HK1051851B

HK1051851B - Method for producing aryl-iminomethyl-carbamic acid esters

Info

Publication number: HK1051851B
Application number: HK03104093.5A
Authority: HK
Inventors: 乔尔格‧布兰登堡; 雷纳‧索伊卡; 罗尔夫‧施密德; 拉尔夫‧安德斯凯维茨; 罗尔夫‧鲍尔; 雷纳‧哈姆; 朱塔‧克罗伯
Original assignee: 贝林格尔英格海姆法玛两合公司
Priority date: 2000-01-12
Filing date: 2001-01-11
Publication date: 2005-05-20

Description

Process for preparing aryl-iminomethyl-carbamates

The invention relates to a method for preparing a compound of general formula (I) for industrial scale

Wherein the radical R¹And R²Having the definitions set out in the description and claims.

Background

It is known from international patent application WO 96/02497 that benzamidines and aryl-iminomethyl-carbamates have highly effective LTB as pharmaceutical compositions₄-antagonistic activity. The compounds of the general formula (I) are of particular importance.

The task of the present invention is how to provide a process suitable for the synthesis of the compounds of formula (I) in high yields on an industrial scale with a high purity of the final product.

Detailed description of the invention

To solve the above problems, the present invention provides a process for preparing a compound of the formula (I)

Wherein

R¹Represents a group selected from methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and-C (Me)₂) A radical of phenyl, which may each be mono-, di-or trisubstituted by hydroxyl;

R²represents a group selected from methyl, ethyl, propyl and benzyl,

which is characterized in that a compound of the general formula (II)

Wherein

R^1’Represents a group selected from methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and-C (Me)₂) Phenyl groups, each of which may be mono-, di-or trisubstituted by a group-O-PG, wherein the group-O-PG represents a protected hydroxy function selected from methoxymethyl, 2-methoxyethoxymethyl, 1-ethoxyethyl, 2-tetrahydropyranyloxy, 1-butoxyethyl, tert-butyl, benzyl and 4-methoxybenzyl,

first with an alkali metal hexaalkyldisilazane in an ether or aromatic solvent and then treated with a compound of formula (III)

R²-O-COX′ (III)

Wherein

R²Is as defined above, and

x' represents chlorine, bromine or-O-R²，

After work-up, the compound of formula (IV) is isolated using an acid of formula HY

Wherein the radical R¹And R²As defined above, and Y represents any acid group,

thereby, the compound of formula (I) is released.

The compounds of formula (I) and formula (IV) also include the corresponding tautomers of formula (I-T) and (IV-T):

as used herein, the term "alkali metal hexaalkyldisilazane" represents the reagent used for the reaction with the compound of formula (II), generally referring to the compound of formula (VIII)

Wherein

Met represents an alkali metal, preferably lithium, sodium or potassium, in particular lithium, and

R³in each case independently represent C_1-4Alkyl, preferably methyl or ethyl, in particular methyl.

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

The "subsequent reaction" with the compound of the formula (III) comprises two steps, wherein the reaction product of the compound of the formula (II) with the alkali metal hexamethyldisilazane is reacted directly with the compound of the formula (III), without any further intermediate reaction, and also encompasses procedures in which the free amidine base is liberated from the product formed at the same time. The reaction product of the compound of the formula (II) with the alkali metal hexamethyldisilazane is preferably reacted directly with the compound of the formula (III), in particular in a "one-pot synthesis".

A preferred process for the preparation of the compounds of the general formula (I) is that in which

R¹Represents a group selected from phenyl, benzyl and-C (Me)₂) The radicals of phenyl, which may each be mono-or disubstituted by hydroxyl,

preferably monosubstituted with hydroxy;

R²represents a group selected from ethyl, propyl and benzyl,

which is characterized in that a compound of the general formula (II)

Wherein

R^1’Represents a group selected from phenyl, benzyl and-C (Me)₂) Phenyl groups, each of which may be mono-or disubstituted, preferably monosubstituted, by a group-O-PG, wherein the group-O-PG represents a protected hydroxy function selected from methoxymethyloxy, 2-methoxyethoxymethyloxy, 1-ethoxyethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert-butyloxy, benzyloxy and 4-methoxybenzyloxy, preferably 2-tetrahydropyranyloxy,

first with an alkali metal hexaalkyldisilazane in an ether or aromatic solvent and then with a compound of formula (III)

R²-O-COX′ (III)

Wherein

R²As defined above, and

x' represents chlorine, bromine or-O-R²，

After the treatment, the compound of formula (IVA) is isolated using an aqueous hydrochloric acid solution

Wherein the radical R¹And R²As defined above, and thereby liberate the compound of formula (I).

A particularly advantageous process for preparing the compounds of the formula (I) is

Wherein

R¹represents-C (Me)₂) Phenyl, which may optionally be monosubstituted by hydroxy, and

R²represents an ethyl group, and the like,

which is characterized in that a compound of the general formula (II)

Wherein

R^1’represents-C (Me)₂) Phenyl, which may optionally be monosubstituted by a group-O-PG, wherein the group-O-PG represents a protected hydroxy function selected from methoxymethyl oxy, 2-tetrahydropyranyl oxy, 1-butoxyethyl oxy, tert-butyl oxy, benzyl oxy and 4-methoxybenzyl oxy, preferably 2-tetrahydropyranyl oxy,

R²-O-COX′ (III)

Wherein

R²As defined above, and

x' represents chlorine, bromine or-O-R²Preferably, the reaction is carried out in the presence of chlorine,

after the treatment, the compound of formula (IVA) is isolated using aqueous hydrochloric acid

In a particularly preferred embodiment of the process according to the invention, the process for the preparation of the compound of formula (II) comprises the following steps:

(a) synthesis of 3-halomethylbenzoic acid C according to Wilkinson's ether_1-4-reaction of an alkyl ester with 4-hydroxybenzonitrile;

(b) reduction of the resulting alkyl 3- (4-cyano-phenoxy) benzoate of the formula (VII)

Wherein R' represents C_1-4-alkyl, being a compound of formula (V)

Wherein X represents a hydroxyl group;

(c) optionally treating a compound of formula (V) wherein X represents hydroxy with a halogenating agent or sulfonyl chloride;

(d) reacting a compound of formula (V), wherein X represents hydroxy, chloro, bromo, trifluoromethanesulfonyloxy (Triflat) or tosyloxy, with a phenol derivative of formula (VI), if desired in the form of the corresponding sodium or potassium phenolate, under basic reaction conditions, preferably in a polar organic solvent

Wherein R is^1’Having the definitions set out in claims 1 to 4.

In the process according to the invention for preparing the compounds of the general formula (I), the hydrochloride of the formula (IVA) is of great importance. It can be prepared directly and in high yield in the form of a good crystalline salt and by-products and/or impurities can be easily removed by crystallization. Accordingly, another object of the present invention is an intermediate product of the formula (IVA)

Wherein the radical R¹And R²As defined above.

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

According to the invention, compounds of the general formula (II)

Wherein R is^1’As defined above, which is carried out under basic reaction conditions in a polar organic solvent

(wherein X represents hydroxyl, chlorine, bromine, mesyloxy, trifluoromethanesulfonyloxy, phenylsulfonyloxy or tosyloxy) with a compound of formula (VI)

Wherein R is^1’As defined above, and wherein the compounds of formula (VI) in their sodium or potassium phenolate form may also be used.

Preference is given to sulphonylating compounds of the formula (V) in which X represents hydroxy, chlorine or methaneThe compounds, especially hydroxy or chloro, are reacted with a compound of the formula (VI) in which R is^1’The compounds of the formula (II) in which R is as defined above and in which the compound of the formula (VI) used is in the form of its alkali metal phenolate, preferably in the form of its sodium phenolate, are prepared^1’As defined above).

The intermediates of the formula (V) are of particular importance when the compounds of the formula (I) are synthesized according to the invention. Thus, another aspect of the invention relates to compounds of the formula (V)

Wherein X is as defined above and is preferably hydroxy or chloro.

Furthermore, the compounds of the formula (VII) which are one of the starting materials for the synthesis of the compounds of the general formula (I) according to the invention are of great importance. Thus, a further aspect of the invention relates to compounds of the general formula (VII)

Wherein R' represents C_1-4-alkyl, preferably methyl or ethyl, most preferably methyl.

For carrying out the process for preparing the compounds of the general formula (I) according to the invention starting from the nitriles of the formula (II), the following processes can be used:

the compound of the general formula (II) is slowly metered into a solution of an alkali metal hexaalkyldisilazane, preferably lithium-bis (trimethylsilyl) -amide, sodium-bis (trimethylsilyl) amide, most preferably lithium-bis (trimethylsilyl) amide, dissolved in an ether or an aromatic organic solvent, preferably selected from tetrahydrofuran, toluene, dioxane, particularly preferably tetrahydrofuran or dioxane, most preferably tetrahydrofuran, preferably under cooling, particularly preferably at a temperature between-50 ℃ and 30 ℃, in particular between-20 ℃ and 10 ℃, most preferably at about 0 ℃. The amount of alkali metal hexaalkyldisilazane is determined by the amount of nitrile of formula (II). At least 1 mol, preferably from 1.01 to 1.15 mol, of alkali metal hexaalkyldisilazane are used per mole of nitrile of the formula (II). The amount of ethereal solvent used per mole of compound of formula (II) is between 0.7 and 1.5kg, preferably between 0.9 and 1.3 kg.

After all the compound of formula (II) has been added, the resulting suspension is stirred at constant temperature (optionally up to 40 ℃ C., preferably about 20-25 ℃ C.) for 6 to 24 hours, preferably 8 to 18 hours. More preferably 10 to 12 hours. Thus, the solids that begin to be suspended are observed as entering the solution during the period when necessary.

The mixture may then optionally be diluted by an additional ether solvent or a non-polar organic solvent, preferably an aromatic organic solvent. Preferably, a solvent selected from toluene, benzene, cyclohexane, methylcyclohexane or xylene is used, with toluene and xylene being more preferred, and toluene being most preferred. If the mixture is diluted, up to 0.5 liter, preferably up to 0.3 liter of solvent is added per mole of compound of formula (II).

Before the addition of the compound of the formula (III), the reaction temperature is brought to a temperature between-50 ℃ and 20 ℃, in particular between-20 ℃ and 10 ℃ and most preferably between-10 ℃ and 0 ℃. The compound of the formula (III) is then added in an amount of at least 1 mol, preferably at least 1.05 to 1.3 mol, in particular 1.1 to 1.2 mol, per mol of compound (II).

After the reaction is complete, the product is hydrolyzed by the addition of an acid of the 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, especially aqueous hydrochloric acid. About 1 mole of acid, preferably hydrochloric acid, is used per mole of the initially used compound of formula (II). According to the invention, it is preferred to add dilute hydrochloric acid (preferably 8 to 15%, in particular 10 to 12%).

After about 10 minutes to 1 hour, the lower aqueous phase is separated off and an organic solvent (selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, optionally a mixture of two of the abovementioned solvents, preferably a mixture of acetone and methyl isobutyl ketone, in a ratio of from 3 to 1: 1, preferably from 2.5 to 1.5: 1) is added to the organic phase. Crystallization of the compound of formula (IVA) is initiated by addition of aqueous hydrochloric acid. About 1 to 1.2 mol of acid, preferably hydrochloric acid, are used per mole of the initially used compound of the formula (II). According to the invention, it is preferred to add 32-37%, most preferably 37%, hydrochloric acid. The compound of formula (IVA) is separated from the reaction mixture in a conventional manner, for example by centrifugation, washed with an organic solvent selected from acetone, methyl isobutyl ketone, methyl ethyl ketone or a carboxylic acid ester, preferably acetone, and dried.

The release of the compounds of formula (I) from the acid addition salts of formula (IV), preferably the hydrochloride of formula (IVA), according to the process described hereinafter is generally carried out using basic reactants under reaction conditions which are as neutral as possible, preferably in the presence of a buffer system.

In a solution of trisodium citrate dihydrate, sodium hydroxide, potassium hydroxide, an alkali or alkaline earth metal salt of a weak organic or inorganic acid, preferably trisodium citrate dihydrate, trisodium citrate or sodium hydroxide, most preferably trisodium citrate dihydrate dissolved in water. An organic solvent selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran or carboxylic esters, preferably acetone, is added at 0-40 ℃, preferably 20-25 ℃, in particular about 20 ℃, after which the compound of formula (IV) is added. About 1-2 moles, preferably about 1.5 moles, of sodium or potassium citrate per mole of compound of formula (IV) placed in the reactor, and about 1 to 3 liters, preferably about 2 liters, of the above organic solvent are used. The mixture is stirred at constant temperature for 20 minutes to 2 hours, preferably 1-1.2 hours.

When a strong base such as sodium hydroxide is used, the addition procedure can be reversed if desired. The crystalline product is isolated, for example, by filtration, washed with water to remove all salts, and finally dried using the organic solvents mentioned above.

As indicated above, the compounds of formula (II) can be obtained by reacting a compound of formula (V) with a compound of formula (VI). The following procedure may be used in accordance with the present invention.

The compound of formula (V), wherein X represents a hydroxyl group, is dissolved as far as possible in an aprotic-polar organic solvent, preferably N, N-dimethylacetamide, acetone, methyl ethyl ketone, methyl isobutyl ketone, N-methylpyrrolidone, N-dimethylformamide, tetraalkyl urea, most preferably N, N-dimethylacetamide. According to the invention, in this case from 0.5 to 1.0, preferably about 0.7, liter of solvent is used per mole of starting compound. The solution thus obtained is then cooled to a temperature of < 10 ℃, preferably to a temperature between +5 ℃ and-20 ℃, most preferably about-10 ℃ to 0 ℃. Then, an aqueous solution of an appropriately substituted sulfonyl chloride, optionally the above-mentioned organic solvent, an organic base, and if necessary, the above-mentioned organic solvent and an inorganic base is added in this order. According to the invention, suitable substituted sulfonyl chlorides may be methanesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl chloride or trifluoromethanesulfonyl chloride. Preferably, methanesulfonyl chloride is used. The organic base may be, for example, dimethylaminopyridine, pyridine, picoline, a tertiary amine, such as trimethylamine, triethylamine, diisopropylethylamine, or a cyclic amine, such as N-methylpyrrolidine or DBU (diazabicycloundecane). Preferred organic amines are N-methylpyrrolidine, trimethylamine, triethylamine or diisopropylethylamine, most preferably triethylamine. The organic base is used in an at least stoichiometric amount, based on the starting compound of formula (V), in a 10-50 molar excess, preferably in an about 30 molar excess, based on the compound of formula (V) used. The aqueous solution of the inorganic base used is usually a hydroxide solution of an alkali metal or an alkaline earth metal, preferably a hydroxide solution of an alkali metal. According to the invention, an aqueous solution of potassium hydroxide and sodium hydroxide is of particular importance. Typically, a 20-50% solution of the above inorganic hydroxide is used. According to the invention, it is preferred to use relatively concentrated solutions, for example 45% solutions, in which the amount of inorganic base used is at least a stoichiometric amount, preferably in a 50 to 100 molar% excess, based on the compound of formula (V) used. The inorganic base used is preferably used in an about 75 mol% excess, based on the compound of the formula (V) added.

If necessary, the reaction mixture may be diluted by adding the above-mentioned organic solvent after adding the appropriately substituted sulfonyl chloride or the organic base. In this case, the amount of the solvent added at the time of starting the addition is 2 to 10%, preferably about 5%.

In any case, after all the aqueous inorganic base solution has been added, the reaction mixture is diluted with the above-mentioned organic solvent. About 0.5 to 1.0 l, preferably 0.7 to 0.8 l, of the solvent is used per mole of the starting compound of the formula (V). Thereafter, an alkoxide of formula (VI) or a metal salt thereof is added. Preference is given to sodium and potassium phenolates which are derivatized using compounds of the formula (VI). According to the invention, it is possible to add stoichiometric amounts, if appropriate substoichiometric amounts or excess amounts of compound (VI) based on the educts of the formula (V) present. After all the compound (VI) has been added, the reaction is allowed to proceed at a temperature of 5-35 deg.C, preferably about 25 deg.C, for about 1-3 hours, preferably about 1.5-2 hours, and finally stirred at a temperature of 50-100 deg.C, preferably about 70-90 deg.C, for about 1-3 hours, preferably about 1.5-2 hours. After the reaction is complete, the product of formula (II) is crystallized by the addition of a suitable polar solvent selected from the group consisting of lower alcohols and water.

In order to obtain a very pure product in high yields, it has proved advantageous according to the invention for the crystallization to add a solvent mixture consisting of a nonpolar organic solvent, preferably xylene or toluene, most preferably toluene, a polar organic solvent, preferably a lower alcohol, such as methanol, ethanol, butanol or isopropanol, in particular isopropanol, and water. The volume ratio of the non-polar organic solvent to the polar organic solvent and water may vary from 1: 7 to 10: 5 to 8, preferably from 1: 8 to 9: 6 to 7. Crystallization of the product of formula (II) is accomplished by cooling to less than 50 ℃, preferably less than about 35 ℃. After separation, the crystalline product is optionally washed with the lower alcohols and water described above.

According to the invention, if the compound of formula (II) is derived from a compound of formula (V) wherein X has a definition other than hydroxy, the following scheme can be used.

The sodium or potassium phenolate derived from the compound of formula (VI) and the compound of formula (V) are dissolved together in water, mixed with a non-polar organic solvent and reacted, optionally under phase transfer conditions. The phase transfer catalysts used according to the invention comprise the halides, sulfates or hydroxides of quaternary ammonium salts, preferably tetradecyltrimethylammonium, hexadecyltrimethylammonium, tetrabutylammonium, tributylmethylammonium or triethylbenzylammonium. According to the invention, the nonpolar organic solvent may be a chlorinated hydroxyl, such as methylene chloride, or preferably an aromatic hydroxyl, such as benzene, toluene, xylene, preferably toluene. The actual amounts of the compounds of formula (V) and (VI) are stoichiometric amounts and, if desired, a slight excess (e.g. 15%) of one of the reactants may be used. The amount of solvent used depends on the amount of educt put in. For each mole of compound of formula (VI), 1-2 liters of water and 0.3 to 1.0 liter of organic solvent, preferably 1.5-1.8 liters of water and 0.5 to 0.7 liters of organic solvent are used.

The reaction is carried out at a temperature of 50 to 100 c, preferably 70 to 80 c, with vigorous stirring for 3 to 9 hours, preferably 5 to 7 hours. Thereafter, a polar organic solvent, preferably a lower alcohol, most preferably isopropanol, is added to the separated organic phase to crystallize the product. Crystallization of the product of formula (II) is accomplished by cooling to less than 50 ℃, preferably less than about 30 ℃. After isolation, the crystalline product of formula (II) is optionally washed with the lower alcohol and water described above.

It has been mentioned above that a further aspect of the invention relates to starting compounds of the formula (V)

It can be prepared analogously to synthesis methods known per se. Compounds of formula (V) wherein X represents hydroxy, can be obtained, for example, by reacting 3-halomethyl-benzoic acid methyl ester with 4-hydroxybenzonitrile according to Wilkinson's ether synthesis. The thus obtained methyl 3- (4-cyano-phenoxy) -benzoate (VII) can be reduced analogously to the current standard procedures to convert to compounds of general formula (V) wherein X ═ hydroxy (═ 4 (3-hydroxymethyl-benzyloxy) -benzonitrile).

The compounds of the formula (V) in which X represents chlorine or bromine can be prepared from compounds of the formula (V) in which X represents hydroxyl, in analogy to synthetic methods known per se, using customary halogenating agents, for example thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, methanesulfonyl chloride, benzenesulfonyl chloride, preferably thionyl chloride or methanesulfonyl chloride.

The compounds of formula (V) wherein X represents a methanesulfonyloxy, trifluoromethanesulfonyloxy or toluenesulfonyloxy group can be prepared in analogy to synthesis methods known per se from compounds of formula (V) wherein X represents a hydroxy group, in the presence of an organic base (preferably selected from dimethylaminopyridine, pyridine, picoline, N-methylpyrrolidine, trimethylamine, triethylamine, diisopropylethylamine and DBU (diazabicycloundecane) with a suitable sulfonyl chloride dissolved in an aprotic, preferably polar, organic solvent (preferably selected from dichloromethane, N-dimethylacetamide, dimethylformamide, acetonitrile, N-methylpyrrolidine, tetraalkylurea).

The following examples illustrate the process of the invention for the synthesis of compounds of formula (I). The above-described method is illustrated by way of example only and not to limit the invention.

Example 1: 3- (4-cyano-phenoxymethyl) -benzoic acid methyl ester:

10.00kg (43.6 mol) of methyl 3- (bromomethyl) benzoate and 5.21kg (43.74 mol) of 4-hydroxybenzonitrile were dissolved in 100 l of acetone and stirred under reflux in the presence of 0.1kg of sodium iodide together with 8.4kg (60.7 mol) of potassium carbonate for about 4 hours. 35 l of acetone are distilled off and 100 l of water are added under reflux. The reaction mixture was cooled to 20 ℃ and the crystallization reaction was completed by adding another 30 liters of water. The crystals formed are separated off, washed with 50 l of water and dried in vacuo.

Yield: 11.1kg (95%) of methyl 3- (4-cyano-phenoxymethyl) -benzoate;

melting point 109-,

TLC (silica gel 60F 254-prepared plate (Merck): Rf 0.5 (toluene: acetone 9: 1)

Example 2: 4- (3-hydroxymethyl-benzyloxy) -benzonitrile:

20.05kg (26.7 mol) of methyl 3- (4-cyano-phenoxymethyl) -benzoate were dissolved in 100 l of THF and 40 l of methanol. 8.51kg of sodium borane were added in portions at 40 to 45 ℃. The reaction mixture was stirred at 61 to 63 ℃ for about 5 hours to complete the reaction. The reaction mixture was then cooled to 25 ℃ and 90 l of 15% sodium hydroxide solution were added. After stirring, the aqueous supernatant was separated and mixed with 30 liters of 22.5% sodium hydroxide solution. After stirring, the aqueous supernatant was separated off and about 100 l of solvent were distilled off therefrom at a bath temperature of 63 to 75 ℃. The distillation residue is crystallized at 50 to 60 ℃ by addition of 20 l of isopropanol and at 40 to 50 ℃ by addition of 150 l of water. After cooling the suspension to 20 to 30 ℃, the crystals are separated off, washed with 60 to 100 l of water and with 25 l of cold isopropanol in portions and dried in vacuo.

Yield: 15.8kg (88%) of 4- (3-hydroxymethyl-benzyloxy) -benzonitrile;

melting point (DSC): 110 ℃ and 115 ℃, white solid

IR: 3444/cm (OH band); 2229 cm (CN spectral band)

Example 3: 4- (3-chloromethyl-benzyloxy) -benzonitrile:

the method A comprises the following steps:

7.18 g (30 mmol) of 4- (3-hydroxymethyl-benzyloxy) -benzonitrile are dissolved in 80 ml of dichloromethane, mixed with 4.13 g (35 mmol) of thionyl chloride and 0.1 g of DMF and stirred while heating to 40 ℃ until the evolution of gas has ended. After cooling, the organic reaction mixture is washed successively with water and dilute sodium hydroxide solution and crystallized by evaporation.

Yield: 6.8 g (88%) of 4- (3-chloromethyl-benzyloxy) -benzonitrile;

TLC (silica gel 60F 254-prepared plate (Merck) Rf 0.9 (toluene-acetone 9: 1),

rf 0.44 (toluene)

The method B comprises the following steps:

7.18 g (30 mmol) of 4- (3-hydroxymethyl-benzyloxy) -benzonitrile are dissolved in 22 ml of N, N-dimethylacetamide, mixed with 4.47 g (39 mmol) of methanesulfonyl chloride and 3.95 g (39 mmol) of triethylamine and stirred at 20-30 ℃ for 10 hours. The precipitated triethylammonium chloride is then filtered off, the filtrate is mixed with 30 ml of isopropanol and the desired 4- (3-chloromethyl-benzyloxy) -benzonitrile is crystallized by metering in 30 ml of water. The suspension was stirred at 10 ℃ for 15 minutes and filtered. The crystals were washed with a mixture of 5 ml isopropanol and 20 ml water and dried under vacuum at 20 ℃.

Yield: 6.8 g (88%) of 4- (3-chloromethyl-benzyloxy) -benzonitrile

Melting point: 65-68 deg.C

Example 4: 4- { 1-methyl-1- [ (4-tetrahydro-pyran-2-yloxy) -phenyl]-Ethyl } phenol sodium salt

121.8kg of bisphenol A were suspended in 480 l of toluene and 46 l of THF. After addition of the catalyst (1.3kg, 37% hydrochloric acid), 44.9kg of 3, 4-dihydro-2H-pyran are metered in such a way that the temperature does not exceed 40 ℃. The solid was then placed in solution. The reaction mixture was then mixed with 26.4kg, 45% sodium hydroxide solution and 260 l of water. The organic phase of the upper layer was separated and about 50 liters of solvent were removed by distillation. The organic phase was washed several times with dilute sodium hydroxide solution at 30 to 40 ℃ to achieve sufficient purity (monitored by TLC). If the pH of the lower aqueous phase is in the range of 11.8 to 12.2, excess bisphenol A is easily separated.

The toluene phase obtained by the purification by extraction was mixed with 11 liters of isopropanol and 80 liters of water and heated to 50 to 55 ℃. A crystalline suspension was obtained by adding 47.4kg of 45% sodium hydroxide solution and cooling the reaction mixture to 20 to 25 ℃. The crystals were isolated by filtration, washed with about 160 l of toluene and then dried in vacuo.

Yield: 96.5kg (54%) (as tetrahydrate)

Example 5: 4- [3- (4- { 1-methyl-1- [4- (tetrahydro-pyran-2-yloxy) -phenyl ] -amide]-ethyl } -phenoxymethyl Radical) -benzyloxy]-synthesis of benzonitrile:

the method A comprises the following steps:(starting from example 2)

28kg (244 mol) of methanesulfonyl chloride, 6 l of N, N-dimethylacetamide, 24.7kg (244 mol) of triethylamine, 6 l of N, N-dimethylacetamide, 29.4kg, 45% sodium hydroxide solution, 143 l of N, N-dimethylacetamide, 59.7kg (178.5 mol) of the product from example 4(≡ 4- { 1-methyl-1- [ (4-tetrahydro-pyran-2-yloxy) -phenyl ] -ethyl } sodium phenolate as tetrahydrate are metered in succession at about-10 to 0 ℃ into 45kg (188 mol) of 4- (3-hydroxymethyl-benzyloxy) -benzonitrile (example 2) dissolved in 133 l of N, N-dimethylacetamide. The reaction mixture was then stirred at 25 ℃ for 2 hours and at 75 to 80 ℃ for a further 1.5 hours. After addition of 32 l of toluene, 255 l of isopropanol and 200 l of water were added to start crystallization, which was completed by cooling to 30 ℃. The crystalline product was isolated by filtration, washed with isopropanol and water, and then dried in vacuo. Yield: 85 kg (90%) of 4- [3- (4- { 1-methyl-1- [4- (tetrahydro-pyran-2-yloxy) -phenyl ] -ethyl } -phenoxymethyl) -benzyloxy ] -benzonitrile;

the method B comprises the following steps:(starting from example 3)

19.4kg (50 mol) of the product of example 4(≡ 4- { 1-methyl-1- [ (4-tetrahydro-pyran-2-yloxy) -phenyl ] -ethyl } phenol sodium as tetrahydrate and 12.2kg (47.5 mol) of the product of example 3 (≡ 4- (3-chloromethyl-benzyloxy) -benzonitrile) were mixed with 85 liters of water, 40% of a phase transfer catalyst (for example: 2.1kg (2.5 mol)) consisting of an aqueous solution of tetradecyltrimethylammonium bromide and 32 liters of toluene and stirred vigorously at about 80 ℃ for about 6 hours. 44 kg of isopropanol are then metered into the separated upper organic phase at from 50 to 70 ℃ and the resulting crystalline suspension is cooled to about 25 ℃ and filtered. The separated crystals were washed twice with 25 l of cold isopropanol and dried in vacuo.

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

example 6: { [4- (3- {4- [1- (4-hydroxy-phenyl) -1-methyl-ethyl]-phenoxymethyl } -benzyloxy) benzene Base of]-imino-methyl } -carbamic acid ethyl ester hydrochloride

132kg (247 mol) of 4- (3- {4- [1- (4-tetrahydropyran-phenyl) -1-methyl-ethyl ] -phenoxymethyl } -benzyloxy) -benzonitrile (example 5) are metered into a solution of 45.5kg (272 mol) of lithium-bis (trimethylsilyl) amide in 266kg of THF at about 0 ℃. The resulting suspension was stirred at about 25 ℃ for about 10 hours. The solid dissolved into the solution. After addition of 68 l of toluene the reaction mixture was cooled to-10 to 0 ℃ and 30.8kg (284 mol) of ethyl chloroformate were added to the reaction vessel at this temperature. After the reaction was complete, 24.3kg of 37% hydrochloric acid (diluted with 50 l of water) were metered in and, after about 20 minutes, the lower aqueous phase was separated off. The desired product was crystallized by adding 106 l of acetone, 48 l of methyl isobutyl ketone and 24.3kg of 37% hydrochloric acid. After centrifugation, washing with acetone and drying in vacuo 123kg (87%) of { [4- (3- {4- [1- (4-hydroxyphenyl) -1-methyl-ethyl ] -phenoxymethyl } -benzyloxy) phenyl ] -imino-methyl } -carbamic acid ethyl ester hydrochloride were obtained.

Melting point: 170 ℃ and 175 DEG C

Example 7: { [4- (3- {4- [1- (4-hydroxy-phenyl) -1-methyl-ethyl]-phenoxymethyl } -benzyloxy) benzene Base of]-imino-methyl } -urethane:

466 l of acetone and 142kg of { [4- (3- {4- [1- (4-hydroxy-phenyl) -1-methyl-ethyl ] -phenoxymethyl } -benzyloxy) benzyl ] -imino-methyl } -carbamic acid ethyl ester hydrochloride (example 6) are added to a solution of 109kg of trisodium citrate dihydrate at 20 ℃. After stirring for 1 hour, the crystalline product was isolated by filtration, washed with water to remove any salts, then with about 100 liters of acetone and finally dried in vacuo.

116kg (90%) of ethyl { [4- (3- {4- [1- (4-hydroxy-phenyl) -1-methyl-ethyl ] -phenoxymethyl } -benzyloxy) phenyl ] -imino-methyl } -carbamate were obtained.

Claims

The invention relates to a method for preparing compounds of general formula (I) in which the radical R is used on an industrial scale¹And R²Having the meaning as given in the description and the claims.

1. A process for the preparation of a compound of formula (I) or a tautomer thereof

Wherein

R¹Represents a group selected from methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and-C (Me)₂) A phenyl group, optionally mono-, di-or trisubstituted with hydroxy;

R²represents a group selected from methyl, ethyl, propyl and benzyl, comprising the following steps

(a) Reacting a compound of formula (II) with an alkali metal hexaalkyldisilazane of formula (VIII) in a solvent selected from tetrahydrofuran, toluene and dioxane,

in the formula (II)

R¹' represents a group selected from methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and-C (Me)₂) Phenyl, each of which is optionally mono-, di-or trisubstituted by a group-O-PG-representing a protected hydroxy function selected from methoxymethyloxy, 2-methoxyethoxymethyloxy, 1-ethoxyethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert-butyloxy, benzyloxy and 4-methoxybenzyloxy,

in formula (VIII):

the Met is an alkali metal and, when used,

R³in each case independently C_1-4An alkyl group;

(b) treating the product of step (a) with a compound of formula (III)

R²-O-COX′ (III)

In the formula (III):

R²as defined in the present claim, and

x' represents chlorine, bromine or-O-R²Wherein R is²As defined in the claims;

(c) treating the product of step (b) with a protic acid of the formula HY, wherein Y is a counterion, to obtain a compound of formula (IV) and/or tautomers thereof,

wherein the radical R¹And R²And Y represents as defined in the preceding claims;

(d) isolating the compound of formula (IV) produced in step (c);

(e) treating the isolated compound of formula (IV) produced in step (d) with a base to produce a compound of formula I.

2. The method according to claim 1, wherein

(a) In the compound of formula 1

R¹Represents a group selected from phenyl, benzyl and-C (Me)₂) A group of phenyl, each group optionally mono-or disubstituted with hydroxyl;

R²represents a group selected from ethyl, propyl and benzyl;

(b) in the compounds of the general formula (II)

R¹' represents a group selected from phenyl, benzyl and-C (Me)₂) A phenyl group, each group optionally mono-or disubstituted with a group-O-PG, the group-O-PG representing a protected hydroxy function selected from methoxymethyl oxy, 2-methoxyethoxymethyl oxy, 1-ethoxyethyl oxy, 2-tetrahydropyranyloxy, 1-butoxyethyl oxy, tert-butyl oxy, benzyl oxy and 4-methoxybenzyl oxy;

(c) in the compound of formula (III)

R²As defined in the preceding claim of the present application,

x' is a chlorine OR bromine atom OR-OR²Wherein R is²As defined in the claims above;

(d) the acid HY is hydrochloric acid and the intermediate product produced in step (c) is a compound of the general formula IVA or a tautomer thereof, wherein R is¹、R²And Y is as defined in the claims above.

3. The method according to claim 1, wherein the first step is carried out in a single step,

wherein (a) in the process of formula I,

R¹represents-C (Me)₂) Phenyl, optionally mono-substituted with hydroxy, and

R²represents an ethyl group, and the like,

(b) in the compounds of the general formula (II)

R¹represents-C (Me)₂) Phenyl, optionally mono-substituted with a group-O-PG representing a protected hydroxy function selected from methoxymethyl-oxy, 2-tetrahydropyranyl-oxy, 1-butoxyethyl-oxy, tert-butyl-oxy, benzyl-oxy and 4-methoxybenzyl-oxy;

(c) in the compounds of the general formula (III),

R²as defined in the present claims, and

x' represents chlorine, bromine or-O-R²Wherein R is²As defined in the preceding claims.

4. A process according to claim 1, wherein the compound of formula (II) is prepared by a process comprising the steps of,

(a) reacting C of the formula_1-4-an alkyl 3-halomethylbenzoate ester,

wherein R' is C_1-4Alkyl and Hal is a halogen atom,

reacting with 4-hydroxybenzonitrile according to the synthesis mode of Wilkinsom ether

(b) Reductive conversion of the alkyl 3- (4-cyano-phenoxy) benzoate of formula (VII) to the compound of formula (V),

wherein R' is as defined in the preceding claims,

wherein X represents a hydroxyl group;

(c) (iv) optionally treating the compound of formula (V) wherein X represents hydroxy with a chlorinating or brominating agent or a sulfonyl chloride selected from the group consisting of methanesulfonyl chloride (1), trifluoromethanesulfonyl chloride (2) and toluenesulfonyl chloride (3); to produce a compound of the formula V,

wherein X represents chlorine, bromine, methanesulfonyloxy (1), trifluoromethanesulfonyloxy (2) or toluenesulfonyloxy (3);

(d) reacting a compound of formula (V), wherein X represents hydroxy, chloro, bromo, mesyloxy (1), trifluoromethanesulfonyloxy (2) or tosyloxy (3), with a phenol derivative of formula (VI)

Wherein R is¹' is selected from the group consisting of methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and-C (Me)₂) A phenyl group, optionally mono-, di-or trisubstituted by-O-PG, -O-PG group means a protected hydroxy function selected from methoxymethyl oxy, 2-methoxyethoxymethoxy, 1-ethoxyethyl oxy, 2-tetrahydrofuranyl oxy, 1-butoxyethyl oxy, tert-butyl oxy, benzyl oxy, and 4-methoxybenzyl oxy; and wherein the phenol derivative of formula VI is reacted in a polar organic solvent, optionally under basic reaction conditions, in the form of the corresponding sodium or potassium phenolate salt, to yield the compound of formula II.

5. An intermediate product of formula (IVA) or a tautomer thereof

Wherein the radical R¹And R²Having the definitions given in claim 1.

6. An intermediate product of formula (IVA) or a tautomer thereof

Wherein the radical R¹And R²Having the definitions given in claim 2.

7. An intermediate product of formula (IVA) or a tautomer thereof

Wherein the radical R¹And R²Having the definitions given in claim 3.

8. Use of an intermediate product of formula (IVA) according to claim 5, for the preparation of a compound of formula (I) according to claim 1.

9. Use of an intermediate product of formula (IVA) according to claim 6, for the preparation of a pharmaceutical composition according to claim 6