WO2004113308A1

WO2004113308A1 - Method for producing aryl oxazolyl ethyl alcohol

Info

Publication number: WO2004113308A1
Application number: PCT/EP2004/006372
Authority: WO
Inventors: Konrad Siegel; Franz-Josef Mais
Original assignee: Bayer Healthcare Ag
Priority date: 2003-06-24
Filing date: 2004-06-14
Publication date: 2004-12-29
Also published as: DE10328174A1

Abstract

The invention relates to a method for producing an aryl oxazolyl ethyl alcohol of formula (I), which constitutes an intermediate stage in the production of medicaments. Said method comprises the reduction of a compound of formula (II) using an aqueous solution of sodium borohydride and the addition of calcium chloride.

Description

Process for the preparation of aryloxazolylethyl alcohol

The present invention relates to a process for the preparation of an aryloxazolylethyl alcohol which serves as an intermediate for the production of medicaments.

The compound produced by the process according to the invention is an intermediate stage for the synthesis of substances which can be used, for example, for the treatment of diabetes, obesity, dislipidemia or arteriosclerosis, as described in WO 03/011842. The synthesis (process 1) of the aryloxazolylethyl alcohol described there is carried out starting from an aspartic acid derivative 1 which is converted to acylated compound 2 in several stages using dichloromethane as solvent and extractant. Intermediates 3 and 4 are each after acetylation, decarboxylation at 90 ° C. and subsequent acidic cyclization. Get extraction. The final reduction to aryloxazolylethyl alcohol 5 takes place in tetrahydrofuran with lithium borohydride, which is added as a solid. The following scheme illustrates the synthesis.

Procedure 1:

Two other methods for the construction of corresponding aryloxazolylethyl alcohols are described in J.

Med. Chem. 1992, 35, 2617-2626 (method 2) and in J. Med. Chem. 1992, 35, 1853-1664 (method 3). The aryloxazolylethyl alcohols mentioned there are used as intermediates in a convergent synthesis to build up compounds which can be used as glucose depressants for the treatment of diabetes. According to process 2, the intermediates 6 and 7 are obtained using dichloromethane as solvent and working up by extraction in two stages. Dehydration and extraction gives compound 8, which is finally reduced to aryloxazolylethyl alcohol 9 with lithium aluminum hydride, which is initially introduced as a solid in diethyl ether (overall yield: 43%). Process 3 differs from process 2 in that, starting from compound 1, intermediate 7 is obtained in one step, but the overall yield is only 18%. The following scheme illustrates the two methods. Procedure 2:

Procedure 3:

EP-A 684 242 (method 4) and US 6,444,827 (method 5) describe the preparation of a substituted 2- (5-methyl-4-oxazolyl) ethyl alcohol ^" as an intermediate in a convergent synthesis for the construction of compounds which are used to treat The desired oxazolylethyl alcohol 9 is obtained in a total of 5 stages using dichloromethane and several extraction stages in method 4. The final reduction is carried out by adding the dissolved compound 14 in a solution of diisobutylaluminum hydride in toluene under a nitrogen atmosphere.

In process 5, starting from compound 1, compound 6 is obtained by acylation in an aqueous medium in the presence of an inorganic base and subsequent extraction with dichloromethane. After acetylation, decarboxylation and dehydration in one step, compound 8 is isolated after extraction. The final reduction to aryloxazolylethyl alcohol 9 is carried out in tetrahydrofuran by adding solid sodium borohydride and starting the reaction with methanol at 60 ° C. The following scheme illustrates that

Synthesis. Procedure 5:

1) Ac ₂ 0, N-methylmorpholine, dimethylamine pyridine, 60 ° C 2) p-toluenesulfonic acid - ^° χ ⁰ CO, CH,

All reduction processes described above involve significant risks when they are carried out on an industrial scale. In process 1, the addition of the solid reducing agent in portions on an industrial scale is difficult to carry out. An exact one

Procedures are usually not possible. Methods 2 and 3 involve handling LitMum aluminum hydride, which is self-igniting with water, and handling Diethylefher, where there is a risk of peroxide formation. Technical handling is very complex with both reagents. Method 4 uses a self-igniting diisobutyl aluminum hydride solution in air. In process 5, sodium borohydride and the ester to be reduced are initially introduced at elevated temperature and the reaction is started by adding methanol. The entire reaction potential of the strongly exothermic reaction is present in the reaction mixture, so that the reaction cannot be reliably prevented, particularly when it is carried out on an industrial scale, and considerable dangers have to be accepted.

In addition, in the processes described, the respective intermediate products are often obtained by extraction and subsequent concentration. This procedure is particularly disadvantageous when implemented on an industrial scale, since they are time-consuming and labor-intensive and consume large amounts of solvent. In particular, concentrating to dryness is a particular problem in reactions in the boiler, since the overheating that may result can lead to a loss of quality and the product can only be discharged from the boiler with difficulty. The use of dichloromethane on an industrial scale also proves to be a disadvantage due to its volatility and toxicity.

The object of the present invention was to provide an industrially applicable process for the preparation of an aryloxazolylethyl alcohol of the formula (I), in which the

Disadvantages of the above methods known from the prior art can be avoided. This object is achieved according to the present invention as follows. The following diagram illustrates the individual reaction steps.

(Vii)

Surprisingly, it has now been found that an aqueous, optionally basic solution of sodium borohydride can be used in the process according to the invention for the preparation of a compound of formula (I) with the addition of calcium chloride, without the ester function in the compound of formula (H) becoming acid is saponified. This aqueous sodium borohydride solution allows simple, meterable addition of the reducing agent and is particularly well suited for use on an industrial scale. If necessary, the reagent solution can be stabilized by adding base. One can so on highly flammable reducing agents or

Avoid submitting solid reducing agents. The controlled dosing of the reducing agent ensures safe implementation on an industrial scale.

Furthermore, it has surprisingly been found that a compound of the formula (H) can be prepared by crystallization without extraction and concentration, which enables the industrial application of this process step.

Furthermore, it was surprisingly found that in the preparation of a compound of the formula (HI) dichloromethane as solvent and extraction and concentration can be dispensed with by using a non-aqueous, water-dilutable solvent which allows the product to crystallize directly from the reaction mixture , This means that less toxic chemicals can be used and the implementation can be used more technically. In detail, the process according to the invention for the preparation of a compound of the formula (I) comprises

wherein

R ^{1 is} phenyl, naphthyl, thienyl, furyl, benzofuranyl or benzothiophenyl and R ^{1 is}

0, 1, 2 or 3 substituents is substituted, the substituents being selected independently of one another from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl , Methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, halogen, nitro, trifluoromethyl, trifluoromethoxy and cyano,

and

R ² denotes methyl, ethyl, n-propyl or isopropyl,

the reduction of a compound of formula (II)

wherein

R ¹ and R ^{2 have} the meaning given above,

and

R ³ denotes methyl, ethyl, n-propyl, isopropyl or benzyl,

with sodium borohydride,

characterized in that sodium borohydride is dissolved in an aqueous solution and the

Reaction with the addition of calcium chloride is carried out. The aqueous solution containing sodium borohydride is preferably basic.

The compound of the formula (H) can be prepared by reacting a compound of the formula (DT)

wherein

R ¹ and R ^{3 have} the meaning given above,

in the presence of a base

with a compound of formula (IV)

wherein

R ^{2 has} the meaning given above,

and, if appropriate after isolating the resulting intermediate, then adding acid until an acidic pH is reached,

characterized in that the compound of formula (II) is obtained from the reaction mixture by crystallization.

According to a preferred embodiment of the present invention, the conversion to a compound of formula (II) takes place in one step without isolation of an intermediate step.

The compound of formula (IH) can be prepared by reacting a compound of formula (V)

worm

R ^{3 has} the meaning given above,

in the presence of a base with a compound of formula (VI) or (VE)

worm

R ^{1 has} the meaning given above and

Y is halogen, preferably chlorine or bromine,

characterized in that the reaction is carried out in an organic, water-dilutable solvent and the compound of formula (1H) is obtained from the reaction mixture by crystallization.

According to a preferred embodiment of the present invention

R ^{1 is} phenyl which is substituted with 0 or 1 substituents selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy.

According to a particularly preferred embodiment of the present invention

R ¹ 4-tolyl,

R ² and R ^{3 are} methyl.

Compounds of the formula (V) are known per se to the person skilled in the art or can be prepared by customary processes known from the literature (D. Coleman, J. Chem. Soc. Chem. Commun. 1951, 2291,

P. Gmeiner at. Al. /. Org. Chem. 990, 55, 3068, FK Brown et. al. , Med. Chem. 1994, 37, 674, K. Ramalingan, RW Woodward, J. Org. Chem. 1988, 53, 1004). Compounds of the formulas (IV), (VI) and (VIT) are known per se to the person skilled in the art or can be prepared by customary processes known from the literature.

The reduction of a compound of formula (H) to a compound of formula (I) is carried out by reacting a compound of formula (IT) which is dissolved in an organic, water-dilutable solvent with an aqueous solution containing dissolved sodium borohydride

Addition of calcium chloride. The reaction takes place at from -10 ° C. to the reflux temperature of the solvent introduced, preferably at from 18 to 50 ° C., particularly preferably at 35 to 45 ° C., for example in the range from 0.5 to 10 hours, preferably within 1 to 5 hours. If appropriate, the reaction solution is subsequently stirred, for example, at 20 to 100 ° C., preferably at 35 to 45 ° C., for up to 15 hours.

The reaction of a compound of the formula (II) to a compound of the formula (I) is preferably carried out by metering an aqueous solution containing dissolved sodium borohydride in a template comprising a compound of the formula (II) and calcium chloride.

Dosage-controlled addition of a solution means in the context of the invention that to everyone

At the time the added amount of solution can be tracked and the addition of the solution can be stopped at any time.

Preference is given to using a basic aqueous solution with a pH of 7-14, particularly preferably with a pH of 12-14, containing an inorganic base such as alkali metal hydroxide or alkali metal carbonate and dissolved sodium borohydride. Sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate are preferred as the inorganic base, and sodium hydroxide or potassium hydroxide are particularly preferred.

Water is preferably used as the solvent for the aqueous solution. However, it is also possible to add water-miscible solvents such as methanol, ethanol, n-propanol or isopropanol in a volume fraction of up to 20%.

Suitable organic, water-dilutable solvents are, for example, ethers such as tetrahydrofuran, dioxane, glycol dimethyl ether or alcohols such as methanol, ethanol, n-propanol or iso-propanol. It is also possible to use mixtures of the solvents mentioned. Methanol, ethanol, n-propanol or iso-propanol are preferred. Methanol is particularly preferred.

Sodium borohydride is used in an amount of, for example, 1 to 10 mol, preferably 1.2 to 5 mol, in each case based on 1 mol of the compounds of the formula (H). The concentration of Sodium borohydride in the aqueous solution is 5 to 50 percent by weight, preferably 10 to 30 percent by weight.

Calcium chloride is generally used in an amount of, for example, 0.5 to 10 mol, preferably 0.9 to 3 mol, in each case based on 1 mol of the compound of the formula (II).

The reaction is generally carried out at normal pressure. But it is also possible to work at overpressure or underpressure (e.g. in a range from 0.5 to 5 bar).

The concentration of the compound of formula (II) in the organic, water-dilutable. Solvent is 5 to 50 percent by weight, preferably 10 to 40 percent by weight.

The reaction of a compound of the formula (HI) with a compound of the formula (IV) to give a compound ^"of the formula (II) is optionally carried out in an inert solvent. First the compound of the formula (III) with a compound of the formula (IV) in the presence of a base at a temperature of 20 to 110 ° C., preferably at 40 to 95 ° C. with stirring of the reaction solution, for example for 1 to 15 hours, preferably for 2 to 8 hours, and an excess of acid is then obtained added to the base used and the reaction mixture stirred at, for example, 50 to 110 ° C., preferably at 80 to 100 ° C. for, for example, 2 to 15 hours, preferably for 2 to 5 hours, The compound of the formula (DI) is preferably obtained from the reaction solution is obtained by crystallization by adding water and methanol to the reaction solution.

As the inert solvent, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or tri suitable ^{'chloroethylene,} or ethers such Mefhyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylenglykoldime hylether, or hydrocarbons such as Benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitro methane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide or acetonitrile. Tetrahydrofuran, dimethylformamide, 1,2-dichloroethane or methylene chloride are preferred.

Suitable bases for this reaction are, for example, amine bases, such as pyridine, lutidine, trimethylpyridine, N, N-dimethylbenzylamine, tributylamine, diisopropylethylamine, triethylamine, or salts of carboxylic acids, such as alkali metal acetates or ammonium acetates. Triethylamine, pyridine or sodium acetate are preferred. Pyridine is particularly preferred. The base is generally used in an amount of, for example, 0.2 mol to 5 mol, preferably in an amount of 0.4 mol to 1.5 mol, in each case based on 1 mol of the compound of the formula (DI). Of the compound of the formula (IV), for example 1 to 25 equivalents, based on 1 mol of the compound of the formula (DI), are used in the reaction. No further solvent is particularly preferably added to the reaction.

Examples of suitable acids for this reaction are sulfonic acids, such as benzenesulfonic acid or methanesulfonic acid, or sulfuric acid. Sulfuric acid is preferred. The acid is used in an amount of, for example, 1.2 to 5 mol, preferably 1.2 to 2 mol, in each case based on 1 mol of the base used.

The two in the reaction of the compound of formula (DI) with a compound of formula

(IV) for the compound of the formula (H) described reaction steps can also be carried out separately from one another by a work-up step, for example isolation of an intermediate product.

The reaction of a compound of formula (V) with a compound of formula (VI) or (VH) to a compound of formula (DI) is carried out in an organic, water-dilutable

Solvent in the presence of a base at a temperature of, for example, -20 to 100 ° C, preferably at -20 to 50 ° C, particularly preferably at -10 to. 30 ° C, with stirring of the reaction solution, for example, for several hours, preferably 2 to 12 hours, particularly preferably 3 to 6 hours. The volume of the reaction solution is then reduced to, for example, one third to two thirds, preferably to half. By adding water and an acid to the reaction mixture, a pH of, for example, 0 to 5, preferably 1 to 3, particularly preferably 1.5 to 2.5 is set, whereby the compound of the formula (HE) is obtained by crystallization becomes.

Suitable organic solvents which can be diluted with water are ethers such as tetrahydrofuran, dioxane or glycol dimethyl ether, or alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol or sec-butanol, or other solvents such as dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile. It is also possible to use mixtures of the solvents mentioned. Alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol or sec-butanol are preferred. Methanol is particularly preferred.

Suitable bases for this reaction are amine bases such as pyridine or tertiary amines such as triethylamine or diisopropylethylamine. It is also possible to add mixtures of the bases mentioned use. Diisopropylethylamine is preferred. The base is generally used in an amount of, for example, 0.5 to 8 mol, preferably in an amount of 0.8 to 5 mol, in each case based on 1 mol of the compound of the formula (V). It is also possible to use the base without adding another solvent.

Suitable acids for this reaction are, for example, inorganic acids, such as preferably

Hydrochloric acid.

Of the compound of formula (VI) or (VD), for example 0.7 to 1.3 mol, preferably 0.9 to 1.1 mol, in each case based on 1 mol of the compound of formula (V), are used in the reaction ,

The reaction is generally carried out at normal pressure. But it is also possible to

To work overpressure or under vacuum (e.g. in a range of 0.5 to 5 bar).

A particularly preferred embodiment of the process according to the invention comprises the preparation of a compound of the formula (I)

wherein

R ¹ 4-tolyl

and

R ² means methyl,

by reduction of a compound of formula (D),

wherein

R ¹ 4-tolyl,

R ² and R ^{3 are} methyl,

with sodium borohydride,

characterized,

that the sodium borohydride is dissolved in a basic aqueous solution and added in a metered manner to a template consisting of a compound of the formula (D) and calcium chloride, the compound of the formula (D) in a one-step process first by reacting a compound of the formula (DI),

wherein

R ¹ 4-tolyl

and

R ³ means methyl,

in the presence of a base with a compound of formula (IV),

wherein

R ² means methyl,

and then prepared by adding acid until an acidic pH is reached and recovered from the reaction mixture by crystallization,

and wherein the compound of formula (DI) by reacting a compound of formula (V),

wherein

R ³ means methyl,

in the presence of a base with a compound of the formula (VI),

wherein

R ¹ 4-tolyl

and

Y means chlorine

prepared in an organic, water-dilutable solvent and from the

Reaction mixture is obtained by crystallization.

The compounds described in the process according to the invention can also be present in the form of their salts, solvates or solvates of the salts. Depending on their structure, the compounds described in the process according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The process according to the invention therefore also includes the production and use of the enantiomers or diastereomers and their respective mixtures. The stereoisomerically uniform ones can be obtained from such mixtures of enantiomers and / or diastereomers

Isolate components in a known manner.

Depending on the structure, the compounds described in the process according to the invention can also be present in the form of their tautomers.

In the context of the invention, preferred salts are physiologically acceptable salts of the compounds used and produced in the process according to the invention.

Physiologically acceptable salts of the compounds used and prepared in the process according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ehanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid,

Citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds used and prepared in the process according to the invention also include salts of conventional bases, such as, for example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclo-hexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-mefhylmorpholine, dihydroabiethylamine and arginylidine diamine, arginylidine diamine.

Within the scope of the invention, such forms as in the invention are considered as solvates

Processes used and produced compounds referred to which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.

The present invention is illustrated below with reference to non-limiting preferred examples and comparative examples. Unless otherwise stated, all quantities refer to percentages by weight. EXAMPLES

List of abbreviations :

Ac Acetyl

Bz benzoyl

CDC1 ₃ chloroform

NMR nuclear magnetic resonance spectroscopy

The melting points specified were measured on a device from Büchi, Melting Point B-545.

The ¹³ C-NMR and -NMR spectra indicated were measured on a device from Bruker, Avance 500 at 500 MHz in CDC1 ₃ .

Example AI: 2- (4-methyl-benzoylamino) -succinic acid 4-methyl ester

L-Aspartic acid-β-methyl ester, hydrochloride (102.5 g; 0.5 mol) is dissolved in methanol (1 1).

Diisopropylethylamine (195.0 g; 1.5 mol) is added at room temperature. P-Methyl-benzoic acid chloride (77.2 g; 0.5 mol) is added dropwise to this solution over a period of 1.4 hours at room temperature and the mixture is then stirred for a further 2.7 hours at this temperature. The reaction mixture is concentrated to a volume of 500 ml by distillation (280 to 180 mbar, 37-42 ° C). Water (1400 ml) is added, the pH is adjusted to 1.7 with hydrochloric acid (36%, 40 ml) at a temperature of 35 ° C. and seed crystals are then added. The mixture is cooled to 3 ° C. within 3.5 h and then stirred at this temperature for 3 h. It is filtered through a suction filter and washed with ice water (200 ml). After drying (300 mbar; 40 ° C), the title compound (119.5 g; 90% of theory) is obtained. Η NMR (500 MHz, CDC1 ₃ ): δ = 2.37 (s; 3H); AB signal δ _A = 3.02; δ _B = 3.15 (/ _AB = 17.7; - 7 ^ = 4.6; J _B, x = 4.3; 2H); 3.69 (s); 5.01 (ddd, J = 4.1, 4.4, 8.0, 1H); 7.21 (d, J = 7.9, 2H); 7.46 (d; J = 7.9, 1H); 7.70 (d; J = 8.2; 2H); 11.48 (brs; 1H).

¹³ C-NMR (500 MHz, CDC1 ₃ ): δ = 10.29; 21.47; 32.00; 52.19; 124.88; 125.98; 129.16; 129.34; 140.10; 145.30; 159.78; 170.86.

Melting point = 106 ° C.

Example A2: methyl r5-methyl-2- (4-methylphenyl ^' ) -1,3-oxazole-4-v-acetic acid

Pyridine (4.0 g; 0.050 mol) is added to a solution of 4- (4-methyl-benzoylamino) -succinic acid 4-methyl ester (26.6 g; 0.100 mol) in acetic anhydride (60 ml) over 20 min room temperature.

The reaction mixture is then stirred at 55 ° C for 8 h. After cooling to room temperature, sulfuric acid (98%; 7.2 g; 0.076 mol) is added within 10 min. The mixture is stirred at 88 ° C. for 2.5 h and then cooled to room temperature over 1 h. Water (160 ml) and methanol (120 ml) are added. It is cooled to 3 ° C., seed crystals are added and, after 0.6 h, more water (in total 350 ml) is added to complete the crystallization.

The mixture is stirred for a further 3 h at 3 ° C. and the product suspension is filtered through a suction filter, which is then washed with water (100 ml). After drying (300 mbar; 40 ° C), the title compound (21.0 g; 85% of theory) is obtained.

Η NMR (500 MHz, CDC1 ₃ ): δ = 2.34 (s; 3H); 2.37 (s; 3H); 3.57 (s; 2H); 3.72 (s; 3H); 7.22 (d, / = 8.2; 2H); 7.87 (d; / = 7.9; 2H).

¹³ C-NMR (500 MHz, CDC1 ₃ ): δ = 10.29; 21.47; 32.00; 52.19; 124.88; 125.98; 129.16; 129.34; 140.10; 145.30; 159.78; 170.86:

Melting point = 71 ° C. Example A3: 2- (5-methyl-2-p-tolyloxazol-4-yl) ethanol

Calcium chloride (8.4.) Is added to the solution of methyl [5-methyl-2- (4-methylphenyl) -1, 3-oxazol-4-yl] acetate (18.3 g; 0.075 mol) in methanol (60 ml) g; 0.075 mol). A solution of sodium borohydride (4.26 g; 0.113 mol) in water (9.8 ml) and aqueous sodium hydroxide solution (1 N; 3.3 ml) is added dropwise at a temperature of 40-42 ° C. over a period of 1/7 h. The mixture is stirred at this temperature for 20 min and, after cooling, water (30 ml), toluene (130 ml) and aqueous hydrochloric acid solution (18%; 20 ml) are added. The phases are separated. The aqueous phase is extracted again with toluene (50 ml) and the combined organic phases are washed with aqueous sodium hydroxide solution (1N; 15 ml) and water (10 ml) _. .washed. The organic phase is about

Concentrated 35 ml and mixed with n-heptane (100 ml) at 40 ° C. The title compound crystallizes while cooling to -5 ° C. and is isolated on a suction filter. After drying (400 mbar; 40 ° C.), 2- (5-methyl-2-p-tolyl-oxazol-4-yl) ethanol (14.0 g; 86% of theory) is obtained.

Η NMR (500 MHz, CDC1 ₃ ): δ = 2.30 (s; 3H); 2.38 (s; 3H); 2.73 (dd;] - 6.0; 6.0; 2H); 3.91 (dd, J = 5.7, 6.0, 2H); 4.36 (brs, 1H); 7.23 (d; J = 7.9; 2H); 7.88 (d; J = 8.2; 2H).

¹³ C-NMR (500 MHz, CDC1 ₃ ): δ = 10.49; 21.93; 28.41; 61.98; 124.40; 126.51; 129.91; 133.33; 141.15; 144.56; 160.10.

Melting point = 6 FC.

Claims

Patentansprflche:

1. Process for the preparation of a compound of formula (I)

wherein

R ^{1 is} phenyl, naphthyl, thienyl, furyl, benzofuranyl or benzothiophenyl and

R ^{1 is} substituted with 0, 1, 2 or 3 substituents, the substituents being selected independently of one another from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, halogen, nitro, trifluoromethyl, trifluoromethoxy and cyano,

and

R ² denotes methyl, ethyl, n-propyl or isopropyl,

comprising reducing a compound of formula (D).

wherein

R ¹ and R ^{2 have} the meaning given above,

and

R ³ denotes methyl, ethyl, n-propyl, isopropyl or benzyl,

with sodium borohydride, characterized in that sodium borohydride is dissolved in an aqueous solution and the reaction is carried out with the addition of calcium chloride.

2. The method according to claim 1, characterized in that

R ^{1 is} phenyl which is substituted with 0 or 1 substituent from the group consisting of methyl, ethyl, n-propyl, isopropyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy.

3. The method according to claim 1, characterized in that

R ¹ 4-tolyl,

R ² and R ^{3 are} methyl.

4. The method according to any one of claims 1 to 3, characterized in that the reaction of the compound of formula (E), as defined in claim 1, to a compound of formula (I), as defined in claim 1, by metering

Add an aqueous solution containing dissolved sodium borohydride to a template consisting of a compound of formula (E) as defined in claim 1 and calcium chloride.

5. The method according to any one of claims 1 to 4, characterized in that the aqueous solution containing sodium borohydride is basic.

6. The method according to any one of claims 1 to 5,

wherein the compound of formula (D) as defined in claim 1 is prepared by reacting a compound of formula (ET)

wherein

R ¹ and R ^{3 have} the meaning given in claim 1,

with a compound of formula (IV)

wherein

R ^{2 has} the meaning given in claim 1,

and then adding acid until an acidic pH is reached,

characterized in that the compound of formula (E) is obtained from the reaction mixture by crystallization.

7. The method according to claim 6, characterized in that the conversion to a compound of formula (E), as defined in claim 1, takes place in one step.

8. The method according to any one of claims 6 or 7,

wherein the compound of formula (EI) as defined in claim 4 is prepared by reacting a compound of formula (V)

embedded image in which

R ^{3 has} the meaning given in claim 1,

with a compound of formula (VI) or (VE)

wherein

R ^{1 has} the meaning given in claim 1 and

Y means halogen,

characterized in that the reaction is carried out in an organic, water-dilutable solvent and the compound of formula (EI) is obtained from the reaction mixture by crystallization.

9. The method according to claim 8, characterized in that

, Y is chlorine or bromine.

10. The method according to claim 1, wherein the reaction of the compound of formula (E),

wherein

R ¹ 4-tolyl,

R ² and R ^{3 are} methyl,

to a compound of formula (I),

wherein

R ¹ 4-tolyl, and

R ² means methyl,

by metering an aqueous solution containing dissolved sodium borohydride into a template consisting of a compound of the formula (E) and calcium chloride,

and the compound of formula (E) in a one-step process first by reacting a compound of formula (EI),

worm

R ¹ 4-tolyl

and

R ³ means methyl,

with a compound of formula (IV)

O O

_{R2 0} A _R2 (IV),

wherein

R ² means methyl,

and the compound of formula (ET) by reacting a compound of formula (V),

wherein

R ³ means methyl,

with a compound of formula (VI)

wherein

R ¹ 4-tolyl

and

Y means chlorine

prepared in an organic, water-dilutable solvent and is obtained from the reaction mixture by crystallization.