KR820001127B1 - Process for preparing cephalosporin derivatives - Google Patents

Abstract

Title compds. (I; n = 0-1; X = H, C1-4 alkyl, carboxymethyl, C1-4 alkoxycarbonylmethyl, cyanomethyl; Y = Me, halogen; A = H, ester, cation) were prepd. from IV (R1 = H, amino protecting group; X1 = X or -CH2CO2R3; R3 = separating group) obtained by reaction of II and III. Thus, 980 mg 7-≮αsyn-methoxyimino-α-(2-amino-5-chloro-thiazol-4-yl)-acetamido≉-cephalosporanic acid was dissolved in a mixed soln. contg. 8 ml 98% formic acid and 2 ml methanol, added 410 mg THF soln. contg. 85% m-chloroperbenzoic acid, and stirred for 1 hr to give 850 mg I.

Description

Method for preparing cephalosporin derivative

The present invention relates to a method for preparing a cephalosporin derivative of the following structural formula (I) which is an antibiotic.

In the above structural formula,

n means 0 or 1,

x is hydrogen, optionally substituted alkyl of 1 to 4 carbon atoms, optionally substituted carboxymethyl, optionally substituted alkoxycarbonyl-methyl alkyl group of 1 to 4 carbon atoms, optionally substituted aminocarbonyl methyl, optionally substituted cyano Methyl,

Y stands for methyl, halogen,

A means hydrogen or an easily separable ester group or a physiologically toxic cation.

If X means alkyl having 1 to 4 carbon atoms, examples include methyl, ethyl, propyl and butyl, preferably methyl. However, these may be substituted with halogen (especially bromine, chlorine), hydroxy, amino groups, and may be monosubstituted or disubstituted with alkyl groups having 1 to 4 carbon atoms.

When the alkyl site means an alcohol carbonyl group having 1 to 4 carbon atoms, examples thereof include methoxycarbonylmethyl and ethoxycarbonyl methyl.

X, which means carboxymethyl, may be represented in the form of a pharmaceutically toxic salt thereof. Alkoxy carbonylmethyl, aminocarbonylmethyl and cyano methyl are particularly preferably alkyl having 1 to 4 carbon atoms in the methylene group. May be monosubstituted or disubstituted with methyl, and two alkyl substituents may be adjacent to form a carbocyclic ring of 3 to 6 elements.

Specifically, X is hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, aminocarbonylmethyl and cyanomethyl There is this.

As an example of Y, methyl, bromine, chlorine, fluorine, etc. are preferable, and chlorine and fluorine are especially preferable.

Esters in the definition of A include tert-butyl ester and trimethylsilyl esterbenzyl, benzhydryl, trichloroethyl, benzoylmethyl, methoxymethyl, P-methoxy benzyl ester and the like, which can be easily cleaved .

Examples of physiologically toxic cations A include alkali metal ions (particularly sodium and potassium ions) alkaline earth metal ions (particularly potassium and magnesium ions), ammonium and triethyl ammonium, diemeammonium, dimethylammonium, morpholinium And substituted alkylated ammonium ions such as benzyl ammonium, procainium, L-arginium, L-lysineium, and especially sodium ions, which are correspondingly physiologically toxic when X is in the form of a salt of the carboxymethyl group. One cation is also possible.

In the compounds of formulas (I), (II), (IV) and (V), the hydroxylimino groups may exist in syn and anti forms, with the syn form being particularly preferred. The definition of syn and anti indicates the spatial position linked to the carboximide group in the compounds of formulas (I) and (III), whereas the spatial position linked to the carboxyl group in the compounds of formula (III) In the compound of formula (V), it represents the spatial position connected to the alkoxycarbonyl group, where the syn position is the same as for the carboxamide, carboxyl, and alkoxycarbonyl group. It means being on the same side.

2-aminothiazoles of formulas (I), (III), (IV) and (V) have two tautomers, which may exist together in equilibrium.

In the present specification, for the sake of convenience, the structural formulas of tautomers are not given in all cases, and the amino-thiazole tautomers are represented by the following structural formulas.

The present invention reacts the lactams of the following structural formula (II) with the carboxylic acids of the following structural formula (III) or active derivatives thereof to obtain a compound of the following structural formula (IV),

a) oxidizing sulfur in the cefme ring of the product obtained to obtain R- or S-sulfoxide, and / or

b) cleaving the protecting group R ', and / or

c) when x 'does not mean x, includes a process for preparing the cefe compound of formula (I) which comprises converting to x.

In the formulas (III) and (IV), R 'is a hydrogen- or amino-protecting group well known in peptide chemistry such as tert-butyl, tert amyl, benzyl p-methoxybenzyl, benzhydryl, Optionally substituted alkyl groups such as trityl, phenylethyl and optionally substituted aliphatic acyl groups such as formyl, chloroacetyl, bromoacetyl, trichloro acetyl, trifluoroacetyl and trichloroethoxycarbonyl, benzyloxy carbonyl And optionally substituted alkoxycarbonyls. x 'means x or can be easily cleaved, for example formyl, trifluoroacetyl, chloro acetyl, bromoacetyl, trityl, tert-amyl, tert-butyl, benzhi Drill, tetrahydro pyranyl and the like, and groups such as tert-butyl, trityl and tetrahydro pyranyl are particularly preferred. Also preferred is a group of the formula-CH ₂ CO ₂ R ³ , wherein R ³ is a group that can be cleaved under mild conditions, for example trichloroethyl, tert-butyl, benzyl, p-methoxyphenyl, Benzhydryl, trityl and the like.

Suitable active derivatives of the carboxylic acid of formula (III) are preferred halides, in particular chlorides and bromide, anhydrides, mixed anhydrides, arides, p-nitrophenols, 2,4-dinitrophenols, methylene-cyanohydrin Active esters with N-hydroxysuccinimide and N-hydroxyphthalimide, in particular 1-hydroxy benzotriazole and 6-chloro-1-H-hydroxybenzotriazole . As mixed anhydrides, mixed anhydrides with lower alkanoic acids such as acetic acid, in particular mixed anhydrides with substituted acetic acids such as trichloroacetic acid, pivalic acid and cyanoacetic acid are suitable. However, mixed anhydrides with carboxylic acid half esters obtained by reacting the carboxylic acid of formula (III) (R ¹ is not hydrogen) with benzyl, p-nitrobenzyl, iso-butyl, ethyl, allyl chloroformate Particularly suitable, the activated derivatives can react in isolation or on their own.

In general, the cefem derivatives of formula (II) are reacted with the carboxylic acid of formula (III) or an active derivative thereof in an inert solvent. Suitable solvents include chlorinated hydrocarbons such as methylene chloride and chloroform; Ethers such as diethyl ether, tetrahydrofuran and dioxane; Amides such as ketones such as acetone and butanol, dimethyl formamide and dimethyl acetamide; Water is present and mixtures of these solvents may be used.

When the cefem compound of formula (II) is reacted with an active derivative of the carboxylic acid of formula (III), it is reacted by itself.

The reaction of the cefem compound of formula (II) with the carboxylic acid or its active derivatives of formula (III) is carried out at a temperature of -50 ° to 80 ° C, preferably at a temperature of -20 ° to 50 ° C, in particular -20 ° C to room temperature. It is good to carry out at a temperature of.

The reaction time depends on the reactants, the reaction temperature, the kind of the solvent or the solvent mixture, and usually 1/4 to 72 hours is preferable.

In each case, the free carboxylic acid of formula (III) is an ester (e.g. tert-butyl, trimethyl silyl) group in which A can be easily cleaved, and the cefme compound of formula (II) wherein n is 0 or 1 It is convenient to make a molar amount of water copolymer react in the addition. Examples of water binders are carbodiimides, in particular dicyclohexylcarbodiimide. This reaction is carried out in an inert solvent such as methylene chloride, dimethyl formamide, tetrahydrofuran, dioxane or mixtures thereof.

The reaction of the active derivative of the carboxylic acid of formula (III) with the cefem compound of formula (II) is preferably carried out in an alkaline medium having a pH of 7 or above. For this purpose, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, hydroxide Bases such as potassium, sodium hydroxide, pyridine, trialkylamines (e.g. triethylamine), methylphoroline, ethyldiisopropylamine, potassium tert-butylate and the like are added to the reaction mixture.

In the compound of formula (IV), when R 'does not mean hydrogen, the R' group is cleaved, and (or) when x 'does not mean x, it is converted to x to prepare the cefe compound of formula (I). It may be.

The R 'group is subjected to the relaxation method commonly used in β-lactam chemistry and peptide chemistry, for example, by hydrolysis in acids such as formic acid and trifluoroacetic acid, and by hydrocracking in the presence of a noble metal catalyst. The groups can be separated. However, depending on the type of protecting group, the reagent used for cleavage can be selected. For example, optionally substituted thioureas are used to remove the α-halogenoacyl group.

If x 'does not mean x, convert it to x using hydrolysis or hydrocracking, a method commonly used in β-lactam chemistry and peptide chemistry, and in inorganic or organic acids such as trifluoroacetic acid or Hydrolysis is good.

The esters of formulas (I) and (IV) obtained according to the reaction according to the invention (when A denotes a group which can be easily cleaved) are hydrolyzed or hydrocracked as described in the known literature to allow A to be hydrogen or Can be converted to a compound of formula (I) which is a physiologically toxic cation.

In the case of abortion, when x 'means -CH ₂ CO ₂ R ³ , R ³ can be separated from the x' group.

The lactam of the formula (II) having n = 0 may be oxidized to form free acids or esters and salts.

First, the 7-amino group can be protected by an easily separable amino-protecting group, which is well known in peptide chemistry. Examples of protecting groups that can be easily separated under acidic conditions include tert-butyl, benzhydryl, 3 Tert-butoxycarbonyl, trityl, benzyloxy carbonyl, 3,5-dimethoxybenzyloxy carbonyl, trimethylsilyl.

Or in the form of a Schiff base which can be separated under acidic conditions by reacting with an active carbonyl compound such as benzaldehyde, salicylicaldehyde, p-nitro benzaldehyde, fulfurol, 5-nitropulfurol, acetyl acetone, ethyl aceto acetate, and the like. It is also possible to protect the amino groups, which can be easily removed by reacting the Schiff's base with hydrazine or phenyl hydrazine, in particular with a ginazine reagent or 2,4-dinitrophenyl hydrazine.

The method for oxidizing the cefe compound of formula (II) having n = 0 forms a sulfoxide by oxidizing sulfides by a known method. (Reference: Methodicum Chimicum, volume 7 (1976), pag (693-698)

Suitable oxidizing agents are peroxides, hydrogen peroxides, peracids, hydogen superoxides, and mixtures thereof with organic or inorganic sulfuric acids (e.g., phosphoric acid, formic acid, acetic acid, trifluoroacetic acid). If mixed, it is obtained by itself. 3-chlorobenzoic acid is most suitable.

In the oxidation reaction, suitable solvents should be stable under the reaction conditions, for example dioxane, tetrahydrofuran, chloroform, methylene chloride, acetic acid, formic acid, trifluoro acetic acid, benzene, tetramethylurea, dimethylformamide, Dimethyl acetamide. The amount of oxidant is appropriately at least an equivalent amount of dioxide (a value corresponding to one active oxygen atom), but a slight excess may be used.

The reaction temperature is in the range of -20 ° to 80 ° C, preferably in the range of -20 ° C to room temperature.

Oxidation of the cefem compound of formula II in which n is 1 to the sulfur position results in sulfoxide, which may be present in the R or S configuration. (See Angew Chemie 78 (1966), page 413).

The cefem compound of formula (II) with n = 0 generally takes on the R configuration if the amino group is protected in the form of a Schiff's base.

Acylamino-protecting groups on 7-amino groups provide 1-sulfoxides with predominantly S configuration, and these two isomers can be distinguished and separated by chromatography. NMR spectroscopy can also be used to distinguish between R-sulfoxide and S-sulfoxide. (See E.H. Flynn, cephalosporzns and Peniillins, chemistry and Biologs Academic Press, 1972)

Compounds of formulas (I) and (II) with n = 1 are subjected to the reaction steps mentioned above, i.e., oxidizing the cefem compound of formula (II) to obtain sulfoxide, followed by formula (III) or an active derivative thereof. It can manufacture also by changing the order of the operation to acylate.

Thus, a cefme compound of formula (II) wherein n = 0 and A is as mentioned above is preferred to be a carboxylic acid of formula (III) wherein R ', X' and Y are mentioned above, or an active derivative thereof Reaction with to obtain a compound of formula IV, wherein R 'X', Y 'and A are as described above and n = 0, and subsequently oxidizing the lactam of formula II Oxidation under the same conditions yields sulfoxide. At this time, acylating the carboxylic acid of Structural Formula (III) eliminates the need to protect the 7-amino group since the 7-amino group is not damaged by an attack by the oxidizing agent.

Oxidation of the compounds of structural formulas (I) and (VI) yields sulfoxides with predominantly S-arrays with small amounts of sulfoxides with R-arrays, which can be separated by the methods described above.

The carboxylic acid of formula (III) used in the acylation reaction can be prepared by various methods. For example, the compound of formula (V) is reacted with a halogenating agent and the R ¹ and / or X 'groups are After conversion to the most suitable form for and / or the ester of formula (V) obtained can be converted to the carboxylic acid of formula (III) to produce a compound of formula III wherein Y stands for halogen.

In the above structural formula

R ¹ X ′ is as mentioned above,

R ² means an alkyl group having 1 to 4 carbon atoms or an aralkyl group such as benzyl or phenylethyl.

Suitable halogenating agents include halogens such as bromine and chlorine, trihalogeno-isocyanuric acids such as trichloroisocyanuric acid, chloramine-T, N-chloroacetamide, and N- such as N-bromoacetamide. N-halogenoimides, such as halogenoamides, N-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide, and N-bromo phthalimide, tert-butyl-char Alkyl chlorates such as chlorate. This reaction is generally carried out in a solvent that can proceed in the forward direction without affecting the reaction. Polar solvents having hydroxyl groups such as formic acid, glacial acetic acid and alkanols such as methanol, ethanol and isopropanol form positive halogen ions. It is preferable in the case of alkyl hypochlorite, N-halogenamide, and N-halogenimide because it promotes the Furthermore, above all, when a halogen element is used, chloroform, methylene chloride, tetrahydrofuran, dioxane, dimethylformamide or mixtures thereof, or a mixture with a solvent having the above-mentioned hydroxyl group is preferable.

The reaction temperature is not critical, but a range of -20 ° C to room temperature is suitable.

The compound of formula (III), wherein Y is halogen, reacts the oxime of the following formula with thiourea, subsequently introduces the R 'group into the amino-protecting group, and / or The ester of V) may be saponified to prepare the carboxylic acid of formula III.

In the above structural formula

Z ¹ and Z ² are the same or different groups and mean bromine, chlorine, fluorine,

X ¹ and R ² are as mentioned above.

The reaction proceeds with a chemical equivalent of thiourea in a water-binding solvent such as ethanol and acetone and lasts for up to 2-3 hours at room temperature.

The compound of formula (III) wherein Y is methyl is reacted with thiourea by the following compound of formula (IV), followed by the introduction of the R 'group in the amino protecting group and / or saponification of the ester obtained Carboxylic acid).

In the above structural formula

Hal means bromine or chlorine

X 'and R ² are as mentioned above.

The reaction is carried out with a chemical equivalent of thiourea in a water-bonding solvent such as acetone or ethanol for up to 3 hours at room temperature. The compounds of formula (V) as starting materials can be prepared according to known methods as known materials.

If the groups are well known as aminoprotecting groups in the field of dipeptide chemistry in formulas (III) and (IV), they can be introduced into amino groups according to methods well known in the field of peptide chemistry. For example, when R ^{1 means a} trityl group, triphenylchloromethane can be introduced in the presence of a base such as triethylamine in an organic solvent such as halogen hydrocarbon.

If in the formulas (III) and (V), X 'denotes a group that can be easily separated, it can be introduced in a conventional manner for the purpose of protecting hydroxyl groups.

를 지니는 출발물질인 구조식(Ⅲ) 및 (Ⅴ)의 제법에서 뿐만 아니라, 모든 중간물질의 제법 및 구조식(Ⅳ) 및 (Ⅴ)의 화합물을 제조하는 반응에 있어서 신(syn) 화합물과의 반응에서 가능한한 완화한 조건, 즉 저온 짧은 반응시간, 산반응물의 과량 사용하지 않는 등의 반응조건을 채택하여 전환 가능한 옥심그룹이 안티(anti)형태로 전환되는 것을 막는 것이 좋다.In the syn position

Not only in the preparation of the structural formulas (III) and (V) as starting materials, but also in the preparation of all intermediates and in the reaction of the compounds of the structural formulas (IV) and (V) with the syn compounds. It is advisable to avoid the conversion of the convertible oxime group to the anti form by adopting the conditions as mild as possible, i.e., short reaction time at low temperature, and not using excessive amounts of acid reactants.

The compound of formula (I) according to the invention has surprising antibacterial efficacy against gram positive and gram negative bacteria.

In addition, since they are effective against bacteria producing penicillin degrading enzyme and cephalosporin degrading enzyme, they have toxicological and pharmacological properties and are effective as chemotherapeutic agents.

The invention also relates to a medicament for use in treating a patient infected with a microorganism.

The product according to the present invention may be used in combination with penicillin, cephalosporin, aminoglycoside crab antibiotics, and may be administered orally, intramuscularly or subcutaneously.

Agents containing one or more compounds of formula (I) as active compounds may contain one or more physiologically toxic diluents or excipients, for example fillers, emulsifiers, suspending agents, flavoring agents, It can be prepared by mixing with the materials necessary to prepare colorants, buffers and suitable formulations (eg tablets, dragees, capsules, solutions, suspensions). Examples of the above-mentioned excipients and diluents include tragacanta, lactose, talc, agar, polyglycols, ethanol and water, and aqueous suspensions and aqueous solutions are suitable for parenteral administration. The active compound can also be administered in the form of a capsule without the addition of excipients or diluents.

A suitable daily dose of the compound of formula (I) is 0.5-20 g / day, preferably 0.5-4 g / day, to an adult 60 kg body weight. It contains 50 to 1000 mg of the active ingredient, preferably 100 to 500 mg.

In addition to the compounds mentioned in the examples, the following compounds can also be prepared according to the present invention.

7- [α-cin-methoxymino-α- (2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporanic acid) 1-s-oxide,

7- [α-cin-methoxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporanic acid)

7- [α-cin-ethoxymino-α- (2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporranic acid and 1-s-oxide thereof,

7- [α-cin-ethoxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporonic acid and 1-s-oxide thereof,

7- [α-cin-n-propoxymino-α- (2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7- [αcin-n-propoxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporanic acid and 1-s-oxide thereof,

7- [α-cin-propoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporranic acid and 1-s-oxide thereof,

7- [α-cin-isopropoxymino-α- (2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7-[[alpha] -Cin-iso-propoxymino- [alpha]-(2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporonic acid and its 1-s-oxide ,

7- [α-cin-iso-propoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7- [α-cin-n-butoxymino-α- (2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7- [α-cin-n-butoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7- [α-cin-carboxymethoxymino-α- (2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7- [α-cin-carboxymethoxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporonic acid and 1-s-oxide thereof,

7-[[alpha] -Cin-ethoxy-carbonyl-methoxymino- [alpha]-(2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporonic acid and its 1- s-oxide,

7-[[alpha] -Cin-ethoxycarbonyl-methoxymino- [alpha]-(2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporonic acid and its 1- s-oxide,

7-[[alpha] -Cin-ethoxycarbonyl-methoxymino- [alpha]-(2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporonic acid and 1-s thereof Oxide,

7- [α-cin-carboxymethoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7- [α-cin-cyanomethoxymino-α- (2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7- [α-cin-cyanomethoxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7- [α-cin-cyanomethoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7-[[alpha] -Cin-aminocarbonylmethoxymino- [alpha]-(2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide,

7-[[alpha] -Cin-aminocarbonyl-methoxymino- [alpha]-(2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporonic acid and 1-s thereof Oxide,

7- [α-cin-aminocarbonylmethoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporonic acid and 1-s-oxide thereof,

7- [α-cin-hydroxymino-α- (2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporranic acid and 1-s-oxide thereof,

7- [α-cin-hydroxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporanic acid and 1-s-oxide thereof,

7- [α-cin-hydroxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporranic acid and 1-s-oxide thereof,

7- [α-cin-hydroxymino-α- (2-amino-5-fluoro-thiazol-4-yl) -acetamido] -cephalosporranic acid and its 1-s-oxide,

7- [α-cin-methoxymino-α- (2-amino-5-fluoro-thiazol-4-yl) -acetamido] -cephalosporanic acid and 1-s-oxide thereof,

7- [α-Cin-n-ethoxymino-α- (2-amino-5-fluoro-thiazol-4-yl) -acetamido] -cephalosporanic acid and 1-s-oxide thereof ,

7-[[alpha] -Cin-n-propoxymino- [alpha]-(2-amino-5-fluoro-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide ,

7- [α-cin-nviso-propoxymino-α- (2-amino-5-fluoro-thiazol-4-yl) -acetamido] -cephalosporonic acid and 1-s- thereof Oxide,

7-[[alpha] -Cin-n-butoxymino- [alpha]-(2-amino-5-fluoro-thiazol-4-yl) -acetamido] -cephalosporanic acid and its 1-s-oxide ,

7- [α-cin-carboxymethoxymino-α- (2-amino-5-fluoro-thiazol-4-yl) -acetamido] -cephalosporanic acid and 1-s-oxide thereof,

7-[[alpha] -Cin-ethoxy-carbonylmethoxymino- [alpha]-(2-amino-5-fluoro-thiazol-4-yl) -acetamido] -cephalosporonic acid and 1-s thereof Oxides and

7- [α-cin-cyanomethoxymino-α- (2-amino-5-fluoro-thiazol-4-yl) acetamido] -cephalosporanic acid and its 1-5-oxide and

7-[[alpha] -Cin-aminocarbonylmethoxymino- [alpha]-(2-amino-5-fluoro-thiazol-4-yl) -acetamido] -cephalosporonic acid and its 1-s-oxide ,

The following examples illustrate the invention.

Rf values reported in the examples are measured by thin layer chromatography coated with silica gel on a 60F254 plate (MessrsMerk Darmstadt).

Example 1

7- [α-cin-methoxymino-α- (2-amino-5-methyl-thiazol-4-yl) -acetamido] -cephalosporanic acid)

First stage

A 45 ml aqueous solution containing 22.8 g (0.3 mole) sodium nitrite was added to a glacial acetic acid solution containing 43 g (0.3 mole) ethylpropionyl acetate with stirring and cooling at 20 to 25 ° C. and the mixture at 10 ° C. After stirring for 1 hour, 90 ml of water are added, further stirred at room temperature for 1 hour and extracted four times with 75 ml of ether each time. The ether extracts are combined and shaken with NaHCO ₃ solution until the solution is neutralized, dried over magnesium sulfate and evaporated to dryness.

이 오일은 더 정제할 필요없이 사용할 수 있다.55 g of ethyl α-hydroxymid-propionyl acetate are obtained as yellow oil, which is triturated at low temperature. Oil

This oil can be used without the need for further purification.

2nd step

The oil obtained in step 1 is dissolved in 250 ml of acetone, 60 g of K ₂ CO ₃ are added followed by 38.5 g (0.3 ml) of dimethyl sulfate over 30 minutes. The mixture is stirred at room temperature for 2 hours, poured into 200 g of ice and stirred with 500 ml of water and extracted three times with CH ₂ Cl ₂ once with 150 ml of ether. Drying over Na ₂ SO ₄ , organic extracts combined and solvent removal yielded 45 g of ethyl α-methoxymino-propionyl acetate as an oil.

The product can be used without further purification.

3rd step

45 g of the oil obtained in step ₂ are dissolved in 300 ml of CH ₂ Cl ₂ , the solution is cooled to 20 ° C. and then 50 ml of CH ₂ Cl ₂ solution containing 39 g (0.24 mole) bromine is added dropwise. The mixture is further stirred at room temperature for 1.5 hours, extracted with 300 ml of water each time, dried over sodium sulphate and the solvent is removed in vacuo. 60 g of ethyl α-methoxymino-6-bromo-propionyl-acetate is obtained as a light brown oil.

Rf = 0.38 (CHCl ₃ ).

This product can be used without further purification.

4th step

13.3 g of oil obtained in the third step is dissolved in 13 ml of ethanol, and this solution is added at 16-18 ° C. in a mixed solution of 13 ml of ethanol and 27 ml of water containing 3.8 g (0.5 mole) of thiourea. . Further 13 ml of ethanol are added and adjusted to pH5 by addition of saturated KHCO ₃ solution, stirred at room temperature for 1 hour. Filtration yields 4.6 g (56%) of ethyl α-cin-methoxymino-α- (2-amino-5-methyl-taazol-4-yl) -acetate. Melting Point: 135-136 ° C

5th step

12.2 g (0.05 mole) of ester obtained in step 4 are dissolved in 23.7 ml of dimethylformamide, 47.5 ml of CH ₂ Cl ₂ is added and the mixture is cooled to -10 < 0 > C. After 7.35 ml of triethylamine is added, the mixture is cooled to -35 [deg.] C. and 16.5 g of tritylchloride is added little by little with stirring. The solution is stirred for 2.5 hours, diluted with 100 ml of CH ₂ Cl ₂ and washed twice with 50 ml of 1N HCl and three times with 100 ml of H ₂ O. The organic layer is dried over sodium sulfate and the solvent is removed in vacuo. The oil obtained can be used without further purification.

6th step

The oil obtained in step 5 is dissolved in 240 ml of ethanol and 10 ml of 10N NaOH is added, then the mixture is stirred at room temperature for 5 hours and the product is filtered off. 10.3 g of the sodium salt of α-cin-methoxymino-α- (2-tritylamino-5-methyl-thiazol-4-yl) -acetic acid are obtained, which can be used without further purification.

7th Step

23 ml of 2N HCl is added while cooling with ice in 80 ml of CH ₂ Cl ₂ and 10 ml of ether solution containing 9.6 g (20 mmol) sodium salt obtained in step 6. CH ₂ Cl _{2 is} separated off and the aqueous layer is extracted again with 10 ml of CH ₂ Cl ₂ . Drying over sodium sulfate and then removing the solvent in vacuo leaves a foamy material. α-Cyn-methoxymino-α- (2-tritylamino-5-methyl-thiazol-4-yl) -acetic acid is obtained, which can be used without further purification.

8th step

The product obtained in step 7 is dissolved in 30 ml CH ₂ Cl ₂ , the solution is cooled with nitrogen atmosphere in an ice bath and then 2.35 g of dicyclohexylcarbodiimide is added. The mixture was stirred at 0 ° C. for 0.5 hour and at room temperature for 1 hour, after which the resulting dicyclochlorohexylurea was filtered off, and the filtrate was cooled to −20 ° C., and 2.72 g of 7-aminocephalosporanic acid and 40 ml of CH ₂ Cl ₂ solution containing 3.3 ml of triethylamine are added. The mixture is stirred for 2.5 hours at room temperature and adjusted to pH 2.75 with 1N HCl.

The CH ₂ Cl ₂ layer is washed twice with 70 ml of H ₂ O, dried over magnesium sulfate and evaporated to dryness in vacuo.

The residue is added in 50 ml of dioxane and 50 ml of ether mixture, then 2.1 ml (20 mmol) of dimethylamine is added and ether is added until turbidity appears. After 48 hours of blocking at -5 [deg.] C. and filtration, 2.6 g of di-ethylammonium Obtained.

α-cin-methoxymino-α- (2-tritylamino-5-methyl-thiazol-4-yl) -acetic acid and 7- [α-cin-methoxymino-α- (2-tritylamino -5-Methyl-thiazol-4-yl) -acetamido] -diethyl ammonium salt of cephalosporonic acid is obtained.

9th Step

7.0 g of the dimethyl ammonium salt mixture obtained in step 8 are dissolved in 30 ml of 98% formic acid and 20 ml of H ₂ O mixture and the solution is stirred at room temperature for 2.5 hours. The formed triphenylcarbinol is removed by filtration, the filtrate is diluted with H ₂ O to 250 ml, and once again filtered to concentrate the filtrate on a rotary evaporator to 30 ml.

To the layer containing the product was adjusted to pH 8.0 by adding saturated NaHCO ₃ solution, extracted with ethyl acetate, 50 ml of ethyl acetate was added, and then adjusted to pH 2.0 using 2N HCl. The aqueous layer is extracted five times with ethyl acetate, the extracts are combined, dried over magnesium sulfate and concentrated on a rotary evaporator.

20 ml of ether was added to the formed oil and stirred for 1 hour to form a solid, which was filtered to 1.5 g of 7- [α-cin-methoxymino-α- (2-amithiazol-4-yl) -acetic acid. Amido] -cephalosporranic acid is obtained.

Rf value: 0.53 (ethyl acetate: isopropanol: water = 6: 4: 3) melting point: 125 to 135 ° C (decomposition)

Example 2

7- [α-Cin-methoxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporic acid

First stage

20 ml of glacial acetic acid solution containing 6.39 g of bromine was dissolved in 50 ml of glacial acetic acid in which 9.15 g (40 mmol) of ethyl α-cin-methoxymino-α- (2-amino-thiazol-4-yl) -acetate was dissolved. Add dropwise at 15 ° C., stir for 15 minutes and add to 150 g ice. The precipitate was filtered off and washed with water to yield 10.9 g of ethyl α-cin-methoxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acetate. Melting Point: 149-151 ℃

When recrystallized from ethanol, melting | fusing point is 157-158 degreeC.

2nd step

3 g of ester obtained in step 1 are dissolved in 8 ml of methanol and 20 ml of 80% hydrazine hydrate is added at 50 ° C. The mixture is stirred at room temperature for 4 hours, cooled to 0 ° C. and the resulting precipitate is filtered off.

2.5 g of α-cin-methoxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acethydrazide are obtained. Melting point: 200 ° C. (decomposition point).

These crystals decompose very quickly and should be used soon.

3rd step

2.5 ml of 1.5 g of hydrazide obtained in step 2 was dissolved in dimethylformamide, the solution was cooled to -20 ° C, and then 3.3 ml of 4.51N hydrochloric acid-dioxane solution was added, and 0.6 ml of tertiary was added. Slowly add 4 ml of dioxane solution containing butyl nitrite.

This pale yellow solution is stirred at -20 ° C for 0.5 hour and 10 ml of dioxane solution containing 1.5 g of triethylamine is added. A solution of 10 ml of dimethylformamide containing 1.36 g of 7-aminocephalosporranic acid and 1.0 g of triethylamine were added dropwise, and 6 ml of dioxane solution containing 0.5 g of triethylamine was divided into three portions. Add. The layer containing the product is added to 100 ml of water, extracted three times with ethyl acetate and the pH adjusted to 4.0. The insoluble material is filtered off and the filtrate is adjusted to pH 1.5 by adding 2N HCl.

The mixture is extracted with ethyl acetate 5: and dried over magnesium sulfate, and the ethyl acetate extract is collected and concentrated. Once oil is obtained, it is treated with ether to solidify. 650 mg of 7- [α-cin-methoxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acetamido] -cephalosporanic acid is obtained. Melting Point: 135-145 ° C (Decomposition Point)

Example 3

7- [α-Cin-n-butoxymino-α- (2-amino-5-bromo-thiazol-4-yl) -acetamido-cephalosporanic acid

First stage

In a similar manner to step 1 of Example 2, using 11 g of ityl α-cin-n-butoxymino-α- (2-amino-thiazol-4-yl) -acetic acid and 6.4 g bromine, Ethyl α-cin-n-butoxymino-α- (2-amino-5-bromo-4-thiazol-4-yl) -acetate is prepared. Melting Point-130 ° C to 140 ° C (in Ethanol)

2nd step

In a similar manner to step 2 of Example 2, 2.8 g of α-cin-n-butoxymino-α- (2-amino-5-bromo-thiazole-4 from 3.2 g of the ester obtained in step 1 above -Yl) -acetohydrazide is prepared. Melting point = -190 ° C (decomposition point)

The product is unstable and should be used soon for the next operation.

3rd step

In a similar manner to step 3 of Example 2, 520 mg of 7- [α-cin-n-methoxymino-α- (2-amino-5-bromo-thia) from 1.68 g of hydrazide obtained in step 2 was obtained. Zol-4-yl) -acetamido] -cephalosporanic acid is prepared. Melting Point: 140 to 150 ° C (Decomposition Point)

Example 4

7- [α-cin-methoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] cephalosporanic acid

First stage

50 g of α-cin-methoxymino-α- (2-amino-thiazol-4-yl) -acetic acid is dispersed in a mixture of 300 ml of CHCl ₃ and 150 ml of glacial acetic acid and 200 ml containing 17.5 g of Cl ₂ Glacial acetic acid solution is added with stirring at 0 ° to 10 ° C. The mixture is stirred at 0 ° C. for 0.5 h and the resulting precipitate is filtered off. The precipitate is dispersed once more in CHCl ₃ and then filtered. The filtered residue is refluxed in 190 ml of tetrahydrofuran for 15 minutes and then the mixture is stirred at room temperature for 2 hours. 30.3 g of α-cin-methoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetic acid, 1HCl, 1H ₂ O tetrahydrofuran are obtained. Melting Point: 150 ° to 153 ° C

2nd step

29 g of the acid obtained in step 1 are dissolved in 100 ml of methanol and 4.85 g of sodium methylate is added. After stirring for 15 minutes at room temperature, the mixture was evaporated to dryness in vacuo, the residue was evaporated 75 ml of anhydrous tetrahydrofuran mother liquor each time, and the residue was recrystallized from a small amount of methanol to yield 13.5 g of α-cin-methoxymino-α. -(2-Amino-5-chloro-thiazol-4-yl) -acetic acid x 1 methanol is obtained. Melting Point 129 to 130 ° C (Decomposition Point)

3rd step

8.0 g of the carboxylic acid obtained in step 2 is dissolved in 100 ml of dimethylacetamide, 100 ml of carbon tetrachloride is added and then evaporated on a rotary evaporator to remove the carbon tetrachloride in step 2 to remove carbon tetrachloride. The residue is cooled to −20 ° C. and 10 ml of dimethyl acetamide solution containing 3.4 g of chloroacetyl chloride are added. It is left for 1/4 hour at -20 ° C, 1/2 hour at 0 ° C, and 1/4 hour at 10 ° C.

The mixture was added to ice, extracted three times with ethyl acetate, dried over sodium sulfate, evaporated to remove the solvent, and 8.2 g of α-cin-methoxymino-α- (2-chloroacetylamino-5-chloro- Thiazol-4-yl) -acetic acid is obtained as a pale yellow oil.

Rf value: 0.54 (ethyl acetate: iso-propanol: water = 6: 4: 3).

4th step

3.1 g of the carboxylic acid obtained in step 3 is dissolved in 15 ml of CH ₂ Cl ₂ , and then 1.45 μl of triethylamine is added. The mixture is cooled to 0 ° C. and 5 ml of methylene chloride solution containing 0.5 ml of thionyl chloride is added dropwise.

The mixture was stirred at 0 ° C. for 1/4 hour, 1.3 ml of triethylamine was added, followed by 20 ml of methylene chloride solution containing 2.5 g of 7-amino cephalosporranic acid and 2.8 ml of triethylamine. do.

The mixture is stirred for 1 hour, then the solvent is removed in vacuo and the residue is added to 40 ml of water. After adjusting the pH to 7.0, the solution is extracted twice with 20 ml of ethyl acetate and the pH is adjusted to 4.0, and then the pH is adjusted to 2.0 by removing the 7-aminocephalosporane dropped from the mixture to the precipitate. 1.5 g of 7- [α-cin-methoxymino-α- (2-chloroacetyl-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid are obtained.

Rf value: 0.49 (ethyl acetate: iso-propanol: water = 6: 4: 3)

5th step

400 mg of thiourea is added to a mixture of 50 ml of ethanol and tetrahydrofuran (1: 1) containing 2.9 g of the product prepared in step 4, and the mixture is stirred at room temperature for 15 hours. It is concentrated to dryness in vacuo and the residue is added to 20 ml of water. The solid is filtered and stirred again in a 10 ml water / ethanol (1: 1) mixture and filtered.

0.92 g of 7- [α-cin-methoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid is obtained.

Melting Point: 135-145 ° C (Decomposition Point)

ㅍ ㅍ

Example 5

7- [α-Cin-ethoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid

First stage

32.1 g of α-cin-ethoxymino using 1.54 g of α-cin-ethoxymino-α- (2-amino-thiazol-4-yl) -acetic acid in a similar manner to step 1 of Example 4 1 ml of -α- (2-amino-5-chloro-thiazol-4-yl) -acetic acid. 1 tetrahydrofuran is prepared.

Melting Point: 106 ° to 108 ° C. (Decomposition Point)

2nd step

30.7 g of α-cin-ethoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetic acid in a similar manner to step 2 of Example 4. Prepare 1 methanol.

3rd step

7.4 g of α-cin-ethoxymino-α- (2-chloro-acetyl-amino-5-chloro-thiazole-4- from 8.4 g of the carboxylic acid mentioned in step 2 in a similar manner to step 3 of Example 4 To prepare) -acetic acid. (Pale yellow oil)

Rf value: 0.56 (ethyl acetate: iso-propanol: water = 6: 4: 3)

4th step

1.9 g of 7- [α-cin-ethoxymino-α- (2-chloroacetylamino-5-chloro-thiazole-4- from 3.25 g of the carboxylic acid obtained in step 3 in a similar manner to step 4 of Example 4 (I) -acetamido] -cephalosporonic acid is prepared.

Rf value: 0.51 (ethyl acetate: iso-propanol: water = 6: 4: 3)

5th step

860 mg of 7- [α-cin-ethoxymino-α- (2-amino-5-chloro-thiazol-4-yl) from 2.8 g of the product obtained in step 4 in a similar manner to step 5 of Example 4 -Acetamido] -cephalosporic acid is prepared.

Melting Point: 140 to 150 ° C (Decomposition Point)

Example 6

1-S-oxide of 7- [α-cin-methoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid

980 mg of the product in step 5 of Example 4 is dissolved in 8 ml of 98% formic acid and 2 ml of methanol mixture and the solution is cooled with ice and 3 ml of tetrahydrofuran solution containing 410 mg of 85% m-chlorofebenzoic acid. Add. The mixture is stirred at room temperature for 1 hour, the solution is added dropwise into 100 ml of ether, the mixture is stirred for 1 hour, and the resulting solid is filtered. The residue is added in 10 ml of ether and the mixture is stirred for 1/4 hour. 850 mg of the title compound are obtained.

Melting Point: 300 ℃ or higher

Example 7

1-S-oxide of 7- [α-cin-ethoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid

910 mg of the title compound is prepared from 1.06 g of the product prepared in step 5 of Example 5 in a similar manner as in Example 6.

Melting Point:> 300 ℃

Example 8

7- [α-Cin-hydroxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporic acid

First stage

10 g of α-cin-trityloxymino-α- (2-tritylamino-thiazol-4-yl) -acetic acid is dispersed in 200 ml of chloroform and cooled to 0 ° C. 15 ml of 1 mol of glacial acetic acid solution containing Cl ₂ is added dropwise and stirred for 2 hours. It is extracted several times with water until the aqueous layer becomes neutral, and then the organic layer is dried and concentrated to dryness in vacuo. 10.8 g of α-cin-trityloxymino-α- (2-tritylamino-5-chloro-thiazol-4-yl) -acetic acid are obtained.

2nd step

3.5 g of the acid obtained in step 1 was dispersed in 40 ml of toluene and 315 mg of dimethylformamide was added to give a clear solution. 3.25 ml of toluene solution containing 2 moles of phosgene is added at −10 ° C. and stirred at this temperature overnight. 30 ml of CH ₂ Cl ₂ /2.0 g triethylamine solution containing 1.36 g of 7-aminocephalosporanic acid are added to the suspension. The mixture is stirred at 10 ° C. for 1 hour and at room temperature for 2 hours. It is diluted with 20 ml of water and adjusted to pH 2.0. The 7-aminocephalosporranic acid dropped into the precipitate is filtered off, and the layers are separated, and the organic layer is washed with water. The solvent is removed in vacuo, the residue is added in acetone and 150 mg of diethylamine are added followed by evaporation of the mixture. The residue is stirred with 20 ml of ether and the resulting solid is stirred for 1 h at a temperature of 50 ° in 20 ml of 80% formic acid and the mixture is extracted twice with 20 ml of toluene and then evaporated. The residue is stirred in 20 ml of ethanol at room temperature for 3 hours, then filtered and added in ethanol and filtered again. The residue was washed with ether and dried in vacuo to give 950 mg of 7- [α-cin-hydroxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cene. Palosporonic acid is obtained.

Example 9

7- [α-Cin-ethoxycarbonyl-methoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid

First stage

400 ml of anhydrous tetrahydrofuran suspension containing 17.18 g of α-cin-hydroxymino-α- (2-trityl amino-thyzol-4-yl) -acetic acid was charged with 9.52 g of potassium tert-butylate. It is added to 80 ml of anhydrous tetrahydrofuran solution containing. 20 ml of an aqueous solution in 4M tetrahydrofuran is added and then stirred at room temperature for 1 hour. 50 ml of tetrahydrofuran solution containing 6.68 g of ethyl bromo acetate was added dropwise to the solution over 1 hour, followed by the addition of 0.95 g of potassium tert-butylate, and the solution was stirred overnight. It is concentrated to dryness and the residue is added to 80 ml of water, extracted with ethyl acetate, and then adjusted to pH 7.4 once and pH 1.5 three times. Dry concentration gives 17.9 g of α-cin-ethoxycarbonyl methoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetic acid from the ethyl acetate extract.

Rf value: 0.52 (glacial acetic acid / acetone = 1/10)

2nd step

2.06 g of the compound obtained in step 1 are dissolved in 50 ml of chloroform, and 4.5 ml of 1M-glacial acetic acid solution containing Cl ₂ is added at 0 °. Stir at 0 ° for 0.5 h, remove chloroform and add the residue slowly with stirring in 100 ml of ice water. Stirring this mixture for 0.5 hour yields 1.4 g of α-cin-ethoxycarbonyl methoxymino-α- (2-trityl-amino-5-chloro-thiazol-4-yl) -acetic acid.

Melting Point: 90 ° to 100 ° C (Decomposition Point)

Rf value: 0.66 (Butyl acetate / CHCl ₃ /85% HCO ₂ H = 6/4/2)

3rd step

2.75 g of the acid obtained in step 2 are dissolved in 150 ml of tetrahydrofuran together with 0.675 g of 1-hydroxybenzotriazole and 1.08 g of dicyclohexylcarbodiimide is added. The mixture is stirred at room temperature for 1 hour and 0.83 g of dicyclohexylurea is filtered off. A mixture of 30 ml of acetone / 5 ml of water containing 1.36 g of 7-aminocephalosporranic acid and 1.52 g of triethylamine was added to the mother liquor while stirring, overnight, concentrated and the residue was added to 50 ml of ethyl acetate. Extract with water at pH 1.8. Evaporation of the ethyl acetate layer left 4.4 g of brown residue. The residue is stirred for 1 h at 50 ° C. in 12 ml of 75% formic acid, extracted twice with toluene and then decolorized by addition of 1 g of activated carbon. This pale formic acid solution is added dropwise while stirring to 56 ml of an aqueous solution containing 26 g of (NH ₄ ) ₂ SO ₄ . 0.8 g of 7- [α-cin-ethoxycarbonyl-methoxymino-α- (2-amino-5-chloro-thiazol-4-yl) -acetamido] -cephalosporanic acid is obtained .

Melting Point: 175 ° ~ 180 ° C (Decomposition Point)

Claims (1)

The lactams of the following structural formula (II) are reacted with the carboxylic acid of the following structural formula (III) to prepare the compound of the following structural formula (IV), and the product is oxidized on the sulfur of the cefe ring or the R 'group in the protecting group is separated. Converting X 'to X to prepare a cephalosporin derivative of formula (I):

In the above structural formula n is 0 or 1, X is hydrogen or optionally substituted alkyl having 1 to 4 carbon atoms, optionally substituted carboxymethyl, optionally substituted alkoxycarbonylmethyl having 1 to 4 carbon atoms in alkyl, optionally substituted amino carbonylmethyl, or optionally substituted cya Means nomethyl, Y stands for methyl or halogen, A means hydrogen or an easily separated ester group or a physiologically toxic cation, R 'refers to an amino-protecting group well known in the hydrogen or peptide chemistry, X 'means X or -CH ₂ CO ₂ R ³ . (However, R ³ is a group that can be separated even under mild conditions.)