KR840001826B1 - Process for preparing 1- oxadethia cephalosporin derivatives - Google Patents

Abstract

1-oxadethia cephalosporin derivatives I (R = 1-methyl-1Htetrazol-5- ilthio, 2-carboxymethylhydroxy-1H-tetr-azol-5-il thio, 4-methyl-5- oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine-3-ilthio, pyridium, 4- carbamoyl-pyridium, 1-dimethylaminoethyl-1-H-tetrazol-ilthio, (un) substituted-tetrazole-(1,5-b)-pyridazine-6-ilthio; Y = H, methoxy; R1 = H, protected carboxy; Z = halo; X = 1-3) were prepd. Thus, II was treated with III to give I. I has bactericidal activity both in vivo and in vitro. Also, it is connected with the chemotherapeutic use of the bactericidal composition containing I derivatives.

Description

Method for preparing 1-oxadetiacephalosporin derivative

The present invention relates to a method for producing a novel antimicrobial 1-oxadetiacephalosporin derivative exhibiting high antimicrobial activity, particularly against β-lactase producing bacteria in vivo and in vitro. The present invention also provides an antimicrobial composition containing 1-oxadethiacephalosporin derivatives, and the chemotherapeutic use of salts and esters thereof of these 1-oxadethiacephalosporins and pharmacologically acceptable these compounds. It is about a method.

Conventionally, many different cephalosporin fluids have been prepared and used for the treatment of fungal infections.

Recently, various derivatives of 1-oxadetiacephalosporin have been synthesized to limit their use for the treatment of fungal infections. (See, eg, US Pat. Nos. 4,001,216; 4,103,648; 4,013,653; 4,031,083; 4,045,438; 4,138,486 and 4,180,571).

The inventors of the present invention have a wide range of objectives to provide novel derivatives of 1-oxadetiacephalosporin having high antibacterial activity against β-lactase products that are generally resistant to Gram-positive bacteria and Gram-negative bacteria and known cephalosporins. The study was conducted.

As a result of the study, the present inventors succeeded in synthesizing new 1-oxadetiacephalosporin derivatives so that their new 1-oxadetiacephalosporin derivatives are known as cephalos.

An object of the present invention is to provide a novel 1-oxadethiacephalosporin derivative having high antimicrobial activity and useful for chemotherapeutic treatment of bacterial infection. Another object of the present invention is to provide a method for preparing the new compound, which can be carried out in an efficient and convenient manner and is suitable for commercial products of the new compound.

Yet another object of the present invention is apparent from the following detailed description. First, the present invention provides novel 1-oxadethiacephalosporin derivatives of the following general formula (1) and their salts and esters thereof.

Wherein R is a heterocyclic group or -S-Het group (Het is a heterocyclic group).

Y is a hydrogen atom or a methoxy group, X and Y are integers 1,2 or 3, respectively, and are pharmacologically acceptable salts and esters thereof.

Secondly, the present invention condenses a 1-oxacefem compound of the following general formula (II) in sulfuric acid with a sulfur amino acid containing the following general formula (II) to produce a condensation product of the following general formula (I '), if necessary Provided is a method for preparing a new 1-oxadethiacephalosporin derivative of formula (I) consisting of a process for removing residual protecting groups from condensation product (I ') in the presence of a protecting group.

Wherein R is a heterocyclic group or -S-Het group (Het is a heterocyclic group), Y is a hydrogen atom or a methoxy group, R 'is a hydrogen atom or a carboxyl protecting group, in particular a known ester forming group as a carboxy protecting group, Z is Halo groups, in particular bromo, chloro or iodo groups, y is an integer of 1,2 or 3;

x is an integer of 1,2 or 3;

Firstly, according to the present invention, the 1-oxadethiacephalosporin derivative of the general formula (I) is an alkali metal such as sodium and potassium, or a basic amino acid such as L-lysine, or a pharmacology such as triethylamine and cyclohexylamine. It is in the form of an acceptable salt with an acceptable organic base. Furthermore, the 1-oxadethiacephalosporin derivative of formula (I) is in the form of a water soluble ester (such as a carboxylate) with a pharmacologically acceptable alcohol.

These esters include lower (C ₁ -C ₆ ) alkyl esters such as methyl, ethyl, propyl or t-butyl esters; Alkylamino-lower alkyl esters such as dimethyl aminoethyl ester,

These esters are phthalidyl, acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, propionyloxyethyl, indanyl, phenyldimethylphenyl, methoxyphenyl, methoxycarbonyloxyethyl, ethoxycar More preferred are carbonylmethyl or phenacyl esters.

In addition, these esters are terminal carboxyl substituents present in the amino acid component added to the 4-carboxyl group of 1-oxafem nucleus or 7-amino group of 1-oxafem nucleus, in the form of a mono-ester or as a di-carbohydrate as these two carboxyl groups. Present in the form of an ester.

The amino acid component added to the 7-amino group of 1-oxacefem nucleus present in the molecule of the compound of general formula (I) exists in the form of either D-stereoisomer or L-stereoisomer within the scope of the present invention. . The D-form typically exhibits higher antimicrobial activity than the L form. Compounds of general formula (I) wherein Y is a methoxy group show higher antimicrobial activity than compounds of general formula (I) wherein Y is hydrogen when used in sensitive bacteria. And the former is more stable and more active than the latter against β-lactase producing bacteria.

In the novel compound of general formula (I) according to the present invention, the 1-oxa cefefem nucleus is a compound of formula -CH ₂ R wherein R is a heterocyclic group or R is an -S-Het group (hereinafter referred to as S-heterocyclic group). 3-chi _{2 of}

The heterocyclic compound has 1 or 2 sulfur atoms added as a hetero atom.

또는 다음의 식인 4- 카르바모일피리디늄잔기

이다.Suitable examples of the heterocyclic group as the R group include a pyridinium residue represented by the following formula.

Or 4-carbamoylpyridinium residues of the following formula

to be.

The suitable example of the heterocyclic group in the symbol Het which exists in said -S-Het is as follows.

1-methyl-1H-tetrazol-5-yl

2-carboxymethyl-1H-triazol-5-yl

4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl

8-substituted or unsubstituted-tetrazol-5- (1,5-b) -pyridazin-6-yl

Wherein Q is a hydrogen atom or an amino, hydroxy or carboxyl group

1-sulfonylmethyl-1H-tetrazol-5-yl

1-sulfonylethyl-1H-tetrazol-5-yl

1-carboxymethyl-1H-tetrazol-5-yl

1-methyl-2-carboxy-1H-triazol-5-yl

1-dimethylaminoethyl-1H-tetrazol-5-yl

Preferred examples of 3-substituted-CH ₂ R include (1-methyl-1H-tetrazol-5-yl) thiomethyl group; (1-carboxymethyl-1H-tetrazol-5-yl) thiomethyl group; (2-carboxymethylhydroxy-

According to a first preferred embodiment of the present invention there is provided a new 1-oxa dethiacephalosporin derivative of the general formula (I ″).

Wherein R "is (1-methyl-1H-tetrazol-5-yl)

Thio group, (1-carboxymethyl-1H-tetrazol-5-yl) thio group; (4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl) thio group; (8-amino-tetrazolo- (1,5-b) -pyridazin-6-yl) thio group; Pyridinium group; 4-carbamoyl-pyridinium group and (1-dimethylaminoethyl-1H-tetrazol-5-yl) thio group, Y is a hydrogen atom or a methoxy group and a pharmacologically acceptable salt and its ester.

A first preferred embodiment of the present invention provides a novel 1-oxadethiacephalosporin derivative of the general formula (I ").

Wherein R '' 'is (1-methyl-1H-tetrazol-5-yl) thio or 4-carbamoylpyridi

Specific examples of the compound of general formula (I) according to the present invention include the following compounds.

(1) 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]- 1-oxadetia-3-cefe-4-carboxylic acid

(2) 7β-[(3D-3-amino-3-carboxy) propylthioacetoamido] -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]- 1-oxadetia-3-cefe-4-carboxylic acid

(3) 7β-[(2D-2-amino-2-carboxy) ethylthiopropioamido] -7-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxadetia-3-cefe-4-carboxylic acid

(4) 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxadetia -3-cefe-4-carboxylic acid

(5) 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -3-[(4-carbamoylpyridinium) methyl] -1-oxadetia-3-cepem-4 -Carboxylic acid

(6) 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -7α-methoxy-3-[(4-carbamoylpyridinium) methyl] -1-oxadetia- 3-cefe-4-carboxylic acid

(7) 7β-[(3D-3-amino-3-carboxy) propylthioacetoamido] -7α-methok

(8) 7β-[(2D-2-amino-2-carboxy) ethylthiopropioabado] -7α-methoxy-3-[(4-carbamoylpyridinium) methyl] -1-oxadetia- 3-cefe-4-carboxylic acid

(9) 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -7α-methoxy-3-[(4-methyl-5-oxo-6-hydroxy-4,5- Dihydro-1,2,4-triazin-3-yl) thiomethyl] -1-oxadetia-3-cepem-4-carboxylic acid

(10) 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -7α-methoxy-3-[(8-amino-tetrazolo- (1,5-b) -pyridazine -6-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylic acid

(11) 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -7α-methoxy-3-[(1-dimethylaminoethyl-1H-tetrazol-5-yl) thiomethyl ] -1-oxadetia-3-cepem-4-carboxylic acid

(12) 1-acetoxyethyl 7β-[(2D-2-amino-2-ethoxycarboxy) ethylthioacetoamido] -7α-methoxy-3-[(1-methyl-1H-tetrazol-5 -Yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylate

(13) 1-acetoxyethyl 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl ) Thiomethyl] -1-oxadetia-3-cepem-4-carboxylate

(14) 1-ethoxyethyl 7β-[(2D-2-amino-2-ethoxycarboxy) ethylthioacet

(15) 7β-[(2D-2-amino-2-ethoxycarboxy) ethylthioacetoamido] -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl ] -1-oxadetia-3-cepem-4-carboxylic acid

(16) 1-ethoxyethyl 7β-[(2D-2-amino-2-ethoxycarboxy) ethylthioacetoamido] -7α-methoxy-3-[(4-methyl-5-oxo-6- Hydroxy-4,5-dihydro 1,2,4-triazin-3-yl) thiomethyl] -1-oxadetia-3-cepem-4-carboxylate

(17) 1-acetoxyethyl 7β-[(2D-2-amino-2-ethoxycarboxy) ethylthioacetoamido] -7α-methoxy-3-[(1-dimethylaminoethyl-1H-tetrazole -5-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylate

The compound of general formula (I) of the present invention has a high in vitro antimicrobial activity against bacteria. Table 1 below shows the lowest concentrations of the compounds prepared in Examples 1-3 below.

TABLE 1

Lowest in vitro concentration (µg / ml)

Example 1 Compound, ie 7B [(2D-2-amino-2-carboxy) ethylthioacetoamido] -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl ] -1-oxadetia-3-cepem-4-carboxylic acid (as mono-sodium salt) was measured and shown in Table 2 below.

The lowest concentration of the test compound that inhibits the growth of various bacteria was pre-cultured in triplicate case soybean juice (BBL. Co.) at 37 ° C. overnight to pre-incubate the plate microorganisms and have the inoculum. Dilute the culture juice to 100 times the capacity with the same soybean juice as used in the above, and inoculate the inoculum prepared in nutrient agar (Digco) as a measuring medium for NIC. (Lowest low concentration), and then incubate at 37 ℃ for 20 hours. It is measured by culturing.

In contrast, US Pat. No. 4,138,486 (hereinafter referred to as 6059-S compound) 7β- (α-P-hydroxyphenyl-α-carboxacetoamido) -7α-methoxy-3-[(1-methyl- 1H-tetrazol-5-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylic acid (as di-sodium salt) and Belgian Patent No. 880,656 (or corresponding US Patent Application No. 104,220) 7β-[(2D-2-amino-2-carboxy) ethylthioaceto] -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) of (referred to as MT-141 compound) The antimicrobial spectrum of thiomethyl] -3-cepem-4-carboxylic acid (as mono-sodium salt) was determined in the same manner as shown in Table 2 below.

TABLE 2

All of the new compounds of general formula (I) according to the present invention are low in toxicity, and 7-8 g / Kg of toxicity LD ₅₀ is obtained when intravenously injected into mice to evaluate the actual toxicity of these compounds. This all shows up. Therefore, the novel compounds of the present invention are useful for the treatment of infections by gram-negative and gram-positive bacteria, including antimicrobial agents.

The new compounds of the present invention and their pharmacologically acceptable salts and esters thereof are orally administered using known pharmaceutical forms by conventional methods of administration and by the same methods of administration to known cephalosporins. It may be administered intraperitoneally, intravenously, subcutaneously or intramuscularly. By way of example, the new compounds of the present invention can be administered orally using pharmaceutical forms known in conventional methods for oral administration.

Examples of pharmaceutical forms for oral administration include powders, capsules, tablets, syrups and the like. The new compounds of the present invention are used in muscle or vein at a dosage of 0.5 to 2.0 g per person 2 to 3 times a day.

Suitable amounts of the novel compounds of the present invention are 2 to 4 g per person per day when administered orally for effective treatment of bacterial infections.

The above dosage should be administered orally in three to four times a day. Moreover, the novel compounds of the present invention can be prescribed as suppositories containing the active compounds in concentrations of 0.5 to 15% by weight in compounds with known suppository bases.

Furthermore, the new compounds of the present invention are useful for the sterilization of surgical instruments.

Thirdly, the present invention provides an antimicrobial composition comprising an antimicrobial effective amount of a new compound of formula (I) or a pharmacologically acceptable salt or ester thereof as an active ingredient in combination with a carrier of the active ingredient. In the composition of the present invention, the active ingredient compound may be composed of 0.1 to 90% by weight of the total composition.

The present invention also provides a method for inhibiting bacterial growth that is configured to administer an antimicrobial useful stable amount of a new compound of the invention by general formula (I) to an animal, including a person susceptible to bacterial growth. Furthermore, the present invention provides a method for inhibiting bacterial growth in vitro, wherein the method is configured by contacting a surface sensitive to bacterial growth with an antimicrobial effective amount of the compound of the present invention.

The new compounds of the present invention according to general formula (I) have high antimicrobial activity in vivo and have a high therapeutic effect in chemotherapeutic treatment of animals including humans infected with bacteria.

To illustrate this effect, inoculation of 2 × 10 ⁷ cells per mouse

Thirty minutes after inoculation, subcutaneous injection was performed with 0.2 ml of the solution of the test compound dissolved in physiological saline.

In this way, the toxicity ED ₅₀ of the test compound was measured. Experiments were also carried out by the same method as above for the purpose of comparing cefoxitin with 6059-S compound (di-sodium salt). The experimental results are shown in Table 3 below.

TABLE 3

The new compounds of the present invention in the table above show a higher therapeutic effect compared to the sepocillin and 6059-S compounds known as useful antimicrobial agents in the chemotherapy treatment of various bacterial infections.

The new compound of general formula (I) of the present invention can be prepared through various routes starting from the following general formula (IV) of 7-amino-1-oxadetia-cefem compound.

Wherein Y is a hydrogen atom or a methoxy group, R ¹ is a heterocyclic group or a -S-Het group and R ² is a hydrogen atom or a known carboxy protecting group. This starting compound (IV) is described in the Canadian Chemical Journal 50,2894 (1972); American Chemical Society 96,7582 (1977); Journal of Medicinal Chemistry 20, 551 (1977); It may be prepared by a known method, such as in the medical journal 22, 757 (1979) and the American Chemical Society 101, 4403 (1979). Basically, the starting material (IV) is an inert solvent such as aromatic hydrocarbon halo hydrocarbons and dioxane at 70-150 ° C. for several hours at a temperature of 70-150 ° C. in order to cyclize general formula (V). Heated at and then organic bases such as pyridine and N, N-di-methylaniline and phosphorus pentachloride at -20 to 40 ° C. to preferably convert the 7-acylamino group (R ₃ ) to the free 7-amino group. It can be prepared by the method of treating the cyclized product.

Wherein Y, R ¹ and R ² are the same as in general formula (IV), R ³ is an acylamino group, and R ³ is an aryl group such as phenyl.

The initial compound of Formula (V) is as defined in US Pat. No. 4,180,571.

In order to prepare the compound of the present invention according to general formula (I), for example, 7-amino-1-oxadetia-cefem compound of general formula (IV) may be replaced with haloalkanoic acid or React with the reactive derivative of (VI) to produce a condensation product of the following general formula (II), and then act with an amino acid compound of the following general formula (III), if necessary remove the carboxy protecting group (R ² ) Can be prepared.

Z- (CH ₂ ) y COX (Ⅵ)

Wherein Z is a halogen atom, in particular bromine or chlorine, X is -OH or bromo or another reactive group functionally corresponding to the -OH group present in the chloro group or carboxy group, y is an integer from 1 to 3.

Wherein R ¹ , R ² , Y, Z and y are the same as in general formula (VI).

Wherein X is an integer from 1 to 3.

In addition, in the second manufacturing process, 7-amino-1-oxadetia-cepem compound of formula (IV) is reacted with a compound of formula (VII) to remove protective residues (A, B) from the condensation product. Ha

Wherein X is another reactive group that functionally corresponds to the -OH group or the -OH group present in the bromo or chloro group or carboxy group, and x and y are integers 1 to 3, respectively.

A is a known carboxyprotecting group, B is a known amino protecting group. Reagents of formulas (VI) and (iii) used in each of the two manufacturing processes mentioned above may be selected from the group consisting of acid halide compounds, mixed acid anhydrides, succinylimino derivatives or p-nitrophenyl esters of active derivatives of carboxylic acids. May exist in the form.

In general formula (A), the amino protecting group (B) includes t-butoxy carbonyl, trichloroethoxycarbonyl and substituted or unsubstituted benzyloxycarbonyl group, and the carboxyl protecting group (A) is diphenylmethyl, trichloro Roethyl, substituted or unsubstituted benzyl and t-butyl groups. All of these protecting groups can be introduced or removed by conventional protection or deprotection methods.

As the halogen atom (Z) of the general formula (II ′) or (VI), chlorine, bromine, or iodine or chlorine and bromine are suitable.

Reaction of 7-amino-1-oxadetia-cepem compound of Formula (IV) with a haloalkanoic acid compound of Formula (VI) or a compound of Formula (VII) in the first and second manufacturing steps Is typically reacted with an inert organic solvent under reaction conditions known to form amido bonds in conventional peptide synthesis.

Solvents used for this purpose include dichloromethane, chloroform, ethyl acetate, dimethylformamide, and the like.

When the reagent compound of formula (VI) or (iii) is used in the form of an acid halide compound as one of the reactive acid derivatives, the reaction with the compound of formula (IV) is known to be known trimethylsilylating agent or trialkylamine, pyridine, dimethyl In the presence of an acid bond which is an organic base of a tertiary amine, such as aniline, it can be carried out at a temperature lower than 0 ° C.

When the reagent compound of formula (VI) or (iii) is used in the form of free carboxylic acid, the reaction is usually carried out by a known active ester in the presence of a dehydrating agent such as N, N-dicyclohexanecarbodiamide. Can be.

The reaction time may vary depending on the reactivity of the carboxylic acid derivatives of general formula (VI) or (iii) and is usually 1 to 5 hours.

Reaction of the 7-amino compound of Formula (IV) with the haloalkanoic acid reagent of Formula (VI) in the first preparation method for the preparation of the compound of Formula (I) is carried out with the condensation product of Formula (II ') It depends on the following reaction of the amino acid compound of formula (III).

This next reaction can be carried out in an inert solvent, preferably in the presence of an alkali metal (hydrogen) carbonate, trialkylamine, pyridine, or the like as an acid binder, at low temperature or room temperature. It mainly depends on the reactivity of the halo group (Z ') present in II'), the nature of the acid binder and the solvent used, but is usually completed in 1 to 5 hours. The manufacturing method of the second invention corresponds in part, i.e., the later stage of the first manufacturing method.

In carrying out the preparation method of the second invention, a water-soluble alkanol such as water-soluble methanol, which can dissolve or suspend the reactant which is the 1-oxacefem compound of the general formula (II), and a liquid anti-medium medium which is water It acts in the same molar or almost identical molar at containing sulfur amino acid of general formula (III).

Reaction temperature is 0-30 degreeC, even if reaction is normally performed at room temperature. When the hydrogen halide compound is released during the condensation reaction, it is preferable that the alkalinity effect the condensation reaction in the presence of an acid binder such as an organic base. D-Cysteine is a preferred example of an amino acid reactant of general formula (II).

The amino acid reactive substance of general formula (III) exists in the form of a functionally equivalent derivative, ie, an alkali metal mercaptide at the end of the thiol group as needed.

Condensation of the general formula (I '), if necessary, when the 1-oxafefem compound of the general formula (II) is used in the form of a carboxy protecting group (a known carboxy protecting group such as an ester forming group wherein R' is an alkyl or aryl group). The product follows a deprotection step in which the carboxyprotecting group (R ') is released by a known method.

When the carboxyprotecting group (R ') is an alkyl or aryl group, the departure of such ester forming groups is completed by acid or alkali hydrolysis in a known manner. If the ester forming group as the R 'group is a pharmacologically acceptable group, it is not necessary to leave such ester forming group in the condensation product of the general formula (I').

When the condensation product of the general formula (I) or (I ') is obtained in the form of free carboxylic acid or carboxylic acid ester, alkali according to a known method of forming carboxylate (salt)

The product of urea of the general formula (I) obtained above can be recovered from the reaction mixture in the form of a free carboxylic acid or in the form of a pharmacologically acceptable carboxylate by conventional treatment.

For example, the reaction mixture containing the desired product (I) is diluted with water and then treated with an absorbent resin or activated carbon for absorption of the desired product and eluted with a water-soluble organic solvent such as water or water-soluble ethanol to give the desired final product. Isolate and purify.

If desired, fine porous nonionic absorbent resins, such as Sephadex LH-20 or G-10 (manufactured by Swedish Pharmacia) or styrene-divinylbenzene copolymers, ie Diaion HP-20 (Japan Gel filter from Mitsubishi Kasei Co., Ltd. can be separated and purified by column chromatography.

The present invention is not limited to the above-mentioned technical content, but will be described according to the following examples.

Example 1

(A) 7β-amino-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylic acid benzyl ester (150 mg ) Was dissolved in a mixture of ethyl acetate (7 ml) and bis (trimethyl-silyl) acetoamide (370 mg), and bromoacetyl bromide (120 mg) solution dissolved in ethyl acetate (2 ml) was added to the solution for 1 hour. The mixture was stirred at -20 ° C for 1 hour at 0 ° C to 5 ° C. With this

The ethyl acetate layer was separated from the aqueous layer, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain 220 mg of an oily product.

The oily product thus obtained was treated with dried methylene chloride (10 mL), and the solution obtained by stirring under ice cooling was mixed with a solution of aluminum trichloride (266 mg) dissolved in nitromethane (4 mL) and an anipot (440 mg). It was.

The mixed solution thus mixed was stirred under ice cooling for 15 minutes and then further stirred at room temperature for 1.5 hours.

60 ml of ethyl acetate was added to the reaction solution thus obtained, washed twice with 2% aqueous hydrochloric acid solution, and then extracted twice with 5% sodium bicarbonate solution.

The ethyl acetate layer was separated from the sap layer and the remaining sap layer was further extracted with 30 ml of ethyl acetate.

The extract (a solution of ethyl acetate) was combined, dried over anhydrous magnesium sulfate, and then concentrated to dryness, and then dried to 7β- (2-bromoacetoamido) -7α-methoxy-3-[(1-methyl-1H-tetrazol- 40 mg of 5-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylic acid was obtained.

(B) The suspension obtained by suspending the product (40 mg) obtained in the above step in water (10 ml) was adjusted to pH 7 by adding sodium bicarbonate solution. As a result, the cefem compound was dissolved in water.

Then, D-cysteine (20 mg) was added to the solution, and reacted at room temperature for 1.5 hours while maintaining the pH of the reaction solution at 7-7.5. After the reaction was completed, the reaction solution was treated with hydrochloric acid, adjusted to pH 5.5 to 6.5, and concentrated. The concentrated solution was passed through a column of absorbent resin and 40 ml of Diaion HP-20 and eluted with water.

The liquid solution containing the required compound was collected, concentrated under reduced pressure, and ice-dried to obtain 7β-[(2-D-2-amino-2-carboxy) ethylthioacetoamido] -7α- as a colorless powder. 45 mg of methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylic acid sodium salt was obtained.

Melting Point: 129 to 135 ° C (Decomposition)

This product showed Rf 0.35 in silica gel thin layer chromatography (developed with n-butanol-acetic acid-water = 2: 1: 1).

Elemental Analysis of C ₁₆ H ₂₀ N ₇ O ₈ S ₂ Na.2H ₂ O (561.53)

Theoretic Value: C34.22, H4.31, N17.46%

Found: C33.91, H4.41, N16.96%

NMR. (80 Hz) (in small and medium water)

3.36 s (2H), 3.41 s (3H), 3.93 s (3H)

4.05 q (2H), 4.46 s (2H), 5.05 s (1H)

Example 2

Treatment of Example 1 Using 150 mg of 7β-amino-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxaderia-3-cefe-4-carboxylic acid benzyl ester Was repeated.

As a result, 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxadetia 50 mg of 3-cefem-4-carboxylate sodium salt were obtained.

Melting Point: 133-138 ℃ (Decomposition)

This product showed Rf 0.39 in silica gel thin layer chromatography (developed with n-butanol-acetic acid-water = 2: 1: 1: 1).

Example 3

The treatment process of Example 1 was carried out using 300 mg of 7β-amino-7α-methoxy-3-[(4-carbamoyl-pyridinium)]-1-oxadethia-3-cepem-4-carboxylic acid benzyl ester. Repeated.

7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -7α-methoxy-3-[(4-carbamoyl-pyridinium) methyl] -1-oxadetia-3- 65 mg of cefem-4-carboxylic acid was obtained.

Elemental Analysis for C ₂₀ H ₂₄ N ₅₀ SH ₂ O (528.53)

Theoretic Value: C45.45, H4.96, N13.25%

Found: C45.42, H5.05, N13.15%

Example 4

(A) 7β-amino-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylic acid benzhydryl ester (150 mg) was dissolved in dichloromethane (5 mL), and a mixed solution of dimethylaniline (0.042 mL) and bromoacetylbromide (70 mg) was added to this solution at -10 ° C, and stirred at -10 ° C for 1.5 hours.

The reaction solution was washed with a hydrochloric acid solution of PH 2, 5% sodium carbonate solution, followed by water and dried over anhydrous sodium sulfate. The mixture was concentrated to dryness under reduced pressure and 7β- (2-bromoacetoamido) -7-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxa as a wet powder. 94 mg of dethia-3-cepem-4-carboxylic acid benzhydryl ester was obtained.

The powdery product obtained as described above was dissolved in anisole (0.5 mL), and trifluoroacetic acid (1 mL) was added at -10 ° C, and the benzylhydryl group was removed with stirring at -10 ° C for 1 hour.

The reaction solution was concentrated under reduced pressure at 30 占 폚 or lower, and concentrated to dryness. The residue was treated with ethyl acetate (20 mL), washed with water and extracted with sodium bicarbonate solution (20 mL) at PH 8. The sap extract was treated with 5N hydrochloric acid solution, adjusted to PH 1.0, and extracted twice with 20 ml of ethyl acetate.

The combined ethyl acetate layers (extracts) were washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to obtain 7β- (2-bromoacetoamido) -7α-methoxy-3-[(1-methyl-1H- 98 mg of tetrazol-5-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylic acid was obtained.

(B) The suspension obtained by the above treatment (93 mg) with 5 ml of water was treated with 5% sodium bicarbonate to adjust to PH 7.0 to dissolve the cefe compound.

The mixture to which D-cysteine (45 mg) was added to this solution was stirred at 5-10 ° C. for 1 hour while maintaining the pH at 6.8 to 7.0 by addition of sodium bicarbonate solution.

The reaction solution was then adjusted to pH 5.0 by treatment with 5N hydrochloric acid solution. The concentrated solution which concentrated the reaction solution to about 2 ml was put into the column of 50 ml of absorbent resin and Amberlite WAD-2 (made by Rohm & Hass, USA), and this column was developed with water.

The aliquots of the eluate containing the required product were collected, concentrated under reduced pressure, and ice-dried to obtain 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -7α-methoxy-cepem-4- as colorless powder. 73 mg of sodium carboxylate was obtained.

m.p 129-135 ° C (decomposition)

Example 5

7β- (2-bromoacetoamido) -7α-methoxy-3 [(1-dimethylaminoethyl-1H-tetrazol-5-yl) thiomethyl] -1-oxadethia-3-cepem-4 The suspension in which carboxylic acid (100 mg) was suspended in water (4 mL) was adjusted to PH 6.8 by addition of 10% sodium bicarbonate solution to dissolve the cefe compound in water.

This solution was mixed with D-cysteine hydrochloric acid (50 mg) to maintain PH6.8-7.0 and stirred at 0-5 ° C. for 2 hours. Then 5N hydrochloric acid was added to the reaction solution to adjust to PH6 and concentrated to about 5ml.

The concentrate was made of a fine porous non-ionic absorbent resin, Diaion Hp-20.

Example 6

7β- (2-bromoacetoamido) -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) diomethyl] -1-oxadetia-3-cepem-4- A suspension in which carboxylic acid (50 mg) was suspended in water (5 mL) was adjusted to PH7.0 by addition of 5% sodium bicarbonate to dissolve the cefe compound in water.

The solution was mixed with D-cysteine ethyl ester hydrochloric acid (18 mg) and stirred at 5-10 ° C. for 3 hours while maintaining the pH at 6.8-7.0. The reaction solution was then adjusted to PH6 by addition of 5N hydrochloric acid, passed through a 30 mL column of Diaion HP-20 resin, washed with water and eluted with 30% ethanol solution.

The aliquots of the eluate containing the required product were collected, concentrated and evaporated under reduced pressure to give a colorless powder of 7β-[(2D-2-amino-2-ethoxycarbonyl) ethylthioacetoamido] -7α-methoxy-3- 41 mg of [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylic acid was obtained.

This product was prepared by silica gel thin layer chromatography (developed with acetone-methanol = 2: 1).

Example 7

7β- (2-bromoacetoamido) -7α-methoxy-3-[(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine- 3-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylic acid (60 mg) suspended in water (3 mL) was adjusted to PH7 by addition of 5% sodium bicarbonate solution. Cefem compound was dissolved in water. The solution was mixed with D-cysteine hydrochloric acid (28 mg) and stirred for 2 hours while maintaining the pH at 6.8-7.0.

This solution was treated in the same manner as in Example 5 to give a colorless powder of sodium 7β-[(2D-2-amino-2-carboxy) ethylthioacetoamido] -7α-methoxy-3-[(4-methyl- 52 mg of 5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylate Got it.

This product showed Rf 0.38 by silica gel thin layer chromatography (developed with n-butanol-acetic acid-water = 2: 1: 1).

Example 8

(A) 7β- (2-gabromoacetoamido) -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxadethia-3-cepem 4-carboxylic acid (100 mg) was dissolved in N, N-dimethylformamide (1 mL), and 0.03 mL of triethylamine was added to this solution at -25 ° C, and then 1-acetoxy ethyl in N, N-dimethylformamide. A solution (0.5 ml) in which 55 mg of the iodine compound was dissolved was added dropwise over 10 minutes.

Then it stirred at -5 ° C to 0 ° C for 1 hour. This reaction solution was diluted with water (5 ml).

The extract of ethyl acetate was washed twice with 5 ml of water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure.

The residue was washed with petroleum ether to give 1-acetoxyethyl 7β- (2-bromoacetoamido) -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] 120 mg of oxadetia-3-cefe-carboxylate was obtained.

(B) The above product was mixed with 5 ml of water in a solution of 2 ml of acetone, and then mixed with 20 mg of D-cysteine methyl ester hydrochloric acid. The reaction mixture was added to PH6.5 by addition of 5% sodium bicarbonate solution. It stirred at 0-5 degreeC for 3 hours, maintaining.

The reaction solution was adjusted to PH8.0 by addition of sodium bicarbonate solution, and then extracted with 20 ml of ethyl acetate. The extract of ethyl acetate was concentrated to 2 ml, and the concentrate was passed through a 40 ml column of Sephadex LH-20 saturated with ethyl acetate.

The column was developed with ethyl acetate, and the aliquots of the eluate containing the required product were collected, concentrated to dryness under reduced pressure, and colorless powder 1-acetoxyethyl 7β-[(2D-2-amino-2-methoxycarbonyl) ethylthio 95 mg of acetoamido] -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -1-oxadethia-3-cepem-4-carboxylate was obtained.

This product showed Rf 0.73 by silica gel thin layer chromatography (developed with ethyl acetate-acetone = 5: 1).

Claims (1)

A 1-oxacefem compound of the following general formula (II) is condensed with a sulfur amino acid containing the following general formula (III) in a solvent to produce a condensation product of the following general formula (I '). Method for producing 1-oxadetiacephalosporin derivative of

Wherein R is 1-methyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio, 2-carboxymethylhydroxy-1H-tetrazol-5-ylthio , 4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine-3-ylthio, pyridinium, 4-carbamoyl-pyridinium, 1-dimethyl Aminoethyl-1H-tetrazol-ylthio, 8-substituted or unsubstituted-tetrazol- (1,5-b) -pyridazin-6-ylthio, 1-sulfonylmethyl (or-em) -1H- Tetrazol-5-ylthio, 1-methyl-2-carboxy-1H-triazole-5-ylthio group, Y is a hydrogen atom or a methoxy group, R ^' is a hydrogen atom or a carboxy protecting group, Z is a halo group , y is an integer 1, 2 or 3, X is an integer 1, 2 or 3.