KR880001760B1 - Process for preparing intermediate products for the preparation of cepharosporins - Google Patents

Abstract

Novel compd. (I) prepd. by reacting (II) with base i.e. potassium tert-butylate, lithium diisopropylamide in a suitable solvent i.e. THF at -50 to -80 deg.C, and with aldehyde of formula R1-CHO. In the formulas, R1 is lower alkyl or (un) substd. phenyl; R2 is alkoxycarbonyl; R3 is lower alkyl; R4 is lower alkyl or trialkylsillylalkyl. React (I) with base, separate Z and E isomers, (selective) sapong. to prepare Z-acid and coupling with cephalosporanic acid, remove protection gp. R2 to give cephalosporine.

Description

Method for preparing intermediates for producing cephalosporins

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 is not yet 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, when R ¹ represents an isopropyl radical, the desired general formula is due to deconjugation of the double bond and Michael addition reaction during the reaction of the compound of formula (III) with thiourea. In addition to the compounds of (IV), the products of the following formulas (VI) and (iii) are obtained in much larger fractions:

Furthermore, when R ¹ represents an alkyl radical, the acid of general formula (V) 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) For example, using hydroxybenzotriazole / DCC), the isomerization of the double bond occurs significantly, resulting in the product of the following general formula:

Wherein R ¹ and X are as defined above. However, compounds of general formula (IV) generally exhibit only about one tenth of the biological activity of compounds of general 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.

Therefore, the present invention is (a) reacting a compound of general formula (VII) with a pyrocarboxylic acid ester of general formula (VIIa); (b) the product of formula (VII) thus obtained is first reacted with a suitable base and then with an aldehyde of formula R ¹ -CHO to obtain a compound of formula (XI); (c) reacting the obtained compound of formula (XI) with a base to obtain a compound of formula (XI); (d) separating the Z and E isomers from the compound of formula (XII) and then saponifying or selectively saponifying to obtain a Z-acid of formula (XIII); (e) reacting a Z-acid of formula (XIII) with a compound of general formula (XV) to obtain a compound of general formula (XVI): (f) a compound of general formula (XVI) Coupling with cephalosporranic acid) and (g) isolating protecting group R ² to provide a compound of formula (I):

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 heterocyclic radical.

In addition, the present invention relates to a compound represented by the following general formula (i) as a novel compound:

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

Further, the present invention relates to a method for preparing a compound of formula (VII), wherein the compound of formula (VII) as described above is reacted with a pyrocarboxylic acid ester of formula (VIIa) as described above in a solvent suitable for the reactants. will be.

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

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

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

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

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 preparing a compound of formula (VII), wherein a compound of formula (XIII) 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, a 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 general formula (VIII) according to the invention include those in which R ² represents O—CO—C (CH ₃ ) ₃ ; R ³ represents O (CH ₃ ) ₃ ; R ⁴ is an optionally substituted alkyl radical of C _1-15, an optionally substituted alkenyl radical of C _3-15, an optionally substituted cycloalkyl radical of C _3-10, an optionally substituted cycloalkenyl radical of C _5-10 , An optionally substituted aryl radical having 1 to 3 rings or an optionally substituted heterocyclyl radical having 1 to 3 rings which may contain up to 5 heteroatoms selected from nitrogen, sulfur and oxygen to be.

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

-Mentioned alkyl, alkenyl, cycloalkyl and cycloalkenyl radicals are alkyl radicals, O- alkyl radicals, halogen C _1-4 of C _1-4 (preferably, chlorine), an optionally substituted phenyl radical, 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 the general formula used in the process according to the invention for the preparation of compounds of the general formula are known per se. See E. Campaine & T. P. Selby, J. Heterocycl. Chem. 17 (1980).

Particularly suitable solvents for the preparation of compounds of general formula are aprotic polar solvents such as acetonitrile, dimethylformamide, hexamethylphosphoric acid triamide or dimethyl sulfoxide, 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 (VIIa) is used in 2 to 2.5 molar equivalents.

Other solvents, high temperature or acylation catalysts (eg 4-dimethylformaminopyridine) significantly promote the formation of undesired products of the general formula:

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 general formula (XI), the compounds of general formula (IV) are generally treated with 1 to 1.1 equivalents of base at low temperature in a solvent suitable for the reactants, followed by general formula 1 to 1.2 equivalents of aldehyde of R ¹ -CHO are added.

The solvent which may be used for this reaction is, for example, dimethylformamide, diethyl ether, tetrahydrofuran or toluene, preferably tetrahydrofuran, and the base which may be used is alcoholate, hydride, amide or organic Metal compounds (preferably potassium tert-butylate, lithium diisopropylamide and butyllithium). In order to carry out the reaction, a base is generally added to a solution of the compound of general formula 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 (XI), the mixture is neutralized and worked up.

Preferred compounds of formula (XI) are as defined above for R ² to R ⁴ ; 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, can be substituted by alkyl, O-alkyl, S-alkyl, alkyl oxycarbonyl, 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 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.

During 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 a compound of formula (XI) to a compound of formula (XI) 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 (VII) to obtain a compound of formula (XI) is not complete, 1 to 1.2 equivalents of base [e.g. hydride, alcoholate or amide (especially potassium tert-butyl) RATE] is added and the reaction mixture is stirred at room temperature for about 10 hours.

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

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

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

In order to produce the Z-carboxylic acid of general formula (XIII), the Z-ester which can be obtained by isolate | separating the E / Z isomer mixture of general formula (XII) ester can be saponified. However, in order to carry out the process for the preparation of the compound of general formula (I), first, under mild conditions, the E-ester is converted into an E-carboxylic acid of general formula (XIV) and separated, and then the remaining Z-ester (where Selectively saponifying the E / Z isomeric mixture of the general formula (XII) ester by saponifying under more violent conditions to obtain a Z-carboxylic acid of the general formula (XIII). More preferred.

Mild conditions for saponification to produce the E-carboxylic acid of formula (XIV) are, for example, ethanol, 2N sodium hydroxide solution, room temperature and 24 hours. After converting the compound of general formula (XI) to the compound of general formula (XI), saponification is effected by adding 2N sodium hydroxide solution directly to the reaction mixture and 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 (XIII) and E-carboxylic acid of general formula (XIV) are obtained. E-carboxylic acids of formula (XIV) are converted to silyl esters using, for example, bistrimethyl silylacetamide, and then the base (eg potassium 3) in a suitable solvent (e.g. diethyl ether or tetrahydrofuran). Tert-butylate), followed by hydrolysis with dilute acid to convert back to a mixture of E-carboxylic acid of general formula (XIV) and Z-carboxylic acid of general formula (XIII).

The Z-carboxylic acid of the general formula (XIII) can also be separated in pure form from a mixture of E / Z isomers, for example by separating on a crystallization or ion exchanger. Since Z-carboxylic acid of general formula (XIII) is more acidic than E-carboxylic acid of general formula (XIV), separation using an ion exchange agent is simple. In other words, E-carboxylic acid of general formula (XIV) is eluted from the weak basic ion exchanger using methanol, while Z-carboxylic acid of general formula (XIIII) is eluted only after the addition of an electrolyte (e.g., 2N sodium hydroxide solution). do. Weak basic ion exchangers are understood to include ion exchangers in solid or liquid form containing tert-amino groups (eg, Lewatit MP 62).

R in compounds of formulas (XIII) and (XIV)^OneAnd R²Is as defined in the compound of general formula (XII). Moreover, in the compound of general formula (XII) R²Is a protecting group (e.g. methyloxycarbonyl group) that can be saponified with alkali before it is saponified, R²May be a hydrogen atom. However, R²When is a protective group, preferably tert-butyloxycarbonyl, which is stable under saponification conditions, it is more advantageous to carry out the process for the production of a compounded compound 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 Z-carboxylic acid of general formula (XIII) and cephalosporranic acid of general formula (XIII), and the yield is very low especially when R ¹ is an alkyl radical. do. This is due to the significant steric hindrance of the carboxyl groups by the radicals R ¹ in the carboxylic acids of general formula (XIII) and the marked tendency for the radical R ¹ to isomerize to the E-form after activation of the carboxyl functional groups, for example acid chlorides. Turned out to be Subsequently, after reacting with 7-aminocephalosporranic acid of the general formula (VII), the desired compound of the general formula (IV) is not obtained, but rather the compound of the following general formula (XI) or a mixture of these two compounds Is obtained:

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

In the present invention, it has been found that the Z-carboxylic acid of general formula (XIII) can be activated in a simple, gentle and inexpensive manner at low temperature without the disadvantages described above, which are converted into mixed anhydrides of general formula (XVI).

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

In these compounds, when R ⁵ is 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 general formula (VI) are optionally wherein R ⁵ is fluorine, chlorine, CN, phenyl, alkyloxycarbonyl, alkyloxy or alkyl, preferably alkyl group in these substituents is C _1-4 . _Represent substituted C _1-10 alkyl radicals, or represent fluorine, chlorine, bromine, CN, alkyl, alkyloxy, alkylthio and alkyloxycarbonyl (preferably alkyl groups in these substituents are C _1-4 ) , Nitro, trifluoromethyl and phenyl radicals optionally substituted by 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 (VI), R ⁵ represents a methyl or P-tolyl radical.

Mixed anhydrides of this kind (XIV) dissolve an equimolar amount of the carboxylic acid of the general formula (XIIII) and a suitable amine in a suitable solvent and react with 1 to 1.05 equivalents of the sulfonic acid derivative of the general formula (XIV). It is preferable to make it.

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 (XIV) can be separated by suction filtration of the formed triethanamine hydrochloric acid using, for example, tetrahydrofuran as the solvent and triethylamine as the base, and distillation of the solvent in vacuo. Can be. However, it is more advantageous to directly react the obtained solution of the general formula (XIV) compound with the general formula (III) cephalosporranic acid. For this purpose, cephalosporranic acid of the general formula 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 the solution is then at this temperature. It is added to the solution of the above-mentioned general formula (XIV) compound. In order to prevent the isomerization of the radical R ¹ in the reaction product of general formula, 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 general formula (VI) compounds may be used to dissolve cephalosporonic acid of the general formula (VII). If such a method does not provide a satisfactory concentration of the cephalosporan acid solution of general formula, the solid solution esters of general formula compounds (e.g. silyl, It is also clear 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) and 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 do.

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

It is a compound which represents.

Compounds of formula (I) wherein R ¹ and X are as defined for compounds of formula (VII) are obtained after separation of protecting group R ² from compounds of formula (VII). As already mentioned for compounds of general formula, 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 (VII).

The process according to the invention and the preparation of the compound according to the invention are illustrated by the following examples:

Example 1

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

186 g (1 mol) of ethyl 2-aminothiazol-4-ylacetate, 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. 3.5 L of ice water is added with ice cooling at a maximum of 20 ° C., and the mixture is stirred for 30 min, after which the precipitate is filtered off with suction, washed with 2 L of water and then placed in 2 L of methylene chloride. 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 2 liters of petroleum ether (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 mole) of tert-butyl 2-aminothiazol-4-yl acetate, 150 ml of dimethyl sulfoxide and 260 g (1.2 mole) 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, then the washings are concentrated on a rotary evaporator, the residue is placed in ether, then 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-butyloxycarbonylimino-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.

Claims (6)

A method for preparing the compound of formula (VII), characterized in that the compound of formula (VII) is reacted with a base in a solvent suitable for the reactants at low temperature, and then reacted with an aldehyde of formula R ¹ -CHO .

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. 2. A process according to claim 1 wherein 1 to 1.1 equivalents of base is used and then 1 to 1.2 equivalents of aldehyde. The method of claim 1, wherein the base is added to a solution of the general formula compound at -50 to -80 ° C, then aldehyde is added at -50 to -60 ° C, and the resulting mixture is about -50 to -60 ° C. Stirring for 12 hours. The method of claim 1 wherein the solvent is tetrahydrofuran. The method of claim 1 wherein the base is potassium tert-butylate, lithium diisopropylamide or butyllithium. The process for preparing a compound of formula (XI) according to claim 1, wherein R ¹ is an optionally substituted C _1-15 alkyl radical.