KR100535253B1 - 1b-methylcarbapenem derivatives having pyrrolidine with aminoethylcarbamoyl derivatives moiety and method for preparation of the same - Google Patents

Abstract

The present invention relates to a 1-betamethylcarbapenem derivative, a method for preparing the same, an intermediate used for the preparation thereof, and a pharmaceutical composition comprising the same, wherein the 1-betamethylcarbapenem has a structure of Formula 1 below. do.

[Formula 1]

(In Formula 1, R is selected from the group consisting of an amino group, a urea substituent containing a cyclic amine, a urea substituent containing a lower alkylamine, a cyclic amine having 4 or more carbon atoms, a lower alkyl sulfamoyl and a guanidine derivative. .)

The 1-betamethylcarbapenem derivative according to the present invention has excellent antibacterial activity by substituting a pyrrolidine thiol derivative including an aminoethyl carbamoyl derivative, and has a strong effect on resistant bacteria. Therefore, the 1-betamethylcarbapenem derivative according to the present invention can be usefully used as an antibiotic.

Description

1-Betamethylcarbapenem derivatives having pyrrolidine with aminoethylcarbamoyl derivatives moiety and method for preparation of the same}

The present invention relates to a novel 1-betamethylcarbapenem derivative useful as an antibiotic, and more particularly includes ethyl carbamoyl derivative as the main functional group at position 2 of the 1-betamethylcarbapenem nucleus represented by the following general formula (1). The present invention relates to a 1-betamethylcarbapenem derivative having a pyrrolidine thiol derivative and a preparation method thereof.

(In Formula 1,

R is selected from the group consisting of amino, urea-containing substituents including cyclic amines, urea-containing substituents including lower alkylamines, cyclic amines having 4 or more carbon atoms, lower alkylsulfamoyl and guanidine derivatives.)

Carbapenem antibiotics were the first in the 1970s when Merck researchers isolated Tyenamycin from Streptomyces. This tyenamycin is known to have activity on both Gram-positive and negative bacteria. However, tyenamycin has a disadvantage in that its activity is easily degraded by dehydropeptidase-I (so-called DHP-I), which is produced in the kidney in the human body. In fact, Imipenem, developed by Merck, which is used as an antibiotic, was used in combination with an enzyme inhibitor, cilastatin, due to its chemically unstable structure. Because of these problems, Kabapenem's research was not active, but in the mid-1980s, a new discovery was made at Merck. It was shown to be chemically stable by substituting a beta-type methyl group at the C-1 position of the carbapenem nucleus. Knowing this fact, many carbapenems having excellent efficacy have been synthesized.

As the condition of good antibiotics, the most important thing is to have strong activity and broad antimicrobial range. In connection with these conditions, the substitution of pyrrolidin in the carbapenem hair nucleus is known to provide antibiotics with a broad antimicrobial range.

Antibiotics developed with a strong selectivity in MRSA (Methicillin Resistant Staphylococcus Aureus) hospital of the microorganism and Pseudomonas aeruginosa (Pseudomonas) This is the most urgent task.

In this context, cabapenem is in a better position than any antibiotic. In particular, it exhibits a wide range of potent medicinal effects on both Gram-positive and negative bacteria, and shows excellent effects on various resistant strains. The prospect of the pharmaceutical industry is also expected to show the strongest growth of carbapenem antibiotics after the 1990s. On the other hand, panipenem, meropenem, and the like have been developed and marketed, but the improved antibiotics also encountered a problem that is very weak against bacterial resistant bacteria.

The present invention is to solve the problems of the prior art as described above, the object of the present invention is to provide an antibiotic with a strong activity and a broad antimicrobial range. In particular, the present invention provides a 1-betamethylcarbapenem derivative having a pyrrolidine substituent including a strong substituent to resistant bacteria and a method for producing the same, in order to exhibit a strong antibiotic effect against resistant bacteria.

It is still another object of the present invention to provide a thiol derivative which provides a structural contribution to the final product 1-betamethylcarbapenem derivative as an intermediate for synthesizing a novel 1-betamethylcarbapenem derivative and a method for producing the same. .

The 1-betamethylcarbapenem derivative having a pyrrolidine containing the ethyl carbamoyl derivative of the present invention for achieving the above object is characterized by the following formula (1).

[Formula 1]

(In Formula 1,

R is selected from the group consisting of amino, urea-containing substituents including cyclic amines, urea-containing substituents including lower alkylamines, cyclic amines having 4 or more carbon atoms, lower alkylsulfamoyl and guanidine derivatives.)

In the 1-betamethyl carbapenem derivative having a pyrrolidine substituent containing an aminoethylcarbamoyl derivative of the present invention, the 1-betamethylcarbapenem derivative represented by Formula 1 above,

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-aminoethylcarbamoyl) pyrrolidine-3-ylthio] -1-methylcarbafen- 2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-methylsulfonylaminoethylcarbamoyl)] pyrrolidine-3-ylthio] -1- Methylcarbafen-2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-N, N-dimethylaminosulfonylaminoethylcarbamoyl)] pyrrolidine-3- Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-N, N-dimethylaminocarbonylaminoethylcarbamoyl)] pyrrolidine-3- Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-morpholinocarbonylamino) ethylcarbamoyl}] pyrrolidine-3- Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-thiomorpholinocarbonylamino) ethylcarbamoyl}] pyrrolidine-3 -Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-piperazinnocarbonylamino) ethylcarbamoyl}] pyrrolidine-3- Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-methylaminothiocarbonylaminoethylcarbamoyl)] pyrrolidine-3-ylthio]- 1-methylcarbafen-2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-formidoaminoethylcarbamoyl)] pyrrolidine-3-ylthio] -1-methyl Carbafen-2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-acetimidoaminoethylcarbamoyl)] pyrrolidin-3-ylthio] -1-methyl Carbafen-2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-guanidinoethylcarbamoyl)] pyrrolidine-3-ylthio] -1-methyl Carbafen-2-m-3-carboxylic acid;

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (thiomorpholino-1 yl) ethylcarbamoyl}] pyrrolidine-3-ylthio ] -1-methylcarbafen-2-m-3-carboxylic acid; or

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (piperazin-1 yl) ethylcarbamoyl}] pyrrolidine-3-ylthio] -1-methylcarbaphen-2-m-3-carboxylic acid.

In the method for preparing 1-betamethylcarbapenem derivative represented by Chemical Formula 1 according to the present invention, a 9th compound of Scheme 1 below is reacted with a thiol derivative represented by Chemical Formula 2 in the presence of a base in a solvent to protect carbapenem Preparing a derivative (the tenth compound) (a); And (b) preparing 1-betamethylcarbapenem derivative (eleventh compound) by deprotecting the protective carbapenem derivative (compound 10) obtained in step (a). It is done.

(In Scheme 1,

R is selected from the group consisting of amino, urea-containing substituents including cyclic amines, urea-containing substituents including lower alkylamines, cyclic amines having 4 or more carbon atoms, lower alkylsulfamoyl and guanidine derivatives.)

In Formula 2, R is selected from the group consisting of amino, urea-containing substituents including cyclic amines, urea-containing substituents including lower alkylamines, cyclic amines having 4 or more carbon atoms, lower alkylsulfamoyl and guanidine derivatives.

In the method for preparing 1-betamethylcarbapenem derivative represented by Chemical Formula 1 according to the present invention, the base of step (a) is characterized in that the diisopropylethylamine.

In addition, the thiol derivative according to the present invention is used to prepare a 1-betamethylcarbapenem derivative, characterized in that represented by the following formula (2).

[Formula 2]

In Formula 2, R is selected from the group consisting of amino, urea-containing substituents including cyclic amines, urea-containing substituents including lower alkylamines, cyclic amines having 4 or more carbon atoms, lower alkylsulfamoyl and guanidine derivatives.

In the thiol derivative according to the present invention, the thiol derivative represented by the formula (2),

(2S, 4S) -2- (2-allyloxycarbonylaminoethylcarbamoyl) -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2- (2-methylsulfonylaminoethylcarbamoyl) -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2- (2-N, N-dimethylaminosulfonylaminoethylcarbamoyl) -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2- (2-N, N-dimethylaminocarbonylaminoethylcarbamoyl) -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2- [2- (1-morpholinocarbonylamino) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2- [2- (1-thiomorpholinocarbonylamino) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2- [2- (1-piperazinnocarbonylamino) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2- [2- (3-methylthioureido) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2-[(2-allyloxycarbonylformidoyl) aminoethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2-[(2-allyloxyacetimidoaminoethylcarbamoyl) aminoethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2-[(2-allyloxyguanidinoethylcarbamoyl) aminoethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine;

(2S, 4S) -2- [2- (thiomorpholin-4-yl) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine; Or (2S, 4S) -2- [2- (piperazin-1yl) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine.

In the method for preparing a thiol derivative represented by Chemical Formula 2 according to the present invention, the N-protected 4-tritylthiopyrrolidine methyl ester (first compound) in Scheme 2 is hydrolyzed under basic conditions to obtain a second method. Preparing a compound of (a); (B) preparing a third compound in which ethanolamine is substituted by a substitution reaction with an acid chloride from the hydrolyzed second compound of step (a); (C) preparing a fourth compound by mechanizing a third compound substituted with carbamoyl in step (b); (D) preparing a seventh compound through substitution reaction from the fourth compound of step (c); And (e) preparing a thiol derivative as an eighth compound by detritylation of the fifth compound of step (d).

In Scheme 2, NHR 'refers to R of Formula 2, wherein R is amino, urea substituent including cyclic amine, urea substituent including lower alkylamine, cyclic amine having 4 or more carbon atoms, lower alkyl Selected from the group consisting of sulfamoyl and guanidine derivatives.

In the method for producing a thiol derivative according to the present invention, the step (d) is,

A seventh compound is prepared through a substitution reaction of heterocyclic amines from the fourth compound of step (c).

Optionally, in the method for preparing a thiol derivative according to the present invention, the step (d) is

Preparing an azide compound (a fifth compound) in which an azide is substituted by replacing the fourth compound of step (c) with the reaction as in Scheme 3;

Reducing the azide compound (the fifth compound) of step (d-1) to prepare a compound (the sixth compound) having an aminoethyl carbamoyl group as an intermediate (d-2); And

A method of producing a thiol derivative, comprising the step (d-3) of preparing a seventh compound by replacing acid chloride and imitate with the sixth compound of step (d-2).

 In Scheme 3, NHR ′ refers to R of Formula 2, wherein R is amino, urea substituent including cyclic amine, urea substituent including lower alkylamine, cyclic amine having 4 or more carbon atoms, lower alkyl Selected from the group consisting of sulfamoyl and guanidine derivatives.

In addition, the antimicrobial pharmaceutical composition according to the present invention is characterized in that it comprises 1-betamethylcarbapenem derivative of Formula 1 or a pharmaceutically acceptable salt thereof.

Hereinafter, the present invention will be described in detail.

The 1-betamethylcarbapenem derivatives of the present invention represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and the pharmaceutical composition according to the present invention may also be a drug of the 1-betamethylcarbapenem derivative of Formula 1 A scientifically acceptable salt may be included as an active ingredient. Here, salts are useful acid addition salts formed by pharmaceutically acceptable free acid. 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 , Gluturonic acid, embonic acid, glutamic acid, aspartic acid, or the like can be used. 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.

Referring to the manufacturing method of the 1-betamethyl-2-thiol-based carbapenem derivative of the formula 1 according to the present invention.

1) The ninth compound of Scheme 1 is reacted with a thiol derivative of Formula 2 (eighth compound) in the presence of a base to obtain a protected carbapenem compound (the tenth compound).

The process can be prepared under the reaction conditions in the preparation of the carbapenem derivative of the general method, it is preferred to use diisopropylethylamine as the base at a reaction temperature of 0-5 ℃.

2) The final compound (11th compound) can be obtained by deprotecting the compound (10th compound) with hydrogen and a palladium hydrooxide catalyst and then purifying with HP-20.

Referring to the manufacturing method of the thiol derivative of Formula 2 according to the present invention.

As in Scheme 4 below, first, using (2S, 4S) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine-2-carboxylic acid (first compound) as a starting material After basic hydrolysis (second compound) and substitution reaction of ethanolamine (third compound) with ethyl chloroformate and triethylamine, the mixture was stirred under ice bath using methanesulphonic chloride and triethylamine. It was mesylated (the fourth compound), and a fifth compound was obtained by substitution reaction with sodium azide to this mesyl compound, and then a sixth compound was synthesized by a reduction reaction using triphenyl phosphine. This intermediate was synthesized by reacting with the acid chloride and the imitate to any one of compounds 7a to 7k, and the tritylthio compound was treated with trifluoroacetic acid in the presence of triethylsilane to any one of compounds 8a to 8m. The compound was made.

Optionally, as shown in Scheme 5 below, the mesyl compound (fourth compound) was directly reacted with the heterocyclic compound to prepare a compound of 71 or 7m.

The antimicrobial pharmaceutical composition containing the compound of formula 1 or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient is a compound of formula 1 orally or parenterally (for example, intravenous injection, intramuscular injection, subcutaneous administration). , Rectal administration, transdermal administration) can be administered to humans and non-human animals. Therefore, the pharmaceutical composition containing the compound of the present invention as an active ingredient may be in a suitable dosage form depending on the route of administration. Specifically, it can be adjusted mainly in the form of any preparation such as injections such as intravenous injections, intramuscular injections, capsules, tablets, granules, powders, pills, granules, oral preparations such as troche tablets, rectal administration, and oleaginous suppositories. . These formulations are conventionally used by using conventional excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, dissolution aids, preservatives, flavors, analgesics, stabilizers, etc. It can manufacture. Non-toxic additives which can be used include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, or salts thereof, gum arabic, polyethylene glycol, syrup, waserine And glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate and the like. The dosage is appropriately determined in consideration of the usage, the age, sex, and severity of the patient.However, for the treatment of an infectious disease, a dosage of about 0.01 to 200 mg, preferably 0.1 mg to 10 mg per kilogram per day, is usually used. These can be administered once or several times a day.

The present invention will be described in more detail with reference to the following Examples. However, the following examples are provided only for the purpose of illustration in order to facilitate the understanding of the present invention, and the scope and scope of the present invention is not limited thereto.

Example 1 Preparation of (2S, 4S) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine-2-carboxylic acid (second compound)

The first compound dissolved in methanol (500 ml) was slowly added dropwise to 4 N- NaOH (38 ml, 0.15 mol) cooled to 0 ° C. and stirred for 5 hours at room temperature, followed by 4 N- HCl (38 ml). Neutralize) and concentrate. The residue was diluted with water (300 ml) and ethyl acetate (200 ml), the precipitate was filtered off, washed with water and dried to afford the second compound (39.4 g, 82.2%) as a white solid mp 202-203 ° C. Got it.

1 H-NMR (CDCl 3) δ 1.98 (m, 1H), 2.75-2.82 (m, 1H), 3.01 (m, 1H), 3.55 (bs, 2H), 3.98 (m, 1H), 4.55 (d, 2H, J = 5.9 Hz), 5.25 (m, 2H), 5.90 (m, 1H), 7.27 (m, 9H), 7.47 (m, 6H).

Example 2 Preparation of (2S, 4S) -2- (2-hydroxyethylcarbamoyl) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine ( third compound )

Dissolve the second compound (23.7 g, 0.05 mol) in purified methylene chloride (300 ml), cool to 0 ° C., add triethylamine (7.4 mL, 0.055 mol) drop wise, ethylchloroformate (5.25 mL, 0.055 mol) was added dropwise and the mixture was stirred for 30 minutes. After cooling, ethanol amine (3.3 mL, 0.055 mol) was added dropwise and stirred for 1 hour. The mixture was washed with 10% sodium bicarbonate solution and saturated brine, the organic solvent was dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and the residue was purified by silica gel chromatography to give a yellow oily third compound (23.1). g, 89.5%).

1 H-NMR (CDCl 3) δ 1.95 (bs, 1H), 2.20 (bs, 1H), 2.75-2.86 (bs, 1H), 2.96 (bs, 1H), 3.55 (t, 2H, J = 5.6 Hz), 4.01 (m, 1H), 4.11 (t, 2H, J = 5.6 Hz), 4.50-4.62 (bs, 3H), 5.28 (m, 2H), 5.87 (m, 1H), 7.27 (m, 9H), 7.48 ( m, 6H)

Example 3 Preparation of (2S, 4S) -2- (2-mesyloxyethylcarbamoyl) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine ( fourth compound )

Dissolve the third compound (20.6 g, 0.04 mol) in purified methylene chloride (200 ml), cool to 0 ° C., add triethylamine (5.9 mL, 0.044 mol) dropwise, methanesulfonyl chloride (5.01 g, 0.044 mol) is added dropwise and stirred for 1 hour. The mixture was washed with 10% sodium bicarbonate solution and saturated brine, the organic solvent was dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and the residue was purified by silica gel chromatography to give a yellow oily fourth compound (21.8). g, 91.7%).

1 H-NMR (CDCl 3) δ 1.99 (bs, 1H), 2.21 (bs, 1H), 2.75-2.82 (bs, 1H), 2.96-3.08 (bs, 4H), 3.55 (t, 2H, J = 5.6 Hz ), 4.01 (m, 1H), 4.25 (t, 2H, J = 5.6 Hz), 4.50-4.59 (bs, 3H), 5.28 (m, 2H), 5.88 (m, 1H), 7.27 (m, 9H) , 7.48 (m, 6 H).

Example 4 Preparation of (2S, 4S) -2- (2-azidoethylcarbamoyl) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (a fifth compound )

Fourth compound (31.5 g, 0.053 mol) and sodium azide (13.8 g, 0.21 mol) were added dropwise to solvent DMSO (300 ml), and the mixture was heated and stirred at 70 0 C for 5 hours, followed by pouring ice water and ethyl acetate ( Extract 300 mL x 2). The organic layer was washed with water (200 mL × 2) and saturated brine, the organic solvent was dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and the residue was purified by silica gel chromatography to give a yellow oily fifth compound (24.5 g, 85.4%).

1 H-NMR (CDCl 3) δ 2.13 (m, 1H), 2.82 (m, 1H), 2.95-3.08 (m, 1H), 3.39-3.48 (m, 5H), 4.05 (bs, 1H), 4.55 (m , 2H), 5.29 (m, 2H), 5.88 (m, 1H), 7.27 (m, 9H), 7.46 (m, 6H).

Example 5 Preparation of (2S, 4S) -2- (2-aminoethylcarbamoyl) -4-tritylthio-1- (allyloxycarboxy) pyrrolidine ( sixth compound )

Compound 5 (1.29 g, 2.4 mmol), triphenylphosphine (0.70 g, 2.6 mmol) and water (0.44 mL, 24.0 mmol) were added dropwise to tetra hydrofuran (10 mL) for 4 hours at 40 ° C. After heating and stirring, the mixture was cooled and diluted with water (20 mL) and ethyl acetate (30 mL), the organic layer was washed with saturated brine, the organic solvent was dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and the residue was purified by silica gel. Purification by chromatography to give the yellow oily compound 6th compound (1.07 g, 86.4%). Got.

1 H-NMR (CDCl 3) δ 1.88 (m, 1H), 2.19 (m, 1H), 2.82-2.94 (bs, 2H), 2.95-3.08 (bs, 1H), 3.30-3.48 (bs, 4H), 4.02 (bs, 1H), 4.55 (bs, 2H), 5.22 (m, 2H), 5.84 (m, 1H), 7.27 (m, 9H), 7.46 (m, 6H).

Example 6 (2S, 4S) -2- (2-allyloxycarbonylaminoethylcarbamoyl) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine ( Compound 7a ) Manufacture

Dissolve the sixth compound (1.3 g, 2.5 mmol) in purified methylene chloride (20 ml), cool to 0 ° C. and add triethylamine (0.37 mL, 2.75 mmol) dropwise, allyl chloroformate (0.34 g, 2.75 mmol) is added dropwise and stirred for 1 hour. The mixture is diluted with water (100 mL) and methylene chloride (100 mL), the organic layer is washed with saturated brine, the organic solvent is dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure, and the residue is purified by silica gel chromatography. The yellow oily compound 7a (1.30 g, 87.1%) was obtained.

1 H-NMR (CDCl 3) δ 1.85 (bs, 1H), 2.22 (m, 1H), 2.63-2.80 (bs, 1H), 3.28-3.55 (bs, 5H), 3.59 (bs, 1H), 4.04 (m , 1H), 4.50-4.62 (bs, 4H), 5.20-5.44 (m, 4H), 5.80-5.98 (m, 2H), 6.24 (bs, 1H), 7.23 (m, 9H), 7.47 (m, 6H ).

Compounds 7b and 7c were prepared in the same manner as in the synthesis of compound 7a using a suitable sulfonyl chloride.

Example 7 of (2S, 4S) -2- (2-methylsulfonylaminoethylcarbamoyl) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine ( compound 7b ) Produce

7b : yield 82.5%. 1 H-NMR (CDCl 3) δ 1.91 (bs, 1H), 2.13 (m, 1H), 2.83-3.12 (bs, 6H), 3.25-3.48 (bs, 4H), 3.93 (m, 1H), 4.55 (bs , 2H), 5.25 (m, 2H), 5.88 (m, 1H), 6.44 (bs, 1H), 7.23 (m, 9H), 7.47 (m, 6H).

Example 8 (2S, 4S) -2- (2-N, N-dimethylaminosulfonylaminoethylcarbamoyl) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine ( Preparation of Compound 7c )

7c : yield 81.8%. 1 H-NMR (CDCl 3) δ 1.94 (bs, 1H), 2.22 (m, 1H), 2.78 (s, 6H), 2.90-3.22 (bs, 2H), 3.20-3.32 (bs, 3H), 3.36-3.51 (bs, 2H), 3.93 (m, 1H), 4.55 (bs, 2H), 5.25 (m, 2H), 5.88 (m, 1H), 6.74 (bs, 1H), 7.23 (m, 9H), 7.47 ( m, 6H).

Example 9 (2S, 4S) -2- (2-N, N-dimethylaminocarbonylaminoethylcarbamoyl) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine ( Preparation of Compound 7d )

Dissolve the sixth compound (1.03 g, 2.0 mmol) in purified methylene chloride (30 ml), cool to 0 ° C, add triethylamine (0.30 mL, 2.2 mmol) dropwise, and para-nitrophenyl chloroformate (0.44 g, 2.2 mmol) is added dropwise and the mixture is stirred for 1 hour. The mixture is diluted with water (30 mL) and methylene chloride (50 mL), the organic layer is washed with saturated brine, the organic solvent is dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure, and the residue is purified by ethanol (20). mL) was dissolved in N, N in-and stirred at diethylamine (room temperature 2 mL) was added dropwise to 1 hours, 6 N-hydrochloric acid, thereby neutralizing the solution. The mixture was washed with ethyl acetate (100 mL) and saturated brine, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and the residue was purified by silica gel chromatography to obtain the yellow oily compound 7d (0.99 g, 81.6%). .

1 H-NMR (CDCl 3) δ 1.92 (bs, 1H), 2.19 (m, 1H), 2.83-2.89 (bs, 1H), 2.96 (2s, 6H), 3.04 (bs, 1H), 3.29-3.56 (bs , 5H), 4.01 (m, 1H), 4.55 (bs, 2H), 5.26 (bs, 2H), 5.85 (m, 1H), 6.86 (bs, 1H), 7.24 (m, 9H), 7.45 (m, 6H).

Compounds 7e-7g were prepared in the same manner as in the synthesis of compound 7d using a suitable amine.

Example 10 (2S, 4S) -2- [2- (1-morpholinocarbonylamino) ethylcarbamoyl] -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine ( Preparation of Compound 7e )

7e : yield 76.2%. 1 H-NMR (CDCl 3) δ 1.90 (bs, 1H), 2.22 (m, 1H), 2.73-2.80 (m, 1H), 2.93-3.03 (bs, 2H), 3.21-3.52 (bs, 8H), 3.65 (bs, 4H), 3.96 (m, 1H), 4.49 (bs, 2H), 5.26 (m, 2H), 5.88 (m, 1H), 6.84 (bs, 1H), 7.27 (m, 9H), 7.47 ( m, 6H).

Example 11 (2S, 4S) -2- [2- (1-thiomorpholinocarbonylamino) ethylcarbamoyl] -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine Preparation of ( Compound 7f )

7f : yield 75.1%. 1 H-NMR (CDCl 3) δ 1.92 (bs, 1H), 2.20 (m, 1H), 2.52 (bs, 4H), 2.73-2.82 (m, 1H), 2.95-3.05 (bs, 2H), 3.29-3.50 (bs, 4H), 3.62 (bs, 4H), 3.95 (m, 1H), 4.49 (bs, 2H), 5.26 (m, 2H), 5.67 (bs, 1H), 5.88 (m, 1H), 6.80 ( bs, 1H), 7.27 (m, 9H), 7.47 (m, 6H).

Example 12 (2S, 4S) -2- [2- (1-piperazinnocarbonylamino) ethylcarbamoyl] -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine ( Preparation of 7 g of Compound )

7g : Yield 74.9%. 1 H-NMR (CDCl 3) δ 1.92 (bs, 1H), 2.23 (m, 1H), 2.73-2.82 (bs, 1H), 2.93-3.05 (bs, 2H), 3.21-3.65 (bs, 12H), 3.96 (m, 1H), 4.49 (bs, 2H), 5.26 (m, 2H), 5.70 (bs, 1H), 5.84 (m, 1H), 6.77 (bs, 1H), 7.27 (m, 9H), 7.47 ( m, 6H).

Example 13 (2S, 4S) -2- [2- (3-methylthioureido) ethylcarbamoyl] -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine Preparation of 7h Compound )

Dissolve the sixth compound (0.80 g, 1.60 mmol) in purified methylene chloride (20 ml), cool to 0 ° C, and triethylamine (0.43 mL, 3.20 mmol) and isocyanate (0.23 mL, 3.20 mmol). Add dropwise and stir for 5 hours. The mixture is diluted with water (20 mL) and methylene chloride (30 mL), the organic layer is washed with water and saturated brine, the organic solvent is dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure, and the residue is purified by silica gel chromatography. Purification gave a yellow oily compound 7h (0.81 g, 88.1%).

1 H-NMR (CDCl 3) δ 1.92 (bs, 1H), 2.15 (m, 1H), 2.71-3.06 (5H), 3.16-3.30 (bs, 3H), 3.74 (bs, 2H), 3.97 (m, 1H ), 4.42 (m, 1H), 5.26 (m, 2H), 5.98 (m, 1H), 6.79 (bs, 1H), 7.23 (m, 9H), 7.48 (m, 6H).

Example 14 (2S, 4S) -2-[(2-allyloxycarbonylformidoyl) aminoethylcarbamoyl] -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine ( Preparation of Compound 7i )

A sixth compound (1.03 g, 2.0 mmol) was dissolved in an ethanol solvent, and ethyl formimidate hydrochloride (0.24 g, 2.2 mmol) was added dropwise, followed by heating for 3 hours. The solvent was removed by distillation under reduced pressure, and the impure residue was cooled by dropwise addition of methylene chloride (20 mL) and triethylamine (0.30 mL, 2.2 mmol) without further purification, and allyl chloroformate (0.27 g, 2.2 mmol) Stir for 1 hour. The mixture was diluted with methylene chloride (100 mL), washed with 10% sodium bicarbonate and saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and the residue was purified by silica gel chromatography to give yellow oily properties. Of compound 7i (1.00 g, 79.8%) Got.

1 H-NMR (CDCl 3) δ1.82 (bs, 1H), 2.19 (m, 1H), 2.80-2.92 (bs, 1H), 3.02-3.17 (bs, 1H), 3,33-3.56 (bs, 3H) , 3.78 (bs, 2H), 3.96 (m, 1H), 4.55 (bs, 2H), 4.72 (d, 2H, J = 5.9 Hz), 5.20-5.44 (m, 4H), 5.85-5.98 (m, 2H ), 7.23 (m, 9H), 7.47 (m, 6H), 8.92 (s, 1H).

The compound of 7j was prepared by the same method as the synthesis process of the compound of 7i using ethyl acetamide hydrochloride.

Example 15 (2S, 4S) -2-[(2-allyloxyacetimidoaminoethylcarbamoyl) aminoethylcarbamoyl] -4-tritylthio-1- (allyloxycarbonyl) pyrroli Preparation of the Dean ( Compound 7j )

7j : yield 70.2%. 1 H-NMR (CDCl 3) δ 1.85 (bs, 1H), 2.19 (m, 1H), 2.24 (s, 3H), 2.80-2.92 (bs, 1H), 3.02-3.17 (bs, 2H), 3,30 -3.56 (bs, 4H), 3.96 (m, 1H), 4.45 (bs, 2H), 4.70 (d, 2H, J = 5.9 Hz), 5.20-5.44 (m, 4H), 5.85-6.04 (m, 2H ), 6.66 (bs, 1 H), 7.23 (m, 9 H), 7.47 (m, 6 H).

The 7k compound was prepared by the same method as the synthesis of the compound of 7i using 1H-pyrazole-1-carboxamidine hydrochloride.

Example 16 (2S, 4S) -2-[(2-allyloxyguanidinoethylcarbamoyl) aminoethylcarbamoyl] -4-tritylthio-1- (allyloxycarbonyl) pyrroli Preparation of the Dean ( Compound 7k )

7k : Yield 75.1%. 1 H-NMR (CDCl 3) δ 1.89 (bs, 1H), 2.19 (m, 1H), 2.80-2.92 (bs, 1H), 2.95-3.07 (bs, 2H), 3,30-3.59 (bs, 4H) , 3.96 (m, 1H), 4.25-4.58 (bs, 4H), 4.72 (d, 2H, J = 5.9 Hz), 5.20-5.57 (m, 6H), 5.75-5.98 (m, 3H), 7.23 (m , 9H), 7.47 (m, 6H), 8.92 (bs, 1H), 8.96 (bs, 1H).

Example 17 (2S, 4S) -2- [2- (thiomorpholin-4-yl) ethylcarbamoyl] -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine Preparation of 7 l of Compound )

A mixture of the fourth compound (1.2 g, 2.0 mmol) and thiomorpholine (0.41 g, 4.0 mmol) was stirred at room temperature for 20 hours, then diluted with 1 N hydrochloric acid solution (30 mL) and ethyl acetate (50 mL). After diluting, the organic layer was dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and the residue was purified by silica gel chromatography to obtain a yellow oily compound 7 l compound (1.03 g, 85.9%).

1 H-NMR (CDCl 3) δ 1.88 (m, 1H), 2.19 (m, 1H), 2.52 (bs, 1H), 2.55-2.98 (bs, 7H), 3.08 (bs, 2H), 3.25-3.44 (bs , 4H), 3.95 (m, 1H), 4.15 (m, 1H), 4.45 (m, 2H), 5.29 (m, 2H), 5.88 (m, 1H), 6.74 (bs, 1H), 7.27 (m, 9H), 7.47 (m, 6H).

Compound 7m was prepared by the same method as the synthesis of compound 7l using piperazine.

Example 18 (2S, 4S) -2- [2- (piperazin-1yl) ethylcarbamoyl] -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (of 7m Preparation of Compound

7m : Yield 72.4%. 1 H-NMR (CDCl 3) δ 1.87 (bs, 1H), 2.18 (m, 1H), 2.37-2.55 (bs, 6H), 2.77-2.89 (bs, 1H), 2.94-3.01 (bs, 2H), 3.22 (bs, 2H), 3.55 (bs, 4H), 4.01 (bs, 1H), 4.43 (bs, 2H), 5.04 5.26 (m, 2H), 5.85 (m, 1H), 6.68 (bs, 1H), 7.24 (m, 9 H), 7.45 (m, 6 H).

Example 19 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-allyloxycarbonylaminenoethylcarbamoyl)]-1- ( Preparation of Allyloxycarbonyl) pyrrolidin-3-ylthio] -1-methylcarbapenem-2-m-3-carboxylate ( compound of Article 10a )

Compound 7a (0.58 g, 1.0 mmol) was dissolved in methylene chloride (2 ml) and cooled to 0 ° C., triethyl silane (0.13 g, 1.1 mmol) and trifluoroacetic acid (2 ml) were added dropwise After stirring for 30 minutes, the solvent was removed under reduced pressure, ethyl acetate was poured out, neutralized with 10% sodium bicarbonate, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. Without allyl- (1R, 5S, 6S) -3- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methylcarbafen-2-m-3-carboxylate ( Ninth compound) (0.50 g, 1.0 mmol) was dissolved in acetonitrile (10 mL) and cooled to 0 ° C. Diisopropylethylamine (0.13 g, 1.0 mmol) was added dropwise, and 5 mL of acetonitrile was dissolved and added dropwise to compound 8a (0.36 g, 1.0 mmol) as a mercapto compound, followed by stirring for 3 hours. At the end of the reaction, the solvent was removed by distillation under reduced pressure, dissolved in 40 mL of ethyl acetate and washed with 30 mL of water. The organic layer was obtained, dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure, and then recovered by chromatography to obtain the purified compound 10a (0.45 g, 71.1%) as a yellow solid.

1 H-NMR (CDCl 3) δ 1.25 (d, 3H, J = 7.1 Hz), 1.36 (d, 3H, J = 6.4 Hz), 2.21 (bs, 1H), 2.46 (bs, 1H), 2.95 (dd, 1H, J = 3.3 and 3.3 Hz), 3.06-3.55 (bs, 7H), 3.90 (bs, 2H), 4.15 (bs, 1H), 4.19 (bs, 1H), 4.45-4.69 (bs, 6H), 5.26 -5.55 (m, 6H), 5.75-6.01 (bs, 3H). IR (KBr): 3410 (OH), 3230 (NH), 1720, 1705,1660 (C = O) cm < -1 >.

Compounds 10b to 10m were prepared by the same method as the synthesis process of compound 10a described above.

Example 20 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-methylsulfonylaminoethylcarbamoyl)]-1- (allyloxy Preparation of Carbonyl) Pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate ( Compound 10b )

10b : yield 63.9%. 1 H-NMR (CDCl 3) δ 1.26 (d, 3H, J = 7.1 Hz), 1.37 (d, 3H, J = 6.2 Hz), 1.91 (m, 1H), 2.39 (bs, 1H), 2.86 (m, 1H), 2.99 (s, 3H), 3.21-3.42 (bs, 4H), 3.54 (m, 2H), 3.82 (bs, 1H), 3.99 (bs, 1H), 4.18 (m, 2H), 4.42 (m 1H) 4.49-4.68 (bs, 4H), 5.25-5.53 (m, 4H), 5.75-6.01 (bs, 2H).

Example 21 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-N, N-dimethylaminosulfonylaminoethylcarbamoyl)] Preparation of -1- (allyloxycarbonyl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate ( compound of formula 10c )

10c : yield 64.3%. 1 H-NMR (CDCl 3) δ 1.25 (d, 3H, J = 7.1 Hz), 1.35 (d, 3H, J = 6.2 Hz), 2.06 (m, 1H), 2.39 (bs, 1H), 2.80 (m, 1H), 2.89 (s, 6H), 3.21-3.33 (bs, 2H), 3.38-3.54 (bs, 3H), 3.58 (m, 1H), 3.82 (bs, 1H), 3.99 (bs, 1H), 4.18 (m, 2H), 4.40 (m. 1H), 4.49-4.68 (bs, 4H), 5.25-5.53 (m, 4H), 5.70-5.99 (bs, 2H).

Example 22 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-N, N-dimethylaminocarbonylaminoethylcarbamoyl)] Preparation of -1- (allyloxycarbonyl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate ( compound of formula 10d )

10d : yield 72.5%. 1 H-NMR (CDCl 3) δ 1.28 (d, 3H, J = 7.0 Hz), 1.37 (d, 3H, J = 6.1 Hz), 1.98 (m, 1H), 2.30 (bs, 1H), 2.86 (m, 1H), 2.87 (s, 6H), 3.21-3.36 (bs, 2H), 3.40-3.55 (m, 3H), 3.60 (m, 1H), 3.82 (bs, 1H), 3.99 (bs, 1H), 4.18 (m, 2H), 4.42 (m. 1H), 4.49-4.68 (bs, 4H), 5.25-5.53 (m, 4H), 5.70-5.96 (bs, 2H).

Example 23 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-morpholinocarbonylamino) ethylcarbamoyl}] Preparation of -1- (allyloxycarbonyl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate ( compound of Chapter 10e )

10e : yield 69.9%. 1 H-NMR (CDCl 3) δ 1.26 (d, 3H, J = 7.0 Hz), 1.38 (d, 3H, J = 6.0 Hz), 1.91 (m, 1H), 2.39 (bs, 1H), 3.21-3.52 ( bs, 9H), 3.54-3.62 (bs, 6H), 3.82 (bs, 1H), 4.03 (bs, 1H), 4.18 (m, 2H), 4.42 (m. 1H), 4.49-4.68 (bs, 4H) , 5.25-5.53 (m, 4H), 5.75-5.97 (bs, 2H).

Example 24 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-thiomorpholinocarbonylamino) ethylcarbamoyl} ] -1- (allyloxycarbonyl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate ( compound of formula 10f )

10f : yield 65.9%. 1 H-NMR (CDCl 3) δ 1.26 (d, 3H, J = 7.0 Hz), 1.38 (d, 3H, J = 6.0 Hz), 2.46 (m, 1H), 2.51 (bs, 4H), 2.79-2.85 ( m, 1H), 3.03-3.16 (bs, 4H), 3.28-3.44 (bs, 3H), 3.54-3.65 (bs, 4H), 3.69 (m, 1H), 3.85 (bs, 1H), 3.99 (bs, 1H), 4.16 (bs, 1H), 4.45 (m. 1H), 4.45-4.67 (bs, 4H), 5.29-5.53 (m, 4H), 5.75-6.01 (bs, 2H).

Example 25 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-piperazinnocarbonylamino) ethylcarbamoyl}] Preparation of -1- (allyloxycarbonyl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate ( compound of 10g )

10 g : yield 68.4%. 1 H-NMR (CDCl 3) δ 1.26 (d, 3H, J = 6.7 Hz), 1.35 (d, 3H, J = 6.2 Hz), 1.97 (m, 1H), 2.34 (m, 1H), 2.70 (m, 1H), 3.10 (bs, 1H), 3.15-3.26 (bs, 5H), 3.30-3.49 (bs, 6H), 3.59 (bs, 2H), 3.94 (m, 1H), 4.12 (bs, 2H), 4.19 (m, 1H), 4.29 (m. 1H), 4.45-4.69 (bs, 6H), 5.26-5.55 (m, 6H), 5.75-6.01 (bs, 3H).

Example 26 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-methylaminothiocarbonylaminoethylcarbamoyl)]-1- ( Preparation of Allyloxycarbonyl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate ( compound of 10h )

10h : yield 65.5%. 1 H-NMR (CDCl 3) δ 1.26 (d, 3H, J = 6.9 Hz), 1.35 (d, 3H, J = 6.3 Hz), 1.99 (m, 1H), 2.45 (m, 1H), 2.89 (bs, 3H), 3.11-3.39 (bs, 4H), 3.44-3.69 (bs, 3H), 3.80 (m, 1H), 3.91 (m, 1H), 4.06 (m, 1H), 4.16 (m, 1H), 4.33 (m. 1H), 4.47-4.69 (bs, 4H), 5.26-5.55 (m, 4H), 5.71-5.98 (bs, 2H).

Example 27 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-formidoaminoethylcarbamoyl)]-1- (allyloxycarb Bonyl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate ( compound of formula 10i )

10i : Yield 66.4%. 1 H-NMR (CDCl 3) δ 1.26 (d, 3H, J = 6.9 Hz), 1.35 (d, 3H, J = 6.1 Hz), 1.90 (m, 1H), 2.50-2.69 (m, 2H), 3.05- 3.33 (bs, 5H), 3.42 (m, 1H), 3.55-3.66 (bs, 2H), 3.70 (bs, 1H), 4.01 (m, 1H), 4.31 (m. 1H), 4.45-4.69 (bs, 4H), 5.26-5.55 (m, 4H), 5.75-5.99 (bs, 2H), 7.88 (d, 1H J = 6.2 Hz).

Example 28 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-acetimidoaminoethylcarbamoyl)]-1- (allyloxycarb Preparation of Bonyl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate ( compound of Article 10j )

10j : yield 62.4%. 1 H-NMR (CDCl 3) δ 1.27 (d, 3H, J = 6.9 Hz), 1.36 (d, 3H, J = 6.1 Hz), 1.99 (m, 1H), 2.15 (s, 3H), 2.59-2.67 ( m, 1H), 3.03 (m, 1H), 3.08-3.39 (bs, 5H), 3.53 (m, 1H), 3.69 (bs, 1H), 3.80 (m, 1H), 4.01-4.15 (bs, 2H) , 4.35 (m. 1 H), 4.45-4.69 (bs, 6H), 5.16-5.55 (m, 6H), 5.70-5.99 (bs, 3H).

Example 29 Allyl (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-guanidinoethylcarbamoyl)]-1- (allyloxycarb Preparation of Bonyl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate ( compound 10k )

10k : yield 66.0%. 1 H-NMR (CDCl 3) δ 1.26 (d, 3H, J = 6.9 Hz), 1.35 (d, 3H, J = 6.1 Hz), 1.98 (m, 1H), 2.59-2.69 (m, 1H), 3.03 ( m, 1H), 3.08-3.62 (bs, 7H), 4.01-4.31 (bs, 3H), 4.35 (m. 1H), 4.45-4.89 (bs, 8H), 5.08-5.55 (m, 8H), 5.75- 6.03 (bs, 4 H).

Example 30 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-aminenoethylcarbamoyl) pyrrolidine-3-ylthio]- Preparation of 1-methylcarbapenem-2-m-3-carboxylic acid ( compound of 11a )

Compound 10a (0.31 g, 0.50 mmol) and Pd (OH) ₂ (10%) were dissolved in a mixture of tetrahydrofuran and phosphate buffer (pH = 7) (1: 1, 10 mL) and 50 psi Hydrogenate for 1 hour at. After completion of the reaction, it was filtered, the organic solvent was distilled under reduced pressure, and the water layer was extracted with 2 x 20 mL of ethyl ether. The water layers were combined and purified using a Diaion HP-20 column using an eluting solvent of an aqueous solution of tetrahydrofuran 2%, and 298 nm portions were collected using UV, and lyophilized to obtain a white final compound of 11a .

Yield 21.8%. -mp 150-165 oC (dec.). UV λ max: 298 nm. -1H-NMR (D2O) δ1.11 (d, 3H, J = 6.8 Hz), 1.17 (d, 3H, J = 5.9 Hz), 1.78 (bs, 1H), 2.63 (m, 1H), 2.94 (m , 1H), 3.01-3.48 (bs, 5H), 3.53-3.65 (bs, 2H), 3.70 (bs, 2H), 4.01 (m, 1H), 4.51 (bs, 1H). -IR (KBr): 3480, 1745, 1666 cm -1. HRMS (FAB) Calcd for C17H26N4O5S 398.1625, Found (M + H) + 398.1999

Compounds 11b to 11m were prepared by the same method as the synthesis procedure for compound 11a described above.

Example 31 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-methylsulfonylaminoethylcarbamoyl)] pyrrolidin-3-yl Preparation of Thio] -1-methylcarbafen-2-m-3-carboxylic acid ( Compound 11b )

Yield 24.4%. -mp 163-175 o C (dec.). UV lambda max: 298 nm. -1 H-NMR (D 2 O) δ 1.10 (d, 3H, J = 7.1 Hz), 1.16 (d, 3H, J = 6.2 Hz), 1.90 (m, 1H), 2.13 (bs, 1H), 2.86 (m , 1H), 2.97 (s, 3H), 3.03 (bs, 2H), 3.18-3.40 (bs, 4H), 3.54 (dd, 1H, J = 5.2 and 5.6 Hz), 3.89 (bs, 1H), 4.04 ( bs, 2H), 4.42 (m. 1H). -IR (KBr): 3390 (NH), 1710, 1680, 1410, 1166 cm-1 -HRMS (FAB) Calcd for C18H28N4O7S2 476.1401, Found (M + H) + 476.1392

Example 32 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-N, N-dimethylaminosulfonylaminoethylcarbamoyl)] P Preparation of Ralidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid ( Compound 11c )

Yield 29.4%. -mp 145-168 oC (dec.). UV lambda max: 298 nm. -1H-NMR (D2O) δ1.10 (d, 3H, J = 7.0 Hz), 1.16 (d, 3H, J = 6.3 Hz), 1.93 (m, 1H), 2.13 (bs, 1H), 2.65 (s , 6H), 2.86 (m, 1H), 3.02 (bs, 2H), 3.21-3.44 (bs, 4H), 3.59 (dd, 1H, J = 5.4 and 5.8 Hz), 3.87 (bs, 1H), 4.11 ( bs, 2H), 4.42 (m. 1H). -IR (KBr): 3390 (NH), 1715, 1690, 1400, 1166 cm-1 -HRMS (FAB) Calcd for C19H31N5O7S2 505.1666, Found (M + H) + 505.1700

Example 33 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-N, N-dimethylaminocarbonylaminoethylcarbamoyl)] py Preparation of Ralidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid ( Compound 11d )

Yield 25.2%. -mp 155-171 oC (dec.). UV lambda max: 298 nm. -1 H-NMR (D 2 O) δ 1.14 (d, 3H, J = 7.0 Hz), 1.25 (d, 3H, J = 6.2 Hz), 1.73 (m, 1H), 2.57 (bs, 1H), 2.68 (s, 6H), 2.96-3.18 (bs. 4H), 3.21-3.44 (bs, 3H), 3.60 (bs, 1H), 3.83 (bs, 1H), 4.14 (bs, 2H), 4.49 (m. 1H). -IR (KBr): 3400, 1755, 1700, 1670, 1415 cm-1 -HRMS (FAB) Calcd for C20H31N5O6S 469.1995, Found (M + H) + 469.1968

Example 34 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-morpholinocarbonylamino) ethylcarbamoyl}] pi Preparation of Ralidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid ( Compound 11e )

Yield 20.2%. UV lambda max: 298 nm. -1H-NMR (D2O) δ 1.06 (d, 3H, J = 6.9 Hz), 1.13 (d, 3H, J = 6.2 Hz), 1.93 (m, 1H), 2.46 (m, 1H), 3.03-3.30 ( bs, 8H), 3.34-3.50 (bs, 2H), 3.54-3.69 (bs, 5H), 3.85 (bs, 2H), 3.99 (bs, 1H), 4.16 (bs, 1H), 4.45 (m. 1H) . -IR (KBr): 3390, 1720, 1700, 1680, 1591, 1400 cm-1.

Example 35 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-thiomorpholinocarbonylamino) ethylcarbamoyl}] Preparation of Pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid ( compound of 11f )

Yield 21.5%. UV lambda max: 298 nm. -1 H-NMR (D 2 O) δ 1.06 (d, 3H, J = 6.6 Hz), 1.13 (d, 3H, J = 6.1 Hz), 1.87 (m, 1H), 2.46 (m, 1H), 2.51 (bs, 4H), 2.79-2.85 (m, 1H), 3.03-3.16 (bs, 4H), 3.28-3.44 (bs, 3H), 3.54-3.65 (bs, 4H), 3.69 (m, 1H), 3.85 (bs, 1H), 3.99 (bs, 1H), 4.16 (bs, 1H), 4.45 (m. 1H). -IR (KBr): 3390, 1720, 1690, 1680, 1591, 1390 cm-1.

Example 36 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-piperazinnocarbonylamino) ethylcarbamoyl}] pi Preparation of Ralidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid ( compound 11g )

Yield 21.9%. UV lambda max: 298 nm. -1 H-NMR (D 2 O) δ 1.03 (d, 3H, J = 6.7 Hz), 1.10 (d, 3H, J = 6.2 Hz), 1.87 (m, 1H), 2.46 (m, 1H), 2.85 (m, 1H), 3.05-3.46 (bs, 10H), 3.54 (bs, 2H), 3.69 (m, 2H), 3.85 (bs, 1H), 4.02 (bs, 2H), 4.18 (m, 1H), 4.45 (m 1H). -IR (KBr): 3390, 1740, 1715, 1680, 1411 cm-1.

Example 37 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-methylaminothiocarbonylaminoethylcarbamoyl)] pyrrolidine-3 Preparation of -ylthio] -1-methylcarbafen-2-m-3-carboxylic acid ( compound of 11h )

Yield 23.8%. UV lambda max: 298 nm. -1H-NMR (D2O) δ 1.07 (d, 3H, J = 7.0 Hz), 1.17 (d, 3H, J = 6.2 Hz), 1.87 (m, 1H), 2.45-2.59 (m, 1H), 2.88 ( bs, 3H), 3.15-3.39 (bs, 4H), 3.44-3.69 (bs, 3H), 3.80 (m, 1H), 3.91 (m, 1H), 4.06-4.12 (bs, 2H), 4.45 (m. 1H). -IR (KBr): 3400, 1730, 1680, 1586, 1400 cm-1

Example 38 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-N-acetylformidoaminoethylcarbamoyl)] pyrrolidine-3 Preparation of -ylthio] -1-methylcarbafen-2-m-3-carboxylic acid ( compound of formula 11i )

Yield 24.3% .- mp 148-162 o C (dec.). UV lambda max: 298 nm. -1 H-NMR (D2O) δ 1.03 (d, 3H, J = 6.8 Hz), 1.11 (d, 3H, J = 6.2 Hz), 1.56 (m, 1H), 2.50-2.59 (m, 1H), 2.95- 3.10 (bs, 2H), 3.12-3.24 (bs, 2H), 3.27-3.40 (bs, 2H), 3.55-3.66 (bs, 2H), 3.70 (bs, 1H), 4.16 (m, 2H), 4.41 ( m. 1 H), 7.68 (d, 1 H J = 6.2 Hz). -IR (KBr): 3397, 1756, 1685, 1655, 1401 cm-1. HRMS (FAB) Calcd for C18H27N5O5S 425.1736, Found (M + H) + 425.1800

Example 39 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-N-acetylacetimidoaminoethylcarbamoyl)] pyrrolidine-3 Preparation of -ylthio] -1-methylcarbafen-2-m-3-carboxylic acid ( compound of 11j )

Yield 22.2%. -mp 196-205 oC (dec.). UV lambda max: 298 nm. -1H-NMR (D2O) δ 1.10 (d, 3H, J = 7.0 Hz), 1.18 (d, 3H, J = 6.3 Hz), 1.60 (m, 1H), 2.05 (s, 3H), 2.59-2.67 ( m, 1H), 2.99 (m, 1H), 3.08-3.39 (bs, 4H), 3.41-3.53 (m, 2H), 3.59 (bs, 1H), 3.73-3.89 (bs, 1H), 4.01-4.15 ( bs, 2H), 4.45 (m. 1H). -IR (KBr): 3490, 1740, 1700, 1650, 1400 cm-1 -HRMS (FAB) Calcd for C 19 H 29 N 5 O 5 S 439.1889, Found (M + H) + 439.1992.

Example 40 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-guanidinoethylcarbamoyl)] pyrrolidine-3-ylthio ] -1-Methylcarbafen-2-m-3-carboxylic acid ( Compound 11k )

Yield 20.0%. -mp 193-205 oC (dec.). UV lambda max: 298 nm. -1 H-NMR (D 2 O) δ 1.02 (d, 3H, J = 7.3 Hz), 1.10 (d, 3H, J = 6.4 Hz), 1.88 (m, 1H), 2.55-2.61 (m, 1H), 3.10- 3.45 (bs, 6H), 3.55 (m, 1H), 3.88 (bs, 2H), 4.03 (bs, 2H), 4.45 (m. 1H). -IR (KBr): 3980, 1710, 1640, 1580, 1405 cm-1 -HRMS (FAB) Calcd for C18H28N6O5S 440.1842, Found (M + H) + 440.1799

Example 41 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (thiomorpholino-1 yl) ethylcarbamoyl}] pyrrolidine Preparation of -3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid ( compound 11 l)

Yield 20.1%. UV lambda max: 298 nm. -1 H-NMR (D 2 O) δ 0.98 (d, 3H, J = 7.1 Hz), 1.06 (d, 3H, J = 6.4 Hz), 1.78 (m, 1H), 2.65-2.79 (bs, 5H), 2.90- 3.01 (bs, 2H), 3.05-3.38 (bs, 5H), 3.55-3.60 (bs, 3H), 3.65 (bs, 1H), 3.80-3.88 (bs, 2H), 4.03 (bs, 2H), 4.45 ( m. 1 H). -IR (KBr): 3470, 1730, 1685, 1580, 1425 cm-1

Example 42 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (piperazin-1 yl) ethylcarbamoyl}] pyrrolidine- Preparation of 3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid ( compound 11m )

Yield 16.9%. -mp 166-175 oC (dec.). UV lambda max: 298 nm. -1H-NMR (D2O) δ1.02 (d, 3H, J = 7.1 Hz), 1.08 (d, 3H, J = 6.4 Hz), 1.88 (m, 1H), 2.45-2.49 (m, 1H), 2.60 -2.69 (bs, 4H), 3.07-3.15 (bs, 4H), 3.25-3.39 (bs, 4H), 3.66-3.78 (m, 2H), 3.89 (m, 2H), 4.03 (m, 2H), 4.26 (m, 1 H), 4.45 (m. 1 H). -IR (KBr): 3370, 1755, 1690, 1580, 1430 cm-1 -HRMS (FAB) Calcd for C21H33N5O5S 467.2203, Found (M + H) + 467.2230

Formulation example

Preparation of Pharmaceutical Formulations

60 mg (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-piperazinnocarbonylamino) ethylcarbamoyl}] pyrrolidine- A unit dosage form was prepared by mixing 3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid (Example 36) with 20 mg lactose and 5 mg magnesium stearate. 85 mg of this mixture was added to No. 3 gelatin capsules. Similarly, when more active ingredients and less lactose were used, other dosage forms were prepared and filled into No. 3 gelatin capsules. Similarly, larger gelatin capsules and compressed tablets or pills can also be prepared. The following examples describe the preparation of pharmaceutical formulations.

Tablets (for oral administration)

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-piperazinnocarbonylamino) ethylcarbamoyl}] pyrrolidine-3- Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid (Example 36) 120 mg

Corn starch 6 mg

Magnesium Stearate 232 mg

Dicalcium phosphate 192 mg

Lactose 250 mg

The active ingredient is mixed with about 1/2 of the dicalcium phosphate, lactose and corn starch and then sieved through. It is dried under high vacuum and filtered again with a sieve having a mesh width of 1.00 mm (No. 16 screen). The remaining corn starch and magnesium stearate are added, and then the mixture is compressed to produce tablets with an individual weight of 800 mg and a diameter of about 1.27 cm (0.5 inch).

Parenteral solution

Ear solution

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-piperazinnocarbonylamino) ethylcarbamoyl}] pyrrolidine-3- Ilthio] -1-methylcarbafen-2-m-3-carboxylic acid (Example 36) 50 mg

Benzalkonium chloride 0.1 mg

1 ml of sterile water (taken from a separate ampoule using a syringe just before use)

Topical creams or ointments

(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- {2- (1-piperazinnocarbonylamino) ethylcarbamoyl}] pyrrolidine-3- Ilthio] -1-methylcarbafen-2-m-3-carboxylic acid (Example 36) 100 mg

Polyethylene Glycol 4000 400 mg

1.0 g of polyethylene glycol 400

The active ingredient of the formulation can be used alone or in combination with other biologically active ingredients, for example other antimicrobial agents such as penicillin or cephalosporin, or other therapeutic agents such as probenicide.

The present inventors performed the experiment on the antimicrobial activity of the pharmaceutical composition containing the compound of formula 1 according to the present invention as an active ingredient.

Experimental Example 1

In order to prove the antimicrobial activity of the 1-betamethylcarbapenem derivative of the present invention, Gram-positive bacteria Streptococcus and Staphylococcus were used. As Gram-negative bacteria, Escherichia coli, Pseudomonas, Salmonella Salmonella, Klebsiella and Enterobacter were used. Each of the test strains were cultured in dilute agar medium, and then treated with the compound according to the present invention. The minimum strain inhibition concentration was expressed in ug per ml and is shown in the following table. Imiphenem and meropenem were used as a comparison group.

In addition, the results of measuring the antimicrobial activity of the methicillin resistant strains (Methicillin resistant strains) as described above are as follows.

As described above, the 1-betamethylcarbapenem derivative according to the present invention has excellent antibacterial activity by replacing pyrrolidin thiol derivatives containing aminoethyl carbamoyl derivatives, and has a strong effect on resistant bacteria. Therefore, the 1-betamethylcarbapenem derivative according to the present invention can be usefully used as an antibiotic. In addition, when the intermediate thiol derivative according to the present invention is used, the 1-betamethylcarbapenem derivative according to the present invention can be easily prepared, and when the thiol derivative preparation method according to the present invention is used, the thiol derivative can be easily prepared. There is an effect that can be produced.

Claims (12)

delete delete delete delete delete delete As a method for producing a thiol derivative represented by the formula [Formula 2] The thiol derivative, (2S, 4S) -2- (2-allyloxycarbonylaminoethylcarbamoyl) -4-thio-1- (allyloxycarbonyl) pyrrolidine; (2S, 4S) -2- (2-methylsulfonylaminoethylcarbamoyl) -4-thio-1- (allyloxycarbonyl) pyrrolidine; (2S, 4S) -2- (2-N, N-dimethylaminosulfonylaminoethylcarbamoyl) -4-thio-1- (allyloxycarbonyl) pyrrolidine; (2S, 4S) -2- (2-N, N-dimethylaminocarbonylaminoethylcarbamoyl) -4-thio-1- (allyloxycarbonyl) pyrrolidine; (2S, 4S) -2- [2- (1-morpholinocarbonylamino) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine; (2S, 4S) -2- [2- (1-thiomorpholinocarbonylamino) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine; (2S, 4S) -2- [2- (1-piperazinnocarbonylamino) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine; (2S, 4S) -2- [2- (3-methylthioureido) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine; (2S, 4S) -2- [2- (thiomorpholin-4-yl) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine; or (2S, 4S) -2- [2- (piperazin-1yl) ethylcarbamoyl] -4-thio-1- (allyloxycarbonyl) pyrrolidine, The method, (A) preparing a second compound by hydrolyzing N-protected 4-tritylthiopyrrolidinemethyl ester (first compound) in Scheme 2 under basic conditions; (B) preparing a third compound in which ethanolamine is substituted by a substitution reaction with an acid chloride from the hydrolyzed second compound of step (a); (C) preparing a fourth compound by mechanizing a third compound substituted with carbamoyl in step (b); (D) preparing a seventh compound through substitution reaction from the fourth compound of step (c); And Detritylating the seventh compound of step (d) to produce a thiol derivative, which is the eighth compound, (e). Scheme 2 In Scheme 2, NHR ′ refers to R of Formula 2. The method of claim 7, wherein the step (d), Method of producing a thiol derivative, characterized in that the seventh compound is prepared through the substitution reaction of the heterocyclic amines from the fourth compound of step (c). The method of claim 7, wherein the step (d), Preparing an azide compound (a fifth compound) in which an azide is substituted by replacing the fourth compound of step (c) with the reaction as in Scheme 3; Reducing the azide compound (the fifth compound) of step (d-1) to prepare a compound (the sixth compound) having an aminoethyl carbamoyl group as an intermediate (d-2); And A method of producing a thiol derivative, comprising the step (d-3) of preparing a seventh compound by replacing acid chloride and imitate with the sixth compound of step (d-2). Scheme 3   In Scheme 3, NHR ′ refers to R of Formula 2. delete As a method of preparing a 1-betamethyl carbapenem derivative having a pyrrolidine substituent containing an aminoethyl carbamoyl derivative, characterized in that represented by the formula (1), [Formula 1] The 1-betamethyl carbapenem derivative, (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-aminoethylcarbamoyl) pyrrolidine-3-ylthio] -1-methylcarbafen- 2-m-3-carboxylic acid; (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-methylsulfonylaminoethylcarbamoyl)] pyrrolidine-3-ylthio] -1- Methylcarbafen-2-m-3-carboxylic acid; (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-N, N-dimethylaminosulfonylaminoethylcarbamoyl)] pyrrolidine-3- Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid; (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-N, N-dimethylaminocarbonylaminoethylcarbamoyl)] pyrrolidine-3- Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid; (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5-2- (1-morpholinocarbonylamino) ethylcarbamoyl] pyrrolidine-3-ylthio ] -1-methylcarbafen-2-m-3-carboxylic acid; (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5-2- (1-thiomorpholinocarbonylamino) ethylcarbamoyl] pyrrolidin-3-yl Thio] -1-methylcarbafen-2-m-3-carboxylic acid; (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5-2- (1-piperazinnocarbonylamino) ethylcarbamoyl] pyrrolidine-3-ylthio ] -1-methylcarbafen-2-m-3-carboxylic acid; (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5- (2-methylaminothiocarbonylaminoethylcarbamoyl)] pyrrolidine-3-ylthio]- 1-methylcarbafen-2-m-3-carboxylic acid; (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5-2- (thiomorpholino-1 yl) ethylcarbamoyl] pyrrolidine-3-ylthio]- 1-methylcarbafen-2-m-3-carboxylic acid; or (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -2- [5-2- (piperazin-1 yl) ethylcarbamoyl] pyrrolidin-3-ylthio] -1 Methylcarbaphen-2-m-3-carboxylic acid, The method, A method of preparing a thiol derivative according to any one of claims 7 to 9, the method comprising: preparing a thiol derivative (a '); Reacting a ninth compound of Scheme 1 with a thiol derivative prepared in the presence of a base in a solvent to prepare a protective carbapenem derivative (the tenth compound); And Deprotecting the protective carbapenem derivative (compound 10) obtained in step (a) to prepare 1-betamethylcarbapenem derivative (compound 11), characterized in that it comprises a (b) Method for producing a 1-betamethyl carbapenem derivative. Scheme 1 The method of claim 11, The base of step (a) is diisopropylethylamine, characterized in that the production of 1-betamethyl carbapenem derivatives.