JPH1087657A - Production of azetidinone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as an intermediate for carbapenem-based antibiotic substances by reacting an azetidinone derivative with imidazole in the presence of a pyridine derivative. SOLUTION: A compound represented formula I (R<1> is H or an amino- protecting group; R<2> is hydroxyl group which may be protected and a substitutable lower alkyl; R<3> is H or a lower alkyl; R<4> to R<7> are each H or a substitutable lower alkyl; X is O or S) is reacted with imidazole in the presence of a pyridine derivative (e.g. 4-dimethylaminopyridine) in a solvent (e.g. ethyl acetate) at 10-100 deg.C to afford a compound represented by formula II. The molar amount of the imidazole used is 1-5 times based on the compound represented by formula I and that of the pyridine derivative used is 0.001-0.5 based on the compound represented by formula I. The pyridine-base catalyst is used to thereby raise the rate of reaction and provide the compound represented by formula II in good yield for a short time.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing an azetidinone derivative useful as an intermediate of a carbapenem antibiotic having an excellent antibacterial activity.

[0002]

2. Description of the Related Art Compounds [III] as intermediates for producing carbapenem antibiotics which are excellent antibacterial agents

Embedded image (Patent Publication No. 5-24155, He
terocycles, vol. 21 (1), 29-4
0 (1984)). This compound is usually a carboxylic acid derivative (IV)

Embedded image Reaction of carbonyldiimidazole with carbonyldiimidazole (Heteroc
cycles, vol. 21 (1), 29-40 (198
4)) or a method of reacting with a carboxylic acid activator to react with imidazole via an acid halide, a mixed acid anhydride or the like (JP-A-5-201967) or a method of formula [V]

Embedded image (Where r ¹ and r ² are the same or different and each represent hydrogen, a lower alkyl group or an aralkyl group) and a method of directly reacting with an imidazole (Tetrah
edoron Letters, Vol. 30, no.
11, 1345-1348 (1989);
284176).

[0003]

SUMMARY OF THE INVENTION A carboxylic acid derivative [I
Since V] is usually obtained by hydrolyzing the amide compound [V], the method of producing directly from this amide compound is an advantageous method as compared with the method via a carboxylic acid derivative. As an example of taking advantage of this advantage and reacting directly with imidazole, a reaction under reflux in acetonitrile (Tet)
rahedronLetters, Vol. 30, N
o. 11, 1345-1348 (1989)) or a reaction at room temperature (JP-A-63-284176).
However, simply mixing imidazole or the like with an amide compound and reacting the mixture slows down the reaction rate, and inevitably reduces the yield due to side reactions and the like. In addition, Japanese Unexamined Patent Publication
In the reaction at room temperature described in 3-284176, the reaction was not completed.

[0004]

Under such circumstances, the present inventors have intensively studied an efficient production method by shortening the reaction time and suppressing side reactions, and as a result, completed the present invention. Reached.

That is, the present invention relates to a compound of the formula [I]

Embedded image (In the formula, R ¹ is a protecting group for hydrogen or an amino group which can be easily removed, R ² is a lower alkyl group which may be substituted with an optionally protected hydroxyl group, and R ³ is a hydrogen atom or a lower alkyl group. R < ⁴ >, R < ⁵ >, R < ⁶ > and R < ⁷ > are the same or different and each represents hydrogen or a lower alkyl group which may have a substituent, and X represents a sulfur atom or an oxygen atom. Is reacted with imidazole in the presence of a pyridine derivative.

Embedded image (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.)
This is a method for producing the compound represented by the formula:

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION As the protecting group for R ^1, a protecting group generally used for protecting N can be used. Specific examples thereof include a tri-substituted silyl group such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, dimethylhexylsilyl, and t-butyldiphenylsilyl; a benzyl group which may be substituted; Nitro group, lower alkoxy group, etc.), lower alkoxycarbonyl group, halogeno lower alkoxycarbonyl group, and optionally substituted benzyloxycarbonyl group (substituents include nitro group, lower alkoxy group, etc.). ), An acetyl group, an acyl group such as a benzoyl group, and the like. The term "lower alkyl" in the lower alkoxy group used herein refers to a linear or branched alkyl group having 1 to 8 carbon atoms, and the number and position of the substituents of the benzyl group and the benzoyl group are arbitrary. )

As the alkyl group for R ² , a linear or branched lower alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, s-butyl, n-butyl, t-butyl, etc. Is mentioned. As the protecting group for the hydroxyl group in R ² , a protecting group generally used for protecting a hydroxyl group can be used. Specific examples thereof include a tri-substituted silyl group such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, dimethylhexylsilyl, and t-butyldiphenylsilyl; a benzyl group which may be substituted; Nitro group, lower alkoxy group, etc.), lower alkoxycarbonyl group, halogeno lower alkoxycarbonyl group, and optionally substituted benzyloxycarbonyl group (substituents include nitro group, lower alkoxy group, etc.). ), An acetyl group, an acyl group such as a benzoyl group, a triphenylmethyl group, a tetrahydropyranyl group, and the like.

The alkyl group represented by R ³ is a straight-chain or a straight-chain having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl and t-butyl. And branched lower alkyl groups.

The lower alkyl group for R ⁴ , R ⁵ , R ⁶ and R ^{7 is} an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, butyl, etc. And a halogen atom such as a lower alkyloxy group having 1 to 6 carbon atoms, a phenyl group, chlorine and bromine.

Examples of the pyridine derivatives include substituted aminopyridines such as 4-dimethylaminopyridine and 4-pyrrolidinopyridine; 2-picoline, 3-picoline, 4-picoline, 2,3-lutidine, 2,4-lutidine, , 5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5
Lower alkyl-substituted pyridines such as -lutidine, 2,4,6-collidine and the like; lower alkoxy-substituted pyridines such as 2-methoxypyridine, 3-methoxypyridine, 4-methoxypyridine and 2,6-dimethoxypyridine.

In the reaction, compound [I] is dissolved or suspended in a solvent, compound [II] and a pyridine derivative are added, and 10-
The reaction is carried out at 100 ° C, preferably at 20-80 ° C.

The amount of compound [II] to be used is 1 to 5 moles compared to compound [I].

The amount of the pyridine derivative to be used is 0.001 to 0.5-fold the molar amount of the compound [I].

The solvent is not particularly limited as long as it does not participate in the reaction. For example, aromatic solvents such as benzene, toluene, xylene and chlorobenzene, acetone,
Ketone solvents such as methyl ethyl ketone, diethyl ketone, isobutyl methyl ketone, methyl acetate, ethyl acetate,
Ester solvents such as propyl acetate, butyl acetate and methyl propionate; halogen solvents such as methylene chloride, chloroform and dichloroethane; hydrocarbon solvents such as hexane and heptane; nitrile solvents such as acetonitrile and benzonitrile; Ter, dioxane,
Ether solvents such as tetrahydrofuran and the like, dimethyl sulfoxide, dimethylformamide and the like may be mentioned, and these may be mixed. In particular, acetonitrile, tetrahydrofuran, and acetates are preferably used.

The compound [I] is known, for example, Tet
rahedron Letters, Vol. 30,
No. 11, 1345-1348 (1989), Tet
rahedron Letters, Vol. 27,
No. 47, 5687-5690 (1986), JP-A-63-284176, etc., and the resulting compound [II] is also known. The formation of this compound was confirmed by HPLC and NMR.

[0016]

Next, the present invention will be described in more detail by way of examples. Example 1 Production of (3S, 4R) -3-[(1R) -1-tert-butyldimethylsilyloxyethyl] -4-[(1R) -1-imidazolylethyl] azetidin-2-one

Embedded image (3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-
(4,4-dimethyl-2-thioxothiazolidine-3-
Yl) ethyl] azetidin-2-one 17.23 g (4
0 mmol) and 80 ml of ethyl acetate, 3.81 g (56 mmol) of imidazole and 0.244 g (2 mmol) of 4-dimethylaminopyridine were added, and the mixture was heated at 60 ° C.
The reaction was carried out. The reaction was completed in about 4 hours. The reaction solution was cooled and analyzed by HPLC.
It contained 7 g (39.2 mmol).

Example 2 Preparation of (3S, 4R) -3-[(1R) -1-tert-butyldimethylsilyloxyethyl] -4-[(1R) -1-imidazolylethyl] azetidin-2-one

Embedded image (3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-
(4,4-dimethyl-2-thioxothiazolidine-3-
Yl) ethyl] azetidin-2-one 17.23 g (4
0 mmol) and 80 ml of ethyl acetate, 3.81 g (56 mmol) of imidazole and 0.976 g (8 mmol) of 4-dimethylaminopyridine were added, and the mixture was heated at 60 °
The reaction was carried out. The reaction was completed in about 2 hours. The reaction solution was cooled and analyzed by HPLC.
It contained 0 g (39 mmol).

Comparative Example Preparation of (3S, 4R) -3-[(1R) -1-tert-butyldimethylsilyloxyethyl] -4-[(1R) -1-imidazolylethyl] azetidin-2-one

Embedded image Example 1 except that no 4-dimethylaminopyridine was added
And 2 1 mol% of unreacted raw material
It took more than 8 hours before and after. The reaction solution was cooled and analyzed by HPLC.
7.1 mmol).

Reference Example 1 (3S, 4R) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-methyl-3-p-nitrobenzyloxycarbonyl-2-oxopropyl] Synthesis of azetidin-2-one

Embedded image (3S, 4R) -3-[(1R)-synthesized in Example 1
1-t-butyldimethylsilyloxyethyl] -4-
[(1R) -1-imidazolylethyl] azetidine-2
6.23 g of triethylamine was added dropwise to a mixed solution of 13.39 g of p-nitrobenzylmalonic acid half ester, 80 ml of ethyl acetate and 3.62 g of anhydrous magnesium chloride at 15-20 ° C. The mixture was added to a magnesium malonate solution prepared in advance and reacted at 50 ° C. for 2.3 hours. After completion of the reaction, the reaction mixture was washed with water, and the ethyl acetate layer was analyzed by HPLC.
It contained 7.4 g.

[0020]

Industrial Applicability According to the present invention, an azetidinone derivative useful as an intermediate of a carbapenem antibiotic having an excellent antibacterial activity can be produced in a short time and with high yield by using a pyridine catalyst to increase the reaction rate. it can.

Claims (2)

[Claims] 1. A compound of the formula [I] (In the formula, R ¹ is a protecting group for hydrogen or an amino group which can be easily removed, R ² is a lower alkyl group which may be substituted with an optionally protected hydroxyl group, and R ³ is a hydrogen atom or a lower alkyl group. R < ⁴ >, R < ⁵ >, R < ⁶ > and R < ⁷ > are the same or different and each represents hydrogen or a lower alkyl group which may have a substituent, and X represents a sulfur atom or an oxygen atom. Is reacted with imidazole in the presence of a pyridine derivative. (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.)
A method for producing a compound represented by the formula: 2. The method according to claim 1, wherein the pyridine derivative is a pyridine substituted with a lower alkyl group or a substituted amino group containing a nitrogen and containing a ring to form a ring with a methylene group.