20 °C to 60 °C, and the most preferably, at temperature range 20-25 °C. In next step, the resulting hydroxyacid 15, present in the reaction mixture as a salt, is converted to free acid form 15. A conversion of carboxylic acid salt to free acid is performed using known methods according to the chemical synthesis art. Free acid 15 is used directly in next step (lactonization).

According to method disclosed in present invention, a lactonization (with inversion of the configuration in the lactone moiety) of the compound 15 is performed in the presence of azo compound and phosphine, optionally in a solvent. The azo compound belongs to the group encompassing diethyl azodicarboxylate, di-/ ^' so-propyl azodicarboxylate, dibenzyl azodicarboxylate, di-ie/if-butyl azodicarboxylate, 1 ,1 '-azobis(/V,/V-dimethylformamide), 1 , 1'- (azodicarbonyl)dipiperidine. Preferably, di- so-propyl azodicarboxylate is used. Typically, from 1 to 5 equivalents of azo compound with respect to the starting alcohol are used; with 1-1.5 equivalent being preferred. The required phosphine is selected from the group involving linear or cyclic trialkylphosphine, dialkylarylphosphine, alkyldiarylphosphine and triarylphosphine. Preferably, triphenylphosphine is used. Typically, from 1 to 5 equivalents of phosphine are used with respect to the starting compound 7, with 1 -1.5 equivalent being preferred. Optionally, instead of the azo compound and phosphine, cyanomethylenetrialkyl phosphates are used in the reaction. The suitable solvents for the reactions are linear or cyclic aliphatic ether, wth tetrahydrofuran being preferred. The reaction is performed at the temperature range from -40 °C to 40 °C, and the most preferably, in the range of from -10 °C to 20 °C.

According to the method disclosed in the present invention, at the step (e) of the route "B", the compound of formula 14 is submitted to the rearrangement step in the presence of a base, optionally a solvent, to afford azetidinone 1.

The base required for the rearrangement step is selected from the group involving alkyl or aryl organomagnesium compounds (e.g. f-BuMgCI), alkyl or aryl organolithium compounds (e.g. f-BuLi), dialkyl amides (e.g. LDA, LiTMP), bis(trialkylsilyl)amides (e.g. KHMDS), sodium amide, alkaline alcoholates (e.g. f-BuOK). The i-BuMgCI is the most preferred base for conversion of compound 14 into azetidinone 1. Typically, from 1 to 5 equivalents of the base with the respect to the amine 14 is used, with 2 equivalents being preferred. The rearrangement reaction is performed at the temperature range from -50 °C to 40 °C, with the range from 0 °C to 20°C being preferred. The suitable solvents for rearrangement step are diethyl ether as the solvent of choice.

Optionally, when R ¹ , R ² and R ³ in a compound of formula 1 are substituents of -OR ⁴ type, wherein R ⁴ is C-|. ₆ -alkyl, aryl, heteroaryl, C ₂ -6-alkenyl, C ₂ -6-alkynyl, C ₃ _ ₇ -cycloalkyl, C ₃ _ ₇ - cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), the additional step is deprotection reaction leading to the free -OH groups formation. The deprotection is performed based on methods known in the literature. The deprotection method depends on the protective group type (Theodora W. Greene and Pether G. M. Wuts, Protective Groups in Organic Synthesis, second edition, 1991 , John Wiley & Sons, Inc.).

The method for producing compounds of formula 1 according to the invention, hereinafter referred to as the route„C" is presented in the Scheme 18.

According to the invention, the method for producing the compounds of formula 1 , hereinafter referred as the route„C" consists of the following steps:

(a) Lewis acid catalyzed or thermally induced 1 ,3-dipolar cycloaddition reaction of nitrone of formula 4 to the lactone 3 resulting in the bicyclic isoxazolidine 5 formation;

(b) an inversion of the absolute configuration in the lactone moiety of compound 5 leading to lactone 16;

(c) cleavage of the N-0 bond in isoxazolidine 16 leading to the aminoalcohol of formula 17;

(d) removal of the OH group in compound 17 affording the lactone 14 formation;

(e) rearrangement leading to the formation of 2-azetidinone of 1 ;

(f) optionally, when R ¹ , R ² and R ³ are substituents of -OR ⁴ type (wherein R ⁴ is C^- alkyl, aryl, heteroaryl, C ₂ -6-alkenyl, C ₂ -6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ . ₇ -cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl) there is used additional step of deprotection resulting in free -OH group formation.

In contrast to the previous routes, in this case, required epimerization step is performed at the early steps of the synthesis. For this purpose the lactone 5 is hydrolyzed to the hydroxyacid 18, which is subsequently lactonized, with the inversion of the configuration to afford the lactone 16.

According to the method disclosed in the present invention, the lactone of formula 5 is hydrolyzed in the presence of a base, optionally in a solvent. The suitable base for the hydrolysis is selected from the group containing alkaline hydroxides, alkaline hydrogen carbonates, and alkaline carbonates. The most preferably, lithium hydroxide, sodium hydroxide, potassium hydroxide are used as a base. The hydrolysis is performed in a solvent selected from the group comprising: water, aliphatic alcohols, aliphatic ethers and the mixtures of these solvents. The most preferably, the hydrolysis is performed in tetrahydrofuran. The hydrolysis is performed at the temperature range from -20 °C to 60 °C, and the most preferably, at temperature range 20-25 °C. In next step, the resulting hydroxyacid 18 present in the reaction mixture as a salt is converted to free acid form 18. A conversion of carboxylic acid salt to free acid is performed using known methods according to the chemical synthesis art. Free acid 18 is used directly in next step (lactonization).

According to the method disclosed in the present invention, a lactonization (with inversion of the configuration in the lactone moiety) of the compound 18 is performed in the presence of azo compound and phosphine, optionally in a solvent. The azo compound belongs to the group encompassing diethyl azodicarboxylate, di- so-propyl azodicarboxylate, dibenzyl azodicarboxylate, di-ie -butyl azodicarboxylate, 1 , 1 '-azobis(/V,A/-dimethylformamide), 1 , 1 '- (azodicarbonyl)dipiperidine. Preferably, di- so-propyl azodicarboxylate is used. Typically, from 1 to 5 equivalents of the azo compound with respect to the starting alcohol are used; with 1-1 .5 equivalent being preferred. The required phosphine is selected from the group involving linear or cyclic trialkylphosphine, dialkylarylphosphine, alkyldiarylphosphine and triarylphosphine. Preferably, triphenylphosphine is used. Typically, from 1 to 5 equivalents of phosphine are used with respect to the starting compound 5, with 1 -1 .5 equivalent being preferred. Optionally, instead of the azo compound and phosphine, cyanomethylenetrialkyl phosphates are used in the reaction. The suitable solvents for the reactions are linear or cyclic aliphatic ether, with tetrahydrofuran being preferred. The reaction is performed at the temperature range from -40 °C to 40 °C, and the most preferably, in the range of from -10 °C to 20 °C.

According to the method disclosed in the present invention, at the step (c) of route "C", compound 5 is submitted to the N-0 bond cleavage to result aminoalcohol 6.

The N-0 bond cleavage in the compound 5 is performed in the presence of a reagent selected from the group comprising: zinc with protic acid, molybdenum compounds, sodium borohydride with transition metal salt (e.g. copper, nickel, and cobalt), palladium on activated carbon, Raney nickel. It is particularly preferred that cleavage of N-0 bond in 5 is performed by treatment with TMSCI/KI mixture. The reaction is performed in a solvent selected from the group encompassing aliphatic ethers, aliphatic nitriles, aliphatic alcohols, carboxylic acids esters with the acetonitrile being preferred. The cleavage is performed at the temperature range from - 50 °C to 60 °C with the range from 10 °C to 30 °C.

According to the method disclosed in the present invention, at the step (d) of route "C", free hydroksyl group in the compound of formula 17 is removed to afford aminolactone 14.

According to the present invention, the compound of formula 17 is deoxygenated to afford the aminolactone 14. For this purpose, the compound 17 is converted into thio-oxoester of formula 19, which is subsequently submitted to the Barton-McCombie deoxygenation reaction, leading to the lactone 14 according to the Scheme 19.

According to the present invention, the thio-oxoester 19 is synthesized from alcohol 17 by treatment with the compound 11 ,

s

11

wherein: X is SR, imidazolyl, OAr, OR; wherein Ar is any aromatic or heteroaromatic ring; R is any linear or branched C^-alkyl substituent; and Y is halogen, imidazolyl;

in the presence of a base, optionally in a solvent. Preferably, Λ/,/V -thiocarbonyldiimidazole is used. The method of the synthesis of the tio-oxoesters method is well known process according to the organic synthesis art.

Alternatively, xanthogenate 19 (wherein X = SR) is obtained in the reaction of alcohol 17 with a carbon disulfide, in the presence of a base, and then treated with alkyl halide, optionally in a solvent.

According to the present invention, thio-oxoester 19 is converted into the compound 14 in the reaction with an organotin compound of formula R ₃ SnH, wherein R: C^alkyl, aryl; in the presence of a radical reaction initiator, optionally in a solvent. Typical suitable organotin compounds are trialkyltin hydrides with /7-Bu ₃ SnH being preferred. Reaction is conducted in the presence of a radical reaction initiator. Typically suitable initiators are, azobisalkyl carbonitrile compounds, with the 2,2'-azobisisobutyl nitrile or 1 , 1 -azobis(cyclohexanecarbonitrile) being preferred. Optionally, as a free-radical reaction initiator acyl peroxides may be used; in particular, benzoyl peroxide may be applied. The procedure of a tio-oxoester group removal is well known and consistent with the organic synthesis art.

Optionally, in order to obtain the lactone 14, the thio-oxoester 19 is submitted to the reaction with a compound of formula R ₂ SiH ₂ or R ₃ SiH (wherein R = C _{1 -6} alkyl, aryl, halogen), in the presence of a radical reaction initiator, optionally in a solvent. In this case, the combination of Et ₃ B/0 ₂ is used as a free-radical reaction initiator. According to another method, the thio- oxoester 19 is converted into the lactone 14 in the presence of a radical reaction initiator (e.g. lauroyl peroxide) in 2-propanol. The reaction procedure is generally known and consistent with the organic synthesis art.

In alternative process of the invention, compound of formula 17 is transformed into the aminolactone 14 through the conversion of 17 into sulfonyl ester of formula 44,

wherein G is linear or branched C^-alky!, trihaloalkyl (e.g. trifluoromethyl), aryl;

and subsequent reduction according to the Scheme 20. The methods of the synthesis of sulfonyl ester of formula 44 are well known and are performed according to the organic synthesis art.

Scheme 20

According to the present invention, the sulfonate 44 is reduced to the lactone 14 by treatment with a reducing agent, optionally in a solvent. The reducing agents which may be employed include alkaline aluminiumhydrides (and their derivatives), alkaline borohydrides (and their derivatives), borane (and its derivatives), alane (aluminum hydride and its derivatives). Among them sodium borohydride is as the reducing agent of choice. The suitable solvents for reduction reaction are ethers, aliphatic hydrocarbons, and aromatic hydrocarbons. Preferably, as the solvent, a compound selected from the group comprising: diethyl ether, tetrahydrofuran, ferf-butyl methyl ether is used.

In the process of the invention compound 17 is submitted to water elimination step leading to the unsaturated lactone of formula 45, which is subsequently reduced to afford lactone 14 according to the Scheme 21 .

Scheme 21

For such purpose, free hydroxyl group in the compound 17 is converted into leaving group, and then treated with a base. The alcohol 17 is treated with a reagent selected from the group consisting of alkyl sulfonyl chlorides, aryl sulfonyl chlorides, carboxylic acids anhydrides (including trihaloacetic anhydride), carboxylic acid chlorides (acyl chlorides), trialkylsilyl chlorides, alkylarylsilyl chlorides, triarylsilyl chlorides in the presence of an organic base selected from the group comprising tertiary alkyl amines (linear and cyclic), alkylaryl and aryl and heteroaromatic amines (e.g. imidazole, pyridine and its derivatives), amidines (DBU and its derivatives), or inorganic base selected from the group encompassing alkaline metal hydroxides, alkaline metal hydrogen carbonates, alkaline metal carbonates. The elimination is performed in a solvent selected from the group comprising chlorinated hydrocarbons (e.g. CH ₂ CI ₂ , CHCI ₃ ), aliphatic hydrocarbons, aromatic hydrocarbons, aliphatic ethers, with methylene chloride being preferred, at the temperature range from -50 °C to 100 °C, with the range from 0 °C to 25 °C being preferred. In another process of the invention, water elimination step may be performed by treatment of the compound 17 with organic acid, selected from the group comprising aliphatic carboxylic acids, aliphatic sulfonic acids, aryl sulfonic acids (including acids immobilized on a polymeric resin - acidic ion exchangers), or with mineral acid selected from the group comprising hydrochloric acid, sulfuric acid, phosphoric acid. The elimination under acidic conditions is performed in a solvent selected from the group comprising aliphatic ethers, aliphatic hydrocarbons, aliphatic nitriles, and the most preferably, from the group consisting of diethyl ether, methyl-ferf-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran. The elimination under acidic conditions is performed at the temperature from 0 °C to 100 °C, with the range of from 20 °C to 80 °C being preferred.

In another process of the invention, water elimination step may be performed by treatment of the compound 17 with azodicarboxylate in the presence of phosphine, optionally in a solvent. Preferably azodicarboxylate belongs to the group consisting of diethyl azodicarboxylate, di-/ ^' so-propyl azodicarboxylate, dibenzyl azodicarboxylate, di-fe/f-butyl azodicarboxylate. Preferably, di-/ ^' so-propyl azodicarboxylate is used. Preferably, from 1 to 5 equivalents of the azo compound is used with respect to the starting alcohol, and with 1 -1 .5 equivalent being preferred. Reaction is performed in the presence of phosphine selected from the group comprising linear or cyclic trialkylphosphines, dialkylarylphosphines, alkyldiarylphosphines, and triarylphosphines. Preferably, triphenylphosphine is used. Typically, from 1 to 5 equivalents of phosphine is used with respect to the starting alcohol 17, with 1 -1 .5 equivalent being preferred. The solvents which can be employed at this step include aliphatic ethers and haloalkanes; tetrahydrofuran is the most preferred. The reaction is performed at the temperature range from -78 °C to 100 °C, with the range from 0 °C to 20 °C being preferred.

In alternative process of the invention, water elimination step may be performed by treatment of the compound 17 with a dehydrating agent, optionally in a solvent. As a dehydrating agent Burgess reagent (Et ₃ N-S02-NH-COOMe) or Martin reagent (Ph ₂ S[0(CF ₃ ) ₂ Ph] ₂ ) can be used with Burgess reagent being preferred. A dehydrating reagent is used in an amount of 1 to 5 equivalents with respect to the starting alcohol 17, with 1 -1 .5 equivalent being preferred. The reaction may be performed a solvent such as aromatic hydrocarbon or haloalkane Preferably, the reaction is performed in toluene. The reactions are performed at the temperature range from 20 °C to 150 °C, with the range of from 40 °C to 100 °C being preffered.

According to the method disclosed in the present invention the double bond in compound of formula 45 is reduced by treatment with a reducing agent, to afford the lactone 14 with a high diastereoselectivity. A reducing agent is selected from the group involving alkaline aluminiumhydrides (and theirs derivatives), alkaline borohydrides (and theirs derivatives), borane (and its derivatives), alane (aluminum hydride and its derivatives). It is most preferred when a reducing agent is selected from the group encompassing lithium tri-sec-butyl borohydride (L-Selectride ^® ), potassium tri-sec-butyl borohydride (K-Selectide ^® ), sodium tri-sec- butyl borohydride (Na-Selectride ^® ). Typically, a reducing agent is used in amount from 1 to 5 equivalents, with the 1.5 equivalent being preferred. Typical suitable solvents are aliphatic ethers, haloalkanes, aliphatic and aromatic hydrocarbons. The most preferred solvents diethyl ether and methylene chloride. The reaction is performed at the temperature range from -78 °C to 20 °C, with the temperature -78 °C being preferred.

In alternative process of the invention, the double bond in compound of formula 45 may be reduced by hydrogenation in the presence of catalyst and optionally in a solvent.

The reduction may be performed in the presence of either heterogenous or homogenous catalyst. The heterogenous catalyst is selected from the group involving platinium, Pt0 ₂ , palladium, Pd(OH) ₂ , ruthenium, rhodium including any form of the listed catalysts supported on any material (e.g. charcoal, asbestos, aluminium oxide, silica gel etc.). Typically, the catalyst is used in the amount of 0.001 to 5 equivalents with respect to the compound 45, with the 0.001 to 0.1 equivalent being preferred. The homogenous catalyst is selected from the group involving salts and complexes of palladium, ruthenium, rhodium, iridium and platinum. Typically, catalyst is used in the amount of 0.001 to 5 equivalents with respect to the compound 45, with the 0.001 to 0.1 equivalent being preferred. Typically suitable solvents for hydrogenation of the lactone 45 are alcohols (e.g. MeOH, EtOH), aliphatic ethers (e.g. t-BuOMe), esters (e.g. AcOEt), aliphatic hydrocarbons (e.g. cyclohexane, hexane), aromatic hydrocarbons (e.g. toluene) and water. As a hydrogenating agent gaseous hydrogen is used. The hydrogen atmosphere is present at 1 to 100 bar, with 1-5 bar being preferred. The hydrogenation is performed at the temperature at the range from 0 °C to 100 °C, with the range from 20 °C to 50 °C being preferred. Alternatively, other hydrogen-donors, selected from the group involving ammonium formate, secondary aliphatic alcohols (e.g. i-PrOH), diminine (HN=NH), linear or branched alkenes (e.g. cyclohexene, cyclohexadiene), Hantsch ester and its derivatives, may be applied.

According to the method disclosed in the present invention, at the step (e) of route "C", the compound 14 is submitted to rearrangement in the presence of a base, optionally in a solvent, to afford the azetidinone 1.

The base required for the rearrangement step is selected from the group involving alkyl or aryl organomagnesium compounds (e.g. f-BuMgCI), alkyl or aryl organolithium compounds (e.g. f-BuLi), dialkyl amides (e.g. LDA, LiTMP), bis(trialkylsilyl)amides (e.g. KHMDS), sodium amide, alkaline alcoholates (e.g. /-BuOK). The f-BuMgCI is the most preferred base for conversion of compound 14 into azetidinone 1. Typically, from 1 to 5 equivalents of the base with the respect to the amine 14 is used, with 2 equivalents being preferred. The rearrangement reaction is performed at the temperature range from -50 °C to 40 °C, with the range from 0 °C to 20°C being preferred. The suitable solvents for rearrangement step are aliphatic ether, diethyl ether as the solvent of choice. Optionally, when R ¹ , R ² and R ³ in a compound of the formula 1 are substituents of -OR ⁴ type, wherein R ⁴ is C^-alkyl, aryl, heteroaryl, C ₂ .6-alkenyl, C ₂ .6-alkynyl, C ₃ . ₇ -cycloalkyl, C ₃ _ ₇ - cycloalkenyl, acyl, alkylsulfonyl, arylsulfonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), the additional step is deprotection reaction leading to the free -OH groups formation. The deprotection is performed based on methods known in the literature. The deprotection method depends on the protective group type (Theodora W. Greene and Pether G. M. Wuts, Protective Groups in Organic Synthesis, second edition, 1991 , John Wiley & Sons, Inc.).

Examples

Example 1.

The zinc dust (39 g, 600 mmol) was added portionwise to the suspension of p- fluoronitrobenzene (300 mmole, 31.8 mL) in the solution of NH ₄ CI (390 mmol, 20.9 g) in water (600 mL) at 60 °C. Then, the last portion of zinc was added, reaction mixture was stirred for additional 15 min. After filtration of zinc oxide, the residue was saturated with sodium chloride and cooled down to 0 °C. After 30 minutes yellow precipitate was filtered off, washed with cooled water and dried under diminished reduced pressure. The crude hydroxylamine was used directly in the next step.

To the solution of crude hydroxylamine (38.0 g, 300 mmol) in acetone (300 mL), p- benzyloxybenzaldehyde (63.7 g, 300 mmol) and CH ₃ S0 ₃ H (12 droplets) were added at room temperature. After 2 hours precipitate was filtered off, washed with acetone (3 x 100 mL) and dried under diminished pressure to afford 57,6 g (60%) of nitrone 27 as a white solid. Melting point 193-195 °C (acetone); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ: 8.49-8.47 (m, 2H), 8.42 (s, 1 H), 7.99-7.95 (m, 2H), 7.50-7.45 (m, 2H), 7.44-7.32 (m, 5H), 7.13 (d, J 5.0 Hz, 2H), 5.20 (s, 2H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ: 162.2 (d, J _CF 245.6 Hz), 159.9, 144.8 (d, J _CF 2.4 Hz), 136.6, 133.0, 130.9, 128.4, 127.9, 127.8, 124.1 , 123.6 (d, J _CF 9.3 Hz), 1 15.7 (d, J _CF 22.9 Hz), 1 14.7, 69.4; HR MS (ESI): m/z calcd for C ₂ oH _{1 s} N0 ₂ FNa [M+Na ⁺ ] 344.1057; found: 344.1055; Elem. Anal, calcd for C ₂₀ H ₁₆ FNO ₂ : C, 74.75; H, 5.02; F, 5.91 ; N, 4.36; found: C, 74.76; H , 5.08; F, 6.03; N, 4.40 Example 2.

yield 97%

e.e.91%

Molecular sieves 4A (6 g) were added to the solution of 272 mg [(f?,f?)-salen-Cr]BF ₄ in 4 ml dry MTBE and cooled down to -30°C.4-Fluorobenzaldehyde (2.48 g, 20 mmol) was added to the reaction mixture followed by slow addition of the dien (3.44 g, 20 mmol). After 24 hours, the solution of trifluoroacetic acid (1 ml) in 40 ml of methylene chloride was added. The mixture was warmed up to the room temperature and the sieves were filtered off. Then, water (1 mL) was added and the resulting mixture was stirred for 2 hours. Organic phase was washed with aqueous NaHC0 ₃ (20 ml), dried (MgS0 ₄ ) and the solvent was removed. The obtained residue was purified by chromatography on silica gel (hexane/ethyl acetate 4:1) to afford (2R)-2-(A- fluorophenyl)-2--pyran-4(3A7)-one as a pale-yellow oil (3.72 g 19.4 mmol, 97%). e.e.91%; [a] _D -83 (c 1.1, CH ₂ CI ₂ ); ¹ H NMR (500 MHz, CDCI ₃ ) δ: 7.47 (1 H, dd, J 6.0, 0.8 Hz), 7.42-7.37 (2H, m), 7.14-7.08 (2H, m), 5.53 (1H, dd, J 6.0, 1.3 Hz), 5.41 (1H, dd, J 14.4, 3.5 Hz), 2.89 (1H, dd, J 16.8, 14.4 Hz), 2.65 (1H, ddd, J 16.8, 3.5, 1.3 Hz); ¹³ C NMR (125 MHz, CDCI ₃ ) δ: 191.8, 163.9, 163.0, 161.9, 133.7, 133.7, 128.1, 127.9, 115.9, 115.7, 107.5, 80.4, 43.3; HRMS (El) m/z calcd forCuHgFOs [M ⁺ ] 192.0586; found 192.0583; IR (film) v.3073, 1677, 1606, 1594, 1514 cm ^"1 .

Example 3.

To the solution of 4.439 g (11,9 mmole) CeCI ₃ -7H ₂ 0 in 27 mL of methanol, 2.090 g (2f?)-2-(4- fluorophenyl)-2--pyran-4(3H)-one in 27 mL DCM was added. After cooling down to -20°C NaBH ₄ (456 mg, 11.9 mmole) was added. After 30 minutes, 5 mL of saturated solution of NH ₄ CI was added and the mixture was warmed up to the room temperature and extracted with CH ₂ CI ₂ (30 mL). The obtained crude (2f?)-2-(4-fluorophenyl)-3,4-dihydro-2/--pyran-4-ol after drying (MgS0 ₄ ) and removal of solvent, was used in the next step without further purification, e.e. 91%, [a] _D +60.2 (c 1.0, AcOEt); ¹ H NMR (500 MHz, CDCI ₃ ) δ: 7.38-7.32 (2 H, m), 7.09-7.03 (2H, m), 6.52-6.50 (2H, m), 4.97 (1H, dd, J 11.9, 2.1 Hz), 4.87 (1H, dt, J6.2, 2.1 Hz), 4.65-4.58 (1H, m), 2.39-2.33 (1H, m), 2.00-1.92 (1H, m); ¹³ C NMR (125 MHz, CDCI ₃ ) δ: 163.4, 145.2, 136.1, 136.1, 127.8, 127.7, 115.5, 115.3, 105.8, 76.2, 63.4, 40.0; HRMS (El) m/z calcd for CnHnFOz [M] 194.0742; found 194.0748; IR (film): 3369, 1642, 1607, 1514 cm ^"1 . Elem. Anal.: calcd for CnH FOz (%): C 68.03, H 5.71, F 9.78; found: C 68.15, H 5.52, F 9.87. Example 4.

To the solution of 1 .90 g (9.7 mmol) (2f?)-2-(4-fluorophenyl)-3,4-dihydro-2H-pyran-4-ol in 50 mL of methanol, 100 mg of an ion exchanger DOWEX 50W X4 was added. After 18 hours, the resin was filtered off and the solvent was removed. The obtained residue was purified by chromatography on silica gel (hexane/AcOEt 9:1) to afford (2f?)-2-(4-fluorophenyl)-6-metoxy- 3,6-dihydro-2H-pyran as a yellowish oil (1.068 g, 52 %). ee 91 %; [a] _D +40.2 (c 1 ,0, acetone); ¹ H NMR (500 MHz, CDCI ₃ ) δ: 7.40-7.36 (2 H, m), 7.09-7.03 (2H, m), 6.14-6.07 (1 H, m), 5.84 (1 H, ddt, J 10.1 , 2.8, 1.4 Hz), 5.03-4.98 (1 H, m). 4.89 (1 H, dd, J 10.7, 3.8 Hz), 2.35-2.19 (2H, m); ¹³ C NMR (125 MHz, CDCI ₃ ) δ: 163.1 , 161.2, 137.8, 137.7, 128.9, 128.8, 127.8, 125.5, 115.3, 1 15.1 , 96.4, 67.8, 55.3, 32.2; HRMS(EI) m/z calcd for C ₁₂ H ₁₃ F0 ₂ [M] 208.0899; found 208.0891 ; IR (film) v. 2894, 1609, 1513, 1399 cm ^"1 . Elem. Anal, calcd for C ₁₂ H ₁₃ F0 ₂ (%): C 69.22, H 6.29, F 9.12; found: C 69.15, H 6.38, F 9.08.

Example 5.

(after crystalization)

The cooled (0°C) solution of 1.0 g (4.8 mmole) (2R)-2-(4-fluorophenyl)-6-metoxy-3,6-dihydro- 2H-pyran in 50 mL of acetone, 10 mL of the solution of 1.75 M of Jones reagent was added slowly. After about 15 minutes 5 mL of / ^' -propanol was added. The mixture was adjusted to the room temperature, filtered through Celit ^® and the solvent was removed. The residue was disolved in AcOEt (40 mL) and washed with saturated NaHC0 ₃ (30 mL). Resulting organic solution was dried (MgS0 ₄ ) and the solvent was removed. The residue was purified by chromatography on silica gel (hexane/AcOEt 6:4). The obtained product was dissolved in MTBE (with heating) and heptane was added until fogging. Resulting precipitate was filtered off and washed with heptane to afford crystalline (6R)-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one (676 mg, 73%). ee 98.5%; [a] _D +220 (c 1.0, CHCI ₃ ); ¹ H NMR (500 MHz, CDCI ₃ ) δ: 7.42-7.36 (2 H, m), 7.1 1-7.05 (2H, m), 7.00-6.94 (1 H, m), 6.15 (1 H, ddd, J 9.7, 2.4, 1.2 Hz), 5.43 (1 H, dd, J 11.4, 4.9 Hz), 2.70-2.56 (2H, m); ¹³ C NMR (125 MHz, CDCI ₃ ) δ: 163.8, 163.7, 161.8, 144.7, 134.3, 134.2, 128.0, 127.9, 121.7, 1 15.7, 1 15.5, 78.6, 31.7; HRMS (El) m/z calcd for Cn H ₉ F0 ₂ [M] 192.0586; found: 192.0779. IR (film): 3071 , 1731 , 1605, 151 1 cm ^"1 . Example 6.

To the suspension of (2R)-2-(4-fluorophenyl)-3,4-dihydro-2/- -pyran-4-ol (195 mg, 1 mmole) in 10 mL of 50% H ₂ O ₂ , 15 mg (0.1 mmole) of M0O ₃ and about 3 mL of f-BuOH were added. After 5 hours, the reaction mixture was diluted with water (30 mL), and then extracted with dichloromethane (3 x 30 mL). Combined extracts were washed with water (5 x 20 mL) until the aqueous layer did not show the presence of H ₂ 0 ₂ (test with Kl). The layer was dried over anhydrous Na ₂ S0 ₄ . After the desiccant agent was removed, the solvent was evaporated to obtain hydroperoxide as a yellowish oil (about 200 mg).

Subsequently, the solution of hydroperoxide in dichloromethane (0.5 mL) was added dropwise to the cooled mixture of pyridine (0.4 mL) and acetic anhydride (0.4 mL). After 2 hours at room temperature, the reaction mixture was poured into water with ice and extracted with methylene chloride (3 x 20 mL). The combined organic phases were washed with NaHC0 ₃ solution and water to neutral reaction, and then dried over Na ₂ S0 ₄ . After the solvent was removed, the obtained crude product was purified by chromatography, and 132 mg (69%) (6 ?)-6-(4- fluorophenyl)-5,6-dihydro-2 -/-pyran-2-one as a solid was obtained.

Example 7.

The solution of LDA (10 mmol) in THF was cooled to -30 °C and it was saturated with acetylene. Next, 1 .38 g (10 mmol) of the epoxide was added dropwise. Next, additional 1 1 mL of 1 M solution of LDA was added slowly followed by passing of dry C0 ₂ through reaction mixture. Then reaction mixture was warmed up to 0 °C, NH ₄ CI aq. was added (3 mL) and the mixture was extracted with ethyl acetate. The organic layer was dried MgS0 ₄ and after the solvent was removed, 1.49 g (72%) of acid was obtained as a white precipitate. ¹ H NMR (600 MHz, CDCI ₃ ) δ: 7.40-7.35 (2H, m), 7.20-7.17 (2H, m), 4.83 (1 H, s), 4.51 (1 H, t, J 6.6 Hz), 2.23-2.15 (2H, m).

Example 8.

To the solution of 1.40 g of acid in 50 mL of methanol Lindlar catalyst was added, and the reaction mixture was saturated with gaseous hydrogen for 18 hours. After filtration through Celit ^® to the residue 100 mg of ion exchanger DOWEX 50W X4 was added. After 20 h min, the ion exchanger was filtered off, and solvent was removed. The residue was recrystallized from the mixture of ethyl acetate and hexane to afford 867 mg (67%) (6R)-6-(4-fluorophenyl)-5,6- dihydro-2A7-pyran-2-one as a white precipitate solid.

Example

Scandium triflate (180 mg, 0.37 mmol) and molecular sieves 4A (1.46 g) were stirred for 30 minutes at room temperature in 28 mL dry toluene, and then 0.70 g (3.66 mmol) (6f?)-6-(4- fluorophenyl)-5,6-dihydro-2A7-pyran-2-one and 1.86 g (5.48 mmol) /V-(4-fluorophenyl)-a-(4- benzyloxyphenyl)nitrone were added. The reaction mixture was maintained at 30 °C. After 72 hours the sieves were filtered off and the solvent was removed under diminished pressure. The residue was chromatographed on silica gel using hexane, and then the mixture of 30% ethyl acetate in hexane as a eluent to afford 1.70 g (3.31 mmol, yield 90%) of isoxazolidine. Melting point 64-66 °C; [a] _D -96 (c 1 , MeOH); ¹ H NMR (600 MHz, CDCI ₃ ) δ: 7.52-7.49 (2H, m), 7.41- 7.30 (5H, m), 7,14-6.97 (10H, m), 5.42 (1 H, d, J 9.1 Hz), 5.06 (2H, dd, J 1 1.9, 1.4 Hz), 5.04 (2H, s), 4.81 (1 H, ddd, J 9.1 , 3.8, 1.4 Hz), 3.95 (1 H, t, J 9.1 Hz), 2.30-2.27 (1 H, m) 2.10-2.05 (1 H, m); ¹³ C NMR (150 MHz, CDCI ₃ ) δ: 168.0, 163.5, 161.9, 159.8, 158.7, 158.2, 145.1 , 145.0, 136.7, 133.9, 133.8, 128.7, 128.6, 128.6, 128.0, 127.9, 127.5, 116.6, 116.5, 1 16.0, 1 15.9, 115.7, 115.5, 114.9, 75.7, 73.5, 71.5, 70.0, 53.2, 34.4; HRMS (ESI) m/z calculated for C ₃ i H ₂₅ F ₂ N0 ₄ Na [M+Na] ⁺ 536.1644; found 536.1666; Elem. Anal, calcd for C ₃₁ H ₂₅ F ₂ NO ₄ (%): C 72.50, H 4.91 , F 7.40, N 2.73; found (%): C 72.74, H 4.93, F 7.61 , N 2.51 ; IR (film) v. 3033, 1729, 1609, 1513, 1501 cm ^"1 .

Example 10.

To the mixture of the isoxazolidine 1.00 g (1.94 mmol) and potassium iodide 0.97 g (58.5 mmol) in 20 mL acetonitrile at room temperature, trimethylsilyl chloride 0.83 mL (58.5 mmol) was added. After 35 minutes, 10 mL of saturated aq. Na ₂ S0 ₄ was added and then the product was extracted with ethyl acetate. After drying of resulting organic extracts (MgS0 ₄ ), the solvent was removed under reduced pressure. The residue was chromatographed on silica gel (hexane/ethyl acetate 9:1 - 1:1) to provide 0.89 g (1.72 mmol, yield 88%) of aminolactone as a pale yellow solid. Melting point 63-65 °C; [a] _D +8,8 (c 1.0, MeOH); ¹ H NMR (600 MHz, CDCI ₃ ) δ: 7.40-7.27 (9H, m), 7,08-6.69 (8H, m), 5.81 (1H, dd, J 11.1, 3.6 Hz), 5.42-5,13 (1H, bs), 5,00 (2H, s), 4.72 (1H, d, J2.4 Hz), 4.63-4.62 (1H, m), 2.37 (1H, dt, J 14.3, 4.0 Hz,) 2.07-2.00 (1H, m); ¹³ C NMR (150 MHz, CDCI ₃ ) δ: 170.8, 163.4, 161.8, 158.2, 156.6, 141.7, 136.8, 135.1, 131.9, 128.6, 128.3, 128,0, 127.7, 127.6, 127.5, 117.7, 117.6, 115.9, 115.8, 115.7, 115.5, 114.8, 78.3, 70.1, 70.0, 60.5, 53.1, 39.1; HRMS (ESI) m/z calcd for C ₃₁ H27F ₂ N0 ₄ Na [M+Na] ⁺ 538.1800; found 538.1810; IR (film) v.3374, 1727, 1609, 1511 cm ^"1 .

Example 11.

To the solution of the aminolactone (420 mg, 0,82 mmol) in 20 mL of tetrahydrofuran, 235 mg (0.89 mmol) of triphenylphosphine was added. After cooling to 0 °C, 180 μL· (0.89 mmol) of di-/- propyl azodicarboxylate was added. After 3 hours, the solvent was evaporated, and to the obtained residue water and methylene chloride were added. The aqueous layer was extracted with methylene chloride (3 x 15 mL). After drying the organic layer with magnesium sulfate, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using the mixture hexane/ethyl acetate 8:2 to provide 287 mg (0.58 mmole, yield 70%) of the product as a white precipitate. Melting point 170-172 °C; [a] _D -60,3 (c 1.0, CHCI ₃ ); ¹ H NMR (600 MHz, CDCI ₃ ) δ: 7.43-7.31 (9H, m), 7,08-6.79 (8H, m), 6.51-6.47 (2H, m), 5.29 (1H, dd, J 12,1, 3.9 Hz ), 5,05 (2H, s), 2.73-2.66 (1H, m) 2.67-2.58 (1H, m); ¹³ C NMR (150 MHz, CDCI ₃ ) δ: 164,0, 163.7, 161.7, 158.7, 138.5, 136.8, 134.1, 134.0, 132.7, 128.8, 128.6, 128.1, 128.0, 127.5, 115.8, 115.7, 115.6, 115.5, 115.2, 78.2, 70.1, 57.9, 31.9; HRMS (ESI) m/z calcd for C ₃ iH ₂ 5F ₂ N0 ₃ Na [M+Na] ⁺ 520.1695; found 520.1710; IR (film) v.3395, 1714, 1609, 1509 cm ^"1 .

The solution of the lactone (480 mg, 0.96 mmole) in dry THF (100 mL) was cooled to -78 °C and then 0.96 mL (0.96 mmole) of L-Selectride ^® was slowly added. After 2 hours the reaction was quenched by addition of aq. NH ₄ CI (10 mL). Then, mixture was adjusted to room temperature, and alkalized (to pH about 8) with the aq. NaHC0 ₃ . After extraction with ethyl acetate (2 x 30 mL), the organic layer was dried over anhydr. MgS0 ₄ . After removal of solvent, the residue was chromatographed on silica gel (hexane/ethyl acetate 8:2) to afford 328 mg (0.66 mmol, yield 68%) of the product as a white solid. Melting point 51 -53 °C; [a] _D +30 (c 1 .0, MeOH); ¹ H NMR (600 MHz, C ₆ D ₆ ) δ: 7.25-7,18 (4H, m), 7, 19-6.68 (13H, m), 6.46-6.43 (2H, m), 4.88 (1 H, d, J 5.3 Hz) 4,63 (2H, s), 4.40-4.37 (1 H, m), 1.32-1 ,17 (4H, m) 1 ,09-1 ,03 (1 H, m); ¹³ C NMR (150 MHz, CDCI ₃ ) δ: 170.2, 163.3, 161.7, 158.6, 137.0, 135.7, 128.8, 128.3, 115.7, 1 15.5, 115.5, 1 15.1 , 1 14.9, 96.1 , 80.8, 69.7, 59.5, 46,1 , 30.6, 22,1 ; HRMS (ESI) m/z calcd for C ₃ i H ₂₅ F ₂ N0 ₃ Na [M+Na ⁺ ] 522.1851 ; found 522.1878; IR (film) v. 3349, 1610, 1512 cm ^"1 .

Example 13.

To cooled to 0 °C solution of the lactone (100 mg, 0.2 mmol) in 8 mL dry diethyl ether, 100 ί (0.4 mmol) of 2M solution of fe/if-butyl magnesium chloride in diethyl ether was added. After 15 min. 3 mL of aq. NH ₄ CI was added. The aqueous layer was extracted with ether (10 mL), and then the organic layer was dried (MgS0 ₄ ), and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel (hexane/ethyl acetate 7:3) to afford 81 mg (0,16 mmole, yield 80%) of the product as a white solid. [a] _D +10.8 (c 1 .1 , CHCI ₃ ); ¹ H NMR (600 MHz, CDCI ₃ ) δ: 7.42-7.20 (11 H, m), 7.02-6.90 (6H, m), 5.04 (2H, s), 4.72-4.68 (1 H, m) 4.55 (1 H, d J 2.2 Hz), 4.55 (1 H, dt J 7.1 , 2.2 Hz) 2.05-1.93 (3H, m) 1.89-1 .82 (2H, m); ¹³ C NMR (125 MHz, CDCI ₃ ) δ: 167.6, 163.0, 161.4, 159.8, 159.0, 158.1 , 140.0, 139.9, 136.6, 133.9, 129.6, 128.6, 128, 1 , 127.5, 127.4, 127.4, 127.2, 1 18.4, 118.3, 115.8, 1 15.7, 1 15.5, 115.4, 115.3, 73.3, 70, 1 , 61 , 1 , 60.3, 36.5, 25,0; HRMS (ESI) m/z calcd for C ₃₁ H ₂₇ F ₂ N0 ₃ Na [M+Na] ⁺ ; 522.1851 ; found 522.1870; IR (KBr) v. 3441 , 1743, 1609, 1510 cm ^"1 .

Example 14.

Benzylated derivative of the ezetymibe (758 mg, 1 ,52 mmol) was dissolved in the mixture of AcOEt/MeOH (1 :1 , 100 mL), and 10 mg 10% Pd/C was added. The mixture was saturated with hydrogen for 18 hours. After filtration through Celit ^® , solvent was removed and the residue was recrystallized from the mixture of AcOEt/hexane to provide ezetimibe 2 (450 mg, 72 %) as a white solid. Melting point 164-166 °C; [a] _D -28.1 (c 0.15, MeOH); ¹ H NMR (600 MHz, DMSO-d ₆ ) δ: 9.49 (1 H, s), 7.28-7.24 (2H, m), 7.19-7.16 (4H, m), 7.1 1 -7.07 (4H, m), 6.75-6.71 (2H, m), 5.25 (1 H, d, J 4.3 Hz), 4.77 (1 H, d, J 2.2 Hz), 4.49-4.59 (1 H, t, m), 3.07-3.04 (1 H, m) 1.84-1.66 (4H, m); ¹³ C NMR (150 MHz, CDCI ₃ ) δ: 167.8, 162.3, 160.7, 159.3, 157.9, 157.7, 142.5, 134.4, 128.7, 128.3, 128.0, 127.9, 1 18.7, 1 18.6, 1 16.3, 116.2, 115.2, 1 15.0, 71.5, 60.0, 59.9, 36.8, 24.9; HRMS (El) m/z calcd for C24H21 F2NO3 [M] 409.1489 found 409.1478; Elem. Anal, calcd for C24H21 F2NO3 (%): C 70.41 , H 5.17, F 9,28, N 3.42 found (%): C 70.46, H 5.23, F 9.24, N 3.34;

Example 15.

To the solution of the lactone (100 mg, 0.2 mmol) in 5 mL THF, lithium hydroxide (6 mg, 0.22 mmol) and 0.5 mL of water were added. After 18 hours, the solvent was evaporated and 3 mL of 5% solution of hydrochloric acid was added. Next, the mixture was neutralized with sodium hydrogen carbonate solution and extracted with methylene chloride (3 x 10 mL). After drying of the organic layer with anhydrous sodium sulfate and removal of the solvent, the residue (80 mg of a yellowish solid) was dissolved in 10 mL of THF. Next, 50 mg (0.19 mmol) triphenylphosphine was added. The reaction mixture was cooled to 0 °C, and then 40 μL· (0.19 mmole) of di- -propyl azodicarboxylate was added. After 3 hours, the solvent was removed, and to the obtained residue water was added and the mixture was extracted with methylene chloride (3 x 15 mL). Then, the organic layer was dried (MgS0 ₄ ), solvent was removed and the residue was chromatographed on silica gel (hexane/ethyl acetate 7:3) to afford 94 mg (0.18 mmole, yield 90%) of the product as a white solid; melting point 52-54 °C; [a] _D -8.6 (c 1.3, CHCI3); ¹ H NMR (600 MHz, CDCI ₃ ) δ: 7.41-7.28 (8H, m), 7.19-6.68 (6H, m), 6.55-6.52 (2H, m), 5.31 (1 H, dd, J 10.0, 3.6 Hz), 5.02 (2H, s), 4.66 (1 H, d, J 6.5 Hz), 3.10-3.06 (1 H, m), 2.10-2.03 (1 H, m), 1.99-1.90 (1 H, m), 1.89-1.78 (2H, m); ¹³ C NMR (150 MHz, CDCI ₃ ) δ: 172.8, 163.3, 161 .7, 158.3, 157.0, 156.3, 155.5, 143.2, 136.8, 134.7, 134.6, 132.6, 128.6, 128.5, 128,0, 127.6, 127.5, 127.5, 1 15.7, 115.6, 1 15.5, 1 15.4, 1 15.4, 1 14.9, 79.5, 70,1 , 58.8, 45,1 , 29.3, 20.8; HRMS (ESI) m/z calcd for C ₃₁ H ₂₅ F ₂ N0 ₃ Na [M+Na ⁺ ] 522.1851 found 522.1864; IR (film) v. 3349, 1610, 1512 cm ^"1 .

Example 16.

To the cooled to 0 °C solution of the lactone (68 mg, 0.13 mmol) in 8 mL dry diethyl ether, 100 μL· (0.3 mmol) 2M solution of /e/f-butyl magnesium chloride in diethyl ether was added. After 2 hours, 3 mL of aq. NH ₄ CI was added. The reaction mixture was extracted with diethyl ether (10 ml). The organic layer was dried over MgS0 ₄ and then the solvent was removed. The residue was chromatographed on silica gel (hexane/ethyl acetate 7:3) to afford 60 mg (0.12 mmol, yield 92%) of 2-azetidinone as a white solid; melting point 130-133 °C; [a] _D -42.2 (c 1.2, CHCI ₃ ); ¹ H NMR (600 MHz, CDCI ₃ ), δ: 7.42-7.20 (1 1 H, m), 7.02-6.90 (6H, m), 5,04 (2H, s), 4.72-4.68 (1 H, m) 4.55 (1 H, d J 2.2 Hz), 4.55 (1 H, dt J 7.1 , 2.2 Hz) 2,05-1.93 (3H, m) 1 .89-1.82 (2H, m); ¹³ C NMR (150 MHz, CDCI ₃ ), δ: 167.6, 163.0, 161 .4, 159.8, 159.0, 158.1 , 140.0, 139.9, 136.6, 133.9, 129.6, 128.6, 128.1 , 127.5, 127.4, 127.4, 127.2, 1 18.4, 118.3, 115.8, 1 15.7, 1 15.5, 115.4, 115.3, 73.3, 70.1 , 61.1 , 60.3, 36.5, 25.0; HRMS (ESI) m/z calcd for C ₃ i H ₂₇ F ₂ N0 ₃ Na [M+Na] ⁺ 522.1851 ; found 522.1862; IR (KBr) v. 3441 , 1743, 1609, 1510 cm ^"1 .

Example 17.

To the solution of isoxazolidine (150 mg, 0.29 mmol) in 5 mL THF, lithium hydroxide (7 mg, 0.30 mmol) and 0.5 mL of water were added. After 18 hours, the solvent was removed and 3 mL 5% aq. HCI was added, and then the mixture was neutralized with aq. NaHC0 ₃ . Subsequently, the mixture was extracted with methylene chloride (3 x 10 mL). The combined organic solutions were dried (Na ₂ S0 ₄ ). Removal of solvent provided 1 14 mg of pale yellow solid, which was dissolved in 10 mL of THF, 56 mg (0.21 mmol) of triphenylphosphine was added and the obtained mixture was cooled to 0 °C. Next, 45 ί (0.21 mmol) of di-/-propyl azodicarboxylate was added. After 3 hours, the solvent was removed, and to the obtained residue water was added and the mixture was three times extracted with CH ₂ CI ₂ . After drying (MgS0 ₄ ), solvent was removed, and the residue was chromatographed on silica gel (hexane/AcOEt 7:3) to provide 94 mg (0,18 mmole, 62 %) of isoxazolidine as a white solid; m.p. 152-154 °C; ¹ H NMR (600 MHz, CDCI ₃ ) δ: 7.52-7.49 (2H, m), 7.41-7.30 (5H, m), 7.14-6.97 (10H, m), 5.23 (1H, d, J 8.2 Hz), 5,09 (2H, dd, J 12.6, 2.1 Hz), 5.06 (2H, s), 4.81 (1H, m), 3.80 (1H, dt, J 9.6, 8.4 Hz), 2.37 (1H, ddd, J 13.9, 6.2, 2.1 Hz) 1.97-1.90 (1H, m) ¹³ C NMR (150 MHz, CDCI ₃ ), δ: 168.4, 163.6, 161.9, 159.9, 158.5, 158.3, 146.3, 146.3, 136.8, 133.9, 133.8, 129.5, 128.9, 128.6, 128.0, 127.9, 127.5, 116.9, 116.8, 115.9, 115.7, 115.6, 115.6, 114.7, 77.5, 73.2, 71.5, 70.0, 50.5, 35.7. HRMS (ESI) m/z calcd for [M+Na ⁺ ] 536.1644; found 536.1631; Elem. Anal, calcd for C31H25F2NO4 (%): C 71.93, H 5.28, F 7.37, N 2.72; found (%): C 72.01, H 5.00, F 7.36, N 2.63.

Example 1

Pt0 ₂ (6 mg) was added to the solution of the lactone (250 mg, 0.50 mmol) in toluene (5 ml_) and the resulting suspension was saturated with hydrogen for 24 h. After filtration and removal of solvent under diminished pressure, the residue was chromatographed on silica gel (hexane/ ethyl acetate 4:1) to provide 202 mg (80%) of the lactone as a white solid. M.p.52-54 °C; [a] _D -8.6 (c 1.3, CHCI ₃ ); ¹ H NMR (600 MHz, CDCI ₃ ) δ: 7.41-7.28 (8H, m), 7.19-6.68 (6H, m), 6.55-6.52 (2H, m), 5.31 (1H, dd, J 10.0, 3.6 Hz) 5.02 (2H, s), 4.66 (1H, d, J 6.5 Hz), 3.10-3.06 (1H, m), 2.10-2.03 (1H, m), 1.99-1.90 (1H, m), 1.89-1.78 (2H, m); ¹³ C NMR (125 MHz, CDCI ₃ ), δ: 172.8, 163.3, 161.7, 158.3, 157.0, 156.3, 155.5, 143.2, 136.8, 134.7, 134.6, 132.6, 128.6, 128.5, 128.0, 127.6, 127.5, 127.5, 115.7, 115.6, 115.5, 115.4(x3), 114.9, 79.5, 70.1, 58.8, 45.1, 29.3, 20.8. HRMS (ESI) m/z calcd for [M+Na ⁺ ] 522.1851; found 522.1864; IR (film) v.3349, 1610, 1512 cm ^"1 .