KR20090048899A - Method of preparing intermediates of penem antibiotics - Google Patents

Abstract

The present invention relates to a method for preparing a bicyclic keto ester compound, which is a key intermediate of carbapenem antibiotics. The method for preparing the carbapenem antibiotic antibiotic intermediate according to the present invention can increase the activity of the rhodium catalyst, change the reaction rate, and reduce the amount of the expensive rhodium catalyst by changing the reaction solvent, which is very economical and useful from an industrial point of view. Do.

Diazo compounds, acyclic ketoester compounds, rhodium catalysts, solvents, penem antibiotics,

Description

Method of preparing intermediates of penem antibiotics {Method of preparing intermediates of penem antibiotics}

The present invention relates to a method for preparing a bicyclic keto ester compound, which is a key intermediate of carbapenem antibiotics.

Reactions are known for producing bicyclic keto esters using rhodium catalysts in diazo compounds, which are penem intermediates.

Scheme 1

In Formula 1, Formula 2 and Scheme 1, R is a protecting group of carboxylic acid, benzyl substituted with C _1-4 alkenyl, or para nitro group, para C _1-4 alkoxy group or para C _1-6 alkyl group Group; R ₁ is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl group; R ₂ is a silyl group trisubstituted with an alkyl group and an aryl group as a protecting group for hydrogen, an acyl group or an alcohol.

In the above formula, X is a nitrogen atom substituted with an oxygen atom or an alkyl group, and R1, R2 and R3 are hydrogen atoms, C ₁ to C ₃₀ alkyl groups, or fluorine substituted alkyl groups.

In general, by using a rhodium catalyst of Formula 3 from the diazo compound of Formula 2, the diazo is liberated and NH insertion reaction is performed through rhodium carbenoid formation. A method of synthesizing a bicyclic keto ester compound of Formula 1 is known. Ethyl acetate, benzene, toluene, tetrahydrofuran using at least 0.1 mol% (diazo compound / rhodium catalyst = 1000: 1 molar ratio) of diodium divalent acetate {dirhodium (II) acetate} A method for synthesizing bicyclic ketoester compounds using (THF) or the like is known. [D. G. Melillo, I. Shinkai, Tetrahedron lett, 1980, 21, 2783; C. P. Mak, C. Mayerl, Tetrahedron Lett, 1983, 24, 347; C. Wenteup, H. W. winter, J. Am. Chem. Soc, 1980, 102, 6161; R. W. Ratcliffe, T. N. Salzmann, Tetrahedron Lett. 1980, 21, 31]

In addition, US Pat. No. 4,287,123 discloses 2.55 mol% of a compound of Formula 2 wherein R is a para-nitrobenzyl group and R ₁ is hydrogen in a toluene organic solvent. A) dichlorodium (II) tetraacetate [Rh ₂ (CH ₃ COO) ₄ ] at 80-85 ° C. for 2 hours 30 minutes, where R is a para-nitrobenzyl group and R ₁ is hydrogen The compound of 1 was prepared. However, these methods have difficulty in industrial application because they use a large amount of expensive rhodium catalyst.

The present inventors have found that the reaction rate due to the activity of the catalyst is different depending on the reaction solvent and also affects the yield of the formula (1). In addition, it is possible to reduce the amount of expensive rhodium catalyst by appropriately adjusting the amount of rhodium catalyst used in the process and to obtain a high yield of the compound of formula 1, n-propyl acetate as a preferred solvent The present invention has been completed by discovering that isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate or mixed solvents thereof and other organic mixed solvents including them are used.

The present invention has been made to solve the above problems, and an object of the present invention is to prepare a bicyclic keto ester compound using a rhodium catalyst in a diazo compound. The purpose of the present invention is to provide a method for economically preparing a target compound by significantly reducing the amount of rhodium catalyst used by increasing the activity of.

In addition, another object of the present invention to prepare a bicyclic keto ester compound using a rhodium catalyst in a diazo compound, a method for improving the reaction rate by increasing the activity of the rhodium catalyst To provide.

Another object of the present invention is also a method for preparing an improved penem intermediate which may exist in the form of various optical isomers due to the presence of asymmetric carbon atoms of diazo compounds and bicyclic keto ester compounds. To provide.

In order to achieve the above object, in the present invention, in the reaction scheme 1, a bicyclic ketoester of formula (I) which is a key intermediate of the carbapenem antibiotic using the catalyst of formula (3) from the diazo compound of formula (2) In preparing bicyclic keto ester) compounds, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate or mixed solvents thereof and other including them Provided is a method of using an organic mixed solvent.

 According to the present invention, the method for preparing the penem antibiotic antibiotic intermediate may increase the efficiency of the rhodium catalyst to be used to improve the reaction speed and significantly reduce the amount of the rhodium catalyst to be used, thereby producing the target product very economically.

The present invention relates to the preparation of a bicyclic keto ester compound of formula 1, which is a key intermediate of the carbapenem antibiotic, using the catalyst of formula 3 from the diazo compound of formula 2 in Scheme 1 Provided is a method of using n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate or mixed solvents thereof and other organic mixed solvents containing them as reaction solvents. do.

<Scheme 1>

In Formula 1, Formula 2 and Scheme 1, R is a protecting group of carboxylic acid, benzyl substituted with C _1-4 alkenyl, or para nitro group, para C _1-4 alkoxy group or para C _1-6 alkyl group Group; R ¹ is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl group; R ² is a silyl group or acyl group tri-substituted with an alkyl group and an aryl group as a protecting group for hydrogen or an alcohol. Formulas 1 and 2 may also exist in the form of various optical isomers due to the presence of asymmetric carbon atoms.

In the above formula, X is a nitrogen atom substituted with an oxygen atom or an alkyl group, and R ₁ , R ₂ and R ₃ are hydrogen atoms, C ₁ to C ₃₀ alkyl groups, or fluorine substituted alkyl groups.

In the present invention, in the reaction of Scheme 1, the reaction of preparing the compounds of Formulas 1-1 and 2-1 from the compounds of Formulas 2-1 and 2-2 through Schemes 1-1 and 1-2, respectively, was studied. . The present invention is to prepare a compound of formula 1 from the compound of formula 1 in general scheme 1 as well as the method of preparing the compound of formula 1-1 and 1-2 through the following schemes 1-1 and 1-2 The same may apply to the method.

<Scheme 1-1>

In Formula 1-1, Formula 2-1 and Scheme 1-1, R is a protecting group of carboxylic acid, C _1-4 alkenyl, or para nitro group, para C _1-4 alkoxy group or para C _{1- 6} alkyl group is a substituted benzyl group.

<Scheme 1-2>

In Formula 1-2, Formula 2-2 and Scheme 1-2, R is a protecting group of carboxylic acid, C _1-4 alkenyl, or para nitro group, para C _1-4 alkoxy group or para C _{1- 6} alkyl group is a substituted benzyl group.

In the present invention, the reactions of Schemes 1-1 and 1-2 were carried out with different reaction solvents. That is, ethyl acetate of the compound of formula 2-1 and the compound of formula 2-1 wherein R is a para nitro group, respectively, has an internal temperature of 70 to 75 ° C .; Toluene, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate have an internal temperature of 0.025 mol% of rhodium acetate of Formula 3 at 90 to 100 ° C. Compound / rhodium catalyst = 4000: 1 molar ratio) as a catalyst and proceeded with stirring in the reactions of Schemes 1-1 and 1-2, and the results of Schemes 1-1 and 1-2 are shown in Table 1 and Table 1, respectively. Summarized in 2.

As shown in the results of Tables 1 and 2 below, the amount of the rhodium catalyst was reduced to 0.025 mol%, and the result was n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate The reaction was completed in 40 to 60 minutes, but the previously known toluene and ethyl acetate were not completed any more so that the reaction time was over 24 hours, and it was confirmed that the initial compound remained. That is, in view of the above results, preferred solvents for preparing the compound of Formula 1 through Scheme 1 are n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert- Butyl acetate or mixed solvents thereof and other organic mixed solvents containing them.

Hereinafter, the present invention will be described in more detail by the following examples and comparative examples. However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the invention.

Example

Comparative Example 1

3.4 g of (3RS, 4RS) -alpha-diazo-3- [1 (RS) -hydroxyethyl] -beta, 2-dioxo-4-azetidinebutanoic acid para-nitrobenzyl ester of formula 2-1 (9.04 mmol) and 1 mg (0.00226 mmol) of dirodium (II) tetraacetate were added to 40 ml of ethyl acetate, and the reaction was stirred while maintaining the temperature at 70 to 75 ° C. After reacting for 24 hours, the reaction solution was concentrated, and then separated by chromatography, (5RS, 6RS) -6-[(RS) -1-hydroxyethyl] -3,7-dioxo-1 as a reaction product. 2.20 g (70%) of azabicyclo [3.2.0] heptane-2-carboxylic acid para-nitrobenzylester were obtained.

Comparative Example 2

3.4 g of (3RS, 4RS) -alpha-diazo-3- [1 (RS) -hydroxyethyl] -beta, 2-dioxo-4-azetidinebutanoic acid para-nitrobenzyl ester of formula 2-1 (9.04 mmol) and 1 mg (0.00226 mmol) of dirodium (II) tetraacetate were added to 40 ml of toluene and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 24 hours, the reaction solution was concentrated, and then separated by chromatography, (5RS, 6RS) -6-[(RS) -1-hydroxyethyl] -3,7-dioxo-1 as a reaction product. 2.27 g (72%) of azabicyclo [3.2.0] heptane-2-carboxylic acid para-nitrobenzyl ester were obtained.

Example 1

3.4 g of (3RS, 4RS) -alpha-diazo-3- [1 (RS) -hydroxyethyl] -beta, 2-dioxo-4-azetidinebutanoic acid para-nitrobenzyl ester of formula 2-1 (9.04 mmol) and 1 mg (0.00226 mmol) of dirodium (II) tetraacetate were added to 40 ml of n-propyl acetate, and the reaction temperature was maintained at 90 to 100 ° C. After reacting for 40 minutes, the reaction solution was concentrated to 6.8 ml, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (5RS, 6RS) -6-[(RS) -1-hydroxyethyl] -3,7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid 2.9 g (92%) of para-nitrobenzylester were obtained.

Example 2

3.4 g of (3RS, 4RS) -alpha-diazo-3- [1 (RS) -hydroxyethyl] -beta, 2-dioxo-4-azetidinebutanoic acid para-nitrobenzyl ester of formula 2-1 (9.04 mmol) and 1 mg (0.00226 mmol) of dirodium (II) tetraacetate were added to 40 ml of isopropyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 40 minutes, the reaction solution was concentrated to 6.8 ml, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (5RS, 6RS) -6-[(RS) -1-hydroxyethyl] -3,7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid 2.87 g (91%) of para-nitrobenzylester were obtained.

Example 3

3.4 g of (3RS, 4RS) -alpha-diazo-3- [1 (RS) -hydroxyethyl] -beta, 2-dioxo-4-azetidinebutanoic acid para-nitrobenzyl ester of formula 2-1 (9.04 mmol) and 1 mg (0.00226 mmol) of dirodium (II) tetraacetate were added to 40 ml of n-butyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 40 minutes, the reaction solution was concentrated to 6.8 ml, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (5RS, 6RS) -6-[(RS) -1-hydroxyethyl] -3,7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid 2.8 g (89%) of para-nitrobenzylester were obtained.

Example 4

3.4 g of (3RS, 4RS) -alpha-diazo-3- [1 (RS) -hydroxyethyl] -beta, 2-dioxo-4-azetidinebutanoic acid para-nitrobenzyl ester of formula 2-1 (9.04 mmol) and 1 mg (0.00226 mmol) of dirodium (II) tetraacetate were added to 40 ml of isobutyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 40 minutes, the reaction solution was concentrated to 6.8 ml, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (5RS, 6RS) -6-[(RS) -1-hydroxyethyl] -3,7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid 2.83 g (90%) of para-nitrobenzylester were obtained.

Example 5

3.4 g of (3RS, 4RS) -alpha-diazo-3- [1 (RS) -hydroxyethyl] -beta, 2-dioxo-4-azetidinebutanoic acid para-nitrobenzyl ester of formula 2-1 (9.04 mmol) and 1 mg (0.00226 mmol) of rhodium (II) tetraacetate were added to 40 ml of sec-butyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 40 minutes, the reaction solution was concentrated to 6.8 ml, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (5RS, 6RS) -6-[(RS) -1-hydroxyethyl] -3,7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid 2.77 g (88%) of para-nitrobenzylester were obtained.

Example 6

3.4 g of (3RS, 4RS) -alpha-diazo-3- [1 (RS) -hydroxyethyl] -beta, 2-dioxo-4-azetidinebutanoic acid para-nitrobenzyl ester of formula 2-1 (9.04 mmol) and 1 mg (0.00226 mmol) of dirodium (II) tetraacetate were added to 40 ml of tert-butyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 40 minutes, the reaction solution was concentrated to 6.8 ml, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (5RS, 6RS) -6-[(RS) -1-hydroxyethyl] -3,7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid 2.87 g (91%) of para-nitrobenzylester were obtained.

Table 1 Comparison of reactivity according to reaction solvent in the N-H insertion reaction of Scheme 1-1.

Usage of Formula 2-1 menstruum Rhodium Catalyst Usage Reaction time yield Comparative Example 1 3.4 g Ethyl acetate 0.025 mol% 24 hours 70% Comparative Example 2 3.4 g toluene 0.025 mol% 24 hours 72% Example 1 3.4 g n-propyl acetate 0.025 mol% 40 minutes 92% Example 2 3.4 g Isopropyl Acetate 0.025 mol% 50 minutes 91% Example 3 3.4 g n-butyl acetate 0.025 mol% 40 minutes 89% Example 4 3.4 g Isobutyl Acetate 0.025 mol% 45 minutes 90% Example 5 3.4 g s-butyl acetate 0.025 mol% 50 minutes 88% Example 6 3.4 g t-butyl acetate 0.025 mol% 60 minutes 91%

Comparative Example 3

(3RS, 4RS) -3-[(R) -hydroxyethyl] -4-[(R) -1-methyl-3-diazo-3-allyloxycarbonyl-1-oxopropyl of formula 2-2 3.54 g (9.04 mmol) of -2-azetidinone and 40 ml of 1 mg ethyl acetate of dilodium (II) tetraacetate were added thereto, followed by stirring while maintaining the reaction temperature at 70 to 75 ° C. After reacting for at least 24 hours, the reaction solution was concentrated, and then separated by chromatography, (4S, 5R, 6S) -6-[(1R) -hydroxyethyl] -4-methyl-3,7 as a reaction product. 2.33 g (71%) of dioxo-1-azabicyclo [3.2.0.] Heptane-2-carboxylate were obtained.

Comparative Example 4

(3RS, 4RS) -3-[(R) -hydroxyethyl] -4-[(R) -1-methyl-3-diazo-3-allyloxycarbonyl-1-oxopropyl of formula 2-2 3.54 g (9.04 mmol) of -2-azetidinone and 1 mg (0.00226 mmol) of rhodium (II) tetraacetate were added to 40 ml of toluene and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for at least 24 hours, the reaction solution was concentrated, and then separated by chromatography, (4S, 5R, 6S) -6-[(1R) -hydroxyethyl] -4-methyl-3,7 as a reaction product. 2.29 g (70%) of -dioxo-1-azabicyclo [3.2.0.] Heptane-2-carboxylate were obtained.

Example 7

(3RS, 4RS) -3-[(R) -hydroxyethyl] -4-[(R) -1-methyl-3-diazo-3-allyloxycarbonyl-1-oxopropyl of formula 2-2 3.54 g (9.04 mmol) of -2-azetidinone and 1 mg (0.00226 mmol) of dirodium (II) tetraacetate were added to 40 ml of propyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After the reaction for 40 minutes, the reaction solution was concentrated to 6.8 ml, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the resultant white solid reaction product was filtered by stirring at 0 ° C. for 2 hours. (4S, 5R, 6S) -6-[(1R) -hydroxyethyl] -4-methyl-3,7-dioxo-1-azabicyclo [3.2.0.] Heptane-2-car as reaction product 3.01 g (92%) of oxylate were obtained.

Example 8

(3RS, 4RS) -3-[(R) -hydroxyethyl] -4-[(R) -1-methyl-3-diazo-3-allyloxycarbonyl-1-oxopropyl of formula 2-2 3.54 g (9.04 mmol) of -2-azetidinone and 1 mg (0.00226 mmol) of rhodium (II) tetraacetate were added to 40 ml of isopropyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 50 minutes, the reaction solution was concentrated to 6.8 ml, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (4S, 5R, 6S) -6-[(1R) -hydroxyethyl] -4-methyl-3,7-dioxo-1-azabicyclo [3.2.0.] Heptane- 2.95 g (90%) of 2-carboxylate were obtained.

Example 9

(3RS, 4RS) -3-[(R) -hydroxyethyl] -4-[(R) -1-methyl-3-diazo-3-allyloxycarbonyl-1-oxo of Formula 2-2 3.54 g (9.04 mmol) of propyl-2-azetidinone and 1 mg (0.00226 mmol) of rhodium (II) tetraacetate were added to 40 ml of n-butyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 45 minutes, the reaction solution was concentrated to 6.8 ml, and then, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (4S, 5R, 6S) -6-[(1R) -hydroxyethyl] -4-methyl-3,7-dioxo-1-azabicyclo [3.2.0.] Heptane- 2.98 g (91%) of 2-carboxylate were obtained.

Example 10

(3RS, 4RS) -3-[(R) -hydroxyethyl] -4-[(R) -1-methyl-3-diazo-3-allyloxycarbonyl-1-oxo of Formula 2-2 3.54 g (9.04 mmol) of propyl-2-azetidinone and 1 mg (0.00226 mmol) of dirodium (II) tetraacetate were added to 40 ml of isobutyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 45 minutes, the reaction solution was concentrated to 6.8 ml, and then, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (4S, 5R, 6S) -6-[(1R) -hydroxyethyl] -4-methyl-3,7-dioxo-1-azabicyclo [3.2.0.] Heptane- 2.78 g (85%) of 2-carboxylate were obtained.

Example 11

(3RS, 4RS) -3-[(R) -hydroxyethyl] -4-[(R) -1-methyl-3-diazo-3-allyloxycarbonyl-1-oxopropyl of formula 2-2 3.54 g (9.04 mmol) of -2-azetidinone and 1 mg (0.00226 mmol) of rhodium (II) tetraacetate were added to 40 ml of sec-butyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 50 minutes, the reaction solution was concentrated to 6.8 ml, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (4S, 5R, 6S) -6-[(1R) -hydroxyethyl] -4-methyl-3,7-dioxo-1-azabicyclo [3.2.0.] Heptane- 2.92 g (89%) of 2-carboxylate were obtained.

Example 12

(3RS, 4RS) -3-[(R) -hydroxyethyl] -4-[(R) -1-methyl-3-diazo-3-allyloxycarbonyl-1-oxopropyl of formula 2-2 3.54 g (9.04 mmol) of -2-azetidinone and 1 mg (0.00226 mmol) of rhodium (II) tetraacetate were added to 40 ml of tert-butyl acetate and stirred while maintaining the reaction temperature at 90 to 100 ° C. After reacting for 55 minutes, the reaction solution was concentrated to 6.8 ml, and then, 13.6 ml of hexane and 13.6 ml of toluene were added to the concentrated reaction solution, and the reaction product was filtered at 0 ° C. for 2 hours to filter the reaction product. As reaction product As reaction product (4S, 5R, 6S) -6-[(1R) -hydroxyethyl] -4-methyl-3,7-dioxo-1-azabicyclo [3.2.0.] Heptane- 2.95 g (90%) of 2-carboxylate were obtained.

TABLE 2 Comparison of reactivity according to reaction solvent in N-H insertion reaction of Scheme 1-2.

Usage of Formula 2-2 menstruum Rhodium Catalyst Usage Reaction time yield Comparative Example 3 3.4 g Ethyl acetate 0.025 mol% 24 hours 71% Comparative Example 4 3.4 g toluene 0.025 mol% 24 hours 70% Example 7 3.4 g n-propyl acetate 0.025 mol% 40 minutes 92% Example 8 3.4 g Isopropyl Acetate 0.025 mol% 50 minutes 90% Example 9 3.4 g n-butyl acetate 0.025 mol% 45 minutes 91% Example 10 3.4 g Isobutyl Acetate 0.025 mol% 45 minutes 85% Example 11 3.4 g s-butyl acetate 0.025 mol% 50 minutes 89% Example 12 3.4 g t-butyl acetate 0.025 mol% 55 minutes 90%

According to the method for preparing the penem intermediate according to the present invention, it is possible to economically prepare a target compound by increasing the activity of an expensive rhodium catalyst and significantly reducing the amount of rhodium catalyst used. In addition, since the reaction time is shortened and has a high yield, it is industrially useful as a new manufacturing method for preparing the penem antibiotic antibiotic intermediate.

1 is a diagram showing a reaction scheme for synthesizing the bicyclic ketoester of the formula (1) from the dizo compound of formula (2) of the present invention. In Chemical Formulas 1 and 2, R is a protecting group of carboxylic acid, and a benzyl group substituted with a C _1-4 alkenyl, or a para nitro group, a para C _1-4 alkoxy group, or a para C _1-6 alkyl group; R ¹ is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl group; R ² is a silyl group trisubstituted with an alkyl group and an aryl group as a protecting group for hydrogen, an acyl group or an alcohol.

2 is a diagram showing the structural formula of a rhodium catalyst used to synthesize the bicyclic ketoester of the formula (1) of the present invention. In the above structural formula, X is a nitrogen atom substituted with an oxygen atom or an alkyl group, R ₁ , R ₂ , R ₃ is a hydrogen atom, an alkyl group of C ₁ ~ C ₃₀ , or a fluorine-substituted alkyl group.

Claims (5)

In Scheme 1, a method for preparing a bicyclic keto ester compound of Formula 1 and an isomer thereof using a catalyst of Formula 3 from a compound of Formula 2 is shown as n-propyl acetate. Using the organic mixed solvent containing at least one solvent selected from the group consisting of isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and tert-butyl acetate to the compound of formula 1 and isomers thereof How to manufacture: <Scheme 1>

(In Formula 1, Formula 2, R is a protecting group of carboxylic acid, C _1-4 alkenyl, or a benzyl group substituted with a para nitro group, a para C _1-4 alkoxy group, or a para C _1-6 alkyl group. R ¹ is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl group, R ² is a silyl group tri-substituted with an alkyl group and an aryl group with a protecting group of hydrogen, acyl group or alcohol; In 3, X is a nitrogen atom substituted with an oxygen atom or an alkyl group, and R ₁ , R ₂ , R ₃ are hydrogen atoms, an alkyl group having ₁ to ₃₀ carbon atoms, or a fluorine-substituted alkyl group.) 2. The method of claim 1, wherein R ^{1 in} Formula 1 and Formula 2 is hydrogen. The method of preparing a compound of Formula 1 and an isomer thereof, according to claim 1, wherein R ^{1 in} Formula 1 and Formula 2 is a methyl group. In Scheme 1, a bicyclic keto ester compound of Formula 1 and an isomer thereof are prepared from a compound of Formula 2 using a catalyst of Formula 3, n-propyl acetate as a reaction solvent. , Using an organic mixed solvent comprising at least one solvent selected from the group consisting of isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and tert-butyl acetate and adding 0.1 mol% ( A process for preparing the compound of formula 1 and isomers thereof using less than the compound of formula 2: compound of formula 3 = 1000: 1 mole ratio). A compound of formula 1 prepared by the method of claim 1 or 4 and an isomer thereof.

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