KR20020005334A - Novel 1β- methylcarbapenem derivatives and process of preparation thereof - Google Patents

Abstract

PURPOSE: Provided is a novel 1-β- methylcarbapenem derivative which has an antibacterial effect on both gram negative and positive bacteria and stability to dihydropeptidase-I, and is thus useful as antibacterial agent. And a pharmaceutical composition containing it and its manufacturing method are also provided. CONSTITUTION: The novel 1-β- methylcarbapenem derivative is represented by the formula(I), wherein R is described as in the description, X is ethoxycarbonyl group or hydroxymethyl group; Y is hydroxymethyl group or ethoxycarbonyl group; and Z is methyl group or carbamoylmethyl group. Its manufacturing method comprises the steps of: reacting enolphosphate with thiol derivative in the presence of base, in appropriate solvent to prepare protected carbapenem derivative; and deprotecting the protected carbapenem derivative to obtain 1-β- methylcarbapenem derivative.

Description

Novel 1β-methylcarbapenem derivatives and process of preparation

The present invention relates to a 1-betamethylcarbapenem derivative useful as an antimicrobial agent, and more particularly, 5'-isoxazolopyrroli as the main functional group at position 2 of the 1-betamethylcarbapenem nucleus represented by the following general formula (1). 1-betamethylcarbapenem derivatives substituted with 5'-isoxazolopyrrolidin-3'-yl thio, pharmaceutically acceptable salts thereof, preparation methods thereof, and the compound as an active ingredient It relates to a pharmaceutical composition for antimicrobial agents.

Formula 1

In Chemical Formula 1,

R is Indicates

X is an ethoxycarbonyl group or a hydroxymethyl group,

Y is a hydroxymethyl group or an ethoxycarbonyl group,

Z is a methyl group or a carbamoylmethyl group.

Carbapenem-based antimicrobial agent exhibits a broader antibacterial activity than conventional cephalosporin-based or penicillin-based antimicrobial agents, and has an excellent effect on resistant bacteria. However, these carbapenem-based antimicrobial agents are reported to lose their antimicrobial activity by being easily degraded and inactivated by the enzyme dehydropeptidase-I (hereinafter referred to as "DHP-I") present in the kidney. It is. ( J. Antibiot . 1991 , 1172-1177, Antimicrobial Agent and Chemotherapy 1992 , 1577-1579.)

Meanwhile, 1-betamethylcarbapenem compounds exhibit broad antimicrobial spectrum against both Gram-positive and Gram-negative bacteria, as well as stability against DHP-I. Meropenem has a 1-betamethyl group in the carbapenem nucleus. Commercialized and related derivatives, BO-2727, S-4661, ZD-4433, ER-35786, FR-21818 and IH201 are in clinical or animal testing. ( J. Antibiot . 1990 , 43 , 519, Yamaji, E. et al . Abstracts of Papers, H141, 35th Interscience Conference on Antimicrobial Agents and Chemotheraphy, San Francisco, CA, 17-20 Sep. 1995, Arakawa, S. et al Abstracts of Papers, F218, 37th Interscience Conference on Antimicrobial Agents and Chemotheraphy, Toronto, Ontario, 28 Sep.-1 Oct. 1997, Pelak, BA et al .Abstracts of Papers, F119, 36th Interscience Conference on Antimicrobial Agents and Chemotheraphy, New Orleans, LA, 15-18 Sep. 1996, Sato, N. et al . Abstracts of Papers, F151, 35th Interscience Conference on Antimicrobial Agents and Chemotheraphy, San Francisco, CA, 17-20 Sep. 1995, Tawara, S. et al . Abstracts of Papers, F145, 35th Interscience Conference on Antimicrobial Agents and Chemotheraphy, San Francisco, CA, 17-20 Sep. 1995, Shin, KJ et al . Bioorg.Med. Chem. Lett. 1998 , 8 , 1607. )

Therefore, the present inventors have conducted research to develop a carbapenem compound showing high stability against DHP-I and showing excellent antimicrobial activity against both Gram-positive bacteria and Gram-negative bacteria, and thus, the main functional group at the position 2 of the carbapenem mother nucleus. A novel 1-betamethylcarbapenem derivative substituted with 5'-isoxazolopyrrolidin-3'-ylthio was prepared as the 1-betamethylcarbapenem. Derivatives have not only exhibited high stability against DHP-I, but have also been found to exhibit significantly superior antimicrobial effects to known Gram-positive bacteria than known antibacterial agents, thus completing the present invention.

It is an object of the present invention to provide 1-betamethylcarbapenem derivatives and pharmaceutically acceptable salts thereof.

It is another object of the present invention to provide a pharmaceutical composition for an antimicrobial agent, which is used as the active ingredient and is stable against DHP-I and exhibits strong antimicrobial activity against both Gram-positive and Gram-negative bacteria.

It is a further object of the present invention to provide a process for producing 1-betamethylcarbapenem derivatives and pharmaceutically acceptable salts thereof economically and in high yield.

Another object of the present invention is to provide a thiol derivative which provides a structural contribution to the final product 1-betamethylcarbapenem derivative as an intermediate for synthesizing a new 1-betamethylcarbapenem derivative.

It is also an object of the present invention to provide a method for preparing the thiol derivative.

In order to achieve the above object, in the present invention, 1-betamethylcarbapenem in which a 5'-isooxazolopyrrolidine-3'-ylthio group is substituted as a main functional group at position 2 of the 1-betamethylcarbapenem parent nucleus Derivatives and pharmaceutically acceptable salts thereof.

Formula 1

In Chemical Formula 1,

R is Indicates

X is an ethoxycarbonyl group or a hydroxymethyl group,

Y is a hydroxymethyl group or an ethoxycarbonyl group,

Z is a methyl group or a carbamoylmethyl group.

Particularly preferred compounds among the compounds of Formula 1 are as follows.

1) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' '-methylisooxazolidinio-5' '-yl) pyrrolidine-3'-ylthio ] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid,

2) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' ', 2' '-dimethylisoxazolidinio-5' '-yl) pyrrolidine-3 '-Ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid chloride,

3) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(3' '-ethoxycarbonylisoxazolino-5' '-yl) pyrrolidin-3'-yl Thio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid,

4) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(3' '-hydroxymethylisoxazolino-5' '-yl) pyrrolidine-3'-ylthio ] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid,

5) (1R, 5S, 6S) -2-[(3'S, 5'R)-{5 '-(3' '-hydroxymethylisoxazolino-5' '-yl) pyrrolidine-3'- Ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid,

6) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(5' '-hydroxymethylisoxazolo-3' '-yl) pyrrolidine-3'-ylthio ] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid, or

7) (1R, 5S, 6S) -2-[(3'S, 5'S)-(5 '-(2' ', 2' '-acetamidomethylisoxazolidinio-5' '-yl) pyrroli Din-3'-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid chloride salt.

1-betamethylcarbapenem derivatives of the present invention represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and acid salts formed by pharmaceutically acceptable free acid are useful as salts. Do. Inorganic acids and organic acids can be used as the free acid. Hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid , Galluxuronic acid, embonic acid, glutamic acid, or aspartic acid. The compound of formula 1 may also be a pharmaceutically acceptable metal salt, in particular an alkali metal salt, formed due to the base. Examples of these are sodium salts and potassium salts.

The present invention also provides a method for preparing a 1-betamethylcarbapenem derivative represented by the following Scheme 1.

(In Scheme 1, R is as defined in Formula 1, PNB is a paranitrobenzyl group and PNZ is a paranitrobenzyloxycarbonyl group.)

Method for producing 1-betamethylcarbapenem compound of the present invention,

1) reacting enolphosphate (II) with thiol derivative (III) in the presence of a base in a suitable solvent to prepare a protective carbapenem derivative (VII), and

2) Deprotecting the protective carbapenem derivative (iii) obtained in step 1 to prepare 1-betamethylcarbapenem derivative (I) (step 2).

Carbapenem intermediate of Structural Formula (II) used as starting material in step 1 was prepared by a known method (Catchpole, CR et al . Antimicrob. Agents Chemother. 1992 , 36 , 1928.).

In more detail, the step 1 may be used as a base, a tertiary organic amine having a low basicity. For example, trimethylamine, triethylamine, diisopropylethylamine, 2,6-lutidine, Preference is given to using organic bases such as picoline, N, N -dimethylaniline, pyridine, 4-dimethylaminopyridine and the like. Step 1 is reacted for 3 to 6 hours at room temperature to obtain a protective carbapenem derivative of formula (iii). At this time, it is preferable to use acetonitrile as the reaction solvent. In addition, the deprotection reaction of the protective carbapenem compound of Structural Formula (iii) was carried out at 20-30 ° C. under phosphate buffer (pH 6) for 3 to 4 hours using a zinc metal catalyst to protect paranitrobenzyl. The group is removed to obtain the desired 1-betamethylcarbapenem derivative of the present invention.

The present invention also provides a thiol compound (III) represented by the formula (2) as an intermediate.

(Wherein R is as defined in formula (1) and PNZ is a paranitrobenzyloxycarbonyl group.)

The present invention also provides a process for preparing a thiol compound of formula (III) according to Schemes 2, 3, 4 or 5 as starting material using a protective proline compound of formula (IV) or formula (V). In the following scheme, TBS represents a t-butyldimethylsilyl group, MsO represents a methanesulfonyl group, and PNZ represents a paranitrobenzyloxycarbonyl group.

The thiol compound of formula (2) used to prepare the 1-betamethylcarbapenem derivative of the present invention,

1) preparing a cyclized isoxazolidiniopyrrolidine compound of formula (VI-1) by reaction with nitrone using the protective proline compound of formula (IV) as a starting material (step 1) ,

2) deprotecting the cyclized isoxazolidiniopyrrolidine compound of formula (VI-1) and then converting it to a methanesulfonyl group (step 2),

3) producing a thioacetate compound of formula (VII-1) through a substitution reaction with an acetylthio group (step 3), and

4) Subsequently, the thioacetate compound of formula (VII-1) is deacetylated to prepare a thiol compound of formula (III) (step 4).

Alternatively, the thiol compound of formula (2) used to prepare the 1-betamethylcarbapenem derivative of the present invention,

1) preparing a cyclized isoxazolinopyrrolidine compound of formula (VI-2) by reacting with a nitrile oxide using the protective proline compound of formula (IV) as a starting material (step 1),

2) converting the cyclized isoxazolinopyrrolidine compound of formula (VI-2) to a methanesulfonyl group after deprotection (step 2),

3) producing a thioacetate compound of formula (VII-2) through a substitution reaction with an acetylthio group (step 3), and

4) Subsequently, the thioacetate compound of formula (VII-2) is deacetylated to prepare a thiol compound of formula (III) (step 4).

Alternatively, the thiol compound of formula (2) used to prepare the 1-betamethylcarbapenem derivative of the present invention,

1) preparing a cyclized isoxazolinopyrrolidine compound of formula (VI-2) by reacting with a nitrile oxide using the protective proline compound of formula (IV) as a starting material (step 1),

2) converting the cyclized isoxazolinopyrrolidine compound of formula (VI-2) to a methanesulfonyl group after deprotection (step 2),

3) reducing the isooxazolinopyrrolidine compound protected with methanesulfonyl group (step 3),

4) producing a thioacetate compound of formula (VII-3) through a substitution reaction with an acetylthio group (step 4), and

5) Subsequently, the thioacetate compound of formula (VII-3) is deacetylated to prepare a thiol compound of formula (III) (step 5).

Alternatively, the thiol compound of formula (2) used to prepare the 1-betamethylcarbapenem derivative of the present invention,

1) reacting with ethyl propiolate using the protected proline compound of formula (V) as a starting material to prepare structure (VI-3), which is a cyclized isoxazolopyrrolidine compound (step 1),

2) converting the cyclized isoxazolopyrrolidine compound of formula (VI-3) to a methanesulfonyl group after the deprotection reaction (step 2),

3) reducing the isooxazolopyrrolidine compound protected with methanesulfonyl group (step 3),

4) producing a thioacetate compound of formula (VII-4) through a substitution reaction with an acetylthio group (step 4), and

5) Subsequently, the thioacetate compound of formula (VII-4) is deacetylated to prepare a thiol compound of formula (III) (step 5).

Reaction Schemes 2 to 5 will be described in more detail.

2-vinylpyrrolidine of Structural Formula (IV) used as a starting material in Schemes 2 to 4 and Step 1 is prepared by the following reaction. N-protected 4-hydroxyproline produced by treatment of trans-4-hydroxy-L-proline with paranitrobenzylchloroformate to produce an N-protective ester compound, wherein the hydroxy group is in the presence of imidazole Treatment with -butyl-dimethylsilyl chloride, followed by reduction with sodium borohydride to produce an alcohol compound. The alcohol compound is oxidized using pyridinesulpertrioxide complex salt in the presence of triethylamine to form a formylpyrrolidine compound, and the formylpyrrolidine compound is methyltriphenylphosphate in the presence of sodium bis (trimethylsilyl) amide. A 2-vinylpyrrolidin compound of formula (IV) is prepared through a reaction of phosphium bromine with Wittig.

In addition, the compound of formula (V) used as a starting material in Scheme 5, step 1 is prepared by treating the formylpyrrolidine compound with hydroxyl amine hydrochloride in the presence of pyridine in an ethanol solvent.

Nitron in Scheme 2, step 1 is produced through the condensation reaction of N-methylhydroxylamine with formaldehyde in the presence of sodium acetate, in step 1 of the cyclized isoxazolidiniopyrrolidine compound A mixture of diastereomeric mixtures is produced, but each isomer is separated using column chromatography. The deprotection reaction in step 2 proceeds to remove the butyldimethylsilyl group with tetrabutylammonium fluoride in THF solvent, and the resulting methanesulfonyl compound is easily replaced by the substitution reaction with potassium thioacetate salt. -1) to thioacetate. In step 4, the deacetylation is carried out by reaction with an aqueous sodium hydroxide solution in a suitable solvent, preferably ethanol, for 30 minutes at room temperature.

The compound of formula (VI-2) in Scheme 3 is prepared by reacting with a nitrile oxide using the protective proline compound of formula (IV) as a starting material, the nitrile oxide is added dropwise triethylamine to ethyl chlorooxyimido acetate Is generated. Steps 2, 3 and 4 thereafter proceed in a similar manner as in Scheme 2 above.

Reaction Scheme 3, Step 1 and Step 2 proceed similarly to Scheme 3, wherein the step of reducing the ester group of the isoxazolinopyrrolidine compound protected in the methanesulfonyl group in step 3 to the hydroxymethyl group is preferably sodium Proceed using borohydride. Subsequent steps proceed in a similar manner to Scheme 3.

The reaction with ethyl propiolate in Scheme 5, step 1 is carried out in the presence of N-chlorosuccinimide and triethylamine in DMF, and the following steps proceed similarly to Scheme 4.

In another aspect, the present invention provides a pharmaceutical composition for antimicrobial agents containing the compound of formula (1) as an active ingredient.

The present invention provides, in addition to non-toxic, inert, pharmaceutically suitable excipients, a pharmaceutical composition containing at least one compound according to the invention or consisting of at least one active compound according to the invention and a process for preparing said composition.

The compound of formula 1 may be administered parenterally during clinical administration and may be used in the form of a general pharmaceutical formulation.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, and lyophilized preparations. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.

In general, in medicine, the effective dose of the compound of formula 1 according to the present invention is 0.1 to 100 mg / kg, preferably 0.1 to 10 mg / kg, and may be administered once to several times a day. However, the dosage may need to be changed, and in particular, may be changed in consideration of the constitution specificity and weight of the subject to be treated, the type and depth of the disease, the nature of the formulation, the nature of the drug administration and the duration or interval of administration.

The 1-betamethylcarbapenem derivatives of the present invention have a significant antimicrobial activity as compared to conventional imipenem or meropenem antimicrobial agents as a result of measurement of Minimum Inhibitory Concentration (MIC, ㎍ / ml). Results were obtained, especially against Gram-positive bacteria, and showed an excellent antimicrobial effect than the known antimicrobial agents, and showed stable results against DHP-I.

Hereinafter, the present invention will be described in detail with reference to Examples. However, the following examples are merely to illustrate the invention and the present invention is not limited by the examples.

<Example 1> (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' '-methylisooxazolidinio-5' '-yl) pyrrolidine-3'-ylthio]- Preparation of 6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid

(Step 1) of (2S, 4R) -4-t-butyldimethylsilyloxy-2- (2'-methylisooxazolidinio-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine Produce

After dissolving 1.80 g (4.60 mmol) of (2S, 4R) -4-t-butyldimethylsilyloxy-2-vinyl-1-paranitrobenzyloxycarbonylpyrrolidine in 20 mL of tetrahydrofuran, sodium acetate 0.56 g and 0.73 mL of 35% formaldehyde were added and stirred for 5-10 minutes. Here, a solution of 0.59 mg of N-methylhydroxylamine hydrochloride dissolved in 20 mL of 80% ethanol was slowly added dropwise to the solution, followed by heating to reflux for the next 5 hours. Water was added, extraction was performed with ethyl acetate, and the organic layer was concentrated under reduced pressure, and then purified by column chromatography to obtain 0.80 g (43.0%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.06 (s, 6H), 0.86 (s, 9H), 1.82-2.03 (m, 1H), 1.96-2.23 (m, 1H), 2.28-2.56 (m, 2H), 2.76 -2.83 (m, 4H), 3.34-3.51 (m, 3H), 4.02-4.22 (m, 1H), 4.47-4.56 (m, 1H), 5.11-5.24 (m, 2H), 7.45 (d, 2H) , 8.15 (m, 2 H).

(Step 2) Preparation of (2S, 4R) -4-methanesulfonyloxy-2- (2'-methylisooxazolidinio-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine

(2S, 4R) -4-t-butyldimethylsilyloxy-2- (2'-methylisooxazolidinio-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine obtained in step 1 above After dissolving 2.00 g (4.30 mmol) in 30 mL of tetrahydrofuran, 6.05 mL (6.05 mmol, 1.4 equiv) of 1M tetrabutylammonium fluoride tetrahydrofuran solution was added and stirred at room temperature for 30 minutes. After distillation under reduced pressure to remove the solvent, 20 mL of saturated brine was added thereto, followed by extraction with 40 mL of ethyl acetate. The organic layer was concentrated under reduced pressure, and then purified by column chromatography (2S, 4R) -4-hydroxy-2- (2 '). 0.85 g (56.3%) of -methylisooxazolidinio-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine was obtained. 0.70 g (2.00 mmol) of (2S, 4R) -4-hydroxy-2- (2'-methylisooxazolidinio-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine was anhydrous. After dissolving in 30 mL of carbon dichloride and cooling to 0 ^° C., 0.40 mL (3.00 mmol, 1.5 equiv) of triethylamine was slowly added dropwise. After stirring for about 15 minutes, 0.22 ml (2.40 mmol, 1.2 equiv) of methanesulfonyl chloride was slowly added dropwise, and the temperature was raised to room temperature and stirred for about 2 hours. After distillation under reduced pressure to remove the solvent, 50 mL of water was added thereto, followed by extraction with 70 mL of carbon dichloride. The organic layer was concentrated under reduced pressure and purified by column chromatography to obtain 0.73 g (84.0%) of the title compound.

(Step 3) Preparation of (2S, 4S) -4-acetylthio-2- (2'-methylisooxazolidinio-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine

0.73 g of (2S, 4R) -4-methanesulfonyloxy-2- (2'-methylisoxazolidinio-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine obtained in step 2 above (1.70 mmol) was dissolved in 20 mL of acetonitrile, and then 0.23 g (1.99 mol, 1.2 equiv) of potassium thioacetic acid salt was added under nitrogen stream and heated to reflux for about 5 hours. After distilling under reduced pressure and distilling under reduced pressure to remove the solvent, 20 mL of water was added, extracted with 30 mL of carbon dichloride, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain 0.58 g (85.5%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.19-2.19 (m, 1H), 2.26 (s, 3H), 2.33-2.46 (m, 2H), 2.56- 2.73 (m, 4H), 3.10-3.15 (m, 1H) , 3.24-3.32 (m, 1H), 3.70-3.78 (m, 1H), 4.01-4.08 (m, 2H), 4.13-4.23 (m, 1H), 4.66-4.74 (m, 1H), 5.13 (s, 2H), 7.46 (d, 2H), 8.15 (d, 2H).

(Step 4) Paranitrobenzyl (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' '-methylisooxazolidinio-5' '-yl) -1'- Paranitrobenzyloxycarbonyl} pyrrolidine-3'-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid Preparation of ester

0.58 g (1.50) of (2S, 4S) -4-acetylthio-2- (2'-methylisooxazolidinio-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine obtained in step 3 above mmol) is dissolved in 20 mL of methanol and then 2N. 1.5 mL of sodium hydroxide is added at room temperature, stirred for 30 minutes, 0.60 mL of acetic acid is added, and the solvent is concentrated by distillation under reduced pressure. Extract with ethyl acetate and water, distill the solvent, add 30 mL of anhydrous acetonitrile, add 0.89 g (1.50 mmol) of carbapenem enol phosphate of formula (II) and 0.21 g (1.63 mmol) of diisopropylethylamine. . After stirring for 1 hour, the mixture was concentrated under reduced pressure and recovered by column chromatography to obtain 0.50 g (60.5%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.18 (d, 3H), 1.29 (d, 3H), 2.19-2.22 (m, 2H), 2.49-2.52 (m, 3H), 2.95 (s, 4H), 3.20-3.29 (m, 3H), 3.48-3.54 (m, 1H), 3.72-3.91 (m, 1H), 4.10-4.26 (m, 2H), 4.65-4.83 (m, 1H), 4.20-4.54 (m, 4H) , 7.45 (d, 2H), 7.58 (d, 2H), 8.15 (d, 4H).

(Step 5) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' '-methylisooxazolidinio-5' '-yl) pyrrolidine-3'- Preparation of Ilthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid

Paranitrobenzyl (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' '-methylisooxazolidinio-5' '-yl) -1' obtained in step 4 above -Paranitrobenzyloxycarbonyl} pyrrolidine-3'-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxyl 0.20 g (0.28 mmol) of the acid ester were dissolved in 10 mL of tetrahydrofuran, 0.8 g of zinc and 20 mL of phosphate buffer (0.33M, pH 6) were added, followed by stirring at room temperature for 3 hours. After extracting with ethyl acetate to remove impurities, the aqueous layer was lyophilized to recover the resulting compound by HP-20 resin column chromatography (1% -tetrahydrofuran / distilled water) to give 30.0 mg (30.4%) of the title compound. .

¹ H NMR (D ₂ O) δ 1.26 (d, 3H, J = 7.1 Hz, β-methyl), 1.32 (d, 3H, J = 6.3 Hz, C H ₃ CHOH), 1.82-1.85 (m, 1H) , 2.51-2.62 (m, 1H), 2.71 (s, 3H), 2.91-3.02 (m, 1H), 3.25-3.28 (m, 1H), 3.32-3.49 (m, 1H), 3.51-3.61 (m, 1H), 3.68-3.92 (m, 1H), 3.91-4.01 (m, 1H), 4.21-4.33 (m, 2H), 4.58-4.66 (m, 1H); FABHRMS m / z Calcd for C ₁₈ H ₂₈ N ₃ O ₅ S (M + H) ⁺ 398.1750, Found 398.1745.

<Example 2> (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' ', 2' '-dimethylisooxazolidinio-5' '-yl) pyrrolidine-3'- Preparation of Ilthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid hydrochloride

Paranitrobenzyl (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' '-methylisooxazolidinio-5' '-yl obtained in Example 1, step 4 above ) -1'-paranitrobenzyloxycarbonyl} pyrrolidine-3'-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m- 0.20 g (0.28 mmol) of 3-carboxylic acid ester was dissolved in 20 mL of acetone, and 0.47 mL (0.75 mmol) of methane iodide was added thereto, followed by stirring at room temperature for 24 hours, followed by distillation under reduced pressure to remove the solvent and excess methane iodide. . 10 mL of tetrahydrofuran, 0.8 g of zinc and 20 mL of phosphate buffer (0.33M, pH 6) were added thereto, followed by stirring at room temperature for 4 hours. Extraction with ethyl acetate removes impurities and freeze-dried the water layer to separate and recover the resulting compound by HP-20 resin tube chromatography (1% -tetrahydrofuran / distilled water) and then ion exchange resin Amberlyst A- Pass through 26 (Amberlyst A-26) to give 36.0 mg (41.0%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.27 (d, 3H, J = 7.1 Hz, β-methyl), 1.36 (d, 3H, J = 6.3 Hz, C H ₃ CHOH), 1.50-1.61 (m, 1H), 1.80-1.98 (m, 1H), 2.02-2.18 (m, 1H), 2.51-2.63 (m, 1H), 2.98 (s, 3H), 3.14-3.22 (m, 1H), 3.26-3.34 (m, 1H ), 3.44-3.61 (m, 3H), 3.70 (s, 3H), 3.82-3.96 (m, 1H), 4.21-4.33 (m, 2H).

<Example 3> (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(3' '-ethoxycarbonylisoxazolino-5' '-yl) pyrrolidine-3'-ylthio] Preparation of -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid

(Step 1) (2S, 4R) -4-t-butyldimethylsilyloxy-2- (3'-ethoxycarbonylisoxazolino-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine Manufacture

After dissolving 8.13 g (0.020 mol) of (2S, 4R) -4-t-butyldimethylsilyloxy-2-vinyl-1-paranitrobenzyloxycarbonylpyrrolidine in 1000 mL of dioxane and 100 mL of carbon dichloride, 6.1 g of ethyl chlorooxyimidoacetate is slowly added at room temperature. After stirring for 20 minutes, a 5.6 mL solution of triethylamine diluted with 5 mL of dioxane was slowly added dropwise and stirred for 2-3 hours. Water was added, extraction was performed with ethyl acetate, and the organic layer was concentrated under reduced pressure, and then purified by column chromatography to obtain 5.0 g (47.0%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.06 (s, 9H), 0.86 (s, 6H), 1.24 (t, 3H), 1.80-1.96 (m, 1H), 2.95 (dd, 1H), 3.26-3.32 (m , 1H), 3.52 (d, 2H), 4.13 (m, 1H), 4.34 (q, 2H), 4.40 (m, 1H), 5.15-5.31 (m, 2H), 5.38-5.56 (m, 1H), 7.51 (d, 2H), 8.21 (d, 2H).

(Step 2) Preparation of (2S, 4S) -4-acetylthio-2- (3'-ethoxycarbonylisooxazolino-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine

(2S, 4R) -4-t-butyldimethylsilyloxy-2- (3'-ethoxycarbonylisoxazolino-5'-yl) -1-paranitrobenzyloxycarbonylpyrroli obtained in step 1 above From Dean, the title compound was obtained through the same reaction procedure as in Step 2 and Step 3 in Example 1 (73%).

¹ H NMR (CDCl ₃ ) δ 1.36 (t, 3H), 1.74-1.77 (m, 1H), 2.33 (s, 3H), 2.30-2.47 (m, 1H), 2.84-3.12 (m, 1H), 3.12 -3.46 (m, 2H), 3.80-3.88 (m, 1H), 4.03-4.18 (m, 2H), 4.34 (d, 2H), 5.22 (s, 2H), 5.28-5.42 (m, 1H), 7.52 (d, 2H), 8.23 (d, 2H).

(Step 3) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(3' '-ethoxycarbonylisoxazolino-5' '-yl) pyrrolidine-3' Preparation of -ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid

Example from (2S, 4S) -4-acetylthio-2- (3'-ethoxycarbonylisooxazolino-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine in step 2 above The title compound was obtained through the same reaction procedure as steps 4 and 5 in 1 (26%).

¹ H NMR (D ₂ O) δ 1.09 (d, 3H, J = 6.9 Hz, β-methyl), 1.24 (d, 3H, J = 6.3 Hz, C H ₃ CHOH), 1.28-1.38 (m, 1H) , 2.30-2.42 (m, 1H), 2.76-2.82 (m, 1H), 3.02-3.18 (m, 1H), 3.21-3.34 (m, 1H), 3.33-3.40 (m, 3H), 3.41-3.52 ( m, 1H), 3.60-3.70 (m, 1H), 3.76 (s, 3H). 4.02-4.18 (m, 2 H), 4.90-4.98 (m, 1 H).

Examples 4 and 5 (1R, 5S, 6S) -2-[(3'S, 5'S and 3'S, 5'R)-{5 '-(3' '-hydroxymethylisoxazolino-5' '- (I) Preparation of Pyrrolidine-3'-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid

(Step 1) (2S, 4R and 2R, 4R) -4-methanesulfonyloxy-2- (3'-hydroxymethylisoxazolino-5'-yl) -1-paranitrobenzyloxycarbonylpyrroli Dean's Preparation

0.82 g (2S, 4R and 2R, 4R) -4-methanesulfonyloxy-2- (3'-ethoxycarbonylisoxazolino-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine (1.60 mmol) are dissolved in 20 mL of tetrahydrofuran, the reaction mixture is cooled to 0-5 ^° C., and 0.13 g of lithium chloride and 0.12 g of sodium borohydride are added. 5 mL of ethanol was slowly added at the same temperature, followed by stirring at room temperature for 3 hours. Water was added, extraction was performed with ethyl acetate, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain 0.26 g (71%) and 0.29 g (78%) of the title compound, respectively.

Isomer 1 (2S, 4R): ¹ H NMR (CDCl ₃ ) δ 2.20 (m, 1H), 2.21-2.31 (m, 1H), 2.80 (dd, 1H), 3.06 (s, 3H), 3.16-3.22 ( m, 1H), 3.74-3.79 (m, 1H), 3.98 (d, 1H), 4.17 (m, 1H), 4.40 (q, 2H), 5.23 (s, 2H), 5.31 (s, 2H), 7.53 (d, 2H), 8.24 (d, 2H).

Isomer 2 (2R, 4R): ¹ H NMR (CDCl ₃ ) δ 2.40 (m, 1H), 3.04 (s, 3H), 3.52 (m, 1H), 3.73 (dd, 1H), 4.05 (d, 1H) , 4.36 (s, 2H), 4.37 (m, 1H), 4.76 (m, 1H), 5.25 (s, 2H), 5.39-5.41 (m, 1H), 7.52 (d, 2H), 8.25 (d, 2H ).

(Step 2) Preparation of (2S, 4S and 2R, 4S) -4-acetylthio-2- (3'-hydroxymethylisoxazolino-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine

(2S, 4R and 2R, 4R) -4-methanesulfonyloxy-2- (3'-hydroxymethylisooxazolino-5'-yl) -1-paranitrobenzyloxycarbonylpy obtained in step 1 above The title compound was obtained from Lolidine (84% and 86%) by the same reaction procedure as in Example 1 and Step 3, respectively.

Isomer 1: ¹ H NMR (CDCl ₃ ) δ 1.83-1.90 (m, 1H), 2.35 (s, 3H), 2.36-2.48 (m, 1H), 2.82-2.92 (m, 1H), 3.14-3.28 (m , 2H), 3.84-3.90 (m, 1H), 4.06-4.12 (m, 1H), 4.14-4.18 (m, 1H), 4.46 (s, 2H), 5.13-5.20 (m, 1H), 5.23 (s , 2H), 7.52 (d, 2H), 8.25 (d, 2H).

Isomer 2: ¹ H NMR (CDCl ₃ ) δ 1.03-1.85 (m, 1H), 2.33 (s, 3H), 2.38-2.46 (m, 1H), 2.52-2.62 (m, 1H), 2.99-3.05 (m , 1H), 3.15-3.22 (m, 2H), 3.76-3.82 (m, 1H), 4.26 (d, 4H), 4.26 (s, 2H), 4.89-4.96 (m, 1H), 5.21 (s, 2H ), 7.52 (d, 2H), 8.23 (d, 2H).

(Step 3) (1R, 5S, 6S) -2-[(3'S, 5'S and 3'S, 5'R)-{5 '-(3' '-hydroxymethylisoxazolino-5' '-yl) Preparation of Lolidine-3'-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid

(2S, 4S and 2R, 4S) -4-acetylthio-2- (3'-hydroxymethylisoxazolino-5'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine in step 2 above The title compound was obtained (32%, 35%) by the same reaction procedure as in steps 4 and 5 in Example 1, respectively.

Isomer 1: ¹ H NMR (D ₂ O) δ 1.05 (d, 3H, J = 7.0 Hz, β-methyl), 1.12 (d, 3H, J = 6.2 Hz, C H ₃ CHOH), 1.34-1.52 (m , 1H), 2.34-2.52 (m, 1H), 2.74-2.92 (m, 1H), 3.01-3.10 (m, 1H), 3.25-3.32 (m, 3H), 3.33-3.42 (m, 1H), 3.55 -3.69 (m, 1 H), 3.75-3.86 (m, 1 H). 4.01-4.12 (m, 2H), 4.23 (s, 2H), 4.91-5.02 (m, 1H).

Isomer 2: ¹ H NMR (D ₂ O) δ 1.10 (d, 3H, J = 7.1 Hz, β-methyl), 1.18 (d, 3H, J = 6.3 Hz, C H ₃ CHOH), 1.32-1.42 (m , 1H), 2.32-2.46 (m, 1H), 2.80-2.96 (m, 2H), 3.10-3.34 (m, 4H), 3.56-3.62 (m, 3H), 4.07-4.15 (m, 2H), 4.27 (s, 2H); FABHRMS m / z Calcd for C ₁₈ H ₂₆ N ₃ 0 ₆ S (M + H) ⁺ 412.1543, Found 412.1527.

<Example 6> (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(5' '-hydroxymethylisoxazolo-3' '-yl) pyrrolidine-3'-ylthio]- Preparation of 6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid

(Step 1) (2S, 4R) -4-t-butyldimethylsilyloxy-2- (5'-ethoxycarbonylisoxazolo-3'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine Manufacture

4.50 g (10.50 mmol) of (2S, 4R) -4-t-butyldimethylsilyloxy-2-hydroxyimino-1-paranitrobenzyloxycarbonylpyrrolidine was dissolved in 60 mL of dimethylformamide followed by N- 1.56 g of chlorosuccinimide were slowly added and the temperature was raised to 60 ^° C. and stirred for 1 hour. After cooling the reaction mixture to 0-5 ^° C., 1.10 g of ethyl propiolate was slowly added and stirred at the same temperature for 20 minutes. To this was added a 1.6 mL solution of triethylamine diluted with 12 mL of dimethylformamide for 0.5-1 hour, followed by stirring at the same temperature for 30 minutes, followed by stirring at room temperature for 3 hours. Water was added, extraction was performed with ethyl acetate, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain 2.70 g (49.0%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.06 (s, 9H), 0.86 (s, 6H), 1.40 (t, 3H), 2.05 (m, 1H), 2.34 (m, 1H), 3.52-3.68 (m, 2H ), 4.40 (q, 2H), 4.50 (m, 1H), 5.01-5.35 (m, 3H), 6.82 (d, 1H), 8.12, 8.20 (dd, 2H), 8.83, 8.86 (dd, 2H).

(Step 2) Preparation of (2S, 4S) -4-acetylthio-2- (5'-hydroxymethylisoxazolo-3'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine

(2S, 4R) -4-t-butyldimethylsilyloxy-2- (5'-ethoxycarbonylisoxazolo-3'-yl) -1-paranitrobenzyloxycarbonylpyrroli obtained in step 1 above The title compound was obtained (80%) from Dean by the same reaction procedure as in Example 1 and Step 3.

¹ H NMR (CDCl ₃ ) δ 2.01-2.11 (m, 1H), 2.20-2.30 (m, 1H), 2.32 (s, 3H), 2.80-2.92 (m, 1H), 3.40-3.48 (m, 1H) , 4.00-4.12 (m, 1H), 4.13-4.24 (m, 1H), 4.70 (s, 2H), 5.20-5.31 (m, 2H), 6.19 (s, 1H), 7.26 (d, 1H), 7.50 (d, 1H), 8.12 (d, 1H), 8.21 (d, 1H).

(Step 3) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(5' '-hydroxymethylisoxazolo-3' '-yl) pyrrolidine-3'- Preparation of Ilthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid

Example 1 from (2S, 4S) -4-acetylthio-2- (5'-hydroxymethylisoxazolo-3'-yl) -1-paranitrobenzyloxycarbonylpyrrolidine in step 2 above The title compound (32%) was obtained through the same reaction procedure as in steps 4 and 5.

¹ H NMR (D ₂ O) δ 1.09 (d, 3H, J = 7.3 Hz, β-methyl), 1.15 (d, 3H, J = 6.3 Hz, C H ₃ CHOH), 1.60-1.76 (m, 1H) , 1.77-1.89 (m, 1H), 2.52-2.70 (m, 1H), 2.82-2.91 (m, 1H), 3.14-3.20 (m, 1H), 3.21-3.26 (m, 1H), 3.66-3.80 ( m, 1H), 4.08-4.17 (m, 1H), 4.18-4.30 (m, 1H), 4.61 (s, 2H), 6.38 (s, 1H); FABHRMS m / z Calcd for C ₁₈ H ₂₄ N ₃ O ₆ S (M + H) ⁺ 410.1387, Found 410.1390.

Example 7 (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' ', 2' '-acetamidomethylisoxazolidinio-5' '-yl Preparation of Pyrrolidine-3'-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid hydrochloride

The title compound was obtained through the same reaction as in Example 2 (21%).

¹ H NMR (D ₂ O) δ 1.23 (d, 3H, J = 7.1 Hz, β-methyl), 1.30 (d, 3H, J = 6.3 Hz, C H ₃ CHOH), 1.62-1.68 (m, 1H) , 1.82-1.85 (m, 1H), 2.38-2.43 (m, 1H), 2.71 (s, 3H), 3.03-3.12 (m, 1H), 3.29-3.41 (m, 4H), 3.42-3.55 (m, 2H), 3.89-3.99 (m, 1 H), 4.21-4.33 (m, 2H).

Experimental Example 1 Antibacterial Activity Test

As the 1-beta-methylcarbapenem Gram-positive bacteria was used in the streptococci (Streptococcus) and Staphylococcus aureus (Staphylococcus) gram-negative bacteria as test organisms to determine the antimicrobial activity of the penem derivative of the present invention, Escherichia coli (Escherichia), Pseudomonas aeruginosa (Pseudomonas), salmonella (Salmonella), keurep when Ella bacteria (Klebsiella) and Enterobacteriaceae (Enterobacter) was used. After culturing the test strains in dilute agar medium, the compounds of the present invention were treated to show the minimum strain inhibition concentration in μg per ml and are shown in Table 1 below. In vitro activity tests on the standard strains were performed on the synthesized novel 1-betamethylcarbapenem. Imiphenem and meropenem were used as a control of the experiment.

The novel 1-betamethylcarbapenem derivative of the present invention showed very balanced and excellent activity against Gram-positive strains including Gram-positive strains and Pseudomonas strains except Streptococcus faecium . Table 1 shows the minimum bacterial inhibition concentration and the DHP-I stability results of the compounds according to the present invention.

Minimum Strain Inhibition Concentration for Standard Strains EXAMPLES Strain ¹ One 2 3 4 5 6 7 IPM ² MPM ³ One S. pyogens 308A 0.007 0.013 0.025 0.013 0.013 0.013 0.007 0.007 0.013 2 S. pyogens 77A 0.004 0.007 0.013 0.007 0.007 0.007 0.004 0.004 <0.002 3 S. faecium MD8b 12.5 12.5 25 6.25 12.5 6.25 12.5 1.563 12.5 4 ^* S .aureus SG511 0.098 0.098 0.195 0.098 0.098 0.098 0.049 0.025 0.098 5 ^* S. aureus 285 0.098 0.195 0.391 0.098 0.098 0.098 0.098 0.025 0.195 6 ^* S. aureus 503 0.049 0.049 0.098 0.049 0.049 0.049 0.025 0.013 0.098 7 E. coli 055 0.098 0.195 0.013 0.025 0.049 0.025 0.098 0.098 0.013 8 E. coli DC 0 0.049 0.098 0.049 0.025 0.049 0.025 0.098 0.098 0.025 9 E. coli DC 2 0.098 0.195 0.049 0.049 0.098 0.025 0.195 0.391 0.025 10 E. coli TEM 0.049 0.098 0.013 0.025 0.049 0.025 0.195 0.195 0.025 11 E. coli 1507E 0.049 0.098 0.013 0.025 0.049 0.025 0.049 0.195 0.025 12 P. aeruginosa 9027 0.391 0.391 0.781 0.391 0.391 1.563 0.195 0.781 0.195 13 P. aeruginosa 1592E 0.391 0.391 0.781 0.391 0.391 1.563 0.391 1.563 0.195 14 P. aeruginosa 1771 0.391 0.391 0.781 0.391 0.391 1.563 0.391 0.781 0.195 15 P. aeruginosa 1771M 0.195 0.195 0.391 0.195 0.098 0.391 0.195 0.195 0.049 16 ^** S. typhimurium 0.098 0.195 0.049 0.049 0.098 0.049 0195 0.781 0.025 17 K. oxytoca 1082E 0.098 0.391 0.098 0.098 0.195 0.098 0.195 0.391 0.049 18 K. aerogenes 1522E 0.098 0.195 0.049 0.049 0.098 0.049 0.195 0.391 0.049 19 ^* E. cloacae P99 0.098 0.391 0.098 0.025 0.195 0.049 0.195 0.391 0.025 20 ^* E .. cloacae 1321E 0.025 0.098 0.025 0.025 0.049 0.025 0.049 0.195 0.025 DHP-I susceptibility ⁴ 1.27 1.50 0.94 0.78 1.09 0.80 1.66 0.19 1.00 One.S .; Streptococcus, ^* S .; Staphylococcus, E .; Escherichia, P .; Pseudomonas, ^** S.; Salmonella, K .; Klebsiella, ^* E .; Enterobacter2. Imipenem 3. Meropenem 4. Relative hydrolysis half-life for meropenem_1/2of hydrolysis to Meropenem)

Experimental Example 2 DHP-I Stability Test

The sensitivity test of the 1-betamethylcarbapenem derivative of the present invention with respect to the DHP-I enzyme secreted by the kidney was performed as follows. The sensitivity test value is set in the _half- life (t _1/2 ) of meropenem for the DHP-I enzyme to 1.00 to calculate the relative stability during hydrolysis of each drug is shown in Table 1 above. The control was performed on the same compound as Experimental Example 1. The stability of the novel carbapenems for the DHP-I enzyme according to the present invention far exceeded the imipenems without 1β-methyl group and showed equivalent or superior stability to meropenem. Examples 2 and 7 of isooxazolidine quaternary salts showed much better stability than meropenem, and Example 7 showed the best stability.

Experimental Example 3 Acute Toxicity in Parenteral Administered Rats

In order to determine the acute toxicity of the compound of Formula 1 was performed the following experiment.

Acute toxicity test was performed using 6 week-old SPF SD rats. The compound of Example 1 was suspended in 1 mL of physiological saline and administered intravenously to the tails of the two rats at a dose of 1000 mg / kg. After administration of the test substance, mortality, clinical symptoms, and changes in body weight were observed. Hematological and hematological examinations were performed. Necropsy was performed to observe abdominal and thoracic organ abnormalities. As a result, there were no clinical symptoms or deaths in all animals treated with the test substance, and no toxicity change was observed in weight change, blood test, blood biochemistry test, autopsy findings, etc. As a result, the compound of Chemical Formula 1 did not show a toxic change in rats up to 2000 mg / kg, and the parenteral administration minimum dose (LD ₅₀ ) was determined to be a safe substance of 2 g / kg or more.

As described above, the 1-betamethylcarbapenem derivative represented by Chemical Formula 1 of the present invention shows excellent antimicrobial activity against both Gram-positive bacteria and Gram-negative bacteria. In addition, the 1-betamethylcarbapenem derivative of the present invention is stable against the DHP-I enzyme secreted by the kidney and has excellent bioavailability, and thus may be usefully used as an antibacterial agent.

Claims (15)

1-betamethylcarbapenem derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof. Formula 1 In Chemical Formula 1, R is Indicates X is an ethoxycarbonyl group or a hydroxymethyl group, Y is a hydroxymethyl group or an ethoxycarbonyl group, Z is a methyl group or a carbamoylmethyl group. The 1-betamethylcarbapenem derivative represented by Formula 1 is 1) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' '-methylisooxazolidinio-5' '-yl) pyrrolidine-3'-ylthio ] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid, 2) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(2' ', 2' '-dimethylisoxazolidinio-5' '-yl) pyrrolidine-3 '-Ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid chloride, 3) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(3' '-ethoxycarbonylisoxazolino-5' '-yl) pyrrolidin-3'-yl Thio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid, 4) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(3' '-hydroxymethylisoxazolino-5' '-yl) pyrrolidine-3'-ylthio ] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid, 5) (1R, 5S, 6S) -2-[(3'S, 5'R)-{5 '-(3' '-hydroxymethylisoxazolino-5' '-yl) pyrrolidine-3'- Ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid, 6) (1R, 5S, 6S) -2-[(3'S, 5'S)-{5 '-(5' '-hydroxymethylisoxazolo-3' '-yl) pyrrolidine-3'-ylthio ] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid, or 7) (1R, 5S, 6S) -2-[(3'S, 5'S)-(5 '-(2' ', 2' '-acetamidomethylisoxazolidinio-5' '-yl) pyrroli Din-3'-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid chloride salt, 1-betamethylcarbapenem derivatives and pharmaceutically acceptable salts thereof. 1) reacting enolphosphate (II) with thiol derivative (III) in the presence of a base in a suitable solvent to prepare a protective carbapenem derivative (VII), and 2) Deprotecting the protective carbapenem derivative (iii) obtained in step 1 to prepare 1-betamethylcarbapenem derivative (I) (step 2) of the 1-betamethylcarbapenem derivative Manufacturing method. Scheme 1 In Scheme 1, R is as defined in Chemical Formula 1, PNB is a paranitrobenzyl group, and PNZ is a paranitrobenzyloxycarbonyl group. 4. The method of claim 3 wherein the base in step 1 consists of trimethylamine, triethylamine, diisopropylethylamine, 2,6-lutidine, picoline, N, N -dimethylaniline, pyridine, 4-dimethylaminopyridine A method for producing the 1-betamethylcarbapenem derivative of claim 1, which is selected from the group. The method for preparing 1-betamethylcarbapenem derivative of claim 1, wherein step 1 is reacted at room temperature for 3 to 6 hours. 4. The method according to claim 3, wherein step 1 is carried out in an acetonitrile reaction solvent. The method for preparing 1-betamethylcarbapenem derivative of claim 1, wherein step 2 is performed at 20-30 ° C. for 3 to 4 hours. 4. The method according to claim 3, wherein step 2 is carried out in a phosphate buffer solution. 4. The process for preparing 1-betamethylcarbapenem derivatives of claim 1, wherein zinc metal is used in step 2. Thiol derivative represented by the following formula (2) used to prepare the 1-betamethylcarbapenem derivative of claim 1. Formula 2 In Chemical Formula 2, R is Indicates X is an ethoxycarbonyl group or a hydroxymethyl group, Y is a hydroxymethyl group or an ethoxycarbonyl group, Z is a methyl group or a carbamoylmethyl group, PNZ is a paranitrobenzyloxycarbonyl group. 1) preparing a cyclized isoxazolidiniopyrrolidine compound of formula (VI-1) by reaction with nitrone using the protective proline compound of formula (IV) as a starting material (step 1) , 2) deprotecting the cyclized isoxazolidiniopyrrolidine compound of formula (VI-1) and then converting it to a methanesulfonyl group (step 2), 3) producing a thioacetate compound of formula (VII-1) through a substitution reaction with an acetylthio group (step 3) and 4) Subsequently, dethiolating the thioacetate compound of formula (VII-1) to prepare a thiol compound of formula (III) (step 4), wherein the thiol derivative represented by the formula (2) . Scheme 2 In Scheme 2, TBS represents a t-butyldimethylsilyl group, MsO represents a methanesulfonyl group, and PNZ represents a paranitrobenzyloxycarbonyl group. 1) preparing a cyclized isoxazolinopyrrolidine compound of formula (VI-2) by reacting with a nitrile oxide using the protective proline compound of formula (IV) as a starting material (step 1), 2) converting the cyclized isoxazolinopyrrolidine compound of formula (VI-2) to a methanesulfonyl group after deprotection (step 2), 3) producing a thioacetate compound of formula (VII-2) through a substitution reaction with an acetylthio group (step 3) and 4) Subsequently, dethiolating the thioacetate compound of formula (VII-2) to produce a thiol compound of formula (III) (step 4), wherein the thiol derivative represented by the formula (2) . Scheme 3 In Scheme 3, TBS represents a t-butyldimethylsilyl group, MsO represents a methanesulfonyl group, and PNZ represents a paranitrobenzyloxycarbonyl group. 1) preparing a cyclized isoxazolinopyrrolidine compound of formula (VI-2) by reacting with a nitrile oxide using the protective proline compound of formula (IV) as a starting material (step 1), 2) converting the cyclized isoxazolinopyrrolidine compound of formula (VI-2) to a methanesulfonyl group after deprotection (step 2), 3) reducing the isooxazolinopyrrolidine compound protected with methanesulfonyl group (step 3), 4) producing a thioacetate compound of formula (VII-3) through a substitution reaction with an acetylthio group (step 4) and 5) Subsequently, a process for producing a thiol derivative represented by the formula (2) of claim 10, comprising the step (step 5) of preparing a thiol compound of the formula (III) by deacetylating the thioacetate compound of the formula (VII-3). . Scheme 4 In Scheme 4, TBS represents a t-butyldimethylsilyl group, MsO represents a methanesulfonyl group, and PNZ represents a paranitrobenzyloxycarbonyl group. 1) reacting with ethyl propiolate using the protected proline compound of formula (V) as a starting material to prepare structure (VI-3), which is a cyclized isoxazolopyrrolidine compound (step 1), 2) converting the cyclized isoxazolopyrrolidine compound of formula (VI-3) to a methanesulfonyl group after the deprotection reaction (step 2), 3) reducing the isooxazoliropyrrolidine compound protected with methanesulfonyl group (step 3), 4) producing a thioacetate compound of formula (VII-4) through a substitution reaction with an acetylthio group (step 4) and 5) Subsequently, dethiolating the thioacetate compound of formula (VII-4) to produce a thiol compound of formula (III) (step 5), wherein the thiol derivative represented by the formula (2) . Scheme 5 In Scheme 5, TBS represents a t-butyldimethylsilyl group, MsO represents a methanesulfonyl group, and PNZ represents a paranitrobenzyloxycarbonyl group. A pharmaceutical composition for an antimicrobial agent comprising the 1-betamethylcarbapenem derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.