WO2004103966A1

WO2004103966A1 - Chiral 2-azetidinone compounds, process and use thereof

Info

Publication number: WO2004103966A1
Application number: PCT/KR2004/001215
Authority: WO
Inventors: Deok-Chan Ha; You Sang Lee; Kyoung Hoon Kim; Tea Won Kang; Kwan Jun Jeon; Hyoung Geun Baek
Original assignee: Ckd Bio Corporation
Priority date: 2003-05-21
Filing date: 2004-05-21
Publication date: 2004-12-02
Also published as: KR20040099963A; WO2004103966B1

Abstract

The present invention relates to a chiral 2-azetidinone compound, a method of its preparation and a use thereof. In particular, the present invention relates to a 2-azetidinone compound with superior stereoselectivity, which is obtained by the reaction between 4-acetoxy-2-azetidinone compound, and a propiophenone derivative or its salt and its use as an intermediate for manufacturing β-methylcarbapenem antibiotics.

Description

CHIRAL 2-AZETIDINONE COMPOUNDS, PROCESS AND USE THEREOF

Technical Field

The present invention relates to a chiral 2-azetidinone compound, a method of its preparation and a use thereof. In particular, the present invention relates to a chiral 2-azetidinone compound with superior stereoselectivity represented by the formula 1 which is obtained by the reaction between 4-acetoxy-2-azetidinone compound represented by the formula 2 and a propiophenone derivative or its salt represented by the formula 3.

In the above reaction, R represents a hydroxy protecting group and R¹, R² and R³ represent a hydrogen atom or a hydroxy group.

This invention also relates to a method for the preparation of a 4-ρropionic acid-2-azetidinone compounds shown by the formula 4, which are intermediates useful for β-methylcarbapenem antibiotics, through oxidation of a 2-azetidinone compound represented by the formula 1. Oxida —tio **,n

In the above reaction, R, R¹, R² and R³ are the same as defined above.

Background Art β-Methylcarbapenem antibiotics, such as meropenem and biapenem, exhibit excellent antibacterial activities for both gram positive and gram negative bacteria and they also have excellent pharmacological effects against those bacteria showing high resistance to the traditional penicillin or cephasporin antibiotics. β-Lactam compounds have been used as essential intermediates for the synthesis of β-methylcarbapenem antibiotics. In particular, numerous studies have been done to elicit the way for selective introduction of a β-methyl group and two methods have been known as such so far.

One method is to hydroformylate a 4-vinyl-2-azetidinone compound represented by the formula 5 in the presence of a palladium catalyst, carbon dioxide, and a hydrogen gas, sequentially oxidize resulting aldehyde to a 4-propionic acid-2- azetidinone compound represented by the formula 4.

In the above reaction, R represents a hydroxy protection group.

The above method is disadvantageous in that it requires a relatively lengthy process comprising steps of introducing an amine protecting group, such as t-Boc group, and a hydroxy protecting group to the compound represented by the formula 5 in order to improve stereoselectivity of a β-methyl group conformation of the resulting compound represented by the formula 4.

Another method comprises preparing an enolate derivative of the formula 6 which are introduced a propionyl group to an amide derivative, performing a condensation reaction of an enolate derivative of the formula 6 with a 4-acetoxy-2- azetidinone compound represented by the formula 2 to produce a compound represented by the formula 7, and converting the resulting compound to a 4- propionic acid-2-azetidinone compound represented by the formula 4.

In the above reaction, R is a hydroxy protecting group, X and Y independently represents an oxygen atom or a sulfur atom, and Ri, R₂, R3 and R4 independently represents a hydrogen atom, a lower alkyl group or an aralkyl group. The amide derivatives used in the second method are chiral or non-chiral oxazolidine derivatives, and the reactants that are used in the preparation of enolate derivatives are expensive ones such as titanic chloride, stannous triflate, dibutylboron triflate, etc. This method enables to maximize stereoselectivity in introducing a β-methyl group to some extent, however, it is still hard to be applied to industry due to the difficulties in the step of forming enolates from oxazolidine derivatives with respect to cost and process.

Korean Pat. No. 231223 discloses a method to overcome the problems in forming enolates in the second method which was developed by Tanabe Corp, Japan. In this method, Reformatsky reaction is performed to treat a compound represented by the formula 7 with magnesium or zinc, and resulting magnesium or zinc enolates are reacted with 4-acetoxy-2-azetidinone compound represented by the formula 2 to produce a compound represented by the formula 9. It also discloses a method for preparing a compound represented by the formula 4 or for obtaining a double- ringed intermediate of carbapenem compound via N-alkylation of the compound represented by the formula 9 and cyclization.

In the above reaction, R is a hydroxy protecting group, Z is a methylene group where one or two alkyl groups are substituted, Y represents an oxygen atom, a sulfur atom or methylene, etc., and ring B represents a benzene ring where a halogen atom, an alkyl group or an alkoxy group is substituted.

Korean Patent Laid-Open No. 2002-13988 discloses a method for preparing carbapenem antibiotics, similar to that of the aforementioned Korean Pat. No. 231223, where a compound represented by the formula 10 undergoes a Reformatsky reaction to produce a compound represented by the formula 11 and this is again used to prepare carbapenem antibiotics.

In the above reaction, R is a hydroxy protecting group, Ri and R are same lower alkyl groups or ring compounds connected to each other, R3 is a lower alkyl group, and R4 is a substituted benzene group.

However, the enolate derivatives used in the above Korean Pat. No. 231223 and Korea Pat. Laid Open No. 2002-13988 as represented by the formulas 8 and 10, respectively, have a few drawbacks from the industrial point of view that the process for the preparation of the enolates is a multi-step process and a strict anhydrous condition is required for performing a Reformatsky reaction with 4- acetoxy-2-azetidinone represented by the formula 2.

In contrast, the present invention selectively uses a propiophenone derivative represented by the formula 3, which can easily replace the enolate derivatives commonly used in the conventional methods, thereby remarkably reducing the entire reaction process, and more specifically, the superior stereoselectivity of 1 β-methyl group allows high yield of the chiral 2-azetidinone compound.

Therefore, the object of the present invention is to provide a noble chiral 2- azetidinone compound, which is a useful intermediate for β-methylcarbapenem antibiotics, and a method for preparing the same.

Disclosure of Invention

The present invention relates to a noble chiral 2-azetidinone compound represented by the following formula 1 which can be a useful intermediate for β- methylcarbapenem antibiotics

(1) wherein R represents a typical hydroxy protecting group containing a silyl or benzyl group, and R¹, R² and R³ respectively represents a hydrogen atom or a hydroxy group.

The present invention is described in greater detail as follows. The compound represented by the above formula 1 is a chiral compound where the position of C-l¹ has an R-configuration.

R of formula 1 represents, as described above, a traditional hydroxy protecting group containing a silyl or benzyl group, preferably a t- butyldimethylsilyl group. The most preferable compound of formula 1 is represented such that R is t-butyldimethylsilyl group, R¹ is a hydroxy group, and R² and R³ are respectively a hydrogen atom.

The present invention also relates to a method for preparing a compound represented by the formula 1, wherein an azetidinone compound represented by the following formula 2 is reacted with a propiophenone derivative represented by the formula 3 in the presence of an amine base and a metal halide compound.

In the above reaction, R, and R¹, R² and R³ are the same as defined in the above formula 1.

Examples of amine bases to be used in the above reaction are trialkyl amines, wherein three lower alkyl groups with same or different number of from 1 to 6 carbon atoms are substituted, such as triethylamine, tripropylamine, and tri-n- butylamine. Examples of metal halide compounds to be used in the above reaction are those which can easily form metal enolates to give a complex with a hydroxy group within a molecule, such as titanium(IV) chloride, aluminum chloride, tin chloride, magnesium chloride, tin bromide, magnesium bromide, etc.

Examples of solvents used in the above reaction are those which can well dissolve metal enolates and maintain Lewis acidity of the metal enolates such as dichloromethane, chloroform, 1,2-dichloroethane, etc.

In the above reaction, a propiophenone derivative represented by the formula 3 can be used 1.0 to 3 molar equivalents, preferably 2.0 to 2.5 molar equivalents per mole of the 4-acetoxy-2-azetidinone represented by the formula 2, preferably 2-2.5 equivalents. Metal halide compound is used the same equivalent with regard to the propiophenone derivative represented by the formula 3. Amine base is used 2.5-3 equivalents with regard to the propiophenone derivative represented by the formula 3.

The formation of a metal enolate by the reaction of a propiophenone derivative represented by the formula 3 with an amine base and a metal halide compound is preferably performed at a temperature of from -80 ^°C to -30 ^°C . The reaction between resulting metal enolate and 4-acetoxy-2-azetidinone represented by the formula 2 is preferably performed at a temperature of from -30 ^°C to 0 ^°C to improve the selectivity of 1 β-methyl conformation of the compound represented by formula 1. The chiral azetidinone compound with a novel structure as represented by the above formula 1 prepared according to the present invention is a very useful intermediate for β-methylcarbapenem antibiotics. Accordingly, an objective of the present invention is to prepare a 4-propionic acid-2-azetidinone compound represented by the formula 4 by oxidation of a chiral azetidinone compound represented by the formula 1

Oxidation

In the above reaction, R, R¹, R² and R³ are the same as defined in the above formula 1.

The above oxidation reaction is performed as follows: a compound represented by the formula 1 is dissolved in a solvent, added with silica gel and the solvent is removed and reacted with ozone to convert 2-hydroxyphenylcarbonyl group to a carboxylic acid group by oxidation.

Examples of solvents to be used in the oxidation reaction are those which can be easily removed under reduced pressure such as dichloromethane, diethyl ether, methanol, ethyl acetate, hexane, etc. The reaction with ozone is preferably performed at a temperature of from -80 °C to -50 ^°C .

In the present invention, 'lower alkyl group' and 'lower alkoxy group' respectively refer to a straight backbone or a branched side chain having carbon atoms of 1 - 6.

This invention is explained in more detail based on the following Examples but they should not be constructed as limiting the scope of this invention. Examples

Example 1: Synthesis of an azetidinone derivative

1.29 mL of 2'-hydroxyρropiophenone was dissolved in 20 mL of dichloromethane. The temperature of the resulting mixture was reduced to -78 ^°C, slowly added with 1.0 mL of titanium(IV) chloride and allowed to react for 30 min. The resulting mixture was added with 6.3 mL of tri-n-butylamine and allowed to react for 30 min. Then its temperature was slowly increased to -40 ^°C and allowed to react for another 30 min. To the above mixture was added dropwisely 1.17 g of (3R,4R)-4-acetoxy-3-[(l'R)-l'-t-butyldimethylsilyloxymethyl]-2-azetidinone and the temperature of the mixture was slowly increased to -20 ^°C and allowed to react. After stirring for 14 hr, the mixture was diluted in ethyl acetate and added with 80 mL of saturated ammonium chloride solution and its aqueous phase was extracted 3 times with 150 mL of ethyl acetate. Then, the extract was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resultant was recrystallized with ethyl acetate and n-hexane and finally obtained 1.2 g (78%, de=98%) of target compound in the form of white solid with cotton shape.

Thus obtained target compound is present as a mixture of stereoisomers of l'R and l'S according to the chirality of a methyl group at C-l' position. Analysis of thus obtained target compound by HPLC (Chiralpak CAPCELL PAK C18 column, eluent: water/ acetonitrile = 4/6) revealed that the ratio between l'R isomer : IS' isomer was 99 : 1.

mp 170.5 °C;

CHCls); 1634, 1760, 3095, 3176; Η NMR(CDC1₃, 300MHz) δ 0.058(d, 6H, J=5Hz), 0.86(s, 9H), 1.15(d, 3H, J=6Hz), 1.34(d, 3H, J=7Hz), 2.92(dd, 1H, J=2, 2 Hz), 3.75(m, 1H), 4.00(dd, 1H, J=2, 2Hz), 4.12(m, 1H), 6.00(s, 1H), 6.93-7.74(m, 4H, aromatic), 12.27(s, 1H).

Example 2: Synthesis of a β- methylcarbapenem derivative

2.7 g of silica gel (70-130 mesh) and 103 mg of (3R,4R)-3-[(lR)-l-t- butyldimethylsilyloxymethyl]-4-[(lR)-l-(2'-hydroxybenzoyl)ethyl]-2-azetidinone were dissolved in 50 mL of dichloromethane, and then dichloromethane was removed under reduced pressure. The temperature of the resulting mixture was decreased to -78 ^°C, introduced with ozone for 10 min, and then the temperature was slowly increased to room temperature. Silica gel was washed with ethyl acetate and the filtrate was distilled under reduced pressure. The white residue was passed through column chromatography (eluent: ethyl acetate/ n-hexane/ formic acid = 100/150/1) and finally obtained 49 mg (60%) of a target compound. Η NMR(CDC1₃, 300MHz) δ 0.072(d, 6H, J=2Hz), 0.87(8, 9H), 1.20(d, 3H, J=6Hz), 1.27(d, 3H, J=7Hz), 2.76(m, IH), 3.04(dd, IH, J=2, 2Hz), 3.95(dd, IH, J=2, 2Hz), 4.21(m, IH), 6.29(s, IH), 7.26(s, IH)

Reference Example

The methods of preparing 2-azetidinone compound with β-methyl group which are known as essential intermediates for the synthesis of β- methylcarbapenem antibiotics has been disclosed [Tetrahedron 52, Vol 2, pp. 331-375, 1996]. The reactions utilizing metal enolates produced from propionic acid derivatives and amine base as in the present invention are summarized in the following Table 1.

Table 1 Synthesis of intermediates for β-methylcarbapenem antibiotics using propionic acid derivatives

Reaction β:α

X Yield Manufacturer Condition Ratio

As shown in the above Table 1, the present invention exhibits much improved selectivity and yield in the introduction of β-methyl group which is essential in the synthesis of β-methylcarbapenem antibiotics as compared to conventional methods.

Industrial Applicability

As mentioned above, the present invention provides a method to effectively introduce a β-methyl group to C-l' position of 4-acetoxy-2-azetidinone compound represented by the formula 2 by using a propiophenone derivative represented by the formula 3, and chiral 2-azetidinone compound represented by the formula 1 produced by this method enables to effectively prepare useful intermediates for carbapenem antibiotics.

Claims

1. Chiral 2-azetidinone compound represented by the following formula 1,

wherein R represents a hydroxy protecting group and R¹, R² and R³ respectively represents a hydrogen atom or a hydroxy group.

2. In claim 1, said R is a t-butyldimethylsilyl group, R¹ is a hydroxy group, and R² and R³ respectively represents a hydrogen atom.

3. A method of preparing chiral 2-azetidinone compound represented by the following formula 1 by reacting a propiophenone compound represented by the formula 3 and 4-acetoxy azetidinone compound represented by the formula 2 in the presence of an amine base and a metal halide compound,

wherein said R, R¹, R² and R³ are the same as defined in claim 1.

4. In claim 3, said amine base is selected from the group consisting of triethylamine, tripropylamine, and tri-n-butylamine.

5. In claim 3, said metal halide compound is selected from the group consisting of titanium(IV) chloride, aluminum chloride, tin chloride, magnesium chloride, tin bromide, and magnesium bromide.

6. A method of preparing a 4-propionic acid-2-azetidinone compound represented by the formula 4 by oxidation of chiral 2-azetidinone compound represented by the following formula 1

Oxidati *o*n

wherein said R, R¹, R² and R³ are the same as defined in claim 1.