KR880001540B1 - Process for preparing cephalesporins - Google Patents

Abstract

Thiazolines (I) [R=protective gp.; R1, R2=(un)substd. alkyl, cycloalkyl, aryl, heterocyclic , useful as intermediates for cephalosporins (II) [R3=(un)substd. alkyl, cycloalkyl, aryl, heterocyclic; R4=appropriate substituent , are prepd. Thus, Et 2- amino-4-thiazolylacetate is treated wtih (Me3CO2C)2O to give (I) (R=Me3CO2C, R1=CMe3, R2=Et) which is treated with MeCHO to give (III) . Sapon. of (III) to the acid, successive reaction with MeSO2Cl and 7-aminocephalosporanic acid, and deblocking give (II) (R3=Me, R4=CH2OAc).

Description

Method for preparing cephalosporin

The present invention relates to certain intermediate compounds for the preparation of particular cephalosporins, methods for their preparation and their use, and methods for preparing cephalosporins.

The cephalosporins of the following general formula (I) have been mentioned for a relatively long time in the patent application P30 37 997.6, which has not been published.

Wherein R ¹ represents an alkyl or aryl radical and X represents a radical suitable as a cephalosporin substituent.

These compounds have a wide range of antimicrobial activity against Gram-positive bacteria as well as Gram-positive bacteria.

According to the method mentioned in the above patent application, the compound of general formula (I) is prepared according to the following scheme:

Wherein R ¹ is as defined above.

In this way, however, compounds of formula (I) in which R ¹ represents alkyl radicals are obtained in unsatisfactory yields. Thus, for example, in the case where R ¹ represents an isopropyl radical, the desired general formula is due to deconjugation of the double bond and Michael addition reaction during the thioureaoa reaction of the compound of formula (III). In addition to the compounds of (IV), the products of the following formulas (VI) and (VII) are obtained in much larger fractions:

Furthermore, when R ¹ represents an alkyl radical, it is described in the above-mentioned patent application to couple the acid of general formula (V) with 7-aminocephalosporanic acid to obtain the product of general formula (I) (eg For example, using hydroxybenzotriazole / DCC), the isomerization of the double bond occurs considerably, resulting in the product of formula (VIII):

Wherein R ¹ and X are as defined above.

However, compounds of formula (VIII) generally exhibit only about one tenth of the biological activity of compounds of formula (I).

The present invention discloses a process for the preparation of compounds of formula (I) which are prepared via novel intermediate products and which do not have the aforementioned disadvantages.

Accordingly, the present invention relates to (a) reacting a compound of formula (IX) with a pyrocarboxylic acid ester of formula (IXa): (b) reacting the product of formula (X) thus obtained first with a suitable base. And then reacted with an aldehyde of formula R ¹ -CHO to give a compound of formula (XI); (c) reacting the obtained compound of formula (XI) with a base to give a compound of formula (X II): (d) separating the Z and E isomers from the compound of formula (X II), Then saponified or optionally saponified to give a Z-acid of formula (X III); (e) reacting a Z-acid of formula (X III) with a compound of formula (XV) to afford a compound of formula (XVI); (f) coupling the compound of formula (X VI) with cephalosporranic acid of formula (X VII); (g) providing a process for the preparation of a compound of formula (I) by isolating protecting group R ² :

Wherein R ¹ represents an optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl radical; X represents a radical suitable as a cephalosporin substituent; R ² represents CO ₂ R ³ ; R ³ and R ⁴ are the same or different and represent an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl or heterocyclyl radical, wherein the heteroatoms as substituents of the radical and the alkenyl and cycloalkenyl radicals At least one carbon atom is present that separates the double bond from the oxycarbonyl group; Z represents a chlorine atom, a bromine atom or -O-SO ₂ -R ⁵ ; R ⁵ represents an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl radical. The present invention also relates to compounds of the general formula (X) as novel compounds:

Wherein R ² , R ³ and R ⁴ are as defined above.

The present invention also relates to a process for the preparation of a compound of formula (X) wherein the compound of formula (IX) as described above is reacted with a pyrocarboxylic acid ester of formula (IXa) as described above in a solvent suitable for the reactants. will be.

The present invention also relates to novel compounds of the general formula (X I):

Wherein R ² , R ³ and R ⁴ are as defined above and R ¹ represents an optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl radical.

In addition, the present invention reacts a compound of formula (X) as described above with a base at a low temperature in a solvent suitable for the reactants, and then reacts with an aldehyde of formula R ¹ CHO, wherein R ¹ is as defined above. The present invention also relates to a method for producing a compound of general formula (XI).

The present invention also relates to novel compounds of the general formula (X VI):

Wherein R ¹ and R ² are as defined above; R ⁵ represents a fluorine atom, optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl radical.

The present invention also relates to a process for the preparation of a compound of formula (XVI) wherein the compound of formula (X III) is reacted with a compound of formula (XV):

Wherein R ¹ , R ² and R ⁵ are as defined above: Z represents a chlorine atom, bromine atom or —O—SO ₂ —R ⁵ .

The process according to the invention for the preparation of compounds of general formula (I) may also be summarized in the following scheme:

Wherein R ¹ , R ² , R ³ , R ⁴ and X are as defined above.

The reaction step for preparing the compound of formula (I) is described in more detail later in this specification.

Particularly preferred compounds of formula (X) according to the invention are those in which R ² represents O-CO-C (CH ₃ ) ₃ : R ³ represents O (CH ₃ ) ₃ : R ⁴ represents C _1-15 An optionally substituted alkyl radical, C _3-15 optionally substituted alkenyl radical, C _3-10 optionally substituted cycloalkyl radical, C _5-10 optionally substituted cycloalkenyl radical, 1 to 3 rings Having an optionally substituted aryl radical or optionally substituted heterocyclyl radical having 1 to 3 rings which may contain up to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

Particularly preferred compounds of general formula (X) according to the invention represent R ² -butoxybutoxycarbonyl radicals; R ³ represents a tert-butyl radical; R ⁴ is a compound representing methyl, ethyl, tert-butyl or trimethylsilyl ethyl radicals.

The alkyl, alkenyl, cycloalkyl and cycloalkenyl radicals mentioned are C _1-4 alkyl radicals, C _1-4 C-alkyl radicals, halogens (preferably chlorine), optionally substituted phenyl radicals, C = N and tri (C _1-5 alkyl) silyl may be substituted.

All aryl and heterocyclyl radicals, including the phenyl radicals mentioned, can be substituted with alkyl, O-alkyl, S-alkyl, alkyl oxycarbonyl, halogen, phenyl, nitro and C = N radicals, where all alkyl radicals May be C _1-4 .

When the radicals R ³ and / or R ⁴ are preferably substituted by the aforementioned substituents, they may contain 1 to 5, preferably 1 or 2 substituents.

When R ² represents a protecting group (e.g. tert-butoxycarbonyl) which is stable to the base and removable in the acid and R ⁴ represents a radical which can be saponified with a base (e.g. methyl or ethyl) Is particularly advantageous.

Compounds of general formula (IX) for use in the process according to the invention for the preparation of compounds of general formula (X) are known per se. See, E. Campaine & T. P. Selby, J. Heterocycl. Chem. 17 (1980).

Particularly suitable solvents for the preparation of compounds of formula (X) are aprotic polar solvents such as acetonitrile, dimethylformamide, hexamethylphosphoric acid triamide or dimethylsulfoxide, in particular hexamethylphosphoric acid triamide Or dimethyl sulfoxide is suitable. It is particularly advantageous to carry out the reaction at room temperature or at low temperatures (eg 10 to -50 ° C.) and generally the components are reacted with each other for 1 to 7 days. In general, the pyrocarboxylic acid ester of the general formula (IXa) is used in 2 to 2.5 molar equivalents.

Other solvents, high temperature or acylation catalysts such as 4-dimethylformaminopyridine, significantly promote the formation of undesired products of the following general formula (XIX).

Wherein R ² , R ³ and R ⁴ are as described above.

In the process according to the invention for the preparation of novel compounds of formula (XI), the compounds of formula (X) are generally treated with 1 to 1.1 equivalents of base at low temperature in a solvent suitable for the reactants and then 1 to 1.2 equivalents of aldehyde of R ¹ -CHO are added.

The solvent which may be used in this reaction is, for example, dimethylformamide. Diethyl ether, tetrahydrofuran or toluene, preferably tetrahydrofuran, and bases which may be used are alcoholates, hydrides, amides or organometallic compounds (preferably potassium tert-butylate, lithium di Isopropylamide and butyllithium). To carry out the reaction, a base is generally added to a solution of the compound of general formula (X) at -50 to -80 ° C, then aldehyde is added at -50 to -60 ° C, and the mixture is about -50 to -60 ° C. Stir for 12 hours. To separate the product of general formula (X I), the mixture is neutralized and worked up.

Preferred compounds of formula (XI) are those in which R ² to R ⁴ are as defined above; R ¹ is C _1-15 optionally substituted alkyl radical, C _3-10 optionally substituted cycloalkyl radical, optionally substituted carbocyclic or heterocyclic aryl radical having 1 to 2 rings, or nitrogen, sulfur And optionally substituted heterocyclic radicals having from 1 to 3 rings which may contain up to 5 heteroatoms selected from oxygen atoms.

Suitable substituents for alkyl and cycloalkyl include C _1-6 alkyl radicals, C _1-6 O-alkyl radicals, C _1-6 S-alkyl radicals, C _1-6 N-alkyl radicals, C _1-6 Alkyloxycarbonyl radicals and optionally substituted phenyl radicals.

All aryl and heterocyclyl radicals, including the phenyl radicals mentioned, may be substituted by alkyl, C-alkyl, S-alkyl, alkyloxycarbonyl, halogen (preferably chlorine) and phenyl radicals, all alkyl The radical may be C _1-6 .

When R ¹ represents a radical substituted (preferably by a substituent as described above), 1 to 5, preferably 1 or 2 substituents are preferred.

R ¹ represents an alkyl radical of C _1-10 or a cycloalkyl radical of C _3-10 , which in each case is to be substituted by 1 to 2 C _1-6 alkyl radicals and / or 1 to 2 phenyl radicals Particular preference is given to compounds which can be employed.

In carrying out the process according to the invention for the preparation of compounds of general formula (I), it is not necessary to separate the compounds of general formula (XI). On the other hand, it is advantageous to directly convert the compound of formula (XI) to the compound of formula (X II) in situ. For this purpose, it is generally sufficient to add the aldehyde R ¹ -CHO and then warm the mixture to room temperature and stir it overnight at room temperature. When the elimination reaction of the compound of formula (XI) to obtain the compound of formula (X II) is not complete, 1 to 1.2 equivalents of base, such as hydrides, alcoholates or amides (particularly potassium tertiary- Butyrate)] and the reaction mixture is stirred at room temperature for about 10 hours.

On the other hand, when the compound of formula (X I) is previously separated to prepare a compound of formula (X II), 1.1 to 2.2 equivalents of base are added to a solution of the compound of formula (X I) in a suitable solvent. Solvents and bases used are those mentioned in the reaction of compounds of formula (X) to obtain compounds of formula (X I), with tetrahydrofuran and potassium tert-butylate being preferred.

The compound of general formula (X II) is obtained as a mixture of E / Z isomers, which may be separated, for example, by column chromatography on recrystallization or silica gel.

R ¹ , R ² and R ⁴ in the compound of formula (X II) are as defined above in the compound of formula (XI).

In order to prepare Z-carboxylic acids of general formula (X III), the Z-esters obtainable by separating the E / Z isomeric mixture of general formula (X II) esters can be saponified. However, in order to carry out the process for the preparation of the compound of general formula (I), first, under gentle conditions, the E-ester is converted to the E-carboxylic acid of general formula (X IV) and separated, and then the remaining Z-ester ( Wherein the ester group is more stericly hindered) to saponify under more intense conditions to obtain a Z-carboxylic acid of general formula (X III). It is more preferable to saponify.

Mild conditions for saponification to produce the E-carboxylic acid of formula (X IV) are, for example, ethanol, 2N sodium hydroxide solution, room temperature and 24 hours. After converting the compound of formula (XI) to the compound of formula (X II), 2N sodium hydroxide solution is added directly to the reaction mixture and saponified by stirring at room temperature or slightly heating until the E-ester saponifies. It is advantageous to carry out. The Z-ester is then extracted under alkaline conditions to separate from the mixture and saponified under more vigorous conditions.

More violent conditions for saponification are, for example, ethanol, 2N sodium hydroxide solution and 24 hour-reflux, although possibly higher sodium hydroxide solutions or high boiling solvents such as dioxane can also be used.

In this way the desired Z-carboxylic acid of general formula (X III) and E-carboxylic acid of general formula (X IV) are obtained. E-carboxylic acids of general formula (X IV) are converted to silyl esters using, for example, bistrimethyl silylacetamide, and then the base (e.g. potassium) in a suitable solvent (e.g. diethyl ether or tetrahydrofuran). Tert-butylate), and then hydrolysed with dilute acid to convert back to a mixture of the E-carboxylic acid of formula (X IV) with the Z-carboxylic acid of formula (X III).

Z-carboxylic acids of general formula (X III) can also be separated in pure form from a mixture of E / Z isomers, for example by separating on crystallization or ion exchangers. Since the Z-carboxylic acid of general formula (X III) is more acidic than the E-carboxylic acid of general formula (X IV), separation using an ion exchanger is simple. That is, the E-carboxylic acid of general formula (X IV) is eluted from the weak basic ion exchanger using methanol, while the Z-carboxylic acid of general formula (X III) is added after the addition of an electrolyte (e.g., 2N sodium hydroxide solution). Only elutes. Weak basic ion exchangers are understood to include ion exchangers in solid or liquid form containing tert-amino groups (eg, Lewatit MP 62).

R ¹ and R ² in the compounds of formulas (X III) and (X IV) are as defined for compounds of formula (X II). In addition, when R ² in the compound of general formula (X II) is a protecting group (eg, methyloxycarbonyl group) which may be saponified by alkali before saponifying, R ² may be a hydrogen atom. However, when R ² is a protective group which is stable under saponification conditions, preferably tert-butyloxycarbonyl, it is more advantageous to carry out the process for the preparation of compounds of general formula (I).

Many assays derived from conventional peptide chemistry are known in the cephalosporin chemistry for coupling carboxylic acids with 7-aminocephalosporins. However, these methods cannot form amide bonds between the Z-carboxylic acid of formula (X III) and the cephalosporranic acid of formula (X VII), especially when R ¹ is an alkyl radical. Goes very low. The reason for this is that such a significant trend, for the general formula (X III) and then the carboxylic acid radical and R significant steric hindrance, the carboxyl functional group of the carboxyl group according to the ^first active in the radical R ¹ to isomerisation to form E-, It was found in the conversion to acid chloride. Subsequently, after reacting with 7-aminocephalosporranic acid of the general formula (X VII), the desired compound of the general formula (X VIII) is not obtained, but rather the compound of the following general formula (XXI) or both compounds A mixture of is obtained:

Wherein R ¹ , R ² and X are as defined above.

The present invention has found that the Z-carboxylic acid of general formula (X III) can be activated in a simple, gentle and inexpensive manner at low temperatures without the drawbacks described above, which are converted to mixed anhydrides of general formula (X VI). .

As mentioned above, the compounds of general formula (X VI) are novel and form a further object of the present invention.

When R ⁵ in these compounds is an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl radical, R ⁵ is halogen, alkyl, aryl, O-alkyl, S-alkyl, CN, alkoxy It may be substituted by a substituent selected from carbonyl and nitro.

Particularly preferred compounds of formula (X VI) are those in which R ⁵ is fluorine, chlorine, CN, phenyl, alkyloxycarbonyl, alkyloxy or alkyl (preferably alkyl groups in these substituents are C _1-4 ). Or an optionally substituted C _1-10 alkyl radical, or fluorine, chlorine, bromine, CN, alkyl, alkyloxy, alkylthio and alkyloxycarbonyl (alkyl groups in these substituents are preferably C _1-4 ) ), Nitro, trifluoromethyl and phenyl radicals optionally substituted with phenyl.

When substituting R ⁵ , it is preferable that 1 to 3 substituents described above are preferably present.

In a particularly preferred compound of formula (X VI), R ⁵ represents a methyl or P-tolyl radical.

Mixed anhydrides of this kind of formula (X VI) dissolve an equimolar amount of carboxylic acid of formula (X III) and a suitable amine in a suitable solvent, which is 1 to 1.05 equivalents of sulfonic acid derivative of formula (XV) It is preferable to prepare by reacting with.

Suitable solvents for the present invention are all solvents which are stable under the reaction conditions (eg diethyl ether, tetrahydrofuran, acetonitrile, acetone, methylene chloride, chloroform or dimethylformamide).

Suitable amines are tertiary-amines (eg triethylamine or tributylamine) and hindered secondary-amines (eg diisopropylamine).

The reaction can be carried out at -80 ° C to room temperature, where low temperatures interfere with the isomerization of substituents on the double bond. Advantageously, the reaction is carried out at −20 to −50 ° C. for 10 minutes to 6 hours.

Compounds of formula (X VI) can be separated by suction filtration of triethylamine hydrochloride formed, for example using tetrahydrofuran as solvent and triethylamine as base, and distilling off the solvent in vacuo. have. However, it is more advantageous to directly react the obtained solution of the general formula (X VI) compound with cephalosporranic acid of the general formula (X VII). For this purpose, cephalosporranic acid of formula (X VII) is dissolved in a suitable solvent with 2 to 4 equivalents of amine, the solution is pre-cooled to the desired subsequent reaction temperature, and then the solution is brought to this temperature. To a solution of the general formula (X VI) compound described above. In order to prevent isomerization of the radicals R ¹ in the reaction product of general formula (X VIII), the reaction is advantageously carried out at -60 to -30 ° C and the mixture is left at room temperature overnight.

The amines and solvents mentioned for preparing the compounds of formula (X VI) can be used to dissolve cephalosporonic acid of formula (X VII). If it is not possible to obtain a satisfactory concentration of the formula (X VII) cephalosporonic acid solution in this way, the solid solution esters of the general formula (XVII) compounds well known in the cephalosporin chemistry (eg silyl, 3 It is also apparent that tert-butyl or diphenylmethyl ester) can be used.

After completion of the reaction, R ¹ and R ² are as defined for compounds of general formula (XVI), X is a suitable group as cephalosporin substituent [e.g. hydrogen, alkyl of C _1-4 , halogen, C _{1- 4} alkoxy, hydroxymethyl, formyloxymethyl, (C _1-4 alkyl) carbonyloxymethyl, aminocarbonyloxymethyl, pyridiniummethyl, 4-carbamoylpyridiniummethyl or heterocyclylthiomethyl { Here, "heterocyclyl" is preferably the following structural formula.

Wherein R ⁶ represents hydrogen, methyl, 2-dimethylaminoethyl, carboxymethyl or sulfomethyl; R ⁷ represents hydrogen or methyl}} to obtain a compound of formula (XVIII) do.

Preferred compounds of formula (XVIII) are those wherein X is hydrogen, chlorine, methoxy, hydroxymethyl, acetyloxymethyl, amino carbonyloxymethyl, pyridiniummethyl,

It is a compound which represents.

Compounds of formula (I) wherein R ¹ and X are as defined for compounds of formula (XVIII) are obtained after separation of protecting group R ² from compounds of formula (XVIII). As already mentioned for compounds of general formula (X), a protecting group stable to the base where R ² may optionally be separated [eg tert-butyloxycarbonyl (separated using trifluoroacetic acid)] In the case of, it is quite advantageous to directly carry out the complete reaction sequence for preparing the compound of formula (I) from the compound of formula (X).

The process according to the invention and the preparation of the compound according to the invention are explained in the following examples.

Example 1

Ethyl 2-3-butoxycarbonylimino-3-tert-butoxycarbonyl-4-thiazolyl-4-ylacetate

186 g (1 mol) of ethyl 2-aminothiazol-4-yl acetate, 300 ml of dimethyl sulfoxide and 500 g (2.3 mol) of 98% di-tert-butyl pyrocarbonate are stirred at room temperature for 7 days. Add 3.5ι of ice water with ice cooling at up to 20 ° C and stir the mixture for 30 min, then filter the precipitate by suction, wash with 2ι of water and then add to methylene chloride 2ι. The water is separated and the methylene chloride phase is dried over Na ₂ SO _{4 and} then concentrated on a rotary evaporator. The oil obtained is immediately crystallized in petroleum ether 2ι (before crystallization begins).

Yield: 78% (302 g)

Melting Point: 90 ℃

Example 2

Methyl 2-3-butoxycarbonyl-3-tert-butoxycarbonyl-4-thiazolin-4-ylacetate

Prepare the title compound in a similar manner to Example 1 using methyl 2-aminothiazol-4-ylacetate.

Yield: 67%

Melting Point: 67-69 ° C

Example 3

Ethyl 2-ethoxycarbonylimino-3-ethoxycarbonyl-4-thiazolin-4-ylacetate

The title compound is prepared in a similar manner to Example 1 using ethyl 2-aminothiazol-4-ylacetate and diethylpyrocarbonate.

Yield: 71%

Melting Point: 102 ℃

Example 4

Tert-butyl 2-3 tert-butoxycarbonylimino-3-tert-butoxycarbonyl-4-thiazolin-4-ylacetate

157 g (0.5 mol) of tert-butyl 2-aminothiazol-4-yl acetate, 150 ml of dimethyl sulfoxide and 260 g (1.2 mol) of 98% di-tert-butyl pyrocarbonate were reacted in a similar manner to Example 1 .

Yield: 62%

Example 5

Trimethylsilylethyl 2-aminothiazol-4-ylacetate

7.9 g (0.05 mol) of 2-aminothiazol-4-ylacetic acid in 50 ml of acetonitrile at 11.2 g (15.8 ml, 0.1 mol) of trimethylsilylethanol, 100 mg of 4-dimethylaminopyridine and 11.4 g of dicyclohexyl carbodiimide at room temperature ) And the mixture is stirred for 2 days. The precipitated urea is then suction filtered, washed with ether, the concentrate is concentrated on a rotary evaporator, the residue is placed in ether, and the ethereal solution is washed with 0.5N hydrochloric acid and NaHCO ₃ solution, followed by MgSO ₄ Dry over phase and then concentrate on rotary evaporator. Concentrate the solution and add petroleum ether to crystallize the desired ester.

Yield: 2.8 g

Example 6

Trimethylsilylethyl 2-3-butyloxycarbonylamino-3-tert-butoxycarbonyl-4-thiazolin-4-ylacetate

Using trimethylsilyl 2-aminothiazol-4-ylacetate, the title compound is prepared in a similar manner to Example 1.

Yield: 50%

Example 7

Ethyl 1- (2-tert-butoxycarbonylaminothiazol-4-yl) -2-tert-butoxycarbonyloxypropanecarboxylate

11.2 g (0.03 mol) of ethyl 2-3-butoxycarbonylimino-3-tert-butoxycarbonyl-4-thiazolin-4-ylacetate was dissolved in 80 ml of anhydrous tetrahydrofuran and under nitrogen 20 ml (0.032 mmol) of a 15% n-butyllithium solution in n-hexane at −50 to −60 ° C. are added followed by 1.91 ml (0.034 mol) of acetaldehyde. After the mixture is stirred at -50 to -60 [deg.] C. for 2 hours, 30 ml of 10% aqueous citric acid solution is added and the mixture is allowed to warm to room temperature. For workup, tetrahydrofuran is distilled in vacuo at room temperature and the residue is extracted with methylene chloride, then the organic extract is dried over Na ₂ SO ₄ and then the solvent is distilled off. 10.8 g of an oil, which is a mixture of diastereomers according to NMR and TLC (cyclohexane / ether 1: 1), are obtained.

Example 8

Ethyl 1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (E, Z) -propenecarboxylate

The mixture is prepared as described in Example 7, except that acetaldehyde is added, then warmed to room temperature, stirred overnight and then worked up as described in Example 7. 9.2 g of an oil is obtained, which is about a 1: 1 mixture of E / Z isomers according to NMR and TLC (cyclohexane / ether 1: 1, Z isomers develop higher). Both compounds can be separated on silica gel 60 (fluid phase: cyclohexane / ether 1: 1).

Z isomer:

¹ H-NMR (250MH _Z CDCI ₃ ): δ = 10.5 (bs; 1H, NH), 6.95 (s; 1H, S-CH), 6.88 (q; J = 7H _Z , 1H, C H -CH ₃ ) , 4.35 (q; J = 7H _Z , 2H, C H -CH ₃ ), 2.04 (d; J = 7H _Z , 3H, CH-C H ₃ ), 1.50 (s; 9H, C (CH ₃ ) ₃ ) , 1.36 (t; J = 7H _Z ; 3H, CH ₂ -C H ₃ )

E isomers:

¹ H-NMR (250MH _Z , CDCI ₃ ): δ = 10.5 (bs; 1H, NH), 7.22 (q; J = 7H _Z , 1H, C H -CH ₃ ), 6.94 (s; 1H, S-CH ), 4.19 (q; J = 7H _Z , 2H, C H ₂ -CH ₃ ), 1.95 (d; J = 7H _Z , 3H, CH-C H ₃ ), 1.52 (s; 9H, C (CH ₃ ) ₃ ), 1.22 (t; J = 7H _Z , 3H, CH ₂ -C H ₃ ).

Example 9

Ethyl 2- (2-tert-butoxycarbonylaminothiazol-4-yl) -2- (E, Z) -benzylidene acetate

3.86 g (0.01 mol) of ethyl 2-3-butoxycarbonylimino-3-tert-butoxycarbonyl-4-thiazolin-4-ylacetate in 40 ml of anhydrous tetrahydrofuran to -50 ° C After cooling, 2.8 g (0.024 mol) of potassium tert-butylate are added, the mixture is stirred until the solution is complete, followed by 1.11 ml (0.012 mol) of benzaldehyde. Warm the mixture to room temperature and stir overnight. To work up, add about 12 ml of 2N HCI while cooling in ice, check the pH until the pH is 4-5, remove the tetrahydrofuran and tert-butanol in vacuo, and then extract the residue with methylene chloride. do. After drying over Na ₂ SO ₄ , methylene chloride is removed in vacuo. 3.1 g of oil is obtained, which is about a 1: 1 mixture of E / Z isomers according to NMR and TLC (cyclohexane / ether 1: 1).

Example 10

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxylic acid

56 g (0.145 mol) of ethyl 2-3-butoxycarbonylimino-3-tert-butoxycarbonyl-4-thiazolin-4-ylacetate and 400 ml of anhydrous tetrahydrofuran were placed under nitrogen, -60 N-butyllithium (0.16 mol) in 100 ml of 15% hexane is added dropwise at -50 占 폚. 9.55 ml (0.17 mol) of acetaldehyde are then added immediately and the mixture is stirred at −60 ° C. for 10 minutes and then at room temperature overnight.

250 ml of 2N sodium hydroxide solution are added and the mixture of the two phases is stirred vigorously for 24 hours at room temperature. Tetrahydrofuran is distilled in vacuo at room temperature and the alkaline phase is washed twice with 100 ml of methylene chloride each time. The aqueous phase is acidified to pH 2-3 and extracted, then 1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (E) -propenecarboxylic acid is obtained.

Yield: 51% (21.0 g)

Melting Point: 195 ° C (from Acetonitrile)

The methylene chloride phase is concentrated in vacuo, the residue is taken up in 250 ml of ethanol, treated with 250 ml of 2N sodium hydroxide solution and heated at 60 ° C. for 24 hours.

After distillation removes ethanol, the alkaline phase is extracted once with 100 ml of methylene chloride, the extract is discarded, the alkaline phase is acidified to pH 2-3 and the desired 1- (2-tert-butoxycarbonylamino Thiazol-4-yl) -1 (Z) -propenecarboxylic acid is extracted with methylene chloride.

Yield: 20% (8.3 g)

Melting Point: 183 ° C (from Acetonitrile)

Example 11

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -butenecarboxylic acid

The title compound is prepared in a similar manner to Example 10, using propanal instead of acetaldehyde.

Yield: 17%

Melting Point: 172 ° C (from Acetonitrile)

Example 12

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -pentenecarboxylic acid

Using the butanal instead of acetaldehyde, the title compound is prepared in a similar manner to Example 10.

Melting Point: 162 to 163 ° C (from acetonitrile)

Example 13

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -hexenecarboxylic acid

Using the pentanal instead of acetaldehyde, the title compound is prepared in a similar manner as in Example 10.

Melting Point: 158 ° C (from Acetonitrile)

Example 14

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -heptenecarboxylic acid

Using the hexanal instead of acetaldehyde, the title compound is prepared in a similar manner as in Example 10.

Melting point: 130 to 131 ° C. (from acetonitrile)

Example 15

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -octencarboxylic acid

The title compound is prepared in a similar manner to Example 10, using heptanal instead of acetaldehyde.

Melting Point: 164 ° C (from Acetonitrile)

Example 16

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -3-methyl-1 (Z) -butenecarboxylic acid

The title compound is prepared in a similar manner to Example 10, using isobutyraldehyde instead of acetaldehyde.

Melting Point: 169 to 171 ° C (from acetonitrile)

Example 17

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -4-methyl-1 (Z) -pentenecarboxylic acid

The title compound is prepared in a similar manner to Example 10, using isovaleraldehyde instead of acetaldehyde.

Melting Point: 173 ° C (from Acetonitrile)

Example 18

2- (2-tert-butoxycarbonylaminothiazol-4-yl) -3-cyclohexyl- (Z) -acrylic acid

Using the cyclohexylaldehyde instead of acetaldehyde, the title compound is prepared in a similar manner as in Example 10.

Melting point: higher than 210 ° C. (from acetonitrile)

Example 19

2- (2-tert-butoxycarbonylaminothiazol-4-yl) -4-phenyl-1 (Z) -butenecarboxylic acid

The title compound is prepared in a similar manner to Example 10, using dihydrocinnamaldehyde in place of acetaldehyde.

Melting Point: 174 ° C (from acetonitrile)

Example 20

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxylic acid

122 g (0.43 mol) of 1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (E) -propenecarboxylic acid in 800 ml of anhydrous tetrahydrofuran was dissolved in 129 ml (0.52 mol) of bistrimethylsilylacetamide. ) And the mixture is stirred at room temperature for 1 hour. It is then cooled to -60 [deg.] C. and 200 g (1.74 mol) of 98% potassium tert-butylate are added, then warmed to room temperature and then stirred at room temperature overnight.

To work up, cool in ice and add 100 ml of water, adjust the pH to 6 to 8 tanks with about 900 ml of 2N HCI, remove the tetrahydrofuran in vacuo, then adjust the pH to 2-3, The mixture is extracted three times with 300 ml of methylene chloride. The extract is dried, concentrated on a rotary evaporator, and the residue is dissolved in 700 ml of methanol. The methanolic solution was passed through a column (2.5 × 80 cm; 400 ml) containing the weakly basic ion exchanger Lewatit MP 62 at a rate of 10 ml min, then the column was washed with 2 m of methanol and methanol / 2N sodium hydroxide (10: 1) Elute with 1ι of solution. The eluate is concentrated, acidified to pH 2-3 with 2N HCI and extracted with methylene chloride. Dry over Na ₂ SO ₄ and methylene chloride is distilled to give 50 g (41%) of the desired Z-propenecarboxylic acid. The methanol wash is evaporated to recover unisomerized E-propenecarboxylic acid from the column.

Example 21

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -pentenecarboxylic acid

The corresponding E-pentenecarboxylic acid is isomerized in a similar manner to Example 20 to prepare the title compound.

Yield: 45%

Example 22

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxyl methanesulfonic anhydride

1.42 g (0.005 mol) of 1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxylic acid and 0.76 ml (0.0055 mol) of triethylamine were dried with anhydrous tetrahydrofuran. Dissolve in 10 ml and cool to -50 ° C. 0.40 ml (0.0051 mol) of methanesulfonyl chloride is then added and the mixture is stirred at −40 to −50 ° C. for 5 hours. Triethylamine hydrochloride is suction filtered while removing water, and tetrahydrofuran is distilled at -10 ° C in vacuo. The mixed anhydride is warmed to give as an oil which is easily isomerized in E form. (NMR).

Example 23

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -butenecarboxyl p-toluenesulfonic anhydride

The title compound is prepared using an appropriate Z-butenecarboxylic acid and p-toluenesulfonyl chloride at −20 to −30 ° C. in a similar manner as in Example 22.

Example 24

7- [1- (2-tert-Butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid

1.42 g (0.005 mol) of 1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxylic acid and 0.76 ml (0.0055 mol) of triethylamine 20 ml of anhydrous methylene chloride Is dissolved in, the mixture is cooled to -50 ° C, then 0.40 ml (0.0051 mol) of methanesulfonyl chloride is added and the mixture is stirred at -50 to -40 ° C for 5 hours.

Then, a solution of 1.63 g (0.006 mol) of 3-acetoxymethyl-7-amino-3-cepem-4-carboxylic acid and 1.80 ml (0.013 mol) of triethylamine in 20 ml of anhydrous methylene chloride was precooled to −50 ° C. Add and warm the mixture to room temperature for 12 hours.

For workup, the mixture is washed twice with 10 ml of H ₂ O, the methylene chloride phase is protected with 40 ml of H ₂ O, and then acidified to pH 2-3 with 1N HCI with stirring and cooling in ice. The organic phase is separated and the H ₂ O phase is extracted twice with 20 ml of methylene chloride, then the combined methylene chloride phases are washed with saturated NaCI solution, dried over Na ₂ SO ₄ and concentrated in vacuo on a rotary evaporator. The desired cephalosporin is obtained almost quantitatively.

Example 25

7- [1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxamido [-3- (1-methyl-1H-tetrazol-5- Yl) thiomethyl-3-cepem-4-carboxylic acid

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxylic acid and 7-amino-3- (1-methyl-1H-tetrazol-5-yl) The title compound is prepared in a similar manner to Example 24 using thiomethyl-3-cepem-4-carboxylic acid.

Yield: 92%

Example 26

7- [1- (2-tert-Butoxycarbonylaminothiazol-4-yl) -1 (Z) -butenecarboxamido] -3-acetoxymethyl-3-cepem-carboxylic acid

Using 1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -butenecarboxylic acid and 3-acetoxymethyl-7-amino-3-cepem-4-carboxylic acid, In the same manner as in Example 24, the title compound is prepared.

Example 27

7 [1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -butenecarboxamido] -3- (1-methyl-1H-tetrazol-5-yl Thiomethyl-3-cepem-4-carboxylic acid

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -butenecarboxylic acid and 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thio Prepare the title compound in a similar manner to Example 24 using methyl-3-cepem-4-carboxylic acid.

Yield: 88%

Example 28

7- [1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -heptencarboxamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid

Using 1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -heptenecarboxylic acid and 3-acetoxymethyl-7-amino-3-cepem-4-carboxylic acid, In the same manner as in Example 24, the title compound is prepared.

Yield: 90%

Example 29

7- [1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -heptencarboxamide] -3- (1-methyl-1H-tetrazol-5-yl Thiomethyl-3-cepem-4-carboxylic acid

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -heptencarboxylic acid and 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thio Prepare the title compound in a similar manner to Example 24 using methyl-3-cepem-4-carboxylic acid.

Yield: 85%

Example 30

7- [1- (2-tert-butoxycarbonylaminothiazol-4-yl) -3-methyl-1 (Z) -butenecarboxamido] -3-acetoxymethyl-3-cepem- 4-carboxylic acid

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -3-methyl-1 (Z) -butenecarboxylic acid and 3-acetoxymethyl-7-amino-3-cepem-4-carboxylic acid Using to prepare the title compound in a similar manner to Example 24.

Yield: 93%

Example 31

7- [1- (2-tert-butoxycarbonylaminothiazol-4-yl) -4-phenyl-1 (Z) -butenecarboxamido] -3-acetoxymethyl-3-cepem- 4-carboxylic acid

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -4-phenyl-1 (Z) -butenecarboxylic acid and 3-acetoxymethyl-7-amino-3-cepem-4-carboxylic acid Using to prepare the title compound in a similar manner to Example 24.

Yield: 95%

Example 32

7- [1- (2-tert-Butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxamido] -3-methyl-3-cepem-4-carboxylic acid

Implementation using 1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxylic acid and 7-amino-3-methyl-3-cepem-4-carboxylic acid In the same manner as in Example 24, the title compound is prepared. However, unlike Example 24, instead of triethylamine, 7-amino-3-methyl-3-cepem-4-carboxylic acid is dissolved in methylene chloride together with an equimolar amount of diisopropyl amine.

Example 33

7- [1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxamido] -3-aminocarbonyloxymethyl-3-cepem-4- Carboxylic acid

1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxylic acid and 7-amino-3-aminocarbonyloxymethyl-3-cepem-4-carboxylic acid To give the title compound in a similar manner to Example 24. However, unlike Example 24, 7-amino-3-aminocarbonyloxymethyl-3-cepem-4-carboxylic acid is not dissolved in methylene chloride with triethylamine, but anhydrous with an equimolar amount of diisopropylamine. It is dissolved in dimethylformamide and the resulting solution is added to mixed carboxyl sulfonic anhydride in methylene chloride.

For workup, the mixture is evaporated in vacuo at 0 ° C., the residue is added to water, extracted with methylene chloride, the aqueous phase is protected with ethyl acetate and then acidified to pH 2-3. The product is separated as oil between phases.

Example 34

Diphenylmethyl 7- [1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxamido] -3-cepem-4-carboxylate

Carried out using 1- (2-tert-butoxycarbonylaminothiazol-4-yl) -1 (Z) -propenecarboxylic acid and diphenylmethyl 7-amino-3-cepem-4-carboxylate In the same manner as in Example 24, the title compound is prepared.

Yield: 93%

Example 35

Example 10 ml of 7- [1- (2-aminothiazol-4-yl) -1 (Z) -propenecarboxamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid trifluoroacetic acid To the Boc-protected cephalosporin obtained at 24, the mixture is stirred for 30 minutes at room temperature. Trifluoroacetic acid is then removed in vacuo at room temperature and the residue is treated with 20 ml of methanol / water (10: 1) and then with 10% NaHCO ₃ solution until a clear solution is obtained at pH 6-7. . Then adjust slowly to pH 3 with 1N HCI, remove methanol slowly in vacuo and adjust again to pH 3 if necessary. The precipitated product is filtered off by suction.

Yield: 70%

[Examples 36 to 44]

The cephalosporins prepared in Examples 25-34 are deprotected in a similar manner as in Example 35.

Yield: 50 to 90%

Claims (1)

(a) reacting a compound of formula (IX) with a pyrocarboxylic acid ester of formula (IXa); (b) reacted with a suitable base with the product of formula (X) obtained and then with an aldehyde of formula R ¹ -CHO to afford the compound of formula (XI); (c) obtained, and then reacting the compound of formula (XI) with a base to give a compound of formula (X II); (d) the Z and E isomers obtained are then separated from the compounds of general formula (X II) and then saponified or optionally saponified to give the Z-acids of the following general formula (XIII); (e) reacting the Z-acid of formula (XIII) with the compound of formula (XV) to afford the compound of formula (XVI); (f) the following obtained compound of formula (X VI) is coupled with cephalosporranic acid of formula (X VII); (g) A process for preparing a compound of formula (I) characterized by separating protective group R ² .

Wherein R ¹ is lower alkyl or substituted or unsubstituted phenyl; R ² is alkoxycarbonyl; R ³ is lower alkyl; R ⁴ is lower alkyl or trialkylsilylalkyl; R ⁵ is lower alkyl or substituted or unsubstituted aryl; Z is chlorine atom, bromine atom or -O-SO ₂ -R ⁵ ; X is acetoxyalkyl, lower alkyl, aminocarbonyloxyalkyl, diarylallyl or substituted or unsubstituted tetrazolthioalkyl.