SK286709B6 - Method for producing aryl-iminomethyl-carbamic acid esters, intermediates and use thereof - Google Patents

Abstract

The invention relates to a method for producing aryl-iminomethyl-carbamic acid esters of the general formula (I) wherein R1 denotes a group selected from among methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and -C(Me2)phenyl, each of which may be mono-, di- or trisubstituted by hydroxy, R2 denotes a group selected from among methyl, ethyl, propyl and benzyl, which can be used on a large scale.

Description

Technical field

The invention relates to a wide range of useful processes for preparing aryliminomethylcarbamic acid esters, intermediates and their use.

BACKGROUND OF THE INVENTION

International Patent Application WO 96/02497 discloses benzamidines as well as aryliminomethylcarbamic acid esters which have high potency as drugs having LTB ₄ antagonist activity. Of particular interest here are the compounds of formula (I).

It is an object of the present invention to provide a process which allows the synthesis of compounds of formula (I) to a large extent with high yields and high purity end products.

SUMMARY OF THE INVENTION

The problem has been solved by a process for producing compounds of formula (I)

(I) where

R ¹ is a radical selected from the group consisting of methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and -C (Me ₂ ) phenyl, each of which may be substituted one, two or three times with hydroxy;

R ² is a radical selected from the group consisting of methyl, ethyl, propyl and benzyl, the essence of which is that a compound of formula (II)

(II), where

R ¹ 'is a radical selected from the group consisting of methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and -C (Me ₂ ) phenyl, each of which may be substituted one, two or three times with -O-PG;

wherein the -O-PG group is a hydroxyl protecting group and is selected from the group consisting of methoxymethyloxy, 2-methoxyethoxymethyloxy, 1-ethoxyethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert-butyloxy, benzyloxy and 4-methoxybenzyloxy, is first treated with an alkali metal hexaalkyldisilazane in an etheric or aromatic solvent and then treated with a compound of formula (III)

R ² -O-COX '(III) wherein

R ² is defined as above and X 'is chloro, bromo or -OR ^2, and the processing of an acid of formula HY, the isolated compound of formula (IV)

wherein R ¹ and R ² are as defined above and Y is any acidic residue, and a compound of formula (I) is isolated from this compound.

Compounds of formulas (I) and (IV) also include the corresponding tautomers of formulas (I-T) and (IV-T):

(l-t) (lv-t)

The term "alkali metal hexaalkyldisilazane" as used to refer to a reagent that reacts with a compound of formula (II) generally means a compound of formula (VIII)

(VIII),

Met is an alkali metal, preferably lithium, sodium or potassium, preferably lithium, and R ³ is independently C _r C ₄ alkyl group, preferably methyl or ethyl, most preferably methyl.

Particularly preferred are lithium hexamethyldisilazane, sodium hexamethyldisilazane and potassium hexamethyldisilazane, especially lithium hexamethyldisilazane.

The term "subsequent conversion" with a compound of formula (III) includes processes in which the product of the conversion of a compound of formula (II) with an alkali metal hexamethyldisilazane directly, without further intermediate conversion, is reacted with a compound of formula (III), as well as processes in which the free amidine base is released in the meantime. Preferably, the conversion product of the compound of formula (II) reacts with an alkali metal hexamethyldisilazane directly, in particular in the so-called "one-pot synthesis", with the compound of formula (III).

Preferred is a process for the preparation of compounds of formula (I) wherein R ¹ is a radical selected from the group consisting of phenyl, benzyl and -C (Me ₂ ) phenyl, each of which may be substituted once or twice, preferably once with hydroxy;

R ² is a radical selected from the group consisting of ethyl, propyl and benzyl, wherein the compound of formula (II) wherein

R ¹ 'is a radical selected from the group consisting of phenyl, benzyl and -C (Me 2) phenyl, each of which may be substituted once or twice, preferably once with -O-PG;

wherein the -O-PG group is a hydroxyl protecting group and is selected from the group consisting of methoxymethyloxy, 2-methoxyethoxymethyloxy, 1-ethoxyethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert-butyloxy, benzyloxy and 4-methoxybenzyloxy, preferably 2-tetrahydropyranyloxy , is treated with an alkali metal hexaalkyldisilazane in an etheric or aromatic solvent and subsequently treated with a compound of formula (III)

R ² -O-COX '(III) wherein

R ² is defined as above and X 'is chloro, bromo or -OR ^2, and the processing means of aqueous hydrochloric acid to give Compound of the formula (IVA)

(IVA), wherein R ¹ and R ² are as defined above, and a compound of formula (I) is isolated from this compound.

Particularly preferred is a process for the preparation of compounds of formula (I) wherein R ¹ is -C (Me ₂ ) phenyl, which may optionally be substituted once with hydroxy; R ² is ethyl, which is a compound of formula (II) wherein

R ¹ 'represents -C (Mc ₂ ) phenyl, which may be optionally substituted once with -O-PG;

wherein the -O-PG group is a hydroxyl protecting group and is selected from the group consisting of methoxymethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert-butyloxy, benzyloxy and 4-methoxybenzyloxy, preferably 2-tetrahydropyranyloxy, with an alkali metal hexaalkyldisilazane in an etheric or aromatic solvent and then treated with a compound of formula (III)

R ² -O-COX '(III) wherein

R ² has the abovementioned meaning and

X 1 is chlorine, bromine or -OR ² , preferably chlorine, and after treatment with aqueous hydrochloric acid, a compound of formula (IVA) is isolated wherein the radicals R ¹ and R ² are as defined above, and a compound of formula (I) is isolated ).

In one particularly preferred embodiment of the process of the invention, the compound of formula (II) is produced by a process comprising the steps of: a) reacting C ₁ -C ₄ alkyl esters of 3-halomethylbenzoic acid with 4-hydroxybenzonitrile in the sense of Wilkinson ether synthesis;

b) reduction conversion of the obtained 3- (4-cyanophenoxy) benzoic acid alkyl esters of the general formula (VII)

CN wherein R is C _r C ₄ alkyl, to a compound of formula (V)

CN (VII), (V), wherein X is hydroxy;

c) optionally treating a compound of formula (V) wherein X is hydroxy with a halogenating reagent or sulfonic acid chloride;

d) reacting a compound of formula (V) wherein X is hydroxy, chlorine, bromine, mesilate, triflate or tosilate with a phenol derivative of formula

(VI), wherein R ¹ 'has the meanings set forth in claims 1 to 4;

optionally in the form of the corresponding sodium or potassium phenolates, under basic reaction conditions, preferably in a polar organic solvent.

The hydrochlorides of the formula (IVA) are of central importance for the process for the preparation of the compounds of the formula (1) according to the invention. These are formed directly as well-crystallizing salts in high yield, from which by-products and / or impurities can be easily separated by crystallization. Accordingly, one embodiment of the present invention is directed to intermediates of formula (IVA)

(IVA) wherein the radicals R ¹ and R ² may be defined.

Of the compounds of formula (IVA), {[4- (3- {4- [1- (4-hydroxyphenyl) -1-methylethyl] phenoxymethyl} benzyloxy) phenyl] iminomethyl} carbamic acid ethyl ester hydrochloride is particularly preferred.

Compounds of formula (II)

wherein R ¹ 'may have the meanings indicated, according to the invention are obtained by reaction of a compound of formula (V)

(V) wherein X is hydroxy, chloro, bromo, mesylate, triflate, benzenesulfonate or tosilate, with a compound of formula (VI)

(VI), wherein R ¹ 'may have the meanings indicated, and wherein the compound of formula (VI) may optionally also be used in the form of its sodium and potassium phenolates, under basic reaction conditions in a polar organic solvent.

Preferred is the preparation of compounds of formula (II) wherein R ¹ 'may have the meanings indicated by reacting a compound of formula (V) wherein X is hydroxy, chlorine or mesylate, preferably hydroxy or chlorine, most preferably chlorine, with a compound of formula (VI) ), wherein R ¹ 'may be as above and wherein the compound of formula (VI) is used as the alkali metal phenolates, preferably in the form of a nátriumfenolátov.

In the synthesis of the compounds of formula (I) according to the invention, the intermediates of formula (V) have central importance. Accordingly, another embodiment of the present invention is directed to compounds of formula (V)

(V) per se, where X may have the meanings indicated, particularly preferably hydroxy or chloro.

Furthermore, one of the starting materials, which is a compound of formula (VII), is of particular importance for the synthesis of the compounds of formula (I) according to the invention. Accordingly, another embodiment of the present invention is directed to compounds of formula (VII)

(VII) per se, wherein R 1 is C 1 -C ₄ alkyl, preferably methyl or ethyl, most preferably methyl.

For carrying out the process for the preparation of the compounds of the formula (I) according to the invention starting from the nitriles of the formula (II), the following is preferably carried out as follows:

To a solution of an alkali metal hexaalkyldisilazane, preferably lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, more preferably lithium bis (trimethylsilyl) amide in an etheric or aromatic organic solvent, preferably a solvent selected from tetrahydrofuran, toluene , dioxane, more preferably tetrahydrofuran or dioxane, most preferably tetrahydrofuran, slowly adds a compound of formula (II), particularly with cooling, preferably at a temperature between -50 ° C and 30 ° C, more preferably at -20 ° C to 10 ° C most preferably at about 0 ° C. The amount of the alkali metal hexaalkyldisilazane used is determined by the amount of the nitrile of the general formula (ID) used. At least 1 mol, preferably from 1.01 to 1.15 moles of the alkali metal hexaalkyldisilazane is used per mol of nitrile of the formula II. 0.7 and 1.5, preferably 0.9 to 1.3 kg, per mole of compound of formula (II) used.

After the addition of the compound of formula (II) is complete, the suspension thus obtained is stirred at a constant temperature, optionally at a temperature of up to 40 ° C, preferably at about 20-25 ° C for 6-24 hours, preferably up to 18 hours, most preferably 10-12. hours. In this case, it can optionally be observed that the suspending solid first goes into solution.

Thereafter, the pellet may be diluted, optionally with either another ethereal solvent or a non-polar organic solvent, preferably an aromatic organic solvent. Preferably a solvent selected from the group consisting of toluene, benzene, cyclohexane, methylcyclohexane or xylene is used, of which toluene and xylene are more preferred, and toluene is most preferred. When the pellet is diluted, addition of up to 0.5 L, preferably up to 0.3 L of solvent per mole of the compound of formula (II) used is sufficient.

The reaction is brought to a reaction temperature of -50 ° C to 20 ° C, preferably -20 ° C to 10 ° C, most preferably -10 ° C to 0 ° C before the addition of the compound of formula (III). A compound of formula (III) is then added, wherein at least 1 mol, preferably 1.05 to 1.3 mol, most preferably 1.1 to 1.2 mol of the compound of formula (III) is added per mole of the compound of formula (11) used. ).

After complete conversion, it is hydrolyzed by the addition of an acid of formula (HX), preferably an inorganic or organic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid and fumaric acid, in particular aqueous hydrochloric acid. Approximately 1 mole of the acid, especially hydrochloric acid, is added per mole of the compound of formula (II) originally used. According to the invention, it is preferred to add dilute hydrochloric acid (preferably 8 to 15%, more preferably 10 to 12%). After about 10 minutes to 1 hour, the aqueous lower phase is separated and an organic solvent selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, optionally also a mixture of the two solvents, preferably a mixture of acetone and methyl isobutyl ketone, is added to the organic phase. to 1): 1, preferably in a ratio of (2.5 to 1.5): 1. Addition of aqueous hydrochloric acid initiates crystallization of the compounds of formula (IVA). About 1 to 1.2 mol of acid, preferably hydrochloric acid, is used per mole of the compound of formula (II) originally used. According to the invention, it is preferable to add preferably 32 to 37%, more preferably 37% hydrochloric acid. The compounds of formula (IVA) are separated from the reaction mixture by conventional means, for example, by centrifugation, and an organic solvent selected from acetone, methyl isobutyl ketone, methyl ethyl ketone or a carboxylic acid ester, preferably acetone, washed and dried.

The release of the compounds of the formula I from the acid addition salts of the formula IV, in particular the hydrochlorides of the formula IVA, is preferably carried out under neutral reaction conditions with basic reaction partners, preferably in the presence of buffer systems according to the following procedure:

To a solution of trisodium citrate dihydrate, sodium hydroxide, potassium hydroxide, alkali metal or alkaline-earth salts of organic or inorganic weak acids, preferably trisodium citrate dihydrate, trisodium citrate or sodium hydroxide, more preferably trisodium citrate dihydrate in water, preferably at 0 to 20 ° C, preferably at 0 to 20 ° C. ° C, most preferably at about 20 ° C, add an organic solvent selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran or a carboxylic acid ester, preferably acetone, followed by the addition of a compound of formula (IV). About 1 to 2 mol, preferably about 1.5 mol of said sodium or potassium citrate, and about 1 to 3 L, preferably about 2 L of said organic solvent are used per mole of the compound of formula (IV) used. At constant temperature, the mixture is stirred for 20 minutes to 2 hours, preferably 1 to 1.2 hours.

If strong bases such as sodium hydroxide are used, the method of addition may optionally be reversed. For example, the crystalline product is collected by filtration, washed with water with the said organic solvent to remove the salt, and then dried.

The compounds of formula (II) are, as already mentioned, available by converting a compound of formula (V) with a compound of formula (VI). According to the invention, it is possible to proceed in the manner described above. The compound of formula (V) wherein X is hydroxy is preferably dissolved in an aprotic-polar organic solvent, preferably Ν, Ν-dimethylacetamide, acetone, methyl ethyl ketone, methylisobutyl ketone, N-methylpyrrolidone, Ν, Ν-dimethylformamide, tetraalkyl urea, more preferably Ν, Ν-dimethylacetamide. According to the invention, from 0.5 to 1.0, preferably about 0.7, of solvent is used per mole of the starting compound. Subsequently, the solution thus obtained is cooled to a temperature of < 10 ° C, preferably to a temperature between + 5 ° C to -20 ° C, more preferably to about -10 ° C to 0 ° C. A suitably substituted sulfonic acid chloride, optionally said organic solvent, an organic base, optionally said organic solvent, as well as an aqueous solution of an inorganic base are then gradually added. Suitable substituted sulfonic acid chloride according to the invention are, for example, methanesulfonic acid chloride, para-toluenesulfonic acid chloride, benzenesulfonic acid chloride or trifluoromethanesulfonic acid chloride. Methanesulfonic acid chloride is preferably used. As organic bases, for example, dimethylaminopyridine, pyridine, methylpyridine, tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, or even cyclic amines such as N-methylpyrrolidine or DBU (diazabicycloundecene) can be used. Preferred organic amines are N-methylpyrrolidine, trimethylamine, triethylamine or diisopropylethylamine, more preferably triethylamine. The organic base is used in at least a stoichiometric amount based on the starting compound of formula (V). Preferably, the organic base is added in an excess of 10 to 50 mol%, more preferably in an approximately 30% excess based on the compound of formula (V) used. As an aqueous solution of the organic base, alkali earth and alkali metal hydroxide solutions are usually used, with alkali metal hydroxide solutions being preferred. Aqueous solutions of potassium hydroxide and sodium hydroxide are of particular importance according to the invention. Usually 20 to 50% solutions of the above inorganic hydroxides are used. Concentrated solutions, such as 45% solutions, are preferred according to the invention. Based on the compound of formula (V) used, the inorganic base is added in at least a stoichiometric amount, but preferably in an excess of 50 to 100 mol%. More preferably, the inorganic base is added in an excess of about 75 mole% based on the compound of formula (V) used.

Optionally, the reaction mixture can be diluted after each addition of a suitably substituted sulfonic acid chloride or organic base by addition of said organic solvents. In this case, 2 to 10%, preferably about 5%, are added at the beginning of the determined amount of solvents.

In any case, after the addition of the aqueous inorganic base solution is complete, the reaction mixture is diluted with the organic solvents mentioned above. In this case, approximately 0.5 to 1.0 l, preferably between 0.7 and 0.8 l of solvent used, are added per mole of the starting compound of the formula (V) used. This is followed by the addition of alcoholates or metal salts of the general formula (VI). Sodium and potassium phenolates which can be derived from the compounds of the general formula (VI) are preferably used. According to the invention, stoichiometric amounts, or, where appropriate, substoichiometric amounts or an excess of the compound of the formula (VI), can be added relative to the starting material of the formula (V) used. After the addition of the compound of formula (VI) is complete, the reaction proceeds for about 1 to 3 hours, preferably about 1.5 to 2 hours at 5 to 35 ° C, preferably at about 25 ° C, and subsequently stirred for about 1 to 3 hours , preferably about 1.5 to 2 hours at 50 to 100 ° C, preferably at about 70 to 90 ° C. Upon completion of the reaction, the product of formula (II) is crystallized by addition of a suitable polar solvent selected from the group of lower alcohols and water.

In order to obtain products of particularly high purity in high yields, it has proved advantageous according to the invention if a solvent mixture consisting of a non-polar organic solvent, preferably xylene or toluene, more preferably toluene, further a polar organic solvent, preferably a lower alcohol, such as methanol, ethanol, butanol or isopropanol, more preferably isopropanol, and water. The ratio of non-polar to polar organic solvent and water volumes may vary from 1: (7 to 10): (5 to 8), preferably 1: (8 to 9): (6 to 7). Cooling to below 50 ° C, preferably to about 30 ° C completes the crystallization of the product of formula (II). After isolation, the crystallized product is optionally washed with said lower alcohol and water.

Where the compounds of formula (II) are obtained starting from compounds of formula (V) in which X has a meaning other than hydroxy, the invention may be carried out as follows.

Sodium or potassium phenolate derived from compounds of formula (VI), together with the compound of formula (V), is added to water, reacted with a non-polar organic solvent, and optionally converted under phase transition conditions. Suitable phase transfer catalysts according to the invention are the group of quaternized ammonium salts, preferably tetradecyltrimethylammonium-, hexadecyltrimethylammonium-, tetrabutylammonium-, tributylmethylammonium- or triethylbenzylammonium- halides, sulphates or hydroxides. As non-polar organic solvents, chlorinated hydrocarbons such as methylene chloride or preferred aromatic hydrocarbons such as benzene, toluene, xylene, preferably toluene can be used. The compounds of formulas (V) and (VI) are used in an approximately stoichiometric ratio, alternatively one of the two reactants may be used in a slight excess (e.g. 15%). The amount of solvent to be used depends on the amount of starting material used. Between 1 and 2 liters of water and between 0.3 and 1.0 liters of organic solvent, preferably between 1.5 and 1.8 liters of water and 0.5 to 0.7 liters per mole of the compound of the formula (VI) used are used. an organic solvent.

The reaction proceeds with vigorous stirring for 3 to 9, preferably 5 to 7 hours, at a temperature of from 50 to 100 ° C, preferably at 70 to 80 ° C. Subsequently, a polar organic solvent, preferably a lower alcohol, most preferably isopropanol, is introduced into a separate organic phase to crystallize the product. Cooling to below 50 ° C, preferably to about 30 ° C completes the crystallization of the product of formula (II). After isolation, the crystallized product of formula (II) is optionally washed with said lower alcohol and water.

Preparation of the starting compounds of the general formula (V)

CN (V), which, as already mentioned, relates to one embodiment of the present invention, may be analogous to known synthesis methods per se. The preparation of a compound of formula (V) wherein X is a hydroxyl group can be carried out by converting, for example, methyl esters of 3-halomethylbenzoic acid with 4-hydroxybenzonitrile in the sense of Wilkinson ether synthesis. The methyl 3- (4-cyanophenoxy) benzoate (VII) obtained by this reaction can be converted to a compound of formula (V) wherein X = hydroxy (= 4- (3-hydroxymethylbenzyloxy) -benzonitrile) by analogy using conventional standard methods.

Compounds of formula (V) wherein X is chlorine or bromine can be obtained in analogy with per se known synthesis methods from a compound of formula (V) wherein X is hydroxy, using conventional halogenating reagents such as thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, methanesulfonic acid chloride, benzenesulfochloride, preferably thionyl chloride or methanesulfonic acid chloride.

Compounds of formula (V) wherein X is mesilate, triflate or tosilate can be obtained in analogy with per se known synthesis methods from a compound of formula (V) wherein X is hydroxy by conversion with the appropriate sulfonic acid chlorides in aprotic, preferably polar organic solvents, preferably selected from dichloromethane, N, N-dimethylacetamide, dimethylformamide, acetonitrile, N-methylpyrrolidone, tetraalkylurea in the presence of organic bases, preferably selected from dimethylaminopyridine, pyridine, methylpyridine, N-methylpyrrolidine, trimethylamine , triethylamine, diisopropylethylamine and DBU (diazabicycloundecene).

The following examples serve to illustrate exemplary synthetic methods of making the compound of formula (I) of the invention. They are to be understood only as possible, by way of example, illustrated, without limiting the invention to their content.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3- (4-Cyanophenoxymethyl) benzoic acid methyl ester

10.00 kg (43.6 mol) of methyl 3- (bromomethyl) benzoate and 5.21 kg (43.74 mol) of 4-hydroxybenzonitrile are dissolved in 100 l of acetone and mixed with 8.4 kg (60.7 mol) of potassium carbonate in the presence of 0.1 kg of sodium iodide for about 4 hours under reflux conditions. Then 35 l of acetone are distilled off and 100 l of water are added under reflux conditions. The reaction mixture was cooled to 20 ° C and crystallization was completed by adding an additional 301 of water. The crystals formed are separated, washed with water (501) and dried in vacuo.

Yield: 11.1 kg (95%) of 3- (4-cyanophenoxymethyl) benzoic acid methyl ester; mp 109-112 ° C, white solid,

DC (quartz 60 F254 - finished plate (Merck): Rf = 0.5 (toluene: acetone = 9: 1)

Example 2

4- (3-hydroxymethyl-benzyloxy) benzonitrile

20.05 kg (26.7 mol) of methyl 3- (4-cyanophenoxymethyl) benzoate were dissolved in 100 L of THF and 40 L of methanol. 8.51 kg of sodium borohydride are added in portions at 40-45 ° C. The reaction is completed by stirring the reaction mixture at 61 to 63 ° C for about 5 hours. The reaction mixture was then cooled to 25 ° C and 90 115% sodium hydroxide solution was added. After mixing, the aqueous upper phase is separated and reacted with 30 l of 22.5% sodium hydroxide solution. After mixing, the aqueous upper phase is separated and about 100 L of solvent is distilled off at 63-75 ° C at the inlet temperature. The distillation residue is crystallized by adding 20 L of isopropanol at 50-60 ° C and 150 L of water at 40-50 ° C. After cooling the suspension to 20-30 ° C, the crystals are separated, washed with 60-100 L of water and dosed with 25 L of cold isopropanol, and dried under vacuum. Yield: 15.8 kg (88%) of 4- (3-hydroxymethylbenzyloxy) benzonitrile; melting point (DSC): 110-115 ° C, white solid IR: 3444 / cm (OH-band); 2229 / cm (CN band).

Example 3

4- (3-Chlórmetylbenzyloxy) -benzonitrile

Method A:

7.18 g (30 mmol) of 4- (3-hydroxymethylbenzyloxy) benzonitrile are dissolved in 80 ml of dichloromethane, treated with 4.13 g (35 mmol) of thionyl chloride and 0.1 g of DMF, and gas evolution is continued until gas evolution ceases. heating to 40 ° C stir. After cooling, the organic reaction mixture is washed successively with water and dilute sodium hydroxide solution and concentrated to crystallize. Yield: 6.8 g (88%) of 4- (3-chloromethylbenzyloxy) benzonitrile; DC (diatomaceous earth 60 F254 - finished plate (Merck): Rf = 0.9 (toluene-acetone = 9: 1) Rf = 0.44 (toluene).

Method B:

7.18 g (30 mmol) of 4- (3-hydroxymethylbenzyloxy) benzonitrile are dissolved in 22 ml of N, N-dimethylacetamide, treated with 4.47 g (39 mmol) of methanesulfonic acid chloride and 3.95 g (39 mmol). of triethylamine and stirred at 20-30 ° C for 10 hours. Subsequently, the triethylammonium chloride formed is filtered off, the filtrate is reacted with 30 ml of isopropanol and the desired 4- (3-chloromethylbenzyloxy) benzonitrile is introduced by the addition of 30 ml of water for crystallization. The suspension was stirred at 10 ° C for 15 minutes and filtered. The crystals were washed with a mixture of 5 ml of isopropanol and 20 ml of water and dried at 20 ° C under vacuum.

Yield: 6.8 g (88%) of 4- (3-chloromethylbenzyloxy) benzonitrile. Melting point: 65-68 ° C.

Example 4

Nátium-4- {l-methyl-l- [4-tetrahydropyran-2-yloxy) -phenyl] -ethyl} -phenol

121.8 kg of bisphenol A are suspended in 480 L of toluene and 46 L of THF. After the introduction of the catalyst (1.3 kg of 37% hydrochloric acid), 44.9 kg of 3,4-dihydro-2H-pyran is metered in such a way that the temperature does not exceed 40 ° C. In this case, the solid passes into solution. The reaction mixture was then treated with 26.4 kg of 45% sodium hydroxide solution and 260 L of water. The organic upper phase was separated and about 50 L of solvent was removed by distillation. At 30 to 40 ° C, the organic phase is washed several times with dilute sodium hydroxide solution so that sufficient purity can be achieved (DC-control). When the aqueous bottom phase has a pH in the range of 11.8 to 12.2, the excess bisphenol A can be well separated. The extracted purified toluene phase is treated with 11 L of isopropanol and 80 L of water and heated to 50-55 ° C. Addition of 47.4 kg of 45% sodium hydroxide solution and cooling the reaction mixture to 20-25 ° C gave a crystal suspension. The crystals were collected by filtration, washed with about 160 L of toluene and then dried in vacuo. Yield: 96.5 kg (54%) (as tetrahydrate).

Example 5

Synthesis of 4- [3- (4- {1-methyl-1- [4-tetrahydropyran-2-yloxy) phenyl] ethyl} phenoxymethyl) benzyloxy] benzonitrile Method A: (starting from Example 2)

To a solution of 45 kg (188 mol) of 4- (3-hydroxymethylbenzyloxy) benzonitrile (Example 2) in 133 L of N, N-dimethylacetamide at approximately -10 to 0 ° C was successively charged: 28 kg (244 mol) of methanesulfonic acid chloride, 6 1 N, N-dimethylacetamide, 24.7 kg (244 mol) triethylamine, 6 1 N, N-dimethylacetamide, 29.4 kg 45% sodium hydroxide solution, 143 1 N, N-dimethylacetamide, 59.7 kg ( 178.5 mol) of the compound of Example 4 (sodium 4- {1-methyl-1- [4-tetrahydropyran-2-yloxy) phenyl] ethyl} phenolate, as tetrahydrate). The reaction mixture was then stirred at 25 ° C for 2 hours and at 75-80 ° C for a further 1.5 hours. After addition of 32 L of toluene, 255 L of isopropanol and 200 L of water, crystallization is started, which is completed by cooling to 30 ° C. The crystalline product is collected by filtration, washed with isopropanol and water and then dried under vacuum. Yield: 85 kg (90%) of 4- (3- (4- {1-methyl-1- [4-tetrahydropyran-2-yloxy) phenyl] ethyl} phenoxymethyl) benzyloxy] benzonitrile.

Method B: (starting from Example 3)

19.4 kg (50 mol) of the compound of Example 4 (sodium 4- {1-methyl-1- [4-tetrahydro-pyran-2-yloxy) phenyl-ethyl} -phenolate as tetrahydrate) and 12.2 kg (47, 5 mol) of the compound of Example 3 (4- (3-chloromethylbenzyloxy) benzonitrile) was reacted with 85 L of water, a phase transfer catalyst (e.g.: 2.1 kg (2.5 mol) of a 40% aqueous solution of tetradecyltrimethylammonium bromide) and 32 L of toluene, and stirred vigorously at about 80 ° C for 6 hours. Thereafter, 44 l of isopropanol is metered into the organic upper phase separated at 50-70 ° C, the crystalline suspension obtained is cooled to approximately 25 ° C and filtered. The separated crystals were washed twice with 25 l of cold isopropanol each and dried in vacuo.

Yield: 22.8 kg (90%) of 4- [3- (4- {1-methyl-1- [4-tetrahydropyran-2-yloxy) phenyl] ethyl} phenoxymethyl) benzyloxy] benzonitrile.

Example 6

{[4- (3- {4- {1- (4-Hydroxyphenyl) -1-methylethyl] phenoxymethyl} benzyloxy) phenyl] imino methyl} carbaminoic acid ethyl ester hydrochloride

To a solution of 45.5 kg (272 mol) of lithium bis (trimethylsilyl) amide and 266 kg of THF was charged 132 kg (247 mol) of 4- (3- {4- {1- (4-tetrahydropyranylphenyl) -1-methylethyl] phenoxymethyl} benzyloxy) benzonitrile (Example 5) at about 0 ° C. The resulting suspension is stirred for about 10 hours at about 25 ° C. In this case, the solid passes into solution. After addition of 68 1 of toluene, the reaction mixture was cooled to -10 ⁰ to 0 DEG C. and at this temperature the reaction vessel was added 30.8 kg (284 mol) of ethyl chloroformate. After complete reaction, 24.3 kg of 37% hydrochloric acid (diluted with 50 L of water) are metered in and approximately 20 minutes later the aqueous lower phase is separated. Subsequent addition of 106 acetone, 48 L of methyl isobutyl ketone and 24.3 kg of 37% hydrochloric acid began to crystallize the target product. 123 kg (87%) of {[4- (3- {4- {1- (4-hydroxy-phenyl) -1-methylethyl] -phenoxy-methyl} -benzyloxy) -phenyl} -iminomethyl} -carbamic acid ethyl ester hydrochloride are obtained after centrifugation, washing with acetone and drying in vacuo. Melting point: 170-175 ° C.

Example 7

{[4- (3- {4- [1- (4-Hydroxyphenyl) -1-methylethyl] phenoxymethyl} benzyloxy) phenyl] iminomethyl} carbamic acid ethyl ester

To a solution of 109 kg of trisodium citrate dihydrate at 20 ° C was added 466 L of acetone and 142 kg of {[4- (3- {4- [1- (4-hydroxyphenyl) -1-methylethyl] -phenoxymethyl} benzyloxy) phenyl ethyl ester hydrochloride iminomethyl} carbamine (Example 6). After stirring for one hour, the crystalline product is collected by filtration, washed with water to remove the salt, then additionally washed with about 100 L of acetone and finally dried under vacuum.

116 kg (90%) of {[4- (3- {4- [1- (4-hydroxyphenyl) -1-methylethyl] phenoxymethyl} benzyloxy) phenyl] iminomethylcarbaminoic acid ethyl ester are obtained.

PATENT CLAIMS

Claims (11)

A process for producing aryliminomethylcarbamic acid esters of general formula (I) (I), wherein: R ¹ is a radical selected from the group consisting of methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and -C (Me ₂ ) phenyl, each of which may be substituted one, two or three times with hydroxy; R ² is a radical selected from the group consisting of methyl, ethyl, propyl and benzyl, characterized in that a compound of formula (II) (Π), wherein R ¹ 'is a radical selected from the group consisting of methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and -C (Me ₂ ) phenyl, each of which may be substituted one, two or three times with -O-PG, wherein the -O-PG group is a hydroxyl protecting group and is selected from the group consisting of methoxymethyloxy, 2-methoxyethoxymethyloxy, 1-ethoxyethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert-butyloxy, benzyloxy and 4-methoxybenzyloxy, with an alkali metal diisilazane in an etheric or aromatic solvent and then treated with a compound of formula (III) R ² -O-COX '(III) wherein R ² is defined as above and X 'is chloro, bromo or -OR ^2, and the treatment with an acid of formula (HY) isolating the compound of formula (IV) and / or the tautomeric form (IV) wherein the radicals R ¹ and R ² is as defined above, and Y is any acidic residue, and a compound of formula (I) is isolated from this compound. A process according to claim 1, wherein in the compound of formula (I), R ¹ is a radical selected from the group consisting of phenyl, benzyl and -C (Me ₂ ) phenyl, each of which may be substituted one or two times with hydroxy; R ² is a radical selected from the group consisting of ethyl, propyl and benzyl, characterized in that it is a compound of formula (II) wherein R ¹ 'is a radical selected from the group consisting of phenyl, benzyl and -C (Me ₂ ) phenyl, each of which may be substituted one or two times with -O-PG, wherein -O-PG is a hydroxyl protecting group and is selected from the group consisting of methoxymethyloxy, 2-methoxyethoxymethyloxy, 1-ethoxyethyloxy, 2-tetrahydropyranyloxy, 1 -butoxyethyloxy, tert-butyloxy, benzyloxy and 4-methoxybenzyloxy, is treated with an alkali metal hexaalkyldisilazane in an etheric or aromatic solvent and subsequently treated with a compound of formula (III) R ² -O-COX '(III) wherein R ² is defined as above and X 'is chloro, bromo or -OR ^2, and the processing means of aqueous hydrochloric acid to give Compound of the formula (IVA) (IVA) wherein the radicals R ¹ and R ² are as defined above and said compound is isolating the compound of formula (I). A process according to claim 1 or 2, wherein in the compound of formula (I), R ¹ is -C (Me 2) phenyl, which may optionally be substituted once with hydroxy, and R ² is ethyl, characterized in that of formula (II) wherein R ¹ 'is -C (Me 2) phenyl, which may be optionally substituted once with -O-PG, wherein -O-PG is a hydroxyl protecting group and is selected from the group consisting of methoxymethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert-butyloxy, benzyloxy and 4-methoxybenzyloxy, is treated with an alkali metal hexaalkyldisilazane in an etheric or aromatic solvent and subsequently treated with a compound of formula (III) R ² -O-COX '(III) wherein R ² is defined as above and X 'is chloro, bromo or -OR ^2, and the treatment with an acid of formula (HY) isolating the compound of formula (IV) wherein the radicals Y, R ¹ and R ² are as defined above and said compound is isolating the compound of formula (I). A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, characterized in that it comprises the following steps: a) reacting a C _r C ₄ alkyl 3-halomethylbenzoates of 4-hydroxybenzonitrile in the manner Wilkinson ether synthesis; b) reductively converting alkyl 3- (4-cyanophenoxy) benzoic acid of formula (VII) (VII) wherein R is C _r C ₄ alkyl, to a compound of formula (V) (V) wherein X is hydroxy; c) optionally treating a compound of formula (V) wherein X is hydroxy with a halogenating reagent or sulfonic acid chloride; d) reacting a compound of formula (V) wherein X is hydroxy, chlorine, bromine, mesilate, triflate or tosilate with a phenol derivative of formula (VI) OH (vi), wherein R ¹ 'has the meanings set forth in claims 1 to 4; optionally in the form of the corresponding sodium or potassium phenolates, under basic reaction conditions in a polar organic solvent, e) converting the obtained compound of formula (II) into a compound of formula (I) by a process according to claims 1 to 3. Intermediates of general formula (IVA) and / or tautomeric forms thereof wherein the radicals R ¹ and R ² have the meanings given in claims 1, 2 or 3 for the preparation of a compound of the general formula (I) by the process according to claim 1. Intermediates of formula (V) (V) wherein X is hydroxy, chlorine, bromine, mesylate, triflate or tosilate for the preparation of a compound of formula (I) by the process of claim 1. Intermediates according to claim 6, wherein X is hydroxy or chlorine. Intermediates of formula (VII) (VII), wherein R 1 is C 1 -C ₄ alkyl. Use of intermediates of formula (IVA) according to claim 5 for the preparation of a compound of formula (I) according to claim 1. Use of intermediates of formula (V) according to claim 6 or 7 for the manufacture of a compound of formula (1) according to claim 1. 10 Use of intermediates of formula (VII) according to claim 8 for the preparation of a compound of formula (I) according to claim 1.