HU187670B - Process for producing n-square bracket-bracket-1-naphtyl-bracket closed-carbonyl-square bracket closed-n-bracket-lower-bracket closed-alkyl-glycine derivatives - Google Patents

Abstract

N-¢(1-Naphthalenyl)carbonyl!-N-(lower alkyl)glycine derivatives, useful as intermediates for pharmacologically active compounds, are produced by reacting an organometallic derivative of a 1-halonaphthalene with a lower alkyl isocyanate and N-alkylating the naphthalenecarboxamide so formed.

Description

The present invention relates to a process for the preparation of N - [(1-naphthyl) carbonyl] -N- (lower) alkylglycine derivatives. The above compounds are intermediates in the preparation of N - [(1-naphthyl) thioxomethyl] -N- (lower) alkylglycine derivatives.

The N - [(1-naphthyl) carbonyl] -N- (lower alkyl) glycine derivatives of the present invention can be readily converted to the corresponding N - [(1-naphthyl) thioxomethyl] -N- (lower) alkyl- glycine derivatives. The latter compounds, thionaphthylglycines, are useful in the treatment of diabetic complications such as nerve weakness, renal failure, visual disturbances, cataracts, or atherosclerosis, and another method for their preparation is disclosed in Canadian Patent Application No. 372,119. According to the above patent, thionaphthylglycines are prepared by coupling a 1-naphthalenecarboxylic acid having the corresponding reactive carboxyl group with a glycine ester, reacting the resulting N - [(1-naphthyl) carbonyl] glycine ester with phosphorus pentasulfide. and the resulting thionaphthylglycine ester is optionally hydrolyzed to give the corresponding thionaphthylglycine. Alternatively, the order of the last two steps can be reversed.

By the process of the present invention, N - [(1-naphthyl) carbonyl] -N- (lower) alkylglycine derivatives are otherwise prepared in good yield and at low cost from readily available starting materials. In the most important step of the present process, a naphthyl Grignard compound or lithium derivative is reacted with a suitable alkyl isocyanate to give the corresponding 1-naphthalenecarboxamide derivative, which is then simply N-alkylated.

Converted to N - [(1-naphthyl) carbonyl] -N- (lower) alkylglycine. Although Gilman, H. and Kinney, C.R. Chem. Soc. 46,493 (1924)] has already been used to prepare benzanilide by reaction of phenyl magnesium bromide with phenyl isocyanate, the reaction of naphthyl magnesium halide or lithium derivative with an alkyl isocyanate and with the help of N- [(1-Naphthyl) carbonyl] -N- (lower) alkylglycine derivatives can be prepared in a simple, direct manner, avoiding the use of expensive or harmful chemicals or the need for protecting groups.

The present invention therefore relates to a process for the preparation of compounds of formula (I). In the general formula (I)

R 'is C 1-4 alkyl, R ^{2 is} hydrogen or C 1-4 alkyl, R ^{3 is} halogen or trifluoromethyl, and R ^{4 is} hydrogen or C 1-4 alkoxy.

According to the invention, there is provided a compound of formula II in the formula

R ³ and R ⁴ are as defined above, X is bromine, chlorine or iodine of the corresponding formula (III)

R ³ and R ⁴ are as defined above and Y is MgX

in the latter formula, X is converted to the above - or lithium atom - organometallic compound and the compound of formula (III) is reacted with a lower alkyl isocyanate of the formula R * NCO - in which

R ¹ is as hereinbefore defined for the reaction of the compound of formula (IV)

R ¹ , R ³ and R ⁴ are as defined above - condensed with a lower alkyl ester of haloacetic acid to give a compound of formula I wherein R ¹ , R ³ and R ⁴ are as defined above and R ² lower alkyl groups, optionally hydrolyzed to give a compound of formula I wherein R ¹ , R ³ and R ⁴ are as defined above and R ^{2 is} hydrogen.

Preferably R 'is methyl, R ^{2 is} hydrogen or methyl, R ^{3 is} bromo, chloro, or trifluoromethyl, and R ⁴ is hydrogen or methoxy.

A lower alkyl group is a C 1 -C 4 linear or C 3 -C 4 branched alkyl group such as methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl or 1,1-dimethyl. represents an ethyl group. C 1-3 alkyl groups are preferred.

A lower alkoxy group is a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, such as methoxy, ethoxy, 1-methylethoxy or butoxy.

The halogen atom may be fluorine, chlorine, bromine or iodine.

The term inorganic proton acceptor refers to an inorganic base, preferably an alkali metal hydride, hydroxide or carbonate such as sodium hydride, sodium hydride dimethyl sulfoxide, potassium hydroxide, sodium carbonate, potassium carbonate or the like.

The term organic proton acceptor refers to an organic base or amine, such as triethylamine, pyridine, N-ethylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene, or the like.

The term proton acceptor refers to an organic or inorganic proton acceptor as defined above.

The process of the invention will be described in detail below.

Compounds of formula (III) are prepared by reacting a compound of formula (II) dissolved in an inert organic solvent, such as diethyl ether or tetrahydrofuran, with magnesium under the conditions commonly used in the Grignard reaction. 1,2-dibromoethane may be used as a catalyst in the formation of the Grignard compound. The reaction temperature is preferably from room temperature (20-22 ° C) to 100 ° C or the boiling point of the reaction mixture, and is preferably from 30 minutes to 4 hours. In this way, an organic metal compound of formula (III) is obtained wherein R ³ and R ⁴ are as defined above and Y is a group of MgX, in the latter case X is bromine, chlorine or iodine.

Alternatively, compounds of Formula II may be reacted with lithium in a neutral solvent under conditions similar to those used in the Grignard reaction.

. 187,670.

The reaction product is a compound of formula III wherein R ³ and R ⁴ are as defined above and Y is lithium.

Compounds of formula (II) are either known or may be prepared by known methods (e.g., Elsevier's Encyclopaedia of Organic Chemistry, F. Radt, Ed., Ser. III, Vol. 12B, 1953, Elsevier Publishing Co., Amsterdam, p. 264). -321).

Next, the organic metal compound of formula (III): - wherein R ³ and. R ⁴ is as defined above and Y is a MgX group in which X is halogen or lithium atom is reacted with a lower alkyl isocyanate R'CNO in which R ¹ is lower alkyl in the presence of an inorganic proton acceptor ( To give a compound of formula IV: wherein R ¹ , R ³ and R ⁴ are as defined above. The reagents are conveniently reacted in a non-polar, neutral solvent at 0-60 ° C for 30 minutes to 6 hours. Suitable solvents include diethyl ether, benzene or tetrahydrofuran.

In the next step, the compound of formula (IV) is N-alkylated with a lower alkyl ester of haloacetic acid in the presence of a suitable proton acceptor, and the reaction product is a compound of formula (I) wherein R ¹ , R ³ and R ⁴ are as defined above and R ² rövodszénláncú alkyl. Suitably the proton acceptor in the N-alkylation reaction is sodium hydride, sodium hydride dimethyl sulfoxide, or an alkali metal hydroxide or carbonate such as sodium hydroxide or potassium carbonate, or triethylamine or pyridine. The reaction medium may be any solvent which does not interfere with the reaction. Suitable solvents include dimethylsulfoxide, dimethylformamide, toluene, acetone or tetrahydrofuran. Preferably, the proton acceptor is sodium hydride dimethyl sulfoxide and the solvent is dimethyl sulfoxide. The reaction temperature and reaction time depend on the reagents used, generally at 20-80 ° C for 30 minutes to 48 hours.

Compounds of formula I wherein R 1, R ³ and R ⁴ are as defined above and R ^{2 is} lower alkyl may, if desired, be hydrolyzed to the corresponding compounds of formula I wherein R ^{2 is} hydrogen. The hydrolysis is conveniently carried out in an aqueous medium in the presence of a base and then acidified to give the desired acid. In the process of the present invention, the hydrolysis may be carried out not only under alkaline conditions, but also by acid catalysis or by other methods such as treatment with lithium iodide in collidine (see LF Fieser and M. Fieser, Reagents for Organic Synthesis, John Wiley and Sons, Inc.). , New York, 1969, pp. 615-617). Acid hydrolysis is particularly preferred for the hydrolysis of tert-butyl esters.

The alkaline hydrolysis is preferably carried out by exposing the ester to a strong base such as sodium or potassium hydroxide in the presence of sufficient water. The hydrolysis is carried out in a suitable solvent such as methanol, ethanol or 2-methoxyethanol. The temperature of the reaction mixture is maintained at 25-100 ° C or at the boiling point of the reaction mixture until hydrolysis is complete. Generally, 30 minutes to 6 hours are sufficient to complete the reaction. The reaction mixture is then acidified with an acid such as acetic acid, hydrochloric acid or sulfuric acid to give the product of formula (I) as the free acid.

The compounds of formula I can then be converted into the corresponding thionaphthylglycine derivatives, i.e., pharmacologically active compounds, either in the form of an acid (R ² is hydrogen) or an ester (R ² is lower alkyl). The latter reaction is carried out by reacting the compounds of formula (I) with phosphorus pentasulfide. The compounds of formula I are conveniently reacted under anhydrous conditions with 2 to 5 molar equivalents of phosphorus pentasulfide in a neutral solvent such as xylene or. toluene. The reaction temperature is 30-150 ° C and the reaction time is 20 minutes to 4 hours. The reaction may take place in the presence of an organic proton acceptor such as N-methylmorpholine, triethylamine or pyridine. It should be noted that when reacting a compound of formula (I) with phosphorus pentasulfide wherein R ^{2 is} hydrogen, the first step in working up the reaction mixture is always to decompose the reaction mixture by adding water. As a result, the corresponding small amount of the thio acid present in the reaction mixture, formed as a result of the reaction of the carboxyl group and the phosphorus pentasulfide, is converted to the corresponding carboxylic acid.

The following examples illustrate the invention.

Example 1

Preparation of 5-bromo-N-methyl-1-naphthalenecarboxamide (IV, R ¹ = CH ³ , R ³ = Br and R ⁴ = H)

1,2-Dibromo-naphthalene (1.2 g, 4.2 mmol), see Hodgson, Η. H. and Whitehurst, J. S., J. Chem. Soc. 80 (1947)] and 0.06 ml of 1,2-dibromoethane in 10 ml of anhydrous freshly distilled tetrahydrofuran, and 119 mg (4, Fine magnesium turnings (9 mmol) were added under a nitrogen atmosphere. The exothermic reaction is complete within 20 minutes. After stirring for half an hour, a mixture of methyl isocyanate (0.18 mL, 4.2 mmol) and diethyl ether (5 mL) was added dropwise at room temperature (20-22 ° C). The reaction mixture was stirred at room temperature for an additional 1.5 hours and then poured into 125 ml of water. The aqueous solution was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated. 818 mg of crude product are obtained, which is purified by chromatography on 45 g of silica gel, eluting with 25% acetone-75% toluene. The appropriate fractions were collected to give 420 mg of pure product. For analysis, part of the product was recrystallized from methylene chloride and hexane. 152-153 ° C; NMR

187,670 (CDCl3): δ 3.03 (d, J = 5Hz, 3H), 6.05 (broad, 1H), 7.6 (m, 6H);

IR (CHCl ₃ ): 3450, 3100, 1655, 1515 cm -1.

Example 2

Preparation of N - ((5-bromo-1-naphthyl) carbonyl] -N-methylglycine methyl ester

- (I, ^R1 and ^R2 = _CH3, ^R3 = Br ^R4 = H)

Sodium hydride (26.3 mg, 0.55 mmol) was added to anhydrous dimethyl sulfoxide (3 mL) in a 50% oil dispersion at 55-60 ° C. After stirring until the effervescence ceased, 132 mg (0.5 mmol) of 5-bromo-N-methyl-1-naphthalenecarboxamide (prepared as in Example 1) were added and the reaction mixture was heated at 55-60 ° C for 5 minutes. stir. Methyl bromoacetate (0.045 mL, 0.55 mol) was added and stirring continued at 55-60 ° C for an additional 2 hours. The reaction mixture was cooled and poured into 50 ml of 2N aqueous hydrochloric acid. The resulting mixture was extracted three times with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to dryness. 138 mg of an evaporation residue are obtained, which is purified by chromatography on 9 g of silica gel, eluting with 20% acetone-80% toluene. The appropriate fractions were collected to give 50 mg of an oily product which crystallized on trituration with diethyl ether. The solid is recrystallized to give the desired product, m.p. 90-92 ° C.

NMR (CDCl 3: δ 2.8 and 3.25 (2s, 3H), 3.6 and 3.85 (2s, 3H), 4.35 (broad, 2H), 7.75 (m, 6H);

IR (CHCl ₃ ): 1745, 1635 cm @ -1.

Example 3

Preparation of N - [(5-bromo-1-naphthyl) carbonyl] -N-methylglycine (I, R ¹ = CH ₃ , R ² and R ⁴ = H and R ³ = Br)

3.7 g (11.0 mmol) of N - [(5-bromo-1-naphthyl) carbonyl] -N-methylglycine methyl ester (prepared as described in Example 2) are suspended in 50 ml of methanol, and 13.2 ml of 1N aqueous sodium hydroxide are added to the suspension. The mixture was stirred at 20-22 ° C for 1.5 hours. The mixture was neutralized with aqueous hydrochloric acid and methanol was distilled off under reduced pressure. The resulting solution was acidified with aqueous hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was recrystallized from ethanol-water to give 3.25 g of product, m.p.

NMR _(DMSO-d6): δ 2.75 and 3.10 (2s, 3H), 2.75 and 3.10 (2s, 3H), 3.75 and 4.25 (2s, 3H), 7. 3-8.3 (m, 6H)

IR (Nujol *): 1745, 1720, inflexion, 1580 cm @ -1; UV Z _max (ethanol): 322 nm (ε680), 316 (1,000), 299 (6,510), 289 (9,055), 279 (7,150), 226 (63,080);

Elemental analysis calculated: C% = 52.19,

H, 3.76; N, 4.35;

* Nujol is a brand name for a white mineral oil found: C% = 52.09,

H, 3.84; N, 4.48.

Proceeding as in Examples 1, 2, 3 and optionally 4, using the appropriate starting materials of formula II and the corresponding lower alkyl isocyanates, other compounds of formula I and thionaphthoylglycine derivatives can also be produced.

Starting with an equivalent amount of 5-bromo-1-methoxy-naphthalene instead of 1,5-dibromo-naphthalene, N - [(5-methoxy-1-naphthyl) -thioxymethyl] -N-methylglycine can be prepared, m.p. C;

NMR _(DMSO-d6): δ 2.93 (s, 3H), 3.90 (s, 3H), 4.65 and 5.16 (2dJ = 17 Hz, 2H), 6.95 (2d, J 7 = 7 Hz, J ₂ = 3 Hz), 7.35 (m, 4H), 8.11 (2d, J = 8 Hz, J ₂ = 2 Hz, 1H).

Using an equivalent amount of 1,5-dichloro-naphthalene instead of 1,5-dibromo-naphthalene gives N - [(5-chloro-1-naphthyl) -thioxymethyl] -N-methyl-glycine, m.p. 153-154 ° C. ;

NMR (CDCl ₃ ): δ 3.03 (s, 3H), 4.67 and 5.33 (d, J = 17 Hz, 2H).

Using an equivalent amount of 5-bromo-1-methylnaphthalene instead of 1,5-dibromo-naphthalene gives N - [(5-methyl-1-naphthyl) thioxomethyl] -N-methylglycine, m.p. 190-191 'C.

NMR (CDCl ₃ ): δ 2.66 (s, 3H), 3.05 (s, 3H), 3.85 and 5.0 (m, 2H), 7.5 (m, 6H), 8.75 (broad, 1H).

Using an equivalent amount of 1-chloro-6- (trifluoromethyl) -6-methoxynaphthalene instead of 1,5-dibromonaphthalene, N - {[(5-trifluoromethyl) -6-methoxy-1-naphthyl] -carbonyl} -N-methylglycine, m.p. 174-175'C, from which Example 4 was obtained.

N - {[(5-trifluoromethyl) -6-methoxy-1-naphthyl] thioxomethyl} -N-methylglycine, m.p. 164-165 ° C.

NMR (CDCl ₃ ): δ 3.05 (s, 3H), 3.95 (s, 3H), 4.55 and 5.4 (d, J = 17 Hz, 2H), 7.6 (m, 5H ), 9.8 (broad, 1H).

Example 4

This example illustrates the conversion of the N - [(1-naphthyl) carbonyl] -N- (lower) alkylglycine (lower) alkyl ester of formula (I) to the corresponding thionaphthoylglycine (lower) alkyl ester, and converting the latter compound to the corresponding acid by hydrolysis.

35.5 g (106 mmol) of N - [(5-bromo-1-naphthyl) carbonyl] -N-methylglycine methyl ester (prepared as in Example 2) are dissolved in 10 ml of anhydrous pyridine and To the solution was added slowly with stirring 44.5 g (200 mmol) of phosphorus pentasulfide. The mixture is refluxed for 1.5 hours with stirring and then poured into one liter of water at 50-60 ° C (care must be taken to produce significant amounts of hydrogen sulfide). The mixture was allowed to cool to room temperature, filtered and the filtrate was extracted with ethyl acetate. The extract was washed with 1 N aqueous hydrochloric acid, saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue was recrystallized from ethanol-water (4: 1) to give N - [(5-bromo-1-naphthyl) thioxomethyl] -N-methylglycine methyl ester, m.p. 85-86 ° C.

187,670

NMR (CDCl ₃ ): δ 3.0 (s, 3H), 3.85 (s, 3H), 4.58 and 5.37 (2d, J = 17 Hz, 2H), 7.1-8.3 (m, 6H)

UV λ _max (ethanol): 281 nm (ε 14,480) 218 (14,480).

7.3 g (20.7 mmol) of the above product are suspended in 75 ml of methanol and 25 ml of 1N sodium hydroxide are added. The mixture was stirred at room temperature (20-22 ° C) for half an hour and then neutralized with aqueous hydrochloric acid to pH 7. Methanol was distilled off under reduced pressure. The remaining solution was acidified with aqueous hydrochloric acid (pH = 2) and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. The residue was recrystallized from ethyl acetate-hexane

5.3 g of N - [(5-bromo-1-naphthyl) thioxomethyl] -N-methylglycine are obtained, m.p. 181 ° C.

NMR _(DMSO-d6): δ 2.95 (s, 3H), 4.65 and 5.2 (2d, J = 16.8 Hz, 2H), 7.85 (m, 6H)

UV λ _max (ethanol): 285 nm (ε 12,300), 280 (12.4000), 221 (42,600)

IR (Nujol); 2900, 1720 cm ^-1 Elemental analysis: Calculated: C% = 49.72,

H, 3.58; N, 4.14;

Found: C, 49.63;

H, 3.63; N, 4.18.

Example 5

The compounds of formula (I) are intermediates in the preparation of the corresponding thionaphthoylglycine derivatives, the latter having an aldose reductase inhibiting effect as described by Hayman, S. and Kinoshita, J.H. Biol. Chem. 240, 877 (1965)] with the exception that the final chromatographic step was omitted for the production of the enzyme from bovine lens.

The aldose reductase inhibitory activity of thionaphthoylglycine derivatives is summarized in Table 1,

l. % Enzyme Inhibition%

Test compound concentration (M)

I0 ^J 10 ⁶ to ¹ N - [(5-bromo-l-naphthalenyl) methyl] -N-methyl- glycine 93 87 47 N - [(5-methoxy-l-naphthalenyl) methyl] -N- methyl-glycine 83 64 17 N - [(5-chloro-1-naphthyl) -loxomethyl] -N-methylglycine 88 75 29 N - [(5-methyl-l-naphthyl) -lioxo-methyl] -N-methyl- glycine 89 74 26 N - [(5-bromo-6-methoxy-1-naphthyl) thioxomethyl] -N-methylglycine 99 91 72 N - {[(5-trifluoromethyl) -6-methoxy-1-naphthyl] thioxomethyl} -N-methylglycine 98 94 65

Thionaphthoylglycine derivatives can be used in both human and veterinary medicine, alone or in pharmaceutical form, for example in capsule or tablet form, in admixture with pharmaceutically acceptable carriers. Thionaphthoylglycine derivatives are preferably administered orally, in solid form such as starch, milk sugar, certain types of substances, but they can also be administered in solution or can be injected parenterally. For parenteral administration, a sterile solution of the compounds at pH 7.2-7.6 should be prepared and the pH should be maintained with a pharmaceutically acceptable buffer.

Dosage of thionaphthoylglycine derivatives depends on the form of application and the particular compound. In addition, the dosage will also depend on the individual being treated. Generally, treatment is initiated with small doses that are substantially lower than the optimum dose of the given compound. Thereafter, the dose is gradually increased until the expected effect is achieved. In general, thionaphthoylglycine derivatives are preferably administered in a concentration that achieves the desired therapeutic effect without causing adverse or adverse health effects. For topical application, the compounds are administered as eye drops in a 0.05-0.2% solution. The frequency of treatment will vary depending on the individual being treated, from 1 drop to 1 drop every 2-3 days. For oral or parenteral administration, the preferred dosage range is from 0.1 to 200 mg / kg / day, subject to the aforementioned dosage adjustment. Generally, a satisfactory therapeutic effect can be achieved with a daily dose of 0.5-30 mg / kg.

Unit dosage forms, such as capsules, tablets, pills, and the like, may contain from 5.0 mg to 250 mg of thionaphthylglycine derivative, in admixture with a suitable amount of a pharmaceutical carrier. For oral administration in capsule form, the capsule may contain from 5.0 to 250 mg of the active ingredient, with or without a pharmacological diluent. The effervescent or ordinary tablets contain from 5.0 to 250 mg of the active ingredient in admixture with conventional carriers. Coated or uncoated tablets of effervescent or common tablets may be prepared according to known procedures. Neutral diluent carriers such as magnesium carbonate or lactose may also be used together with conventional disintegrants such as magnesium stearate.

Syrups and elixirs for oral use may be prepared from water-soluble salts of thionaphthoylglycine derivatives such as sodium N - {[5- (trifluoromethyl) -6-methoxy-1-naphthyl] thioxymethyl} -N-methyl- glycine, solvent or preservative, preferably glycerol or ethanol.

Claims (7)

Patent claims A process for the preparation of a compound of formula (I): wherein: R ^{1 is C} 1 -C 4 alkyl, R ^{2 is} hydrogen or C 1 -C 4 alkyl, R ^{3 is} halogen or trifluoromethyl, and R ^{4 is} hydrogen or C 1 -C 4 alkoxy, ) in the formula R ³ and R ⁴ are within the scope of the invention and X is bromo, chloro or iodo, the corresponding formula (III) being -5187 670 R ³ and R ⁴ are as defined herein and Y is MgX, the latter of which X is as above, or a lithium atom into an organometallic compound to give the compound of formula (III) to form an R * NCO (lower carbon) alkyl isocyanate, wherein R * is as defined herein, to give the compound of formula IV, wherein R ¹ , R ³ and R ⁴ are as hereinbefore condensed with a lower alkyl ester of haloacetic acid in the presence of a proton acceptor and the resulting compound of formula (I) R ¹ , R ³ and R ⁴ are as defined above and R ² is lower alkyl - optionally hydrolyzed. 2. A process according to claim 1 for the preparation of a compound of formula I wherein: R ^{1 is} methyl, R ^{2 is} hydrogen or methyl, R ^{3 is} bromo or trifluoromethyl and R ^{4 is} hydrogen or methoxy, characterized in that the starting compound used is a compound of formula II wherein R ³ and R ⁴ are and X is as defined in claim 1 and methyl isocyanate and methyl haloacetic acid are used as reagents. 3. A process according to claim 1 wherein the proton acceptor is a sodium hydride dimethyl sulfoxide mixture. 4. A process according to claim 1 wherein the compound of formula II wherein R ³ , R ⁴ and X are as defined in claim 1 is converted to an organic metal compound of formula III wherein R ³ and R ⁴ are as defined above and Y is MgX, the latter of which is X above, which is reacted with a lower alkyl isocyanate of the formula R'NCO, wherein R 'is as defined in claim 1. , condensing the resulting compound of formula (IV) with a lower alkyl ester of haloacetic acid in the presence of a proton acceptor in the presence of R ¹ , R ^3, and R ⁴ , and the resulting compound of formula (I) wherein R ^1, R ³ and R ⁴ are as defined above and R ² to the report of a lower alkyl group - optionally ^five hydro lysed. 5. The process of claim 1 wherein the compound of formula II wherein R ³ , R ⁴ and X are as defined in claim 1 is converted to an organometallic compound of formula III wherein R ³ and R ⁴ are as defined above and Y is a lithium atom, which is a lower alkyl isocyanate of the formula R ² NCO - wherein R ¹ is as defined in claim 1. as defined in claim - is reacted with ¹⁵ (IV) compound of the formula: - wherein R ^1, R ³ and R ⁴ are as ^stated above - a proton acceptor in the presence of condensing a halogen acid (lower) alkyl ester, and yielded (I) of formula compound - wherein R ^1, R ^{3 0} and R ⁴ is as defined above and R ² represents a lower alkyl group - optionally hydrolysed. The method according to 6 of claim 1 embodiment for the preparation of compounds (I) of the formula which is ^{25 R1} is methyl, ^R2 is hydrogen or methyl, R ³ is bromo and R ⁴ represents a hydrogen atom, characterized in that the starting compound (II) A compound of the general formula wherein R ³ and R ⁴ are as defined in claim ³⁰ and X is as defined in claim 1, and methyl isocyanate and methyl haloacetic acid are used as reagents. . Seventh embodiment The method according to claim 1 of formula (I) compounds of general formula ³⁵ at lítására wherein ^R1 is methyl, ^R2 is hydrogen or methyl, ^R3 is trifluoromethyl, ^R4 is hydrogen or methoxy, characterized in that the starting material (II) offers using Compound ⁴⁰ general wherein R ³ and R ⁴ is and X is as defined in claim 1 and methyl isocyanate and methyl haloacetic acid are used as reagents.