KR100950699B1 - Acid addition salts of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives, process for the preparation thereof and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention provides acid addition salts of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives, methods for their preparation, and pharmaceutical compositions comprising the same. The acid addition salt of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative is obtained in a stable crystal form, and exhibits high oral absorption. In addition, the active metabolites of the acid addition salts of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives exhibit a wide range of antimicrobial activities against Gram-positive and Gram-negative bacteria, and MRSA (methicillin resistant strain) and QRS (quinolone). Good antimicrobial activity against resistant strains).

Kabapenem

Description

Acid addition salts of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives, preparation methods thereof, and pharmaceutical compositions comprising the same THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME}

The present invention relates to acid addition salts of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives, methods for their preparation, and pharmaceutical compositions comprising the same.

Carbapenem antibiotics have the strongest antibacterial effect among beta-lactam antibiotics, and are excellent antibiotics used to treat seriously ill patients in children or elderly people with weak immunity due to their excellent safety and therapeutic effects. In addition, since it shows excellent antimicrobial effect against resistant bacteria that are difficult to treat, it has been used as a treatment for it.

Carbapenem antibiotics are widely administered to severe patients because of their broad efficacy and excellent properties. Currently commercially available imipenem and meropenem can be used only for injection. Although oral solvents are being developed to enhance the convenience of patients, there are no commercial products, and Tebipenem compounds have been developed as carbapenem esters in the form of precursors for oral use. Patent No. 5,783,703), which is currently in Phase III clinical trials.

The inventors of the present invention have developed and reported 2-arylmethylazetidine-carbapenem-3-carboxylic acid having the following antimicrobial activity against Gram-negative bacteria and Gram-positive bacteria, and having a therapeutic effect against resistant bacterial infections including MRSA infection. (International Patent Publication No. WO2006 / 025634 and Korean Patent Registration No. 10-0599876).

Wherein, R ₁ is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyloxy group, a hydroxyl group, an amine group, an alkylamine group, an alkyl thiol group, a methyl group or a halogen atom, trifluoromethyl; M is hydrogen or an alkali metal.

The compound is a substance obtained by introducing an arylmethylazetidine group at position 2 of carbapenem, and exhibits a wide range of antimicrobial effects, in particular, a special antimicrobial effect on resistant bacteria. In addition, it was safe for dihydropeptidase-1 enzymes in the kidney, excellent pharmacokinetic properties, and very safe in toxicity tests such as nephrotoxicity.

In addition, the present inventors have developed an ester derivative in which a compound is introduced as an ester bond in a specific structure at the 3-position of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid, and the ester derivative has a high oral absorption rate. Oral administration is possible, and its active metabolite exhibits broad antimicrobial activity against Gram-positive and Gram-negative bacteria and shows excellent antimicrobial activity against MRSA (methicillin resistant strain) and QRS (quinolone resistant strain) (Korean patent) Application 10-2007-0120038, unpublished.

[Document 1] US Patent No. 5,783,703

[Patent 2] International Patent Publication No. WO2006 / 025634 (Korean Patent Registration No. 10-0599876)

[Document 3] Korean Patent Application No. 10-2007-0120038 (Unpublished)

An object of the present invention is to provide an acid addition salt of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative which is excellent in stability and exhibits high oral absorption.

Moreover, an object of this invention is to provide the manufacturing method of the said acid addition salt.

Moreover, an object of this invention is to provide the antibiotic composition containing the said acid addition salt as an active ingredient.

The present invention provides acid addition salts of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives, methods for their preparation, and pharmaceutical compositions comprising the same. Acid addition salts of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives are obtained in crystalline form, which shows high stability and high oral absorption. In addition, the active metabolites of the acid addition salts of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives exhibit a wide range of antimicrobial activities against Gram-positive and Gram-negative bacteria, and MRSA (methicillin resistant strain) and QRS (quinolone). Good antimicrobial activity against resistant strains).

According to one aspect of the present invention, an acid addition salt of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of Formula 1 is provided:

Wherein R ₁ is hydrogen or a C ₁ -C ₄ alkyl group; R ₂ is C ₄ -C ₇ cycloalkyl optionally substituted with or substituted with an unsubstituted straight chain or branched C ₁ -C ₁₂ alkyl group, or C ₁ -C ₄ alkyl or unsubstituted C ₄ -C ₇ A cycloalkyl group; n is 0 or 1;

According to another aspect of the invention, the 2-arylmethylazetidine-carbapenem-3-carboxylic acid of formula 1 comprising reacting a 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of formula 1 with an acid Methods of preparing acid addition salts of ester derivatives are provided:

<Formula 1>

In the formula, R ₁ , R ₂ and n are as defined above.

According to another aspect of the present invention, there is provided an antibiotic composition comprising an acid addition salt of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative as an active ingredient and a pharmaceutically acceptable carrier.

The acid addition salt of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative according to the present invention is obtained in crystalline form, and the acid addition salt of the crystalline form is excellent in stability and can be stored for a long time, as well as in free base form. It is about 2.7 times higher than the oral absorption rate. In addition, acid addition salts of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives not only have excellent safety, but also their active metabolites exhibit a wide range of antibacterial activity against Gram-positive and Gram-negative bacteria, and MRSA (methicillin Resistant strain) and QRS (quinolone resistant strain).

The present invention includes acid addition salts of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives of Formula 1:

<Formula 1>

Wherein R ₁ is hydrogen or a C ₁ -C ₄ alkyl group; R ₂ is C ₄ -C ₇ cycloalkyl optionally substituted with or substituted with an unsubstituted straight chain or branched C ₁ -C ₁₂ alkyl group, or C ₁ -C ₄ alkyl or unsubstituted C ₄ -C ₇ A cycloalkyl group; n is 0 or 1;

In the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of Chemical Formula 1, preferably R ₁ is hydrogen or a C ₁ -C ₄ alkyl group; R ₂ is a straight or branched C ₁ -C ₁₀ alkyl group, C ₄ -C ₇ Cycloalkylmethyl, C ₄ -C ₇ Cycloalkyl, or C ₁ -C ₄ C ₄ -C ₇ substituted with alkyl Cycloalkyl; n is 0 or 1; More preferably R ₁ is hydrogen or methyl; R ₂ is methyl, t-butyl, isobutyl, isopropyl, n-hexyl, n-nonyl, cyclohexylmethyl, cyclohexyl, or 1-methylcyclohexyl; n is 0 or 1;

In the acid addition salt of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative according to the present invention, the acid may be an inorganic acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, bromic acid, iodic acid, and nitric acid; Or acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trichloroacetic acid, fumaric acid, maleic acid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, p-nitrobenzoic acid, benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,4,6-triisopropylbenzenesulfonic acid, and diphenylphosphinic acid. . Preferably the acid is phosphoric acid, hydrochloric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, or lactic acid, and thus the acid addition salts obtained are phosphates, hydrochlorides, maleates, fumarates, benzenesulfone Acid, p-toluenesulfonate, trifluoroacetate, or lactate forms.

Preferred compounds as acid addition salts of the 1-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of Formula 1 are as follows:

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Phosphate of 1-methyl-carbafen-2-m-3-carboxylate;

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Hydrochloride of 1-methyl-carbafen-2-m-3-carboxylate;

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Hydrochloride of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Hydrochloride of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Maleic acid salt of 1-methyl-carbafen-2-m-3-carboxylate;

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Maleic acid salt of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Maleic acid salt of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Fumarate of 1-methyl-carbafen-2-m-3-carboxylate;

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Fumarate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Fumarate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Benzenesulfonate of 1-methyl-carbafen-2-m-3-carboxylate;

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Benzenesulfonate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Benzenesulfonate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- P-toluenesulfonate of 1-methyl-carbafen-2-m-3-carboxylate;

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 P-toluenesulfonate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 P-toluenesulfonate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Trifluoroacetic acid salt of 1-methyl-carbafen-2-m-3-carboxylate;

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Trifluoroacetic acid salt of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Trifluoroacetic acid salt of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Lactic acid salt of 1-methyl-carbafen-2-m-3-carboxylate;

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Lactic acid salt of hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate;

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Lactic acid salt of hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate.

Particularly preferred compounds as acid addition salts of the 1-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives of the general formula (1) are pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorine) Rhobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate.

Acid addition salts of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives according to the invention are obtained in crystalline form, which shows high stability. In addition, when orally administered, it is absorbed through the digestive tract with high absorption rate, and in vivo, 2-arylmethylazetidine-carbapenem-3-carboxylic acid, that is, (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid. Said (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl- Carbafen-2-m-3-carboxylic acid shows a wide range of antimicrobial activity against gram positive and gram negative bacteria, and shows good antibacterial activity against MRSA (methicillin resistant strain) and QRS (quinolone resistant strain).

The present invention includes a process for preparing acid addition salts of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives of the general formula (1). That is, the acid addition salt of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of Formula 1, comprising reacting the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of Formula 1 with an acid. Manufacturing methods include:

<Formula 1>

In the formula, R ₁ , R ₂ and n are as defined above.

The acid is an inorganic acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, bromic acid, iodic acid, and nitric acid; Or acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trichloroacetic acid, fumaric acid, maleic acid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, p-nitrobenzoic acid, benzenesulfonic acid, can be selected from the group consisting of p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,4,6-triisopropylbenzenesulfonic acid, and diphenylphosphinic acid, More preferably, it may be phosphoric acid, hydrochloric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, or lactic acid, particularly preferably phosphoric acid.

The acid addition salt forming reaction may be performed in an organic solvent selected from one or more selected from the group consisting of acetone, ethyl acetate, isopropyl alcohol, tetrahydrofuran, and acetonitrile. For example, the acid addition salt formation reaction may be performed by dissolving the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of Formula 1 in the organic solvent and then adding an inorganic or organic acid to react. The resulting acid addition salt can be crystallized using water, n-hexane, methylene chloride / n-hexane, or ethyl acetate / n-hexane.

The amount of the acid used may be 1 to 3 molar equivalents, preferably 1 to 2 molar equivalents, based on 1 molar equivalent of the compound of Formula 1, but is not particularly limited. In addition, the reaction temperature between the compound of Formula 1 and the acid may range from about -20 ° C to about 50 ° C, but is not limited thereto. For example, when the acid is an inorganic acid, the reaction can be carried out in the range of 0 ° C to 30 ° C, and in the case of organic acid may be carried out at -20 ° C to 50 ° C. The reaction time may range from 10 minutes to 5 hours, but is not limited thereto.

Acid addition salts of the compound of formula (1) obtained according to the preparation method can be separated and purified according to a conventional method, for example, to separate the acid addition salt of the compound of formula (1) from the reaction solution, extraction, washing, decompression Purification can be carried out according to conventional methods such as concentration and recrystallization.

The acid addition salt of the compound of Formula 1 is obtained as a powder in crystalline form and has excellent stability.

The compound of formula 1 used as a starting material in the preparation method may be prepared by reacting a compound of formula 2 with a compound of formula 3:

Wherein M is hydrogen or an alkali metal; X is halogen; R ₁ , R ₂ and n are as defined above.

Reaction of the compound of Formula 2 with the compound of Formula 3 is shown in Scheme 1 below.

M in Scheme 1 is hydrogen or an alkali metal (preferably sodium or potassium, more preferably potassium); X is halogen (preferably chloro or iodo); R ₁ , R ₂ and n are as defined above.

The compound of Formula 2 may be prepared according to International Patent Publication No. WO2006 / 025634 (Korean Patent Registration No. 10-0599876). If necessary, the compound of the formula (2) in the form of an alkali metal salt can be used by converting the pH in an aqueous solution thereof into a compound in free base form by adjusting the acidity. Compounds of Formula 3 can be prepared with reference to US Pat. No. 5,886,172.

The reaction of the compound of formula 2 with the compound of formula 3 may be carried out in the presence of a base, the base comprising an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; And a base selected from at least one organic base such as triethylamine, N, N-diisopropylethylamine, pyridine. For example, the base may use triethylamine and / or potassium carbonate.

In addition, the reaction of the compound of formula 2 with the compound of formula 3 may be carried out in the presence of a quaternary ammonium salt, in addition to the base, wherein the quaternary ammonium salt is tetraethyl ammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide Benzyltriethylammonium chloride, and the like.

In addition, the reaction of the compound of Formula 2 with the compound of Formula 3 may be carried out by ethers such as diethyl ether, tetrahydrofuran and dioxane; Hydrocarbons such as toluene, xylene and cyclohexane; Halogenated hydrocarbons such as dichloromethane and chloroform; It can be preferably performed in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile or dimethyl sulfoxide. Among the solvents, N, N-dimethylformamide and N, N-dimethylacetamide may be more preferably used.

The amount of the compound of Formula 3 may be used in an amount of 1 to 3 molar equivalents, preferably 1 to 2 molar equivalents, based on 1 molar equivalent of the compound of Formula 2, but is not particularly limited. In addition, the amount of the base and the quaternary ammonium salt may be used in an amount of 1 to 3 molar equivalents based on 1 molar equivalent of the compound of Formula 2, but is not particularly limited.

In the reaction of the compound of Formula 2 with the compound of Formula 3, the reaction temperature may range from about -20 ° C to about 75 ° C, but is not limited thereto. For example, in the compound of Formula 3, when X is chlorine, the reaction may be performed in the range of 40 ° C to 75 ° C, and when X is iodine, it may be performed at -20 ° C to 40 ° C. The reaction time may range from 10 minutes to 2 hours, but is not limited thereto.

Compound of formula (1) prepared according to the method of the present invention can be separated and purified according to a conventional method, for example, to separate the compound of formula (1) from the reaction solution, extraction, washing, concentrated under reduced pressure, column chromatography It can refine | purify in accordance with conventional methods, such as photography and recrystallization.

The present invention includes an antibiotic composition comprising, as an active ingredient, an acid addition salt of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of Formula 1 and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may contain an acid addition salt of the compound of formula 1 in an amount of 0.1 to 75% by weight, preferably 1 to 50% by weight, based on the total weight of the composition.

The pharmaceutical composition of the present invention may be administered orally or parenterally, preferably orally. Oral compositions may be in the form of tablets, pills, soft or hard capsules, solutions, suspensions, emulsions, syrups, powders, granules, and the like, and diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, Cellulose, glycine, and the like), and lubricants (eg, silica, talc, stearic acid or magnesium or calcium salts thereof, polyethylene glycol, etc.). Tablets may also include binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidine. In addition, the oral composition may further contain a disintegrant such as starch, agar, alginic acid or its sodium salt, and / or absorbents, colorants, flavors, and sweeteners. The composition may be formulated according to conventional methods such as mixing, granulating and coating.

In addition, the pharmaceutical compositions of the invention may be in the form of injections, preferably isotonic solutions or suspensions. The pharmaceutical composition may be sterile and / or contain preservatives, stabilizers, hydrating agents, emulsifiers, auxiliaries such as salts and / or buffers for osmotic pressure control and other therapeutically useful substances.

Typical daily dosages of acid addition salts of compounds of formula 1 may range from 2.5 to 200 mg / kg body weight, preferably 5 to 100 mg / kg body weight for mammals, including humans, It may be administered orally or parenterally in several occasions.

The following examples and preparations are intended to illustrate the invention, not to limit the scope of the invention.

Production Example  1: 1- Iodoethyl Of isopropyl carbonate  Produce

(1) Preparation of 1-chloroethyl isopropyl carbonate

1-chloroethyl chloroformate (31.7 g, 0.22 mol) was dissolved in 200 ml of methylene chloride, and then 39.7 ml (0.52 mol) of isopropanol were added under ice cooling. 23 ml (0.28 mol) of pyridine was added to the reaction mixture over 15 minutes, and then the temperature was gradually raised to room temperature and stirred for 30 minutes. The reaction mixture was washed with water, 5% brine and 5% aqueous potassium hydrogen sulfate solution in that order, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to obtain 25 g (68%) of 1-chloroethyl isopropyl carbonate.

bp _{55 mmHg} : 92-94 ° C .;

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.33 (d, J = 6.0 Hz, 6H), 1.79 (d, J = 6.0 Hz, 3H), 4.84 (heptet, J = 6.0 Hz, 1H), 6.37 (q , J = 6.0 Hz, 1H)

(2) Preparation of 1-iodoethyl isopropyl carbonate

1-Chloroethyl isopropylcarbonate (13 g, 78 mmol) prepared in step (1) was dissolved in 40 ml of acetonitrile and sodium iodide (4.2 g, 280 mmol, 3.58 equiv) was added. The reaction mixture was stirred at 60 ° C. for 70 minutes and then cooled to room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent. Water and ethyl acetate were added and extracted to the obtained residue. The separated organic layer was washed with 5% aqueous sodium thiosulfate solution, dried over anhydrous magnesium sulfate and filtered. The filtrate obtained was distilled under reduced pressure to obtain 12.3 g of 1-iodoethyl isopropyl carbonate. The product was unstable and used immediately for the next reaction.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.33 (d, J = 6.0 Hz, 6H), 2.28 (d, J = 6.0 Hz, 3H), 4.82 (heptet, J = 6.0 Hz, 1H), 6.43 (q , J = 6.0 Hz, 1H)

Production Example  2: 1- Iodoethyl Of cyclohexyl carbonate  Produce

(1) Preparation of 1-chloroethyl cyclohexyl carbonate

Cyclohexanol (19 ml, 0.18 mol) was dissolved in 300 ml of methylene chloride and then pyridine (14.8 ml, 0.18 mol) was added under ice cooling. 1-chloroethyl chloroformate (20 ml, 0.185 mol) was added to the reaction mixture over 15 minutes, and then the temperature was gradually raised to room temperature and stirred for 16 hours. The reaction mixture was washed sequentially with water, brine and 5% sodium thiosulfate aqueous solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain 26.06 g (70%) of 1-chloroethyl cyclohexylcarbonate.

bp _{55 mmHg} : 101-103 ° C;

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.0-2.3 (m, 10H), 1.38 (d, J = 5.8 Hz, 3H), 4.60-4.80 (m, 1H), 6.40 (q, J = 5.8 Hz, 1H).

(2) Preparation of 1-iodoethyl cyclohexyl carbonate

1-Chloroethyl cyclohexylcarbonate (2.6 g, 13 mmol) prepared in step (1) was dissolved in 80 ml of acetonitrile and sodium iodide (8.5 g, 56.7 mmol, 4.36 equiv) was added. The reaction mixture was stirred at 60 ° C. for 70 minutes and then filtered. The obtained filtrate was cooled to room temperature and distilled under reduced pressure to remove the solvent. The obtained residue was extracted with water and diethyl ether. The separated organic layer was washed with 5% aqueous sodium thiosulfate solution, dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was distilled under reduced pressure to obtain 2.68 g of 1-iodoethyl cyclohexyl carbonate. The product was unstable and used immediately for the next reaction.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.9-2.2 (m, 10H), 2.20 (d, J = 5.8 Hz, 3H), 4.60-4.80 (m, 1H), 6.81 (q, J = 5.8 Hz, 1H).

Production Example  3: Iodomethyl Pivalate  Produce

Chloromethyl pivalate (15.0 g, 0.1 mol) and sodium iodide (65 g, 0.43 mol) were dissolved in 600 ml of acetonitrile, and then 22.5 g (93%) of iodomethyl pivalate was prepared in the same manner as in Preparation Example 2. Obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.24 (s, 9H), 5.92 (s, 2H).

Production Example  4: (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylic acid  Produce

Potassium (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl prepared according to WO2006 / 025634 (Korean Patent Registration No. 10-0599876) ) Thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (20 g, 44.9 mmol) was dissolved in 60 ml of water and pH 5.5 with acetic acid. Adjusted to. The reaction mixture was separated and purified by C18 reversed phase chromatography (eluent: water, 10% acetonitrile / water, and 20% acetonitrile / water). The fraction obtained was lyophilized to give the title compound (17.3 g, 95% yield, HPLC purity 99%) as a white solid.

¹ H-NMR (300 MHz, D ₂ O) δ 1.17d, J = 7.3 Hz, 3H, 1.31d, J = 6.1 Hz, 3H), 3.20, 1H), 3.41 (m, 1H), 3.69 (m, 2H), 4.07 (s, 1H), 4.18 (m, 5H), 7.20 (m, 2H), 7.40 (m, 2H).

Example  One: Pivaloyloxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate

Method A

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl- Carbafen-2-m-3-carboxylic acid (1.77 g, 4 mmol) is dissolved in 35 ml of N, N-dimethylformamide, triethylamine (0.526 g, 5.2 mmol) and powdered potassium carbonate (0.55) under ice cooling g, 4 mmol) was added. Iodomethyl pivalate (0.968 g, 4 mmol) prepared in Preparation Example 3 was slowly added to the reaction mixture, stirred at the same temperature for 1 hour, and further stirred for 1 hour while raising the temperature to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1, v / v) to obtain 1.6 g (72%) of the title compound as a white powder.

mp 65-67 ° C;

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.18 (d, J = 7.2 Hz, 3H), 1.23 (s, 9H), 1.32 (d, J = 9.3 Hz, 3H), 3.01-3.17 (m, 1H) , 3.18-3.28 (m, 3H), 3.59 (s, 2H), 3.64-3.80 (m, 2H), 3.82-4.01 (m, 2H), 4.12-4.28 (m, 2H), 5.90 (AB-q, 2H), 7.01 (m, 2H), 7.21 (m, 2H); LCMS (m / e) 521 (M ⁺ ), 491, 407, 389, 320.

Method B

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba Phen-2-m-3-carboxylic acid (2.0 g, 4.9 mmol), benzyltriethylammonium chloride (2.22 g, 9.8 mmol), and chloromethyl pivalate (1.47 g, 9.8 mmol) were added to N, N-dimethylformamide. Dissolve in 50 ml and add triethylamine (1.4 ml, 9.8 mmol). The reaction mixture was stirred at 65-70 ° C for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1, v / v) to obtain 2.11 g (83%) of the title compound as a white powder. The analysis was identical to the material obtained in Method A.

Example  2: 1- ( Isopropyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate

Method A

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba Phen-2-m-3-carboxylic acid (1.0 g, 2.25 mmol) was dissolved in 20 ml of N, N-dimethylformamide and powdered potassium carbonate (0.48 g, 4.5 mmol) was added under ice cooling. 1-iodoethyl isopropylcarbonate (0.5 g, 2.47 mmol) prepared in Preparation Example 1 was slowly added to the reaction mixture, stirred at the same temperature for 1 hour, and further stirred for 1 hour while raising the temperature to room temperature. It was. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1, v / v) to obtain 0.84 g (72%) of the title compound as a white powder.

mp 85-87 ° C;

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.18 (d, J = 7.2 Hz, 3H), 1.31-1.61 (m, 9H), 1.33 (d, J = 9.3 Hz, 3H), 1.48 (t, J = 24 Hz, 3H), 2.05 (d, J = 7.2 Hz, 3H), 3.02-3.08 (m, 1H), 3.18-3.28 (m, 2H), 3.59 (s, 2H), 3.64-3.80 (m, 2H ), 3.82-4.01 (m, 2H), 4.12-4.28 (m, 2H), 4.85-4.94 (m, 1H), 6.94 (m, 1H), 6.96-7.05 (m, 2H), 7.21-7.28 (m) , 2H); LCMS (m / e) 521 (M ⁺ ), 496, 400, 389, 320.

Method B

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba Phen-2-m-3-carboxylic acid (2.0 g, 4.9 mmol), benzyltriethylammonium chloride (2.22 g, 9.8 mmol) and 1-iodoethyl isopropylcarbonate (1.6 g, 9.8 mmol) prepared in Preparation Example 1 ) Was dissolved in 50 ml of N, N-dimethylformamide and triethylamine (1.4 ml, 9.8 mmol) was added. The reaction mixture was stirred at 65-70 ° C for 2 hours. The reaction mixture was stirred at the same temperature for 1 hour and then further stirred for 1 hour while raising the temperature to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1, v / v) to obtain 1.4 g (52%) of the title compound as a white powder. The analysis was identical to the material obtained in Method A.

Example  3: 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate

Method A

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba Phen-2-m-3-carboxylic acid (1.0 g, 2.25 mmol) was dissolved in 20 ml of N, N-dimethylformamide and powdered potassium carbonate (0.48 g, 4.5 mmol) was added under ice cooling. 1-iodoethyl cyclohexylcarbonate (0.74 g, 2.47 mmol) prepared in Preparation Example 2 was slowly added to the reaction mixture, stirred at the same temperature for 1 hour, and further stirred for 1 hour while raising the temperature to room temperature. It was. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1, v / v) to give 1.06 g (82%) of the title compound as a white powder.

mp 110-113 ° C;

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.18 (d, J = 7.2 Hz, 3H), 1.31-1.61 (m, 9H), 1.33-1.91 (m, 13H), 3.02-3.15 (m, 2H), 3.18-3.24 (m, 2H), 3.60 (s, 2H), 3.68-3.80 (m, 2H), 3.82-4.01 (m, 1H), 4.18-4.23 (m, 4H), 4.60-4.72 (m, 1H ), 6.94 (m, 1 H), 7.01 (t, 2 H), 7.21-7.28 (m, 2 H); LCMS (m / e) 577 (M ⁺ ), 428, 389, 320.

Method B

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba Phen-2-m-3-carboxylic acid (2.0 g, 4.9 mmol), benzyltriethylammonium chloride (2.2 g, 9.8 mmol), and 1-chloroethyl cyclohexylcarbonate (2.0 g, 9.8 mmol) prepared in Preparation Example 2 ) Was dissolved in 50 ml of N, N-dimethyl formamide and triethylamine (1.4 ml, 9.8 mmol) was added. The reaction mixture was stirred at 65-70 ° C for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was washed with 5% brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1, v / v) to obtain 1.9 g (70%) of the title compound as a white powder. The analysis was identical to the material obtained in Method A.

As a halogen substituted derivative of formula 3 (see US Pat. No. 5,886,172), cyclohexylacetoxymethyl chloride, (1-methylcyclohexanecarboxy) methyl chloride, isovaleroylmethyl chloride, n-decanoyloxymethyl chloride, and The compounds of Examples 4 to 8 were prepared in the same manner as in Example 3, using 1- (n-hexyloxycarbonyloxy) ethyl chloride as starting materials, respectively.

Example  4: Cyclohexylacetoxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba The title compound was prepared in the same manner as in Example 3 using phen-2-m-3-carboxylic acid and cyclohexylacetoxymethyl chloride. (Reaction temperature: 60 ° C., reaction time: 2 hours, yield: 76%)

¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.81-1.00 (m, 2H), 1.00-1.23 (m, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.25 (d, J = 7.3 Hz, 3H), 1.55-1.81 (m, 5H), 2.18 (d, J = 6.9 Hz, 2H), 3.01-3.14 (m, 2H), 3.10 (quint., 1H, J = 7.25 Hz), 3.17-3.24 ( m, 2H), 3.60 (s, 2H), 3.68-3.81 (m, 2H), 3.82-4.01 (m, 1H), 4.18-4.23 (m, 4H), 4.60-4.72 (m, 1H), 5.83 ( d, J = 5.61 Hz, 5.61 (d, J = 5.61 Hz, 1H), 7.00 (m, 2H), 7.22-7.30 (m, 2H).

Example  5: (1- Methylcyclohexanecarboxy ) methyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba The title compound was prepared in the same manner as in Example 3 using phen-2-m-3-carboxylic acid and (1-methylcyclohexanecarboxy) methyl chloride. (Reaction temperature: 65 ° C., reaction time: 2 hours, yield: 72%)

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.11-1.54 (m, 8H), 1.16 (s, 3H), 1.21 (d, J = 7.2 Hz, 3H), 1.31 (d, J = 7.3 Hz, 3H), 1.55-1.81 (m, 2H), 2.21 (d, J = 6.9 Hz, 2H), 3.01-3.14 (m, 2H), 3.17-3.24 (m, 2H), 3.60 (s, 2H), 3.68-3.81 (m, 2H), 3.82-4.01 (m , 1H), 4.18-4.23 (m, 4H), 4.60-4.72 (m, 1H), 5.84 (d, J = 5.61 Hz, 5.60 (d, J = 5.61 Hz, 1H), 7.00 (m, 2H), 7.22-7.30 (m, 2H).

Example  6: Isovaleroylmethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba The title compound was prepared in the same manner as in Example 3 using phen-2-m-3-carboxylic acid and isovaleroylmethyl chloride. (Reaction temperature: 70 deg. C, reaction time: 2 hours, yield: 76%)

¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.94 (d, J = 6.6 Hz, 6H), 1.17 (d, J = 7.2 Hz, 3H), 1.26 (d, J = 7.26 Hz, 3H), 2.05-2.15 (m, 1H), 2.23 (d, J = 6.6 Hz, 2H), 3.02-3.0 (m, 1H), 3.18-3.30 (m, 2H), 3.59 (s, 2H), 3.64-3.80 (m, 2H ), 3.82-4.01 (m, 2H), 4.12-4.28 (m, 2H), 4.85-4.94 (m, 1H), 5.85 (d, J = 5.61 Hz, 5.91 (d, J = 5.61 Hz, 1H), 7.05 (m, 2 H), 7.22-7.31 (m, 2H).

Example  7: n- Decanoyloxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba The title compound was prepared in the same manner as in Example 3 using phen-2-em-3-carboxylic acid and n-decanoyloxymethyl chloride. (Reaction temperature: 65 ° C., reaction time: 2 hours, yield: 81%)

¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.78-0.82 (m, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.17-1.23 (m, 12H), 1.27 (d, J = 7.26 Hz, 3H), 1.51-1.58 (m, 2H), 2.31 (t, J = 7.58 Hz, 2H), 3.03-3.17 (m, 1H), 3.18-3.30 (m, 2H), 3.59 (s, 2H), 3.64 -3.81 (m, 2H), 3.82-4.01 (m, 2H), 4.13-4.29 (m, 2H), 4.85-4.95 (m, 1H), 5.77 (d, J = 5.61 Hz, 5.86 (d, J = 5.61 Hz, 1H), 7.06 (m, 2H), 7.22-7.33 (m, 2H).

Example  8: 1- (n- Hexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba The title compound was prepared in the same manner as in Example 3 using phen-2-m-3-carboxylic acid and 1- (n-hexyloxycarbonyloxy) ethyl chloride. Reaction temperature: 70 DEG C, reaction time: 2 hours, yield: 65%

¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.79-0.81 (m, 3H), 1.15 (d, J = 7.2 Hz, 3H), 1.16-1.27 (m, 9H), 1.27 (d, J = 7.26 Hz, 3H), 1.51-1.62 (m, 3H), 3.03-3.17 (m, 2H), 3.17-3.30 (m, 2H), 3.59 (s, 2H), 3.64-3.83 (m, 2H), 3.82-4.01 ( m, 2H), 4.13-4.29 (m, 2H), 4.85-4.95 (m, 1H), 6.77-6.83 (m, 1H), 7.05 (m, 2H), 7.20-7.33 (m, 2H).

Example  9: 1- ( Acetoxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate

(1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1-methyl-carba Phen-2-m-3-carboxylic acid (5 g, 12.3 mmol) was dissolved in 20 mL of N, N-dimethylacetamide, tetrabutylammonium bromide (6 g, 18.45 mmol) was added and stirred. 1- (acetoxy) ethyl bromide (2.7 g, 16 mmol) and N, N-diisopropylethylamine (2.6 mL, 18.45 mmol) were added to the reaction mixture, which was stirred for 2 hours at 35 ° C. The reaction mixture was cooled to room temperature and extracted by adding 100 mL of water and 100 mL of ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane: acetone = 4: 1, v / v) to obtain 4.6 g (yield: 77%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.05 (d, 3H), 1.13 (d, 3H), 1.43 (d, 3H), 1.96 (s, 3H), 3.03 (m, 1H), 3.22 ( m, 1H), 3.35-3.69 (m, 4H), 3.59 (s, 2H), 3.93 (m, 1H), 4.05 (m, 1H), 4.12 (m, 1H), 5.07 (m, 1H), 6.80 (m, 1H), 7.12 (m, 2H), 7.28 (m, 2H)

Example  10: Pivaloyloxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate  phosphate

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- 1-Methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) was dissolved in 1 ml of acetone and phosphoric acid (20 ml, 0.2 mmol) was added at 5 ° C., followed by stirring for 30 minutes. After adding 1 ml of water to the reaction solution, the organic solvent was distilled under reduced pressure, and then filtered. The obtained solid was washed with water and dried in vacuo to give 94 mg (80% yield) of the title compound as a white crystalline form.

m.p. 124 ° C .;

¹ H NMR (200 MHz, DMSO-d ₆ ) δ 1.25 (t, 11H), 1.38 (d, 3H), 1.89 (br, 1H), 4.3-3.6 (m, 8H), 4.65 (m, 3H), 5.87 (d, 2H), 7.24 (t, 2H), 7.64 (t, 2H)

Example  11: Pivaloyloxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate  Hydrochloride

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- 1-Methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) was dissolved in 1 ml of ethyl acetate and 5 ml of hydrochloric acid solution in ethyl acetate at 0 ° C. was added and stirred for 30 minutes. The reaction solution was distilled under reduced pressure, and the obtained residue was dissolved in 1 ml of ethyl acetate, and then 10 ml of n-hexane was added thereto. The reaction mixture was distilled under reduced pressure to obtain 0.53 g (50% yield) of the title compound as a powder.

m.p. 130 ° C. decomposed;

¹ H NMR (200 MHz, DMSO-d ₆ ) δ 1.25 (t, 11H), 1.38 (d, 3H), 1.89 (br, 1H), 4.3-3.6 (m, 8H), 4.65 (m, 3H), 5.87 (d, 2H), 7.24 (t, 2H), 7.64 (t, 2H)

Example  12: 1- ( Isopropyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate  Hydrochloride

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) and 5 ml of a hydrochloric acid solution in ethyl acetate were reacted in the same manner as in Example 11 to give a powdery title 80 mg (73% yield) of compound were obtained.

m.p. Decomposed at 110 ° C;

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.84 (m, 3H), 1.11-1.27 (m, 9H), 1.54-1.57 (m, 3H), 3.82-4.81 (m, 12H), 6.86 (m, 1H ), 7.00-7.19 (t, 2H), 7.21-7.26 (m, 2H)

Example  13: 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate  Hydrochloride

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.15 mmol) and 5 ml of hydrochloric acid solution in ethyl acetate were reacted in the same manner as in Example 11 to obtain a powdery form. 81 mg (90% yield) of the title compound were obtained.

m.p. 117 ° C. decomposed;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.16 (d, 3H), 1.11-1.48 (m, 16H), 3.77-4.88 (m, 12H), 6.83-6.86 (m, 1H), 7.07-7.20 (m , 2H), 7.37-7.44 (m, 2H)

Example  14: Pivaloyloxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Maleate

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Dissolve 1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) in 1 ml of ethyl acetate and cool to 0 ° C., add maleic acid (23.4 mg, 0.20 mmol) for 5 hours Was stirred. The reaction mixture was distilled under reduced pressure, and the obtained residue was dissolved in 1 ml of methylene chloride, and then 10 ml of n-hexane was slowly added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered, the obtained solid was washed with n-hexane and dried under reduced pressure to give 60 mg (yield 50%) of the title compound as a powder.

m.p. 107-109 ° C .;

¹ H NMR (200 MHz, CD ₃ OD) δ 1.21-1.31 (m, 15H), 3.23-3.35 (m, 2H), 3.88-3.96 (m, 2H), 4.21-4.48 (m, 4H), 4.48- 4.59 (m, 2H), 4.64 (m, 1H), 5.77-5.88 (dd, J = 5.69 Hz, 2H), 6.34 (s, 2H), 7.09-7.17 (t, J = 8.54 Hz, 2H), 7.29 -7.47 (m, 2H)

Example  15: 1- ( Isopropyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Maleate

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) was dissolved in 1 ml of isopropyl alcohol, maleic acid (22.7 mg, 0.19 mmol) was added and at room temperature Stir for 5 hours. The reaction mixture was distilled under reduced pressure, and the obtained residue was dissolved in 1 ml of methylene chloride, and then 10 ml of n-hexane was added slowly. The reaction mixture was filtered, the obtained solid was washed with n-hexane and dried under reduced pressure to give 110 mg (93% yield) of the title compound as a powder.

m.p. 129-130 ° C.,

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.84 (m, 3H), 1.11-1.27 (m, 9H), 1.54-1.57 (m, 3H), 3.82-4.81 (m, 12H), 6.34 (s, 2H ), 6.86 (m, 1H), 7.00-7.19 (t, 2H), 7.21-7.26 (m, 2H)

Example  16: 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Maleate

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.18 mmol) is dissolved in 1 ml of isopropyl alcohol, maleic acid (21.7 mg, 0.18 mmol) is added and at room temperature Stir for 5 hours. Subsequent treatment in the same manner as in Example 15, 113 mg (93% yield) of the title compound were obtained in powder form.

m.p. 134-135 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.16 (d, 3H), 1.11-1.48 (m, 16H), 3.77-4.61 (m, 12H), 6.32 (s, 2H), 6.83-6.86 (m, 1H ), 7.08-7.15 (m, 2H), 7.27-7.41 (m, 2H)

Example  17: Pivaloyloxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Fumarate

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Dissolve 1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) in 1 ml of isopropyl alcohol, then add fumaric acid (23.4 mg, 0.20 mmol) and stir at room temperature for 3 hours. It was. Slowly adding 12 ml of n-hexane to the reaction mixture to form a precipitate. The precipitate obtained by filtration was washed with n-hexane and dried to give 60 mg (50% yield) of the title compound in powder form.

m.p. 110-115 ° C .;

¹ H NMR (200 MHz, CD ₃ OD) δ 1.25 (m, 12H), 1.39 (d, 3H), 3.65 (m, 2H), 3.82 (m, 1H), 4.13 (m, 3H), 4.18-4.37 (m, 5H), 5.77-5.88 (dd, J = 5.69 Hz, 10.17 Hz, 2H), 6.70 (s, 2H), 7.07-7.20 (t, J = 8.95 Hz, 2H), 7.38-7.48 (m, 2H)

Example  18: 1- ( Isopropyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Fumarate

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) was dissolved in 1 ml of isopropyl alcohol, fumaric acid (22.7 mg, 0.19 mmol) was added and room temperature Stirred for 3 h. The reaction mixture was distilled under reduced pressure, and the obtained residue was dissolved in 1 ml of methylene chloride, and 10 ml of n-hexane was slowly added to form a precipitate. The precipitate obtained by filtration was washed with n-hexane and dried to give 115 mg (93% yield) of the title compound in powder form.

m.p. 162-165 ° C;

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.84 (m, 3H), 1.11-1.27 (m, 9H), 1.54-1.57 (m, 3H), 3.82-4.81 (m, 12H), 6.75 (s, 2H ), 6.86 (m, 1H), 7.00-7.19 (t, 2H), 7.21-7.26 (m, 2H)

Example  19: 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Fumarate

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.18 mmol) was dissolved in 1 ml of isopropyl alcohol, fumaric acid (21.7 mg, 0.18 mmol) was added and room temperature Stirred for 3 h. Thereafter, the same process as in Example 18, 115 mg (95% yield) of the title compound were obtained in powder form.

m.p. 157-158 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.16 (d, 3H), 1.11-1.88 (m, 16H), 3.77-4.62 (m, 12H), 6.79 (s, 2H), 6.83-6.86 (m, 1H ), 7.07-7.15 (m, 2H), 7.27-7.41 (m, 2H)

Example  20: Pivaloyloxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine - 3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Benzene sulfonate

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Dissolve 1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) in 1 ml of isopropyl alcohol, then add benzenesulfonic acid (31.9 mg, 0.20 mmol) and for 5 hours at room temperature. Stirred. 12 ml of n-hexane was slowly added to the reaction mixture to form a precipitate. The precipitate obtained by filtration was washed with n-hexane and dried to give 99.3 mg (77% yield) of the title compound in powder form.

m.p. 113-115 ° C .;

¹ H NMR (200 MHz, CD ₃ OD) δ 1.25 (m, 11H), 1.39 (d, 3H), 3.68-4.28 (m, 11H), 5.77-5.89 (dd, J = 5.69 Hz, 10.17 Hz, 2H ), 6.97-7.05 (m, 5H), 7.23-7.31 (m, 4H)

Example  21: 1- ( Isopropyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Benzene sulfonate

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) was dissolved in 1 ml of isopropyl alcohol, benzenesulfonic acid (30.9 mg, 0.19 mmol) was added Stir at room temperature for 5 hours. Thereafter, the same procedure as in Example 20 was carried out to obtain 109.5 mg (83% yield) of the title compound in powder form.

m.p. 105-106 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.84 (m, 3H), 1.11-1.27 (m, 9H), 1.54-1.57 (m, 3H), 3.82-4.81 (m, 12H), 6.86-6.97 (m , 4H), 7.26-7.39 (m, 4H), 7.79-7.83 (m, 2H)

Example  22: 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Benzene sulfonate

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.18 mmol) was dissolved in 1 ml of isopropyl alcohol, benzenesulfonic acid (29.6 mg, 0.18 mmol) was added And stirred at room temperature for 5 hours. Thereafter, the same procedure as in Example 20 was carried out to obtain 110 mg (85% yield) of the title compound in powder form.

m.p. 120-121 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.16 (d, 3H), 1.11-1.88 (m, 16H), 3.77-4.72 (m, 12H), 6.86-6.88 (m, 1H), 7.04-7.10 (m , 3H), 7.38-7.45 (m, 4H), 7.71-7.75 (d, 2H)

Example  23: Pivaloyloxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate  p- Toluenesulfonate

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Dissolve 1-methyl-carbafen-2-m-3-carboxylate ( 100 mg, 0.19 mmol) in 2 ml of isopropyl alcohol, then add p-toluenesulfonic acid (34.7 mg, 0.20 mmol) and at room temperature Stir for 5 hours. Slowly adding 12 ml of n-hexane to the reaction mixture to form a precipitate. The precipitate obtained by filtration was washed with n-hexane and dried to give 109 mg (83% yield) of the title compound in powder form.

m.p. 120-121 ° C .;

¹ H NMR (200 MHz, CD ₃ OD) δ 1.25 (m, 11H), 1.39 (d, 3H), 2.34 (s, 3H), 3.85-4.65 (m, 11H), 5.77-5.88 (dd, J = 5.69 Hz, 10.17 Hz, 2H), 7.10-7.22 (m, 4H), 7.62-7.72 (m, 4H)

Example  24: 1- ( Isopropyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate  p- Toluenesulfonate

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) was dissolved in 1 ml of isopropyl alcohol and p-toluenesulfonic acid (33.6 mg, 0.19 mmol) was added. Add and stir for 5 hours at room temperature. Thereafter, the same procedure as in Example 23 was carried out to obtain 121 mg (90% yield) of the title compound in powder form.

m.p. 129-130 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.16 (d, 3H), 1.11-1.88 (m, 16H), 2.37 (s, 3H), 3.77-4.72 (m, 12H), 6.86-6.88 (m, 1H ), 7.00-7.09 (t, 2H), 7.17-7.21 (d, 2H), 7.38-7.45 (d, 2H)

Example  25: 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate  p- Toluenesulfonate

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate ( 100 mg, 0.18 mmol) was dissolved in 1 ml of isopropyl alcohol and p-toluenesulfonic acid (32.2 mg, 0.18 mmol) was added. Add and stir for 5 hours at room temperature. Subsequent treatment in the same manner as in Example 23 gave 112 mg (85% yield) of the title compound in powder form.

m.p. 129-130 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.16 (d, 3H), 1.11-1.88 (m, 16H), 2.37 (s, 3H), 3.77-4.72 (m, 12H), 6.86-6.88 (m, 1H ), 7.00-7.09 (t, 2H), 7.17-7.21 (d, 2H), 7.38-7.45 (d, 2H)

Example  26: Pivaloyloxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Trifluoroacetic acid salt

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- 1-Methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) was dissolved in 1 ml of ethyl acetate and cooled to 0 ° C. and trifluoroacetic acid (26.3 mg, 0.23 mmol) was added. And stirred at room temperature for 50 minutes. The reaction mixture was cooled to 0 ° C., and 12 ml of n-hexane were slowly added to form a precipitate. Stirred at the same temperature for 1 hour and filtered. The precipitate obtained was washed with n-hexane and dried to give 112 mg (93% yield) of the title compound in powder form.

m.p. 80-81 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.25 (m, 12H), 1.39 (d, 3H), 3.65-4.45 (m, 11H), 5.80-5.91 (dd, J = 5.69 Hz, 10.17 Hz, 2H) , 7.07-7.16 (t, J = 8.95 Hz, 2H), 7.40-7.44 (m, 2H)

Example  27: 1- ( Isopropyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Trifluoroacetic acid  salt

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate ( 100 mg, 0.19 mmol) was dissolved in 1 ml of ethyl acetate and cooled to 0 ° C. and trifluoroacetic acid (25.5 mg , 0.22 mmol) was added and stirred at room temperature for 50 minutes. Thereafter, the mixture was treated in the same manner as in Example 26, to obtain 114 mg (93% yield) of the title compound in powder form.

m.p. 70-71 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.84 (m, 3H), 1.11-1.27 (m, 9H), 1.42-1.58 (m, 3H), 3.95-4.88 (m, 12H), 6.86 (m, 1H ), 7.01-7.18 (m, 2H), 7.28-7.38 (m, 2H)

Example  28: 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Trifluoroacetic acid salt

1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) was dissolved in 1 ml of ethyl acetate and cooled to 0 ° C. and trifluoroacetic acid (25.5 mg , 0.22 mmol) was added and stirred at room temperature for 50 minutes. Thereafter, the mixture was treated in the same manner as in Example 26, to obtain 115 mg (95% yield) of the title compound in powder form.

m.p. 85-86 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.16 (d, 3H), 1.11-1.88 (m, 16H), 3.80-4.83 (m, 12H), 6.83-6.86 (m, 1H), 7.07-7.17 (t , 2H), 7.37-7.44 (d, 2H)

Example  29: Pivaloyloxymethyl  (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Lactate

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- 1-Methyl-carbafen-2-m-3-carboxylate ( 100 mg, 0.19 mmol) was dissolved in 2 ml of isopropyl alcohol, then lactic acid (18.2 mg, 0.20 mmol) was added and stirred at room temperature for 5 hours. . 12 ml of n-hexane was slowly added to the reaction mixture to form a precipitate. The precipitate obtained by filtration was washed with n-hexane and dried to give 79 mg (68% yield) of the title compound as a powder.

m.p. 111-112 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.25 (m, 12H), 1.39 (m, 6H), 3.65-4.40 (m, 12H), 5.77-5.88 (dd, J = 5.69 Hz, 10.17 Hz, 2H) , 07-7.20 (t, J = 8.95 Hz, 2H), 7.38-7.48 (m, 2H)

Example  30: 1- ( Isopropyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Lactate

Isopropyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl] -1 -Methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) was dissolved in 1 ml of isopropyl alcohol, then lactic acid (20.0 mg, 0.22 mmol) was added and stirred at room temperature for 5 hours. Thereafter, the same procedure as in Example 29 was carried out to obtain 82 mg (69% yield) of the title compound in powder form.

m.p. 110-112 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.84 (m, 3H), 1.11-1.27 (m, 12H), 1.42-1.58 (m, 3H), 3.95-4.88 (m, 13H), 6.86 (m, 1H ), 7.01-7.18 (m, 2H), 7.28-7.38 (m, 2H)

Example  31: 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[(1- (4- Fluorobenzyl ) Azetidine -3 days) Thio ] -6-[(R) -1-hydroxyethyl] -1- methyl - Kabafen -2-m-3- Carboxylate Lactate

1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (100 mg, 0.19 mmol) and lactic acid (16.8 mg, 0.19 mmol) were reacted in the same manner as in Example 29 to give the title compound. 80 mg (63% yield) were obtained in powder form.

m.p. 115-117 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.16 (d, 3H), 1.11-1.88 (m, 19H), 3.81-4.80 (m, 13H), 6.83-6.85 (m, 1H), 7.08-7.17 (t , 2H), 7.38-7.45 (d, 2H)

Test Example  1: powder X-ray spectroscopy test ( powder  X- ray diffractometry )

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 prepared in Example 10 Phosphate of -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was found to exhibit crystallinity when observed with a polar microscope, and the results of powder X-ray spectroscopy were Table 1 is as follows.

2 θ d-spacing Intensity value Intensity (I / I ₀ ) FWHM 7.0600 12.5110 2027 338 0.2600 8.6400 10.2260 5363 1000 0.2200 9.8000 9.0180 1453 192 0.1200 10.1200 8.7337 950 90 0.3000 10.9600 8.0659 993 105 0.2600 12.6400 6.9975 1024 95 0.2600 14.1000 6.2759 1509 158 0.0800 15.1600 5.8395 1340 85 0.2800 15.7000 5.6399 3521 519 0.3400 16.5600 5.3488 2849 377 0.2800 17.6000 5.0350 1857 161 0.2800 18.2200 4.8651 2273 272 0.2800 19.2600 4.0047 1965 212 0.2400 19.8200 4.4757 4396 768 0.1000 20.1600 4.3968 2727 370 0.1200 20.4800 4.3330 1733 170 0.2000 22.9200 3.8769 1663 149 0.2000 23.3200 3.8113 1352 90 0.2200 24.4400 3.6392 1491 138 0.2200 24.6600 3.5786 1247 97 0.2000 25.8800 3.4399 2279 2279 0.2800 26.3500 3.3783 1269 1269 0.1400 28.8500 3.0911 1303 1303 0.3800 30.0500 2.9704 1086 1086 0.2800 30.6600 2.9136 1027 1027 0.2400

Test Example  2: stability test

Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 prepared in Example 10 A stability test was performed on the phosphate salt of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate. HPLC purity was measured at 1 week, 2 weeks, 3 weeks, and 1 month while 500 mg of the compound prepared in Example 10 was placed in a glass bottle and kept at 40 ° C. and 75% humidity conditions. HPLC purity represents the percentage measured by HPLC in each test cycle relative to the content initially determined by HPLC. The results are shown in Table 2 below.

Test substance HPLC Purity (%) Early 1 week 2 weeks 3 weeks 1 month  Example 10 99.83 99.85 99.78 99.74 99.69

As can be seen from the above results, it can be seen that the conversion of the ester derivative to the acid addition salt form shows excellent stability.

Test Example  3: Acute Toxicity Test

Acute toxicity to the compounds of Examples 10 and 17 was measured using two groups of ICR mice (5 mice / 2 groups). The compound of Example 10 or 17 was orally administered at a dose of 1,000 mg / kg, 2,000 mg / kg, 3,000 mg / kg, and body temperature change, weight change, and death were observed over 7 days after administration. As a result, none of the animals died in all the administration groups, and no significant body temperature change or weight loss was observed (see FIGS. 2 and 3). Thus, LD ₅₀ is at least 3,000 mg / kg or more, and the compounds of the present invention are antibiotics with little toxicity.

Figure 1 shows the acute toxicity test results for the compound prepared in Example 10.

Figure 2 shows the acute toxicity test results for the compound prepared in Example 17.

Claims (14)

Acid addition salts of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives of Formula 1: <Formula 1>

Wherein R ₁ is hydrogen or a C ₁ -C ₄ alkyl group; R ₂ is C ₄ -C ₇ cycloalkyl optionally substituted with or substituted with an unsubstituted straight chain or branched C ₁ -C ₁₂ alkyl group, or C ₁ -C ₄ alkyl or unsubstituted C ₄ -C ₇ A cycloalkyl group; n is 0 or 1; The method of claim 1, wherein the acid is selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, bromic acid, iodic acid, and nitric acid; Or acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trichloroacetic acid, fumaric acid, maleic acid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, p-nitrobenzoic acid, benzenesulfonic acid, p-nitrobenzene 2-arylmethylase, characterized in that it is an organic acid selected from the group consisting of sulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,4,6-triisopropylbenzenesulfonic acid, and diphenylphosphinoic acid Acid addition salts of thidine-carbapenem-3-carboxylic acid ester derivatives. The 2-arylmethylazetidine-carbapenem-3 according to claim 2, wherein the acid is phosphoric acid, hydrochloric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, or lactic acid. Acid addition salts of carboxylic ester derivatives. The acid addition salt of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative according to claim 1, which is selected from the group consisting of: Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Phosphate of 1-methyl-carbafen-2-m-3-carboxylate; Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Hydrochloride of 1-methyl-carbafen-2-m-3-carboxylate; 1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Hydrochloride of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Hydrochloride of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Maleic acid salt of 1-methyl-carbafen-2-m-3-carboxylate; 1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Maleic acid salt of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Maleic acid salt of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Fumarate of 1-methyl-carbafen-2-m-3-carboxylate; 1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Fumarate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Fumarate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Benzenesulfonate of 1-methyl-carbafen-2-m-3-carboxylate; 1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Benzenesulfonate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Benzenesulfonate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- P-toluenesulfonate of 1-methyl-carbafen-2-m-3-carboxylate; 1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 P-toluenesulfonate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 P-toluenesulfonate of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Trifluoroacetic acid salt of 1-methyl-carbafen-2-m-3-carboxylate; 1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Trifluoroacetic acid salt of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Trifluoroacetic acid salt of -hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; Pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1-hydroxyethyl]- Lactic acid salt of 1-methyl-carbafen-2-m-3-carboxylate; 1- (isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Lactic acid salt of hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate; And 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R) -1 Lactic acid salt of hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate. The compound of claim 1, wherein the compound is pivaloyloxymethyl (1R, 5S, 6S) -2-[(1- (4-fluorobenzyl) azetidin-3-yl) thio] -6-[(R The acid addition salt of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative characterized in that it is a phosphate of) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate. Process for preparing acid addition salt of 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of formula (1) comprising reacting 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of formula (1) with an acid : <Formula 1>

Wherein R ₁ , R ₂ and n are as defined in claim 1. The composition of claim 6, wherein the acid is selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, bromic acid, iodic acid, and nitric acid; Or acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trichloroacetic acid, fumaric acid, maleic acid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, p-nitrobenzoic acid, benzenesulfonic acid, p-nitrobenzene And an organic acid selected from the group consisting of sulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,4,6-triisopropylbenzenesulfonic acid, and diphenylphosphinic acid. 8. A process according to claim 7, wherein the acid is phosphoric acid, hydrochloric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, or lactic acid. 7. A process according to claim 6, wherein the reaction is carried out in an organic solvent selected from at least one of the group consisting of acetone, ethyl acetate, isopropyl alcohol, tetrahydrofuran, and acetonitrile. The method of claim 6, wherein the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative of Formula 1 is prepared by reacting a compound of Formula 2 with a compound of Formula 3 Manufacturing Method <Formula 2>

<Formula 3>

Wherein M is hydrogen or an alkali metal; X is halogen; R ₁ , R ₂ and n are as defined in claim 1. The method of claim 10, wherein the reaction of the compound of Formula 2 with the compound of Formula 3 is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, N, N-diisopropyl Ethylamine, and pyridine, characterized in that carried out in the presence of at least one base selected from the group consisting of. The method according to claim 11, wherein the reaction of the compound of Formula 2 with the compound of Formula 3 is selected from at least one selected from the group consisting of tetraethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, and benzyltriethylammonium chloride. A process characterized in that it is carried out in the presence of a primary ammonium salt. The method of claim 10, wherein the reaction of the compound of Formula 2 with the compound of Formula 3 is diethyl ether, tetrahydrofuran, dioxane, toluene, xylene, cyclohexane, dichloromethane, chloroform, N, N-dimethylformamide , N, N-dimethylacetamide, acetonitrile and dimethyl sulfoxide in the presence of at least one organic solvent selected from the group consisting of. An antibiotic composition comprising an acid addition salt of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative according to any one of claims 1 to 5 as an active ingredient and a pharmaceutically acceptable carrier.

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