WO2010097350A1

WO2010097350A1 - A process for the preparation of an aldehyde beta-lactam compound

Info

Publication number: WO2010097350A1
Application number: PCT/EP2010/052171
Authority: WO
Inventors: Marek Chmielewski; Bartlomiej Furman; Sebastian Stecko; Adam Mames; Irma Panfil
Original assignee: Adamed Sp. Z O.O.
Priority date: 2009-02-24
Filing date: 2010-02-22
Publication date: 2010-09-02
Also published as: PL387331A1

Abstract

The invention relates to a process for the preparation of an aldehyde beta-lactam compound of formula (I), wherein P¹ is H or a protecting group, useful in the preparation of ezetimibe, from a nitrone compound of formula (II). The nitrone compound Il is prepared by reacting 4-fluorophenylhydroxyloamine with OH- protected 4-hydroxybenzaldehyde. The nitrone compound of formula (II) is reacted with an acetylene compound of formula (III) to form a compound of formula (IV), and the compound of formula (IV), after optional deprotection, is oxidized to obtain an aldehyde of formula (V), which undergoes isomerisation to the compound of formula (I). The subject of the invention are also novel compounds of formulas (II) and (IV).

Description

A process for the preparation of an aldehyde beta-lactam compound

The invention relates to the process for the preparation of an aldehyde beta- lactam compound useful in the preparation of ezetimibe, new intermediate compounds useful in this process, the process for the preparation of the same and the use thereof in the preparation of ezetimibe.

Ezetimibe is the INN name for ('3R,4Sj-1 -(4-fluorophenyl)-3-/('3Sj-3-(4-fluoro- phenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one 1 , a pharmacologically active substance which is the ingredient of hypolipidemic pharmaceutical preparations.

Ezetimib

European patent EP 0906278 discloses a process for the preparation of ezetimibe, which comprises reaction of hydroxybutanolide 1a with imine 1b to form a chiral diol 1c, which after oxidation provides a beta-lactam compound having an aldehyde group 1d, according to the Scheme I.

Scheme I

_H

Resulting beta-lactam compound 1d is reacted with an enol ether compound 1e to form the adduct 1f, which after hydrogenation of the double carbon-carbon bond and the reduction of carbonyl group in the side chain using a chiral reducing reagent, and the subsequent deprotection of the phenolic hydroxyl group leads to ezetimibe 1 , according to the following Scheme II.

Scheme Il

The aim of the present invention is to provide a new process for the preparation of an aldehyde beta-lactam compound, intermediate compounds, a process for preparation of intermediate compounds and the use of an intermediate compound.

The process of the invention for the preparation of an aldehyde beta-lactam compound of formula (I)

wherein P¹ represents hydrogen atom or a protecting group for aromatic hydroxyl, comprises:

- preparing a nitrone compound of formula (II)

(H) wherein P¹ represents hydrogen atom or a protecting group for aromatic hydroxyl, in the reaction of a compound of formula (Vl)

(Vl) with a compound of formula (VII)

CHO

Q

(VII), or by oxidation of a compound of formula (VIII)

(VIM) with a peroxide reagent, wherein in said formulas (VII) and (VIII) P¹ has the meaning as defined above, ™ represents single bond and a is 1 , or — represents double bond and a is 0, - reacting the nitrone compound of formula (II)

(H) with an acetylene compound of formula P²³O.

(III) wherein each P^2a and ^P2b represents hydrogen atom or a protecting group for aliphatic hydroxyl, or P^2a and P^2b represent joint protecting group for an aliphatic 1 ,2-diol, and R represents hydrogen atom or Ci_-6alkyl, in the presence of a base and a copper compound, optionally in a solvent, to obtain a compound of formula (IV)

(IV), wherein P¹, P^2a, P^2b, and R have the meanings as defined above, optionally removing one of the protecting groups P^2a and P^2b' or both protecting groups P^2a and P^2b to obtain a compound of formula (IV), wherein one of P^2a and P^2b is H or each of P^2a and P^2b is H, and oxidation of the compound of formula (IV) in a solvent using the compound of an element in the high oxidation state as an oxygen reagent to obtain an aldehyde of formula (V)

(V) wherein P¹ has the same meaning as defined above, wherein said compound of formula (V), in a solvent, optionally in the presence of a base, undergoes isomerization to the compound of formula (I)

(I)-

Preferably, P¹ represents hydrogen atom, Ci_-6alkyl, Ci_-6alkenyl, Ci_-6alkynyl, Ci-io alkanoyl, C_6-ioaroyl, C6-ioaryl-Ci_-6alkyl, Ci-ealkoxy-Ci-ealkyl, C_4-5 cyclic ether group, Ci-βalkanesulfonyl, Cβ-ioarenesulfonyl, or (Ci-₆alkyl)_n(C₆-ioaryl)_msilyl, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3; and each of P^2a and P^2b is selected from the group consisting of hydrogen atom, Ci_-6alkyl, Ci_-6alkenyl, Ci _-6alkynyl, Ci-i₀alkanoyl, C_6-ioaroyl, C₆-ioaryl-Ci-6 alkyl, Ci-βalkoxy-Ci-βalkyl, C_4-5 cyclic ether group, and (Ci-₆alkyl)_n(C₆-ioaryl)_m, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3; or P^2a and P^2b are joined with each other and together represent a methylene group, which is unsubstituted or substituted with 1 -2 Ci_-4alkyl substituents, wherein said two Ci_-4 alkyl substituents may be joined with each other to form together with the methylene group carbon atom a cycloalkyl ring.

In particular, the copper compound is at least one copper(l) compound, preferably selected from the group consisting of copper(l) iodide, copper(l) bromide, copper(l) chloride, and copper(l) triflate.

In particular, the copper compound is at least one copper(ll) compound combined with a reducing compound, preferably selected from the group consisting of combinations: copper(ll) sulphate/sodium ascorbate, copper(ll) chloride/sodium ascorbate and copper(ll) acetate/sodium ascorbate.

Especially, at most 3 equivalents of the copper compound relative to the acetylene compound (III) are used, preferably from 0.01 to 1 equivalent of the copper compound.

Preferably, the base in the reaction of the compound of formula (II) with the compound of formula (III) is a secondary or tertiary amine. In particular, the amine can be selected from the group consisting of trialkyl- amines, such as triethylamine or N,N-diisopropylethylamine; alkyldi(cycloalkyl)- amines, such as N-methyldicylohexylamine; dialkylamines with branched alkyl substituents, such as diisopropylamine; di(cycloalkyl)amines, such as dicyclohexylamine; and heterocyclic amines, such as pyridine.

Optionally, triethylamine can be used in an amount of at least 4 equivalents relative to the acetylene compound (III).

Preferably, the base used in the reaction of the compound of formula (II) with the compound of formula (III) is an alkali metal or an alkaline earth metal carbonate. In particular, the base can be chosen from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate.

Preferably, the solvent in the reaction of the compound of formula (II) with the compound of formula (III) can be selected from the group consisting of aromatic hydrocarbons, chlorinated aliphatic hydrocarbons, aliphatic ethers, aliphatic nitriles, and

amides.

In particular, the solvent can be selected from the group consisting of acetonitrile, toluene, benzene, and N,N-dimethylformamide.

Especially, the compound of an element in the high oxidation state that is used as the oxygen reagent can be a periodate compound, preferably periodic acid, sodium periodate, potassium periodate or tetraalkylammonium periodate, such as tetrabutylammonium periodate, cetyltrimethylammonium periodate; or lead tetraacetate.

Preferably, the solvent used in the oxidation reaction of the compound of formula (IV) to the compound of formula (V) can be selected from the group consisting of tetrahydrofuran, acetonitrile and their mixtures with water.

Preferably, the solvent used in the isomerisation reaction of the compound of formula (V) to the compound of formula (I) can be selected from the group consisting of tetrahydrofuran, acetonitrile and their mixtures with water. Preferably, in the isomerisation reaction of the compound of formula (V) to the compound of formula (I) at least catalytic amount of the base is used, said base being selected from the group consisting of alkali metal carbonates and bicarbonates, and non-nucleophilic organic amines, such as 1 ,5-diazabicyclo- [4.3.0]non-5-ene and 1 ,8-diazabicyclo [5.4.0]undec-7-ene.

In particular, the oxidation of the compound of formula (IV) to the compound of formula (V) and the isomerisation of the compound of formula (V) to the compound of formula (I) can be carried out without isolation of the compound of formula (V). Preferably, the peroxide reagent can be selected from the group consisting of dimethoxydioxirane, H₂O₂ZMeReO₃, H₂O₂/Na₂WO₄, H₂O₂/SeO₂, Oxone^®/SeO₂, Oxone^®, m-chloroperbenzoic acid, tert-butyl peroxide, cumyl peroxide, and Davis reagent.

The object of the invention is also a compound of formula (II)

(H) wherein

P¹ represents hydrogen atom, C_halky!, d-βalkenyl, d-βalkynyl, Ci-ioalkanoyl, C_6-ioaroyl, C6-ioaryl-Ci_-6alkyl, Ci-ealkoxy-Ci-ealkyl, C_4-5cyclic ether group, Ci_-6- alkanesulfonyl, C_6-ioarenesulfonyl, or (Ci-₆alkyl)_n(C₆-ioaryl)_msilyl, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3, in the form of the isomer Z and/or isomer E.

The preferred compound of the formula (II) is a compound in which P¹ represents hydrogen atom, methyl, ethyl, n-propyl, allyl, propargyl, acetyl, pivaloyl, benzoyl, benzyl, methoxymethyl, 2-tetrahydrofuranyl, 2-tetrahydropyranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methane- sulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, benzenesulfonyl, or p-toluene- sulfonyl, in the form of the isomer Z and/or isomer E.

Particular compounds of formula (II) can be selected from the group consisting of the following:

(Z)-Λ/-(4-(hydroxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(benzyloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(methoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(ethoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(n-propoxy)benzylidene)-4-fluoroaniline-N-oxide,

(Z)-Λ/-(4-(methoxymethoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tetrahydro-2/-/-pyran-2'-yloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tetrahydrofuran-2'-yloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-acetoxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-benzoyloxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-pivaloyloxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(methylsulfonyloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tosyloxy)benzylidene)-4-fluoroaniline-N-oxide, and (Z)-Λ/-(4-(fe/t-butyldiphenylsilyloxy)benzylidene)-4-fluoroaniline-N-oxide, In a further aspect, the invention relates to a compound of formula (IV)

(IV) wherein

P¹ represents hydrogen atom, Ci_-6alkyl, Ci_-6alkenyl, Ci_-6alkynyl, Ci-i₀alkanoyl, C_6-ioaroyl, C6-ioaryl-Ci_-6alkyl, Ci-ealkoxy-Ci-ealkyl, C_4-5 cyclic ether group, Ci_-6alka- nesulfonyl, Cβ-ioarenesulfonyl, or (Ci-6alkyl)_n(C6-ioaryl)_msilyl, where n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3; each of P^2a and P^2b is selected from the group consisting of hydrogen atom, Ci-βalkyl, d-βalkenyl, d-βalkynyl, Ci-ioalkanoyl, Cβ-ioaroyl_, Cβ-ioaryl-Ci-βalkyl, Ci-ealkoxy-Ci-ealkyl, C_4-5cyclic ether group and (Ci-6alkyl)_n(C6-ioaryl)_msilyl, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3; or P^2a and P^2b are joined with each other and together represent a methylene group unsubstituted or substituted with 1 -2 Ci_-4alkyl substituents, wherein said two Ci_-4alkyl substituents may be joined with each other to form together with the methylene group carbon atom a cycloalkyl ring, and R represents hydrogen atom or Ci-6 alkyl. Preferably, P¹ represents hydrogen atom, methyl, ethyl, n-propyl, allyl, propargyl, acetyl, pivaloyl, benzoyl, benzyl, methoxymethyl, 2-tetrahydrofuranyl, 2-tetrahydro- pyranyl, trimethysilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methanesulfonyl, thfluoromethanesulfonyl, ethanesulfonyl, benzenesulfonyl, or p-toluenesulfonyl, and each of P^2a and P^2b is independently selected from the group consisting of hydrogen atom, methyl, ethyl, n-propyl, allyl, propargyl, acetyl, pivaloyl, benzoyl, benzyl, methoxymethyl, 2-tetrahydrofuranyl, 2-tetrahydropyranyl, trimethysilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl, or P^2a and P^2b together represent methylene, ethylidene, isopropylidene, cyclopentylidene or cyclohexylidene, and

R represents hydrogen atom or Ci-6 alkyl.

Particular compounds of formula (IV) are selected from the group consisting of the following: (3R4S)-4-(4-(benzyloxy)phenyl)-3-((4'R)-2',2'-dimethyl-1 ',3'-dioxolan-4'-yl)-1 -(4- fluorophenyl)azetidine-2-one, and

(3R4S)-4-(4-(benzyloxy)phenyl)-3-((rR)-1 ',2'-dihydroxyethyl)-1 -(4-fluorophenyl)- azetidine-2-one. A process of the present invention for the preparation of the compound of formula (IV)

(IV) wherein P¹ represents hydrogen atom or a protecting group for aromatic hydroxyl, each of P^2a and P^2b represents hydrogen atom or a protecting group for aliphatic hydroxyl, or P^2a and P^2b represent joint protecting group for aliphatic 1 ,2-diol, and R represents a hydrogen atom or Ci-β alkyl, comprises reaction of the nitrone compound of formula (II),

(I I) wherein P¹ represents hydrogen atom or a protecting group for aromatic hydroxyl, with the acetylene compound of formula (III), p2a₀

P^2bO→( R

(III) wherein each of P^2a and P^2b represents hydrogen atom or a protecting group for aliphatic hydroxyl, or P^2a and P^2b represent joint protecting group for aliphatic 1 ,2- diol, and R represents hydrogen atom or C_halky!, in the presence of a base and a copper compound, and optionally in a solvent. Preferably, P¹ represents hydrogen atom, Ci_-6alkyl, Ci_-6alkenyl, Ci_-6alkynyl, Ci-ioalkanoyl, Cβ-ioaroyl, Cβ-io aryl-Ci-6 alkyl, Ci-βalkoxy-Ci-βalkyl, C_4-5 cyclic ether group, Ci-βalkanesulfonyl, Cβ-ioarenesulfonyl or (Ci-₆alkyl)_nC₆-ioaryl)_msilyl, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3, and each of P^2a and P^2b is selected from the group consisting of hydrogen atom, Ci_-6alkyl, Ci_-6alkenyl, Ci_-6alkynyl, Ci-i₀alkanoyl, C_6-ioaroyl_, C₆-ioaryl-Ci_-6alkyl, Ci_-6 alkoxy-Ci-βalkyl, C_4-5 cyclic ether group, and (Ci-6alkyl)_nC6-ioaryl)_msilyl, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3; or P^2a and P^2b are joined with each other and together represent a methylene group unsubstituted or substituted with 1 -2 Ci_-4alkyl substituents, wherein said two Ci_-4alkyl substituents may be joined with each other to form together with the methylene group carbon atom a cycloalkyl ring.

In particular, the copper compound can be at least one copper(l) compound, preferably selected from the group consisting of copper(l) iodide, copper(l) bromide, copper(l) chloride, and copper(l) triflate.

In particular, the copper compound can be at least one copper(ll) compound combined with a reducing agent, preferably selected from the group consisting of combinations: copper(ll) sulphate/sodium ascorbate, copper(ll) chloride/sodium ascorbate, and copper(ll) acetate/sodium ascorbate. Especially, at most 3 equivalents of the copper compound relative to the compound of formula (III), and preferably from 0.01 to 1 equivalent of the copper compound, can be used.

Preferably, a secondary or tertiary organic amine can be used as the base. In particular, the amine can be selected from the group consisting of trialkyl- amines, such as triethylamine or N,N-diisopropylethylamine; alkyldi(cycloalkyl)- amines, such as N-methyldicyclohexylamine; dialkylamines with branched alkyl substituents, such as diisopropylamine; di(cycloalkyl)amines, such as dicyclo- hexylamine; and heterocyclic amines, such as pyridine.

Optionally, triethylamine in an amount of at least 4 equivalents relative to the compound of formula (III) is used.

In particular, the base can be an alkali or an alkaline earth metal carbonate.

In particular, the base can be selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate.

Preferably, the solvent can be selected from the group consisting of aromatic hydrocarbons, chlorinated aliphatic hydrocarbons, aliphatic ethers, aliphatic nitriles, and N,N-di-(Ci-6alkyl)aliphatic amides.

In particular, the solvent is selected from the group consisting of acetonithle, toluene, benzene, and N,N-dimethylformamide.

According to the further aspect of the present invention, the compound of formula (II) is used in the process for the preparation of ezetimibe.

Preferably, in said process the following compounds of formula (II) can be used: (Z)-Λ/-(4-(hydroxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(benzyloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(methoxy)benzylidene)-4-fluoroaniline-N-oxide,

(Z)-Λ/-(4-(ethoxy)benzylidene)-4-fluoroaniline-N-oxide,

(Z)-Λ/-(4-(n-propoxy)benzylidene)-4-fluoroaniline-N-oxide,

(Z)-Λ/-(4-(methoxymethoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tetrahydro-2/-/-pyran-2'-yloxy)benzylidene)-4-fluoroaniline-N-oxide,

(Z)-Λ/-(4-(tetrahydrofuran-2'-yloxy)benzylidene)-4-fluoroaniline-N-oxide,

(Z)-Λ/-(4-acetoxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-benzoyloxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-pivaloyloxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-/V-(4-(methylsulfonyloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tosyloxy)benzylidene)-4-fluoroaniline-N-oxide, or (Z)-Λ/-(4-(te/t-butyldiphenylsilyloxy)benzylidene)-4-fluoroaniline-N-oxide,

The process of the present invention allows to obtain the aldehyde beta-lactam compound, which is an important intermediate in the preparation of ezetimibe, from easy available, inexpensive starting materials and reagents. Intermediate compounds obtained in the reaction sequence according to the process of the invention can also be used for the synthesis of other useful beta-lactam compounds.

Within the present description and claims, the term "protecting group P¹" denotes a protecting group for aromatic hydroxyl. Aromatic hydroxyl can be also referred to as "phenolic hydroxyl group" There are no particular limitations of the type of a protecting group for aromatic hydroxyl that may be used for carrying out the invention. Examples of typical protecting groups can be found e.g. in the monograph "Protecting Groups in Organic Synthesis" (Theodora W. Greene and Peter G. M Wuts, second edition, 1991. John Wiley & Sons, Inc.). In accordance with the invention, the term "protecting group for aromatic hydroxyl" preferably comprises d-βalkyl, d-βalkenyl, d-βalkynyl, Ci-ioalkanoyl, Cβ-ioaroyl, Cβ-ioaryl-Ci-βalkyl, d-βalkoxy- Ci_-6alkyl, C_4-5 cyclic ether group, Ci_-6alkanesulfonyl, C_6-ioarenesulfonyl, and (Ci-6alkyl)n(C6-ioaryl)mSilyl, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3. Within the present description and claims, the terms "protecting group P^2a" as well as "protecting group P^2b" relate to protecting groups for aliphatic hydroxyl. Protecting groups P^2a and P^2b can be joined with each other, thus forming a joint protecting group for vicinal hydroxyl groups in an aliphatic 1 ,2-diol. There are no particular limitations of the type of the protecting group for aliphatic hydroxyl or protecting group for athen aliphatic 1 ,2-diol that can be used in carrying out the invention. Examples of typical protecting groups can be found e.g. in the monograph "Protecting Groups in Organic Synthesis "(Theodora W. Greene and Peter G. M. Wuts, second edition, 1991. John Wiley & Sons, Inc.).

According to the invention, the aliphatic hydroxyl protecting group is preferably selected from among the following: Ci_-6alkyl, Ci_-6alkenyl, Ci_-6alkynyl, Ci-ioalkanoyl, Cβ-ioaroyl_, Cβ-ioaryl-Ci-βalkyl, Ci-βalkoxy-Ci-βalkyl, C_4-5 cyclic ether group, and (Ci-6 alkyl)_n(C6-io aryl)_msilyl, wherein n and m represents an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3. According to the invention, the protecting group for aliphatic 1 ,2-diol is preferably a methylene group, unsubstituted or substituted with 1 -2 Ci_-4 alkyl substituents, wherein said two Ci_-4 alkyl substituents may be joined with each other to form together with the methylene group carbon atom a cycloalkyl ring. Exemplary C_halky! groups are methyl, ethyl, n-propyl.

Exemplary d-βalkenyl group is allyl.

Exemplary Ci_-6alkynyl group is propargyl.

Exemplary Ci-i₀alkanoyl groups are acetyl and pivaloyl.

Exemplary Cβ-ioaroyl group is benzoyl. Exemplary Cβ-ioaryl-Ci-βalkyl group is benzyl.

Exemplary Ci-βalkoxy-Ci-βalkyl group is methoxymethyl.

Exemplary C_4-5 cyclic ethers groups are 2-tetrahydrofuranyl and 2-tetrahydro- pyranyl.

Exemplary d-βalkanesulfonyl groups are methanesulfonyl, trifluoromethane- sulfonyl, and ethanesulfonyl.

Exemplary C_6-io arenesulfonyl groups are benzenesulfonyl and p-toluenesulfonyl. Exemplary (Ci-₆alkyl)_n(C6-ioaryl)_msilyl groups (where n and m represents an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3) are trimethyl- silyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl.

Exemplary methylene groups unsubstituted or substituted with 1-2 Ci_-4 alkyl substituents, wherein said two Ci_-4 alkyl substituents may be joined to form together with the methylene group carbon atom a cycloalkyl ring are methylene, ethylidene, isopropylidene, cyclopentylidene, and cyclohexylidene.

Within the present description and claims, the term "oxygen compound of an element in the high oxidation state" relates to an inorganic or organic compound, in which the central atom of the element, which in its ground state has partially filled d orbitals, is bound with several oxygen atoms and is in the oxidation state of n or n-1 , n being the highest oxidation state for this element. Exemplary oxygen compounds of the element in the high oxidation state are lead tetraacetate Pb(OAc)₄, and periodic acid or its salts, e.g. alkali metal pehodates such as sodium and potassium periodates, and tetraalkylammonium periodates such as tetrabutylammonium periodate, thmethyldodecylammonium periodate and cetylthmethylammonium periodate.

In the process of the invention the aldehyde beta-lactam compound of formula (I) is prepared (Scheme III). In the reaction of the nitrone compound of the formula (II) (wherein P¹ represents hydrogen atom or a protecting group for aromatic hydroxyl), with the acetylene compound of formula (III) (wherein each of P^2a and ^P2b represents hydrogen atom or a protecting group for aromatic hydroxyl, or P^2a and P^2b are joined with each other thus forming a joint protecting group for vicinal hydroxyl groups in an aliphatic 1 ,2-diol, and R represent hydrogen atom or Ci-β alkyl), in the presence of the base and the copper compound, optionally in the solvent, the compound of formula (IV) is obtained. After optional removal of one or both protecting groups P^2a and P^2b, the compound of formula (IV), in which one of P^2a and P^2b represents hydrogen atom, or each of P^2a and P^2b represents hydrogen atom, is oxidized using the oxygen compound of an element in the high oxidation state reagent, to obtain the aldehyde compound of formula (V). The compound of formula (V) in solution, optionally in the presence of the non- nucleophilic base, preferably in the presence of catalytic amounts of the non- nucleophilic base, undergoes isomerization to the aldehyde beta-lactam compound of formula (I).

Scheme III

1 deprotectioπ

2 NaIO j

The nitrone compound of formula (II) is prepared according to the Scheme IV. Scheme IV

According to another embodiment, the nitrone compound of formula (II) is prepared according to the Scheme V. Scheme V

As the oxidizing agent, a peroxide reagent such as dimethoxydioxirane, H₂O₂/MeReO₃ H₂O₂/Na₂WO₄ H₂O₂/SeO₂ Oxone^®/SeO₂ Oxone^®, m-chloroper- benzoic acid, tert-butyl peroxide, cumyl peroxide, or Davis reagent, can be used.

In another embodiment, the nitrone compound of formula (II) is prepared according to the scheme Vl.

Scheme Vl

As the oxidizing agent a peroxide reagent can be used, such as dimethoxydioxirane, H₂O₂/MeReO₃, H₂O₂/Na₂WO₄, H₂O₂/SeO₂, Oxone^®/ SeO₂, or Davis reagent.

Formula (II) represents the nitrone compound of the invention in the form of the preferred isomer Z. It should be noted, however, that the nitrone compound may also occur in the form of isomer E, as well as mixtures of isomers Z and E, containing these isomers in different proportions. Typically, process for the preparation of the nitrones according to the invention yields mixtures of isomers Z and E, in which the isomer Z prevails, or isomer Z substantially devoid of isomer E. Isomer E can be transformed into preferred isomer Z under reaction conditions. The process for the preparation of acetylene compounds of formula (III) is known (J. Pietruszka, A. Witt, J. Chem. Soc, Perkin Trans. 1. 2000, 4293-4300) and consists in reaction of L-hydroxyaldehyde derivatives with Bestmann-Ohira reagent CH₃C(O)C(N₂)P(O)(OME)₂, according to the scheme VII. Bestmann-Ohira reagent is prepared using known method (J. Pietruszka, A. Witt, Synthesis 2006, 24, 4266-4268).

Scheme VII

(H i)

The absolute configuration of asymmetric carbon atom C-3 in the compound of formula (III) corresponds to the configuration of the asymmetric alpha carbon atom in the starting L-hydroxyaldehyde compound. The retention of this configuration in the reaction of the nitrone compound (II) with the acetylene compound (III) is necessary to obtain the compound of formula (IV) with the structure exactly as depicted in the Scheme III. The absolute configuration of the asymmetric atom C-3 in the compound of formula (III) is as depicted by the structure in formula wherein the OP^2b substituent is directed below the plane defined by the carbon atoms C-1 , C-2, C-3 and C-4, and hydrogen atom linked with C-3 atom (not shown) is directed above the plane.

When in formula (III) R represents Chalky!, then the C-4 atom is also an asymmetric one. However, the absolute configuration of the C-4 atom in the acetylene compound (III) is not essential for the asymmetric induction occurring in the reaction of the nitrone compound (II) with the acetylene compound (III) and resulting in formation of the compound of formula (IV) of desired structure. Therefore, if in formula (III) R represents Ci-β alkyl the compound of formula (III) may exist as a single diastereomer, another diastereomer (with the opposite configuration at C-4 atom) or mixtures of these diastereomers, and each of these compounds can be used in the process according to the invention. The reaction of the nitrone compound of formula (II) with the acetylene compound of formula (III) resulting in the compound of formula (IV) (in said formulas P¹, R^2a, R^2b and R have the meanings as given above) is carried out in the presence of the base and the copper compound.

The base can be an inorganic or organic base. Preferably, the organic base is a secondary or tertiary organic amine. More preferred amines are thalkylamines, such as triethylamine or N,N-diisopropylethylamine; alkyldi(cycloalkyl)amines, such as N-methyldicyclohexylamine; dialkylamines with branched alkyl substituents, such as diisopropylamine; di(cycloalkyl)amines, such as dicyclohexylamine; or heterocyclic amines such, as pyridine.

The reaction in the presence of the organic amine can be carried out without a solvent. In such a case, an additional amount of the organic amine can be used, greater than equimolar relative to the compound of formula (III), to serve as a diluent of the reaction mixture. Preferably, this additional amount of the organic amine is at least 3 molar equivalents relative to the compound of formula (III).

Preferably, the inorganic base is an alkali metal compound, more preferably alkali metal carbonate or bicarbonate, such as potassium carbonate, sodium carbonate, sodium bicarbonate, or potassium bicarbonate.

The copper compound can be a copper(l) compound, preferably copper(l) iodide, copper(l) bromide, copper(l) chloride, and/or copper(l) triflate.

In another embodiment, the copper compound is a copper(ll) compound combined with a reducing compound. Preferred are the combinations of copper(ll) sulphate with sodium ascorbate, copper(ll) chloride with sodium ascorbate, and/or copper(ll) acetate with sodium ascorbate.

In the reaction of the nitrone compound of formula (II) with the acetylene compound of formula (III) the copper compound is used in an equimolar amount relative to the acetylene compound (III), in an amount less than equimolar relative to the acetylene compound (III), or in an amount greater than equimolar relative to the acetylene compound (III). Preferably, the amount of the copper compound does not exceed 3 moles per mole of the acetylene compound (III). More preferably, the amount of copper compound is 0.01 to 1 molar equivalent relative to the acetylene compound (III), for example 1 equivalent, 0.5 equivalent, 0.1 equivalent or 0.05 equivalent.

The reaction of the nitrone compound of formula (II) with the acetylene compound of formula (III), in the presence of the base and the copper compound, is preferably carried out in the presence of the solvent. There are no specific limitations of the type of the solvent used in this reaction, provided that it has no adverse effect on the reaction or the reagents used, and dissolves at least to some degree the nitrone compound (II) and/or the acetylene compound (III). Examples of suitable solvents include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons, such as methylene chloride or 1 ,2- dichloroethane; ether derivatives, such as diethyl ether or tetrahydrofuran; esters, such as ethyl acetate; amide derivatives, such as N,N-dimethylformamide; nitriles, such as acetonithle; or mixtures of these solvents. Preferred solvents are acetonithle, toluene, benzene, and N,N-dimethylformamide. The reaction can be carried out in a wide range of temperatures and precise reaction temperature is not essential. A suitable reaction temperature will depend on such factors as the type of the solvent, starting materials or reagents. However, in general, it is convenient to carry out the reaction at a temperature between -60⁰C and 60⁰C, more preferably between -40°C and 20⁰C. The time required for the reaction may also vary within a wide range, depending on many factors, especially the reaction temperature and the type of starting materials and a solvent. However, the reaction time usually ranges from 1 hour to 72 hours, more preferably from 6 hours to 48 hours.

Optional removal of one or both protecting groups P^2a and P^2b from the compound of formula (IV) to obtain the compound of formula (IV), in which one of P^2a and P^2b represents hydrogen atom, or each of P^2a and P^2b represents hydrogen atom, is carried out by known methods, e.g. such as disclosed in the monograph

"Protecting Groups in Organic Synthesis" (Theodora W. Greene and Peter GM

WUTS, second edition, 1991 John Wiley & Sons, Inc.). Ci_-6Alkoxy-Ci_-6alkyl, C_4-5 cyclic ether groups, and methylene group unsubstituted or substituted with 1 -2 Ci_-4 alkyl substituents (wherein said two Ci_-4 alkyl substituents may be joined with each other forming together with the methylene group carbon atom a cycloalkyl ring) can be removed in a solvent in the presence of an inorganic acid such as hydrochloric acid, sulphuric acid or hydrofluoric acid, or in the presence of an organic acid, such as acetic acid.

The reaction is usually carried out in solvents such as water, ethanol, tetrahydrofuran, and their mixtures. (Ci-₆Alkyl)_n(C6-ioaryl)_msilyl groups, wherein n and m represents an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3, can be removed in a solvent in the presence of a source of fluoride ions. The source of fluoride ions may be an alkali metal fluoride, such as potassium fluoride, tetraalkylammonium fluorides, such as tetrabutylammonium, or hydrofluoric acid and its addition salts with amines such as pyridine. The reaction is usually carried out in ether solvents, such as tetrahydrofuran. C_MO Alkanoyl groups and C_6-io aroyl groups are usually removed in a solvent in the presence of a base, such as an alkali metal hydroxide or tetraalkylammonium hydroxide or an alkali metal carbonate. The reaction is usually carried out in alcoholic solvents such as methanol or ethanol, or in hydro-alcoholic solvents. Ci-6 Alkenyl groups, in particular allyl group, are removed in the presence of a transition metal catalyst, such as tris(triphenylphosphino)rhodium chloride. C₆-ioAryl-Ci-6 alkyl groups, in particular benzyl group, can be removed by hydrogenation in the presence of a catalyst, such as palladium on activated carbon.

After optional removal of one or both protecting groups P^2a and P^2b, the compound of formula (IV), in which one of P^2a and P^2b represents hydrogen atom, or each of P^2a and P^2b represents hydrogen atom, is oxidized using an oxygen compound of an element in the high oxidation state reagent, to obtain the aldehyde compound of formula (V). The oxidation reaction is usually carried out in a solvent using a periodate compound. The preferred periodate reagent is periodic acid, sodium pehodate or tetraalkylammonium periodate. More preferably, 1 -2 equivalents of the reagent relative to the compound of formula (IV) are used, and most preferably 1.5 equivalent. Preferably, the reaction is carried out in tetrahydrofuran or acetonitrile, or in their mixtures with water. Preferably, the reaction is carried out at temperature from -20⁰C to 60⁰C, more preferably from 10°C to 25°C.

If necessary, protecting group P¹ can also be removed using the above procedures and optionally deprotected hydroxyl group may be protected with another P¹ protecting group, using known and standard procedures, such as disclosed in the monograph "Protecting Groups in Organic Synthesis" (Theodora W. Greene and Peter GM WUTS, second edition, 1991 , John Wiley & Sons, Inc.), for example to introduce such protecting group like benzyloxyl.

The compound of formula (V) in solution, optionally in the presence of a catalytic amount of a non-nucleophilic base, is subjected to isomerisation to the aldehyde beta-lactam compound of formula (I). In a preferred embodiment, isomerisation reaction of the compound of formula (V) to the beta lactam compound of formula (I) is carried out without isolation of the compound of formula (V), in an organic solvent such as tetrahydrofuran or acetonithle, or a water-organic mixture such as tetrahydrofuran-water or acetonitrile-water mixture. Preferably, the reaction is carried out at the temperature from -20⁰C to 60°C, more preferably from 10⁰C to 25°C. Optionally, the base can be chosen from the group consisting of alkali metal carbonates and bicarbonates and non-nucleophilic amines, such as 1 ,5-diaza- bicyclo[4.3.0]non-5-ene and 1 ,8-diazabicyclo[5.4.0]undec-7-ene. In a particularly preferred embodiment, the oxidation of the compound of formula

(IV) (in which one of P^2a and P^2b represents hydrogen atom, or each of P^2a and P^2b represents hydrogen) to the compound of formula (V) and the isomerisation of the compound of formula (V) to the aldehyde beta-lactam compound of formula (I) are carried out without isolation of the compound of formula (V), in a single reaction batch without exchange of the solvent.

After completion of the reactions described above, desired compound of formula (IV),

(V) or (I) can be isolated from the reaction mixture in the conventional manner. For example, it can be separated by neutralization of the reaction mixture, if necessary, removing insoluble materials by filtration, the addition of solvents not miscible with each other, such as water and ethyl acetate, washing with water, separation of the organic layer containing the desired compound, drying it over anhydrous magnesium sulphate or sodium sulphate, and then distilling off the solvent.

If necessary, obtained desired compound of formula (IV), (V) or (I) is separated and purified using conventional methods such as crystallization or dissolution and re- precipitation, or by chromatographic methods. If necessary, to isolate and purify the desired compound a combination of two or more of these techniques can be employed.

Examples Example 1 (Z)-Λ/-4-(Benzyloxy)benzylidene)-4-fluoroaniline-Λ/-oxide Step 1. 4-Fluorophenylhydroxylamine

To the intensively stirred mixture of 4-fluoronitrobenzene (3.5 g, 25 mmol) and ammonium chloride solution (1.7 g in 50 ml of water) at 50⁰C 3.3 g (50 mmol) of zinc dust is added portionwise during 15 min. After the addition of zinc is completed, the reaction mixture is filtered while hot through Celite. The resulting filtrate is cooled in an ice bath to 0⁰C and then the resulting precipitate is filtered off. 4-Fluorophenylhydroxylamine in the form of quickly darkening solid is obtained with 90% yield (2.8 g). The obtained compound is used directly in the next step.

Step 2. (Z)-Λ/-(4-(benzyloxy)benzylidene)-4-fluoroaniline-N-oxide The solution of 4-benzyloxybenzaldehyde (12 mmol) and 4-fluorophenylhydroxyl- amine (12 mmol) in 20 ml of anhydrous ethanol is heated under reflux for 1 hour. After cooling and removing the solvent the residue is crystallized from benzene. The title nitrone in the form of yellowish crystals is obtained with 88% yield (3.2 g).

¹H NMR (CDCI₃, 400 MHz), δ: 8.44 (2H, m), 7.87 (1 H, s), 7.79 (2H, m), 7.50-7.22 (5H, m), 7.19-7.05 (4H, m), 5.15 (2H, s). ¹³C NMR (CDCI₃, 100MHz): 190.3, 162.5 (d, Jc-F 248 Hz), 160.7, 136.3, 134.1 , 131.1 , 128.7, 128.2, 127.5, 123.8, 123.5. (d, Jc-F 9Hz), 116.0 (d, Jc-F 23 Hz), 114.9, 70.1. HR MS (ESI): calc. for C₂₀Hi₆NO₂FNa [M+Na⁺] 344.1057; found: 344.1055. Anal.: calc. for C₂₀Hi₆FNO₂: C 74.75, H 5.02, N 4.36; found: C 74.71 , H 4.98, N 4.33. Example 2

(Z)-N-(4-(Methoxy)benzylidene)-4-fluoroaniline-N-oxide

The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-methoxybenzaldehyde. 1H NMR (CDCI₃, 400 MHz), δ: 8.38 (2H, m), 7.82 (1 H, s), 7.77 (2H, m), 7.15 (2H, m), 7.00 (2H, m), 3.88 (3H, s). ¹³C NMR (CDCI₃, 100MHz): 190.2, 163.0 (d, J_C-_F 250 Hz), 161.7, 145.0, 134.4, 131.9, 131.2, 123.5 (d, J_C-F 9HZ), 116.0 (d, J_c-F 23 Hz), 114.0, 55.4. HR MS (ESI): calc. for Ci₄Hi₂NO₂FNa [M+Na⁺] 268.0744; found: 268.0747. Anal.: calc. for Ci₄Hi₂FNO₂: C 68.56, H 4.93, N 5.71 ; found: C 68.50, H 4.91 , N 5.69.

Example 3 (Z)-N-(4-(Hydroxy)benzylidene)-4-fluoroaniline-N-oxide

The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-hydroxybenzaldehyde. 1H NMR (CDCI_3, 400 MHz), δ: 8.28 (2H, m), 7.81 (1 H, s), 7.75 (2H, m), 7.15 (2H, m), 6.92 (2H, m), 5.01 (1 H, br s). ¹³C NMR (CDCI₃, 100MHz) 190.3, 164.0 (d, J_c-F 250 Hz), 161.1 , 148.0, 132.4, 131.0, 127.2, 123.1 (d, J_C-F 9HZ), 116.1 (d, J_c-F 23 Hz), 114.0. IR (film): 3183 cm^"1. HRMS (ESI): calc. for Ci₃Hi₀NO₂FNa: [M+Na⁺] 254.0588; found: 254.0590. Anal.: calc. for C_{I 3}H_I0FNO₂: C 67.53, H 4.36, N 6.06; found: C 67.50, H 4.37, N 6.04.

Example 4

(Z)-N-(4-(Acetoxy)benzylidene)-4-fluoroaniline-N-oxide

The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-acetoxybenzaldehyde. 1H NMR (CDCI_3, 400 MHz), δ: 8.26 (2H, m), 7.85 (1 H, s), 7.74 (2H, m), 7.38-7.22 (4H, m), 2.12 (3H, s). ¹³C NMR (CDCI₃, 100MHz): 190.2, 171.2, 163.4 (d, J_c-F 250 Hz), 161.2, 145.8, 133.4, 132.1 , 131.0, 124.1 (d, J_c-F 9Hz), 116.3 (d, J_c-F 23 Hz), 114.2, 22.1. IR (film) 1740 cm^"1. HRMS (ESI): calc. for Ci₅Hi₂NO₃FNa [M+Na⁺] 296.0699; found: 296.0694. Anal.: calc. for Ci₅Hi₂FNO₃: C 65.93, H 4.43, N 5.13; found: C 65.91 , H 4.44, N 5.11.

Example 5 (Z)-N-(4-(Benzoyloxy)benzylidene)-4-fluoroaniline-N-oxide The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-benzoyloxybenzaldehyde.

¹H NMR (CDCI₃, 400 MHz), δ: 8.26 (2H, m), 7.85 (1 H, s), 7.74 (4H, m), 7.38-7.22 (7H, m). ¹³C NMR (CDCI₃, 100MHz): 190.0, 174.2, 162.9 (d, J_c-F 250 Hz), 160.9, 146.8, 134.2, 133.1 , 132.6, 131.3, 130.28, 130.26, 124.1 (d, J_c-F 9Hz), 116.3 (d, J_c-F 23 Hz), 114.2. IR (film) 1740 cm^"1. HRMS (ESI): calc. for C₂₀Hi₄NO₃FNa [M+Na⁺] 358.0855; found: 358.0853. Anal.: calc. for C₂₀Hi₄FNO₃: C 71.64, H 4.21 , N 4.18; found: C 71.62, H 4.20, N 4.19.

Example 6

(Z)-N-(4-(tert-Butyldiphenylsilyloxy)benzylidene)-4-fluoroaniline-N-oxide The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-tert-butyldiphenylsilyloxybenzaldehyde.

¹H NMR (CDCI_3, 400 MHz), δ: 8.17 (2H, m), 7.74-7.70 (5H, m), 7.40-7.24 (7H, m), 7.14 (2H, m), 6.85 (2H, m), 1.11 (9H, s). ¹³C NMR (CDCI₃ 100MHz): 190.8, 164.0 (d, Jc-F 250 Hz), 158.5, 144.7, 136.2, 132.9, 132.1 , 130.9, 128.7, 124.3 (d, J_C-F 9Hz), 120.9, 116.4 (d, J_c-F 23 Hz), 114.3, 26.4. HRMS (ESI): calc. for C₂₉H₂₈NO₂FSiNa [M+Na⁺] 492.1756; found: 492.1754. Anal.: calc. for C₂₉H₂₈FNO₂Si: C 74.17, H 6.01 , N 2.98; found: C 74.15, H 5.98, N 3.00.

Example 7

(Z)-N-(4-(Tetrahydro-2H-pyran-2'-yloxy)benzylidene)-4-fluoroaniline-N-oxide The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-(tetrahydro-2H-pyran-2'-yloxy)- benzaldehyde.

¹H NMR (CDCI_3, 400 MHz), δ: 8.40 (2H, m), 7.84 (1 H, s), 7.75 (2H, m), 7.15 (2H, m), 6.92 (2H, m), 5.62 (1 H, m), 3.64-3.53 (2H, m), 2.14 (1 H, m), 1.93 (1 H, m), 1.68-1.58 (4H, m). ¹³C NMR (CDCI₃, 100MHz): 190.2, 163.0 (d, J_c-F 250 Hz), 161.7, 145.0, 134.4, 131.9, 131.2, 123.5 (d, J_c-F 9Hz), 116.0 (d, J_c-F 23 Hz), 114.0, 104.2, 64.1 , 30.7, 25.6, 20.2. HRMS (ESI): calc. for Ci₈Hi₈FNO₃Na [M+Na+] 338.1168; found 338.1162; Anal.: calc. for Ci₈Hi₈FNO₃: C 68.56, H 5.75, N 4.44; found: C 68.49, H 5.72, N 4.43.

Example 8

(Z)-N-(4-(Tetrahydrofuran-2'-yloxy)benzylidene)-4-fluoroaniline-N-oxide The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-(tetrahydrofuran-2'-yloxy)- benzaldehyde.

¹H NMR (CDCI_3, 400 MHz), δ: 8.39 (2H, m), 7.83 (1 H, s), 7.76 (2H, m), 7.14 (2H, m), 6.95 (2H, m), 5.71 (1 H, m), 3.82-3.74 (2H, m), 2.36 (1 H, m), 2.15 (1 H, m), 1.93-1.79 (2H, m). ¹³C NMR (CDCI₃, 100MHz): 190.2, 163.0 (d, J_c-F 250 Hz), 161.7, 145.0, 134.4, 131.9, 131.2, 123.5 (d, J_C-F 9 Hz), 116.0 (d, J_c-F 23 Hz), 114.6, 109.6, 66.4, 34.2, 24.2. HRMS (ESI): calc. for Ci₇Hi₆FNO₃Na [M+Na⁺] 324.1012; found 324.1009. Anal.: calc. for Ci₇Hi₆FNO₃: C 67.76, H 5.35, N 4.64; found: C 67.69, H 5.37, N 4.62.

Example 9

(Z)-N-(4-(Ethoxy)benzylidene)-4-fluoroaniline-N-oxide The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-etoxybenzaldehyde.

¹H NMR (CDCI_3, 400 MHz), δ: 8.38 (2H, m), 7.86 (1 H, s), 7.74 (2H, m), 7.15 (2H, m), 6.93 (2H, m), 4.12 (2H, q), 1.32 (3H, t). ¹³C NMR (CDCI_3, 100MHz): 190.2. 163.0 (d, J_C-_F 250 Hz), 161.7, 145.0, 134.4, 131.9, 131.2, 123.5 (d, J_c-F 9Hz), 116.0 (d, J_C-_F 23 Hz), 114.0, 64.3, 15.2. HRMS (ESI): calc. for Ci₅Hi₄FNO₂Na [M+Na+] 282.0906; found 282.0902. Anal.: calc. for Ci₅Hi₄FNO₂: C 69.49, H 5.44, N 5.40; found: C 69.43, H 5.41 , N 5.38. Example 10

(Z)-N-(4-(n-Propoxy)benzylidene)-4-fluoroaniline-N-oxide

The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-n-propoxybenzaldehyde. 1H NMR (CDCI₃, 400 MHz), δ: 8.38 (2H, m), 7.86 (1 H, s), 7.74 (2H, m), 7.15 (2H, m), 6.93 (2H, m), 4.03 (2H, q), 1.83 (2H, m), 1.32 (3H, t). ¹³C NMR (CDCI₃, 100MHz): 190.2, 163.0 (d, J_c-F 250 Hz), 161.7, 145.0, 134.4, 131.9, 131.2, 123.5 (d, Jc-F 9Hz), 116.0 (d, Jc-F 23 Hz), 114.0, 66.4, 23.1 , 10.7. HRMS (ESI): calc. for Ci₆Hi₆FNO₂Na [M+Na+] 296.1063; found 296.1059. Anal.: calc. for Ci₆Hi₆FNO₂ C 70.31 , H 5.90, N 5.12; found: C 70.26, H 5.86, N 5.09.

Example 11 (Z)-N-(4-(n-Pivaloyloxy)benzylidene)-4-fluoroaniline-N-oxide

The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-pivaloyloxybenzaldehyde. 1H NMR (CDCI_3, 400 MHz), δ: 8.26 (2H, m), 7.85 (1 H, s), 7.74 (2H, m), 7.38-7.22 (4H, m), 1.01 (9H, s). ¹³C NMR (CDCI₃, 100MHz): 190.2. 171.2. 163.4 (d, J_c-F 250 Hz), 161.2, 145.8, 133.4, 132.1 , 131.0, 124.1 (d, J_c-F 9Hz), 116.3 (d, J_c-F 23 Hz), 114.2, 21.1. IR (film) 1740 cm^"1. HRMS (ESI): calc. for Ci₈Hi₈NO₃FNa [M+Na⁺] 338.1168; found: 338.1165. Anal.: calc. for Ci₈Hi₈FNO₃: C 68.56, H 5.75, N 4.44; found: C 68.50, H 5.77, N 4.43.

Example 12 (Z)-N-(4-(Methoxymethoxy)benzylidene)-4-fluoroaniline-N-oxide

The title compound is obtained by following the procedure of Example 1 but replacing 4-benzyloxybenzaldehyde with 4-(methoxymethoxy)benzaldehyde. 1H NMR (CDCI_3, 400 MHz), δ: 8.38 (2H, m), 7.86 (1 H, s), 7.74 (2H, m), 7.15 (2H, m), 6.93 (2H, m), 5.72 (2H, m), 3.34 (3H, s). ¹³C NMR (CDCI_3, 100MHz): 190.2, 163.0 (d, Jc-F 250 Hz), 161.7, 145.0, 134.4, 131.9, 131.2, 123.5 (d, J_c-F 9Hz), 116.0 (d, Jc-F 23 Hz), 114.0, 95.1 , 57.4. HRMS (ESI): calc. for Ci₅Hi₄FNO₃Na [M+Na+] 298.0855; found 298.0852. Anal.: calc. for Ci₅Hi₄FNO₃: C 65.45, H 5.13, N 5.09; found: C 65.40, H 5.11 , N 5.06.

Example 13

(Z)-N-(4-(Benzyloxy)benzylidene)-4-fluoroaniline-N-oxide Step 1. (E)-N-(4-(benzyloxy)benzylidene)-4-fluoroaniline

4-Benzyloxybenzaldehyde (10.0 g, 47 mmol), 4-fluoroaniline (5.2 g, 47 mmol), p- toluenesulfonic acid (0.8 g, 4.7 mmol ) and freshly distilled benzene (100 ml) are placed in a round-bottomed flask equipped with Dean-Stark trap. The resulting solution is heated under reflux for 24 hours until the separation of water in the azeotropic trap ceases. To the cooled solution 0.1 g of potassium carbonate is added and the mixture is magnetically stirred for 1 hour. After filtration through Celite and removal of the solvent the imine (E)-N-(4-(benzyloxy)benzylidene)-4- fluoroaniline is obtained.

Step 2. (Z)-N-(4-(benzyloxy)benzylidene)-4-fluoroaniline-N-oxide (E)-N-(4-(Benzyloxy)benzylidene)-4-fluoroaniline-N-oxide (14.4 g, 47 mmol) is dissolved in 100 ml of methanol. To the solution cooled to 0⁰C MeReO₃ (0.6 g, 2.4 mmol) is added followed by portionwise addition of H₂θ2-urea (13.3 g, 141 mmol). After 5 hours the solvent is removed and the residue is crystallized from benzene. The title compound is obtained with 80% yield (12.1 g). 1H NMR (CDCI_3, 400 MHz), δ: 8.44 (2H, m), 7.87 (1 H, s), 7.79 (2H, m), 7.50-7.22 (5H, m), 7.19-7.05 (4H, m), 5.15 (2H, s).

Example 14

(Z)-N-(4-(Methylsulfonyloxy)benzylidene)-4-fluoroaniline-N-oxide The title compound is obtained by following the procedures of Example 13, step 2, but substituting (E)-N-(4-(benzyloxy)benzylidene)-4-fluoroaniline with (E)-N-(4- (methylsulfonyloxy)benzylidene)-4-fluoroaniline.

¹H NMR (CDCI_3, 400 MHz), δ: 8.39 (2H, m), 7.83 (1 H, s), 7.76 (2H, m), 7.14 (2H, m), 6.95 (2H, m), 3.41 (3H, s). ¹³C NMR (CDCI₃, 100MHz): 190.2, 163.0 (d, J_c-F 250 Hz), 161.7, 145.0, 134.4, 131.9, 131.2, 123.5 (d, J_C-F 9 Hz), 116.0 (d, J_c-F 23 Hz), 115.7, 34.6, HRMS (ESI): calc. for Ci₄Hi₂FSNO₄Na [M+Na⁺] 332.0369; found 332.0363. Anal.: calc. for Ci₄Hi₂FSNO₄: C 54.36, H 3.91 , N 4.53; found: C 54.30, H 3.97, N 4.51.

Example 15 (Z)-N-(4-(Tosyloxy)benzylidene)-4-fluoroaniline-N-oxide

The title compound is obtained by following the procedures of Example 13, step 2, but replacing (E)-N-(4-(benzyloxy)benzylidene)-4-fluoroaniline with (E)-N-(4-

(tosyloxy)benzylidene)-4-fluoroaniline.

¹H NMR (CDCI₃, 400 MHz), δ: 8.47 (2H, m), 7.89 (1 H, s), 7.75 (2H, m), 7.50-7.22 (4H, m), 7.17-7.01 (4H, m), 2.26 (3H, s). ¹³C NMR (CDCI₃, 100MHz): 190.3, 162.5 (d, Jc-F 248 Hz), 160.7, 136.3, 134.1 , 131.1 , 128.7, 128.2, 127.5, 123.8, 123.5 (d, Jc-F 9Hz), 116.0 (d, Jc-F 23 Hz), 114.9, 21.1. HRMS (ESI): calc. for C₂₀H₂₆NO₄FSNa [M+Na⁺] 408.0682; found: 408.0679. Anal.: calc. for C₂₀H₂₆FSNO₄: C 62.33, H 4.18, N 3.63; found: C 62.28, H 4.15, N 3.61. Example 16

(Z)-N-(4-(Benzyloxy)benzylidene)-4-fluoroaniline-N-oxide

To the solution of N-(4-(benzyloxy)benzyl)-4-fluoroaniline (5 g, 16.3 mmol) in 100 ml of methanol cooled to 0⁰C MeReO₃ (0.2 g, 0.8 mmol) is added followed by portionwise addition of H₂O₂-urea (4.6 g, 49 mmol). After 10 hours the solvent is removed and the residue is crystallized from benzene to afford 3.9 g (75%) of the title compound.

¹H NMR (CDCI_3, 400 MHz), δ: 8.44 (2H, m), 7.87 (1 H, s), 7.79 (2H, m), 7.50-7.22 (5H, m), 7.19-7.05 (4H, m), 5.15 (2H, s).

Example 17 (R)-(-)-4-Ethynyl-2,2-dimethyl-1 ,3-dioxolane

The solution of L-glyceraldehyde acetonide prepared from ascorbic acid (Ch. Hubschwerlin, Synthesis 1986. 962-964) (1.03 g, 7.90 mmol) and Bestmann-Ohira reagent (2.42 g, 12.6 mmol) in methanol (50 ml) is cooled to 0⁰C. Potassium carbonate (2.33 g, 16.8 mmol) is then added portionwise during 30 min, followed by stirring the reaction mixture at room temperature for 12 hours. Then a saturated solution of NH₄CI (50 ml) is added and the resulting solution is extracted with pentane (2 x 250 ml). The combined organic layers are dried over magnesium sulfate and after removal of the solvent the residue is subjected to silica gel chromatography (pentane/diethyl ether 10:1 ) to afford 0.7 g (70%) of (R)-(-)-4- ethynyl-2 ,2-dimethyl-1 ,3-dioxolane in the form of yellow oil.

[α]_D -40° (c 1.2, CH₂CI₂). IR (film): 2121 cm^"1.

¹H NMR (200 MHz, CDCI₃), δ: 4.67 (1 H, m), 4.15 (1 H, dd, J 8.1. 6.4 Hz), 3.91 (1 H, dd, J 8.1. 6.2 Hz), 2.47 (1 H, d, J 2.3 Hz), 1.47 (3H, s, Me), 1.35 (3H, s, Me). Example 18

(3R,4S)-4-(4-(Benzyloxy)phenyl)-3-((4^lR)-2^l,2'-dimethyl-r,3^l-dioxolan-4^l-yl)-1-(4- fluorophenyl)azetidin-2-one

To the Schlenk flask containing the suspension of copper(l) iodide (0.5 mmol, 95 mg) in acetonitrile (3 ml) under inert atmosphere, 0.28 ml (2.0 mmol) of triethylamine is added. After cooling to 0⁰C 0.5 mmol (65 mg) of (R)-4-ethenyl-2,2- dimethyl-1 ,3-dioxolane is added. The resulting solution is stirred at 0⁰C for 20 min. Then a suspension of (Z)-N-(4-(benzyloxy)benzylidene)-4-fluoroaniline-N-oxide (1.0 mmol, 321 mg) in acetonitrile (3 ml) is added. The resulting slurry is mixed under inert atmosphere for 24 hours. Next the mixture is diluted with diethyl ether (20 ml), filtered through Celite and concentrated in vacuo. The resulting residue is subjected to chromatography on neutralized silica gel with hexane/ethyl acetate (2:1 ) mixture as eluent. Resulting title compound is crystallized from ethanol, to obtain 160 mg (70%) of colourless crystals.

¹H NMR (500 MHz, CDCI₃), δ: 7.50-6.80 (13H, Ar), 5.23 (1 H, d, J 5.6 Hz, H-4), 5.05 (2H, m, CH₂OBn), 4.00-3.90 (2H, m, H-5'), 3.85 (1 H, m, H-4'), 3.74 (1 H, dd, J

9.2. 5.6 Hz, H-3), 1.35 (3H, s, Me), 1.04 (3H, s, Me). ¹³C NMR (125 MHz, C₆D₆, carbon atoms of Ar groups are omitted): 159.1 , 72.5, 70.9, 67.3, 61.7, 58.3, 57.3,

26.8, 25.4. IR (film) 1756 cm^"1. HRMS(ESI): calc. for C₂₇H₂₆FNO₄Na [M+Na⁺]

470.1744; found: 470.1740. Anal.: calc. for C₂₇H₂₆FNO₄: C 72.47, H 5.86, N 3.13; found: C 72.40, H 5.85, H 3.13. Example 19

(3R,4S)-4-(4-(Benzyloxy)phenyl)-3-((1¹R)-I \2'-dihydroxyethyl)-1 -(4-fluorophenyl)- azetidin-2-one

To a solution of (3R_J4S)-4-(4-(benzyloxy)phenyl)-3-((4^lR)-2'_J2^l-dimethyl-1 ^l _J3¹- dioxolan-4'-yl)-1 -(4-fluorophenyl)azetidin-2-one (0.5O g, 1.1 mmol) in a tetrahydro- furan/water mixture (1 :1 , 50 ml) 0.57 g of thfluoroacetic acid (5.0 mmol) is added.

After stirring for 24 hours the reaction mixture is diluted with tetrahydrofuran (25 ml), cooled to 0⁰C, potassium carbonate (0.41 g, 3.0 mmol) is added and the mixture is stirred for further 15 min. Then 10 ml of water is added and the resulting mixture is extracted with ethyl acetate (3x50 ml). The combined organic layers are dried over anhydrous sodium sulphate. After removing solvent 0.40 g (90%) of the title compound is obtained in the form of thick oil.

¹H NMR (500 MHz, CDCI₃/D₂O), δ: 7.46-6.92 (13H, Ar), 5.30 (1 H, d, J 5.4 Hz, H- 4), 5.05 (2H, m, CH₂OBn), 3.97-3.88 (2H, H-2'), 3.75 (1 H, m, H-T), 2.81 (1 H, m, H-3). IR (film): 3330, 1754 cm^"1. HRMS (ESI): calc. for C₂₄H₂₂FNO₄Na [M+Na⁺] 430.1431 ; found: 430.1428. Anal.: calc. for C₂₄H₂₂FNO₄: C 70.75, H 5.44, N 3.44; found: C 70.71 , H 5.42, N 3.45.

Example 20

(3S,4S)-4-(4-(Benzyloxy)phenyl)-1 -(4-fluorophenyl)-3-formyl-azetidin-2-one To a solution of (3R,4S)-4-(4-(benzyloxy)phenyl)-3-((1¹R)-I \2'-dihydroxyethyl)-1 -

(4-fluorophenyl)azetidin-2-one (0.1 g, 0.25 mmol) in acetonitrile (25 ml) sodium bicarbonate (20 mg, 0.25 mmol) is added, and after cooling to 5°C a solution of

NaIO₄ (80 mg, 0.37 mmol) in 2 ml of water is added dropwise. The reaction progress is controlled successively by performing ¹H NMR spectra that show the initial formation of (3R,4S)-4-(4-(benzyloxy)phenyl)-1 -(4-fluorophenyl)-3-formyl- azetidin-2-one and then its disappearance and the formation of the title compound

(as a result of isomerisation of 3,4-cis-azetidinone to 3,4-trans-azetidinone). After stirring for 4 hours at room temperature, the reaction mixture is placed in a separatory funnel and extracted with toluene (3 x 20 ml). The combined toluene layers are washed with brine (10 ml), and then dried over sodium sulphate. Removal of solvent afforded 80 mg (85%) of crystalline product with melting point 75-77°C.

(3S,4S)-4-(4-(Benzyloxy)phenyl)-1-(4-fluorophenyl)-3-formyl-azetidin-2-one:

[α]_D +43° (c 1.1 , CH₂CI₂). ¹H NMR (500 MHz, CDCI₃), δ: 9.80 (1 H, d, J 1.1 Hz), 7.40-6.80 (13H₁ Ar), 5.30 (1 H, d, J 2.5 Hz), 5.00 (2H, m), 4.12 (1 H, dd, J 2.5. 1.1 Hz). IR (film): 1755. 1729 cm^"1. HRMS (ESI): calc. for C₂₅H₂₄FNO₄Na [M+EtOH+Na⁺] 444.1587; found 444.1584. Anal.: calc. for C₂₃Hi₈FNO₃: C 73.59, H, 4.83, N 3.73; Found: C 73.55, H 4.80, H 3.72.

Example 21 Compound of formula 1g

To a solution of aldehyde 1d (10 g, 26.7 mmol) in toluene (50 ml) borium trifluoride etherate (3.2 ml, 26.7 mmol) is added. While cooling to -30⁰C, enol ether 1e (5.6 g, 26.7 mmol) is added dropwise. After completion of the aldol reaction the reaction mixture is added dropwise to the mixture of saturated aqueous sodium bicarbonate (100 ml), t-butylmethyl ether (200 ml) and hydrogen peroxide (30%, 15 ml) cooled to 0⁰C. The resulting mixture is allowed to warm to room temperature, the organic layer is separated and the aqueous layer extracted with toluene. The combined organic layers are concentrated, and after addition of molecular sieves (20 g) and p-toluenesulfonic acid (2.5 g, 13.3 mmol) are heated at 40-50°C for 4 hours. Then the mixture is cooled, filtered through a silica gel pad and concentrated. The crude product is dissolved in methylene chloride (40 ml) and 0.7 g (0.8 mmol) of tris(triphenylphosphine)rhodium chloride is added. Resulting mixture is hydrogenated under a pressure of 4.5 bars for 18 hours. After evaporation of the solvent the residue is purified by column chromatography (hexane/ethyl acetate 9:1 ) to afford compound 1g (9.0 g). ¹H NMR (CDCI₃), δ: 2.28 (m, 1 H), 2.40 ( m, 1 H), 3.16 (m, 1 H), 3.28 (m, 1 H), 3.65 (m, 1 H), (4.68. d, 1 H), 5.04 (s, 2H), 6.55 (m, 4H), 7.12 (t, 2H), 7.25 (m, 4H), 7.41 (m, 5H), 7.98 (dd, 1 H).

Example 22 Compound of formula 1h

To the solution of compound 1g (6.2 g, 12.5 mmol) in methylene chloride (60 ml) at -20⁰C a catalyst (0.1 eq) and borate-dimethyl sulphide complex (6.3 ml, 12.5 mmol) are added portionwise during 2 hours. The reaction is allowed to warm to

0⁰C, stirred for 1 hour and treated with methanol. Then the mixture is concentrated and extracted with methylene chloride. The organic layer is concentrated and the residue is crystallized from a mixture of ethyl acetate and hexane to obtain 4.1 g of compound 1h.

¹H NMR (CDCI₃), δ: 1.95-1.75 (m, 4H), 2.10-2.20 (m, 1 H), 2.97-3.05 (m, 1 H), 4.50 (d, 1 H), 4.60-4.70 (m, 1 H), 4.98 (s, 2H), 6.80-7.00 (m, 6H), 7.15-7.45 (m, 11 H).

Example 23 Compound of formula 1

Pd/C (10%, 0.1 g), ammonium bicarbonate (1.14 g, 18. 1 mmol), compound 1h (1.8 g, 3.63 mmol) and methanol (25 ml) are placed in a flask under nitrogen atmosphere. Then pH is adjusted to 3-5 using acetic acid and the mixture is heated at 45-55°C for 3 hours. Then the mixture is filtered, the solvent is evaporated and the residue is dissolved in t-butylmethyl ether and washed with water. Organic layer is dried over Na2SO₄ and the solvent is evaporated. The crude product is crystallized from aqueous methanol (0.5 g).

¹H NMR (DMSO-de), δ: 1.70-1.9 (m, 4H), 3.10 (m, 1 H), 4.50(m, 1 H), 4.82 (d, 1 H), 5.3 (d, 1 H), 6.77 (d, 2H), 7.35 (m, 4H), 7.21 (m, 4H), 7.32 (dd, 2H), 9.54 (s, 1 H).

Claims

1. A process for the preparation of an aldehyde beta-lactam compound of formula (I)

(I) wherein P¹ represents hydrogen atom or a protecting group for aromatic hydroxyl, characterized in that it comprises

- preparing a nitrone compound of formula (II)

(Vl) with a compound of formula (VII)

(VII) or by oxidation of a compound of formula (VIII),

(VIII) with a peroxide reagent, wherein in said formulas (VII) and (VIII) P¹ has the meaning as defined above, and ^₁ represents single bond and a is 1 , or — represents double bond and a is 0,

- reacting the nitrone compound of formula (II)

(H) with an acetylene compound of formula (III) p2a₀

P^2bO→( R

(ill) wherein each of P^2a and P^2b represents hydrogen atom or a protecting group for aliphatic hydroxyl, or P^2a and P^2b represent a joint protecting group for aliphatic 1 ,2-diol, and R represents hydrogen atom or Ci_-6alkyl, in the presence of a base and a copper compound, optionally in a solvent, to obtain a compound of formula (IV)

(IV), wherein P¹, P^2a, P^2b and R have the meanings as defined above, and then optionally removing one of the protecting groups P^2a and P^2b or both protecting groups P^2a and P^2b to obtain the compound of formula (IV), wherein one of P^2a and P^2b represents H or each of P^2a and P^2b represents H, and oxidation of the compound of formula (IV) in a solvent using a compound of the element in the high oxidation state as an oxygen reagent, to obtain an aldehyde of formula (V)

(V) wherein P¹ has the meaning as defined above, and - isomerisation of said compound of formula (V) in a solvent, optionally in the presence of a base, to the compound of formula (I)

(I)-

2. The process of claim 1 characterized in that P¹ represents hydrogen atom, d-βalkyl, d-βalkenyl, d-βalkynyl, Ci-ioalkanoyl, Cβ-ioaroyl, C6-ioaryl-Ci-6alkyl, Ci-ealkoxy-Ci-ealkyl, C_4-5cyclic ether group, Ci_-6alkanesulfonyl, C_6-io arenesulfonyl or (Ci-6alkyl)n(C6-ioaryl)mSilyl, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3, and each of P^2a and P^2b is selected from the group consisting of hydrogen atom, C_halky!, d-βalkenyl, Ci_-6alkynyl, C_6-io alkanoyl, C_6-ioaroyl, C_6-io aryl-Ci_-6alkyl, Ci_-6alkoxy-Ci_-6alkyl, C_4-5 cyclic ether group, and (Ci-₆ alkyl)_n(C₆-io aryl)_msilyl, wherein n and m represents an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3, or P^2a and P^2b are joined with each other and together represent a methylene group optionally substituted with 1 -2 Ci_-4alkyl substituents, wherein said two Ci_-4 alkyl substituents may be joined with each other to form together with the methylene group carbon atom a cycloalkyl ring.

3. The process according to claim 1 or 2 characterized in that the copper compound is at least one copper(l) compound, preferably selected from the group consisting of copper(l) iodide, copper(l) bromide, copper(l) chloride and copper(l) triflate.

4. The process according to claim 1 or 2 characterized in that the copper compound is at least one copper(ll) compound combined with a reducing compound, preferably selected from the group consisting of the combinations copper(ll) sulphate/sodium ascorbate, copper(ll) chloride/sodium ascorbate and copper(ll) acetate/sodium ascorbate.

5. The process according to claim 3 or 4 characterized in that at most 3 equivalents of the copper compound relative to the compound of formula (III) are used, preferably from 0.01 to 1 equivalent.

6. The process according to any of the claims 1 -5 characterized in that in the reaction of the compound of formula (II) with the compound of formula (III) a secondary or tertiary organic amine is used as the base.

7. The process according to claim 6 characterized in that the amine is selected from the group consisting of thalkylamines, such as triethylamine or N₁N- diisopropylethylamine; alkyldi(cycloalkyl)amines, such as N-methyldicyclohexyl- amine; dialkylamines with branched alkyl substituents, such as diisopropylamine; di(cycloalkyl)amines, such as dicyclohexylamine; and heterocyclic amines, such as pyridine.

8. The process according to claim 7 characterized in that triethylamine is used in an amount of at least 4 equivalents relative to the compound of formula (III).

9. The process according to any of claims 1 -5 wherein in the reaction of the compound of formula (II) with the compound of formula (III) an alkali metal or alkaline earth metal carbonate is used as the base.

10. The process according to claim 9 wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate.

11. The process according to any of the claims 1 -7 or 9 or 10 wherein the solvent in the reaction of the compound of formula (II) with the compound of formula (III) is selected from the group consisting of aromatic hydrocarbons, chlorinated aliphatic hydrocarbons, aliphatic ethers, aliphatic nitriles, and N,N-di- (Ci-6alkyl)aliphatic amides.

12. The process according to claim 11 wherein the solvent is selected from the group consisting of acetonitrile, toluene, benzene, and N,N-dimethylformamide.

13. The process according to any of the claims 1 -12 wherein the oxygen compound of the element in the high oxidation state reagent is a pehodate compound, preferably periodic acid, sodium periodate, potassium periodate or tetralkylammonium periodate, such as tetrabutylammonium periodate and cetylthmethylammonium periodate; or lead tetraacetate.

14. The process according to any of the claims 1 -13 wherein the solvent in the oxidation reaction of the compound of formula (IV) to the compound of formula (V) is selected from the group consisting of tetrahydrofuran, acetonitrile and their mixtures with water.

15. The process according to any of the claims 1 -14 wherein the solvent in the isomerisation reaction of the compound of formula (V) to the compound of formula (I) is selected from the group consisting of tetrahydrofuran, acetonitrile and their mixtures with water.

16. The process according to any of the claims 1 -15 wherein in the isomerisation of the compound of formula (V) to the compound of formula (I) at least a catalytic amount of the base is used, said base being selected from the group consisting of alkali metal carbonates and bicarbonates and non-nucleophilic organic amines, such as 1 ,5-diazabicyclo[4.3.0]non-5-ene and 1.8-diazabicyclo- [5.4.0]undec-7-ene.

17. The process according to any of the claims 1 -16 wherein the oxidation of the compound of formula (IV) to the compound of formula (V) and the isomerisation of the compound of formula (V) to the compound of formula (I) are carried out without isolating the compound of formula (V).

5 18. The process according to any of the claims 1 -17 wherein the peroxide reagent is selected from the group consisting of dimethoxydioxirane, H₂O₂ZMeReO₃, H₂O₂ZNa₂WO₄, H₂O₂/SeO₂ , Oxone^®/SeO₂ , Oxone^®, m-chloroper- benzoic acid, tert-butyl peroxide, cumyl peroxide and Davis reagent.

19. A compound of formula (II)

(H) wherein

P¹ represents hydrogen atom, Ci_-6alkyl, Ci_-6alkenyl, Ci_-6alkynyl, Ci-i₀alkanoyl, C_6-ioaroyl, C6-ioaryl-Ci_-6alkyl, Ci-ealkoxy-Ci-ealkyl, C_4-5cyclic ether group, Ci_-6alkane- i5 sulfonyl, Cβ-ioarenesulfonyl, or (Ci-₆alkyl)_n(C₆-ioaryl)_msilyl, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3, in the form of the isomer Z and/or isomer E.

20. The compound of claim 19 characterized in that P¹ represents hydrogen atom, methyl, ethyl, n-propyl, allyl, propargyl, acetyl, pivaloyl, benzoyl, benzyl,

20 methoxymethyl, 2-tetrahydrofuranyl, 2-tetrahydropyranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methanesulfonyl, thfluoromethanesulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, in the form of the isomer Z and/or E.

21. The compound according to claim 20 which is selected from the group 25 consisting of the following:

(Z)-Λ/-(4-(hydroxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(benzyloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-/\/-(4-(nnethoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(ethoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(n-propoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-/V-(4-(methoxynnethoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tetrahydro-2/-/-pyran-2'-yloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tetrahydrofuran-2'-yloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-acetoxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-benzoyloxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-pivaloyloxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-/V-(4-(methylsulfonyloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tosyloxy)benzylidene)-4-fluoroaniline-N-oxide, and (Z)-Λ/-(4-(fe/t-butyldiphenylsilyloxy)benzylidene)-4-fluoroaniline-N-oxide,

22. A compound of formula (IV)

(IV) wherein

P¹ represents hydrogen atom, Ci_-6alkyl, Ci_-6alkenyl, Ci_-6alkynyl, Ci-i₀alkanoyl, C_6-ioaroyl, C₆-ioaryl-Ci_-6alkyl, Ci-ealkoxy-Ci-ealkyl, C_4-5cyclic ether group, Ci_-6alka- nesulfonyl, Cβ-ioarenesulfonyl, or (Ci-₆alkyl)_n(C₆-ioaryl)_msilyl, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3, and each of P^2a and P^2b is selected from the group consisting of hydrogen atom, Ci_-6alkyl, Ci_-6alkenyl, Ci_-6alkynyl, Ci-i₀alkanoyl, C_6-ioaroyl, C6-ioaryl-Ci_-6alkyl, Ci_-6- alkoxyCi-βalkyl, C_4-5cyclic ether group, and (Ci-6alkyl)_n(C6-ioaryl)_msilyl, wherein n and m represents an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3, or P^2a and P^2b are joined with each other and together represent a methylene group unsubstituted or substituted with 1 -2 Ci_-4alkyl substituents, wherein said two Ci_-4alkyl substituents may be joined with each other to form together with the methylene group carbon atom a cycloalkyl ring, and R represents hydrogen atom or C_halky!.

23. The compound according to claim 22 wherein P¹ represents hydrogen atom, methyl, ethyl, n-propyl, allyl, propargyl, acetyl, pivaloyl, benzoyl, benzyl, methoxymethyl, 2-tetrahydrofuranyl, 2-tetrahydropyranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylosilyl, methanesulfonyl, thfluoromethanesulfonyl, ethanesulfonyl, benzenesulfonyl, or p-toluenesulfonyl, and each of P^2a i P^2b is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, allyl, propargyl, acetyl, pivaloyl, benzoyl, benzyl, methoxymethyl, 2-tetrahydrofuranyl, 2-tetrahydropranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl, or P^2a and P^2b together represent methylene, ethylidene, isopropylidene, cyclopentylidene or cyclohexylidene, and

R represents hydrogen atom or Ci-β alkyl.

24. The compound according to claim. 23 wherein said compound is selected from the group consisting of:

(3R,4S)-4-(4-(benzyloxy)phenyl)-3-((R)-2^l,2'-dimethyl-r,3^l-dioxolan-4^l-yl)-1 -(4- fluorophenyl)azetidin-2-one, and

(3R,4S)-4-(4-(benzyloxy)phenyl)-3-((R)-1 ',2'-dihydroxyethyl)-1-(4-fluorophenyl)- azetidin-2-one.

25. A process for the preparation of a compound of formula (IV)

(IV) wherein P¹ represents hydrogen atom or a protecting group for aromatic hydroxyl, each of P^2a and P^2b represents hydrogen atom or a protecting group for aliphatic hydroxyl, or P^2a i P^2b represent joint protecting group for aliphatic 1 ,2-diol, and R represents hydrogen atom or Ci_-6alkyl, characterized in that it comprises reacting a nitrone compound of formula (II)

(H) wherein P¹ represents hydrogen atom or a protecting group for aromatic hydroxyl, with an acetylene compound of formula (III) p2a₀

P²O^

R

wherein each of P^2a and P^2b represents hydrogen atom or a protecting group for aliphatic hydroxyl, or P^2a and P^2b represent joint protecting group of aliphatic 1 ,2- diol, and R represents hydrogen atom or Ci_-6alkyl, in the presence of a base and a copper compound, optionally in a solvent.

26. The process according to the claim 25 characterized in that P¹ represents hydrogen atom, Ci_-6alkyl, Ci_-6alkenyl, Ci_-6alkynyl, Ci-i₀alkanoyl, C_6-ioaroyl, C_6-io aryl-Ci_-6alkyl, Ci-ealkoxy-Ci-ealkyl, C_4-5 cyclic ether group, Ci_-6alkanesulfonyl, Cβ-ioarenesulfonyl, or (Ci-₆alkyl)_n(C₆-ioaryl)_msilyl, wherein n and m represent an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3, and each of P^2a and P^2b is selected from the group consisting of hydrogen atom, Ci_-6 alkyl, Ci_-6 alkenyl, Ci_-6alkynyl, Ci-i₀alkanoyl, C_6-ioaroyl, C6-ioaryl-Ci_-6alkyl, Ci-ealkoxy-Ci-e- alkyl, C_4-5cyclic ether group, d-βalkanesulfonyl, Cβ-ioarenesulfonyl, and (Ci-6alkyl)_n(C6-ioaryl)_msilyl, wherein n and m represents an integer from 0 to 3, inclusive, with the proviso that the sum m+n is 3, or P^2a and P^2b are joined with each other and together represent a methylene group unsubstituted or substituted with 1 -2 Ci_-4 alkyl substituents, wherein said two Ci_-4alkyl substituents can be joined with each other to form together with the methylene group carbon atom a cycloalkyl ring.

27. The process according to claims 25 or 26 wherein the copper compound is at least one copper(l) compound, preferably chosen from the group consisting of copper(l) iodide, copper(l) bromide, copper(l) chloride, and copper(l) triflate.

28. The process according to claims 25 or 26 wherein the copper compound is at least one copper(ll) compound combined with a reducing agent, preferably selected from the group consisting of combinations: copper(ll) sulphate/sodium ascorbate, copper(ll) chloride/sodium ascorbate, and copper(ll) acetate/sodium ascorbate.

29. The process according to claims 27 or 28 wherein at most 3 equivalents of the copper compound relative to the compound of formula (III) are used, and preferably from 0.01 to 1 equivalent.

30. The process according to any of the claims 25-29 wherein the base is a secondary or tertiary organic amine.

31. The process according to claim 30. wherein the amine is selected from the group consisting of thalkylamines, such as thethylamine or N,N-diisopropylethyl- amine; alkyldi(cycloalkyl)amines, such as N-methyldicyclohexylamine; dialkyl- amines with branched alkyl substituents, such as diisopropylamine; di(cycloalkyl)- amines, such as dicyclohexylamine; and heterocyclic amines, such as pyridine.

32. The process according to claim 30 wherein triethylamine is used in an amount of at least 4 equivalents relative to the compound of formula (III).

33. The process according to any of the claims 25-29 wherein the base is an alkali metal or alkaline earth metal carbonate.

34. The process according to claim 33 wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate.

35. The process according to any of the claims 25-31 or 33 or 34 wherein the solvent is selected from the group consisting of aromatic hydrocarbons, chlorinated aliphatic hydrocarbons, aliphatic ethers, aliphatic nitriles, and N,N-di- (Ci_-6alkyl)aliphatic amides.

36. The process according to claim 35. wherein the solvent is selected from the group consisting of acetonitrile, toluene, benzene, and N,N-dimethylformamide.

37. The use of a compound of formula (II) for the preparation of ezetimibe.

38. The use according to claim 37 wherein the compound of formula (II) is: (Z)-Λ/-(4-(hydroxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(benzyloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(methoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(ethoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(n-propoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(methoxymethoxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tetrahydro-2/-/-pyran-2'-yloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tetrahydrofuran-2'-yloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-acetoxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-benzoyloxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-pivaloyloxybenzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(methylsulfonyloxy)benzylidene)-4-fluoroaniline-N-oxide, (Z)-Λ/-(4-(tosyloxy)benzylidene)-4-fluoroaniline-N-oxide, or (Z)-Λ/-(4-(fe/t-butyldiphenylsilyloxy)benzylidene)-4-fluoroaniline-N-oxide.