EA007741B1 - Process for preparing -2-(substituted phenyl)-2-hydroxy-ethyl carbamates - Google Patents

Abstract

The invention concerns a new process for preparing (S)-(+)-2-(substituted phenyl)-2-hydroxy-ethyl carbamates and to novel intermediates used in this process. It further relates to polymorphic forms of said carbamates and to processes for preparing said polymorphic forms.

Description

SUMMARY OF THE INVENTION

The present invention relates to a method for producing a compound of formula (I) he to ¹

0) where K is halogen;

K ¹ and K ² independently represent hydrogen or C _1-4 alkyl optionally substituted with phenyl or substituted phenyl, where substituted phenyl has substituents selected from halogen, C _1-4 alkyl, C _1-4 alkyloxy, amino, nitro and cyano ;

comprising (a) recovering an ester of the formula

where P represents a protective group for alcohol; K ³ is C _1-4 alkyl;

an appropriate reducing agent designed to reduce the ester to alcohol, to obtain an alcohol of the formula

(B) reacting an alcohol of formula (III) with a carbonyl compound of formula O

αν>

where X and Υ are the corresponding deleted groups; and then with an amine of the formula

(c) removing the protective group P to obtain a compound of formula (I).

In some cases, one or more substituents K ¹ , K ² and K ³ may have asymmetric carbon atoms and, therefore, can cause the appearance of compounds of formula (I) in stereoisomeric forms

- 2 007741 max. Such stereoisomeric forms are intended to be included within the scope of the present invention. Preferred compounds of formula (I) are those compounds wherein K is 2-chloro, K ¹ and K ² are hydrogen.

Group P is an appropriate protecting group for alcohol. Preferred groups P are ether type groups. In particular, the preferred protecting group P is 2- (2-methoxy) propyl.

In a preferred embodiment of the process, the carbonyl compound of formula (IV) is selected from 1,1'-carbonyldiimidazole and phenyl chloroformate.

In a specific embodiment, K ³ is methyl.

Another implementation of the method is one in which the corresponding reducing agent of the ester to alcohol is a metal hydride or complex metal hydride.

In accordance with another aspect, the invention relates to a compound of the formula

where K, K ¹ and K ² are as defined in claim 1 or 2 of the claims, and P is a suitable hydroxy protecting group.

In accordance with another aspect, the invention relates to a compound of the formula

where K is as defined in claim 1 or 2 of the claims, and P is a suitable hydroxy protecting group.

In accordance with yet another aspect, the invention relates to a compound of the formula

(C>

where K is as defined in claim 1 or 2 of the claims, K ³ means C _1-4 alkyl; and P is an appropriate protecting group for hydroxy.

Compounds of formula (IV), (III) or (II) are preferred, wherein P is 2- (2-methoxy) propyl. Also preferred are compounds of formula (II) wherein K ³ is methyl.

In accordance with another aspect, the invention relates to a method for producing a compound of formula (VI), characterized by the above steps of method (a) and (b).

In accordance with another aspect, the invention relates to a method for producing a compound of formula (III), characterized by the aforementioned step of method (a).

In accordance with another aspect, the invention relates to a method for producing a compound of formula (II), characterized by the above steps of method (b) and (e).

The invention further relates to a method for producing a compound of formula (I), characterized by the steps of method (b) and (e), which will be disclosed below, and the steps of method (a), (b) and (c) above.

In accordance with a further aspect, the present invention relates to the presence of polymorphic forms of (8) - (+) - 2- (substituted phenyl) -2-hydroxyethyl carbamates. In particular, it relates to two polymorphic forms of the compound 2- (2-chlorophenyl) -2- (2- (2-methoxy) propyl) ethyl carbamate.

The invention also relates to methods for producing said novel polymorphic forms.

DETAILED DESCRIPTION OF THE INVENTION

An object of the present invention is a method for producing the above compounds of formula (I) and intermediates of formula (II), (III), (IV) and (V) presented and defined above.

Compounds and intermediates as defined herein are preferred, wherein K is 2-chloro, K ¹ and K ² are hydrogen. The compound of formula (I), where the substituents have the last indicated meanings, may be referred to as 'K ^ 1-333369' and represented by the structural formula

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

“C _1-4 alkyl” means straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2methyl-1 propyl, 2-methyl-2-propyl.

“C _1-4 alkyloxy” means C _1-4 alkyl radicals bound to an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy and the like.

“Substituted phenyl” is phenyl substituted with the above substituents. Substituted phenyl preferably has 1, 2 or 3 substituents. A preferred substituent is halogen, more preferably chlorine.

P, as indicated above, is an appropriate hydroxy protecting group. It is preferable to choose it in such a way that it is stable during the stage of recovery (II) in (III), as well as in the subsequent stage of the reaction of transformation (III) to (VI). A preferred reduction operation involves the use of complex hydrides, which will be described below, while group P must be stable with respect to said complex hydrides and the reaction products obtained from them. Alkaline conditions are required for reduction with complex hydrides and, therefore, the P group should not be split in an alkaline environment. Group P should preferably be able to be removed in an acidic environment, which should be such that the carbamate functional group is not split. Particularly preferred are protecting groups P which are capable of being removed at a pH of about 1 or slightly higher.

In particular, ether type P groups are applicable. As examples of group P, methoxymethyl esters (MOM) may be mentioned; which can be obtained from methoxymethyl chloride or formaldehyde dimethyl acetal;

tetrahydropyran ethers (THP ethers) derived from dihydropyran; tetrahydrothiopyranyl ethers derived from dihydrothiopyran;

chloro-substituted tetrahydrofuranyl ethers derived from 2-chlorotetrahydrofuran; tetrahydrothiofuranyl esters derived from dihydrothiofuran;

1-ethoxyethyl esters derived from ethyl vinyl ethers or 1-ethoxyethyl chloride;

1-methyl-1-methoxyethyl esters derived from methyl vinyl ethers of particular interest;

triphenyl ethers and their corresponding derivatives, which can be obtained from the corresponding chlorides;

benzyl esters and their corresponding derivatives, which can be obtained from the corresponding bromides or iodides;

4-methoxytetrahydropyranyl ethers derived from 5,6-dihydro-4-methoxy-2H-pyran; 4-methoxytetrahydrothiopyranyl ethers derived from 5,6-dihydro-4-methoxy-2H-thiopyran. It is even more advantageous to use groups P that do not produce a mixture of diastereoisomers, i.e. groups P without an asymmetric center. Under certain circumstances, for example, depending on the nature of the reducing agent, individual silyl ethers, in particular tert-butyldimethylsilyl (ΤΒΌΜ8), triisopropylsilyl, tribenzylsilyl and the like, can be used as the corresponding groups P.

Stage (a). Obtaining 2- (substituted phenyl) -2- (protected hydroxy) ethanol (III).

According to the first step of the process of the present invention, the ester (II) is reduced to the corresponding alcohol of formula (III) using an appropriate reducing agent for reducing the ester to alcohol. The reducing agent may be a metal hydride or a complex metal hydride, such as lithium aluminum hydride, or its derivatives.

Particular reducing agents for this reaction are silane agents, such as trialkylsilanes, dialkylsilanes, trialkoxysilanes, and preferably polymethyl hydrogen hydrogen siloxane ('PMH8'), in the presence of a suitable catalyst. The latter, in particular, is a transition metal halide or carboxylate, and preferably the latter is zinc carboxylate, such as zinc hexanoate or a derivative thereof, more preferably zinc 2-ethylhexanoate, in the presence of a metal hydride such as an alkali metal or alkaline earth metal hydride or aluminum hydride, for example lithium, sodium, potassium, calcium hydride, or a complex hydride such as borohydride or aluminum hydride, in particular alkali metal borohydride or aluminum hydride, for example

- 4 007741 measures, in the presence of lithium, sodium or potassium borohydride or aluminum hydride. As a catalyst mixture, a combination of zinc 2-ethylhexanoate and sodium borohydride is most preferably used. Said and similar reducing agents are presented in patent application XVO 96/12694 (1995) and in: 1. I1tap, Thé Llétée, 1999, 59, 1 £.

The reaction of this step of the method is carried out in a suitable solvent, for example, ether or polyether or hydrocarbon, in particular in an aromatic hydrocarbon. Specific examples of suitable solvents include diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, diglyme and toluene.

The reducing agent can be formed by mixing a mixture of the EK8 A and EK8 B reagents in a separate reaction vessel (EK8 = ester reduction system commercially available from Ροϊιιη & Naak). EK8 A is a solution of NaBH ₄ in tetraglim, while EK8 B is a solution of Ζη (carboxylate) ₂ H ₂ O, in particular Ζη (2-ethylhexanoate) ₂ -H ₂ O in tetrahydrofuran. EK8 A and EK8 B are preferably mixed at elevated temperature, for example, at a temperature in the range of 50 to 90 ° C., in particular at 70 ° C., for several minutes, for example for 30 minutes. Then a mixture of EK8 A and EK8 B is added to the ester (II) and EK8 C is added. EK8 C is polymethylhydrogen siloxane.

The reducing agent can also be obtained ίη κίΐιι in the reaction vessel, which is especially attractive. In such an embodiment, intermediate (II) is dissolved in a suitable solvent, preferably toluene, at an elevated temperature of 80-90 ° C. First, EK8 B is added in one portion, then EK8 A is also added in one portion. Then, EK8 C is immediately added over one hour while the temperature is controlled and maintained at elevated values, in particular at about 95 ° C.

The starting ester of mandelic acid (II) is prepared as indicated below and can be isolated and optionally purified and used as such in the reduction step. The ester (II) can also be stored dissolved in the solvent in which it is prepared and used as such in the reduction step.

The substituted mandelic acid (II) ester is preferably methyl ester.

In a particular embodiment of the process step, the starting ester (II) is either used dissolved in the solvent of the previous reaction step or it can be dissolved in a suitable solvent, for example, such as ether, for example, di-n-butyl ether or preferably toluene. The reductant obtained as indicated above is added in one portion to the solution, then EC8 C is added over one hour. The reaction mixture may optionally be heated to 90 ° C before adding EC8 C. Then the temperature is raised to 90 ° C and maintained at the indicated temperature until, during the control of the method, the degree of conversion will be at least 99%. The reaction time is approximately 1 hour. After completion of the reduction, the mixture is cooled to a temperature of 15-20 ° C and first carefully hydrolyzed with methanol and then with an aqueous alkali metal hydroxide solution, which is preferably a solution of ΝαΟΗ taken in a small excess (for example, 1.3 mol equivalent when using a 30% solution).

The mixture was then heated under reflux for 1 h at a temperature of about 50 ° C and the layers were separated at room temperature. The organic layer was washed with water and a saturated aqueous solution of Νηί'Ί at room temperature.

The amount of EC8 C is in the range from 2 to 4, in particular from 2.2 to 3 mol. Eq., Preferably 2.3 mol. EK8 C. The reaction usually ends after it takes about 1 hour.

After completion of the reduction reaction, an excess of EC8C can be destroyed by a suitable ester, in particular ethyl acetate. After adding the indicated ester, the mixture is stirred for one hour and hydrolyzed at 90 ° C by adding an aqueous solution of a base, preferably a solution of ΝαΟΗ or KOH (for example, 33%), and then preferably using methanol. Further processing involves separation of the organic layer and washing with an aqueous alkaline solution (e.g., 33% KOH solution) and water.

The resulting methyl ester is an oil and, if necessary, can be distilled for purification.

Stage (b). Obtaining 2- (substituted phenyl) -2- (protected hydroxy) ethyl carbamate (VI).

At this stage, the alcohol of formula (III) is reacted with a carbonyl compound of the formula

- 5 007741

αν) where X and Υ are the corresponding deleted groups. Preferably, one of the group X or Υ is more chemically active than the other. X and Υ may be halogen, in particular chlorine or bromine, but preferably X and Υ are imidazolyl groups. If X is halogen, Υ is preferably an aryloxy or alkoxy group. In the latter case (V) is an alkyl or aryl haloformate. Specific aryl groups in (IV) are phenyl or substituted phenyl, such as halophenyl or C1 _-4 alkyl. Preferred example (IV) includes phenylchloroformate or 1,1'-carbonyldiimidazole.

The reaction is carried out in a suitable solvent, such as a hydrocarbon, in particular an aromatic hydrocarbon, for example toluene, or in ether, for example THF. The reaction temperature depends on the chemical activity of the reagent (IV), but usually it is room temperature or lower. In the case where Ν, Ν'-carbonyldiimidazole is used as a reagent, the reaction is preferably carried out at room temperature (i.e., at about 25 ° C.).

The reaction is usually completed after it takes place for less than 1 hour, for example after it takes about 1/2 hour. The product of this reaction is usually not isolated; it can be represented by the following formula

where Υ is as defined above, and, in particular, represents an imidazolyl group or an aryloxy group, for example a phenoxy or substituted phenoxy group. The intermediates of formula (S-a) are intended to be novel and constitute an additional aspect of the present invention. Intermediates of formula (1U-a) are preferred, where Υ is imidazol-1-yl.

The product of the previous reaction, i.e. the intermediate of formula DU-a) is usually not isolated and is immediately reacted with the amine of formula (V) above. A preferred amine is ammonia, but it can also be an ammonium salt. In this case, ammonia or ammonium salt is in the aqueous medium and is added to the solution of the intermediate product DN-a) at room temperature.

When using (V) in an aqueous medium, strong mixing is recommended due to the presence of a two-phase system. The reaction is completed in a few hours, in particular after about 4 hours. The organic phase is separated off and the product may optionally be isolated and purified. The organic phase with the product (VI) dissolved in it can also be used as such in the subsequent reaction step.

Stage c. Obtaining 2- (substituted phenyl) -2-hydroxyethylcarbamate (I).

This reaction step involves deprotection of the hydroxyl functional group and depends on the nature of group R.

When P is 2-methoxy-2-propyl, removal is accomplished by the addition of an appropriate acid, for example hydrochloric acid.

In a preferred embodiment, the product (VI) is used dissolved in the solvent of the previous step. With stirring, water and concentrated hydrochloric acid are added. After a few minutes, the reaction is complete and the final product (I) begins to precipitate. The reaction mixture is stirred for a couple of hours, in particular for about 4 hours, due to the fact that in this case the final product can be more easily filtered. Then the final product is filtered and washed.

The final product (I) can be recrystallized from a suitable solvent, such as an alcohol, for example methanol, preferably by the addition of acidified water.

Source products.

Starting materials (II) are obtained by a process that is characterized by:

(b) an esterification reaction of a suitably substituted mandelic acid of the formula

- 6 007741

with the receipt of the corresponding ester of the formula pH

(K) where in (VIII) and (IX), K and K ³ are as defined above, and K is preferably 2-chloro and / or K ^{3 is} preferably methyl; and (e) treating the ester (IX) with a suitable hydroxy protecting group generating reagent, thereby obtaining an intermediate of formula pp

(P) where K and P are as defined above.

The ester (IX) is reacted with an appropriate reagent capable of introducing a hydroxy protecting group. A preferred reagent is 2-methoxypropene.

Alternatively, the sequence of the above steps may be reversed, i.e. a hydroxy protecting group may be introduced and then an ester formed.

Stage (b). Obtaining esters of substituted mandelic acid (IX).

In accordance with this reaction step, the starting acid (VIII) is reacted in alcohol, from which the ester (IX) is obtained. Commonly used C _1-4 alkanol, preferably methanol, thereby to obtain respective complex C1 _-4 alkyl esters or, preferably, methyl ester of formula (VIII).

The reaction is carried out with an excess of strong acid, preferably hydrohalic acid, such as HC1, in particular with 1-4 mol. Eq., Preferably with 2.5 mol. Eq. concentrated HC1. The reaction also occurs with a catalytic amount of sulfuric acid or also with 8OC1 ₂ . In the latter case, the reaction is highly exothermic, which requires the adoption of appropriate measures to control the temperature.

The reaction is preferably carried out at room temperature or slightly elevated temperatures, preferably not higher than about 30 ° C. The reaction time is usually less than about 1 hour, for example about 30 minutes. The resulting ester (IX) is usually an oily compound, which is used as such in the subsequent steps of the process. In a preferred embodiment of the process, the ester (IX) is stored in the solvent in which it is prepared and then used dissolved in the solvent.

Stage (e). Obtaining esters of substituted mandelic acid with a protected hydroxyl group.

The reaction conditions of this stage depend on the nature of the protective group R.

In a preferred embodiment, P is 2-methoxy-1-propyl, which is derived from 2-methoxypropene. The latter is dissolved in a suitable solvent, in particular in a solvent in which other reaction steps are carried out. The resulting solution is added to a solution of intermediate (IX) in a suitable solvent, which has been acidified by the addition of, for example, hydrochloric acid, in particular by introducing gaseous hydrochloric acid over the solution. The pH should preferably be low, for example pH 1-2. The solvent of intermediate (IX) should preferably be the same as the solvent in which 2-methoxypropene was dissolved, and more preferably it should be the same as the solvent used in other reaction steps.

The reaction is completed in less than 1 hour, usually within half an hour.

The method in accordance with the present invention gives the final product (I) in high yield and

- 7 007741 with a high degree of purity and can be expanded to production scale batches. A special aspect of the present method is that it leaves untouched the stereochemical integrity of the asymmetric center in the carbon atom bearing a hydroxyl functional group, i.e. the present method shows a slight racemization or lack thereof.

Various intermediates of the process, including the steps for preparing the starting materials, can be isolated and, if necessary, further purified before further use in the next step. Alternatively, all steps of the process, if necessary, including also steps for the preparation of the starting materials, can be carried out in the same solvent, i.e. without isolation and optional purification of intermediate products. In the latter case, it may be advantageous to distill off a certain amount of solvent or add a certain amount of solvent during one or more reaction steps. A suitable solvent for carrying out the process with the same solvent is an aromatic hydrocarbon, preferably toluene. It is also possible to carry out a number of steps in one solvent and other steps in another solvent.

Carrying out the entire method in one solvent has the particular advantage that the method is much simpler and can be carried out more quickly without throwing out or regenerating the solvents, which is advantageous from an economic point of view as well as from an environmental point of view.

Polymorphic modifications.

The present invention further relates to new crystalline structures of a compound of formula (I) in which B is 2-chloro, B ¹ and B ² are hydrogen, this compound will hereinafter be referred to as compound (1-a).

The crystalline forms of compound (S-a) can be obtained by appropriate recrystallization of the compound of formula (S-a) from a suitable organic solvent. Depending on the recrystallization technique, either Form A or Form B can be obtained.

One crystalline form of compound (Ι-a) is designated as 'form A' and is obtained by recrystallization of compound (Ι-a) from a suitable solvent. In this recrystallization technique, the temperature is maintained below 60 ° C, in particular below 50 ° C. Suitable solvents are those in which the compound of formula (S-a) dissolves at elevated temperature and is relatively poorly soluble at lower temperature, for example, at a temperature below 20 ° C, or below 10 ° C, or even below 0 ° C, or -10 ° C. Suitable solvents are lower alkanols, i.e. C _1-4 alkanols and, in particular, methanol.

In one embodiment, compound (Ι-a) is dissolved by heating or boiling under reflux in methanol or by heating in lower alkanol. The temperature should not rise above 60 ° C. The solution is then cooled, preferably slowly, for example, simply allowing the solution to cool. At a temperature of about 50 ° C, crystallization is already beginning. The mixture is stirred at room temperature for 15-20 hours after the addition of acidified water. The water is preferably acidified with a strong acid, for example hydrochloric acid or the like, to a pH of from about 3 to 4, in particular to about 3.5. Then the mixture is cooled to about 0-10 ° C, in particular to about 5 ° C, and stirred at this temperature for a long period of time, for example for about 1 hour. Then, the crystalline final product is filtered and dried.

In an additional aspect, the present invention relates to compound (Ι-a), which is predominantly in the form A. The invention, in particular, relates to compound (Ι-a), which is in the form of a polymorphic mixture, which mainly contains form A. More specifically, the invention relates to compound (S-a), which is in the form of a polymorphic mixture containing at least 90% or more of Form A, in particular 95% or more of Form A, and most preferably 99% or more of Form A.

Therefore, the above recrystallization of the compound of formula (S-a) gives a new crystalline form of the compound (S-a), denoted in this description 'form A'.

The compound (Ι-a) in the form A has a specific crystalline form, i.e. monoclinic crystalline form.

One crystalline form of compound (S-a) is designated as 'Form B' and obtained by recrystallization of compound (S-a) from a suitable solvent. In this recrystallization technique, a temperature is set above 60 ° C, in particular above 70 ° C. Suitable solvents are those in which the compound of formula (S-a) dissolves at elevated temperature and is relatively poorly soluble at lower temperature, for example, at a temperature below 20 ° C, or below 10 ° C, or even below 0 ° C, or -10 ° C. Suitable solvents are lower alkanols, for example C _3-4 alkanols, and in particular propanol (n-propanol or 2-propanol). Other suitable solvents are esters, such as ethyl acetate or the like, or mixtures thereof with low boiling halogenated hydrocarbons, such as trichloromethane or dichloromethane, which is preferred. In this case, the starting material is preferably first dissolved in ethyl acetate, after which a halogenated hydrocarbon is added. Used halogen volume

- 8 007741 of a saturated hydrocarbon is approximately five times (v / v) greater than the volume of ethyl acetate, the volume ratio (ethyl acetate: halogenated hydrocarbon) is preferably in the range from about 1: 2 to about 1: 5, for example, it can be about 1: 3 . Even more suitable solvents are polyols, in particular glycols, such as ethylene glycol, which is preferred, or propylene glycol, butylene glycol and the like. Water may be added, in particular when polyols are used as solvent. If water is added, it can be acidified with a suitable strong acid, such as hydrochloric acid, to a low pH, for example, to a pH that is in the range of pH 2-5, for example, to a pH that is about 3.

Water can be added in various quantities. For example, when ethylene glycol or similar glycols are used, the volume ratio of glycol to added water is in the range from 1: 1 to about 1: 8 or from 1: 2 to 1: 5, for example, about 1: 4 (glycol: water, vol. /about).

In one type of embodiment, compound (Ι-a) is dissolved by heating or refluxing in 2-propanol, ethyl acetate or an ethyl acetate / dichloromethane mixture, more preferably in an ethyl acetate / dichloromethane mixture, with a ratio of said components in a 1: 3 mixture. The solution is then allowed to cool, after which the desired product crystallizes.

This technique can also be used to convert form A to form B, i.e. substitution in the above procedure for the compound (Ι-a) with form A.

Form B can also be obtained in high-purity form by heating Form A to 130 ° C for a period of 60 minutes in the form of three-wedge crystals (experiment using DSC (E8C)).

In an additional aspect, the present invention relates to compound (Ι-a), which is predominantly in the form B. The invention, in particular, relates to compound (Ι-a), which is in the form of a polymorphic mixture, which mainly contains form B. More specifically, the invention refers to compound (Ι-a), which is in the form of a polymorphic mixture containing at least 90% or more of form B, in particular 95% or more of form B, and most preferably 99% or more of form B.

The new crystalline forms of the compounds of formula (Ι-a) can be characterized by their respective X-ray powder diffraction patterns using appropriate powder diffractometers, in particular, using the methodology presented in the examples.

In accordance with a further aspect, the present invention relates to a method for preparing Form A of a compound of formula (Ι-a) or a compound of formula (Ι-a) mainly in form A, the method comprising dissolving a compound of formula (Ι-a) in a suitable solvent, heating solvent to a temperature below about 60 ° C and above about 50 ° C and then allowing this solution to cool. Suitable solvents are alcohols, in particular C1-4 alkanols, preferably methanol. In a particular embodiment of this method, the heated solution is allowed to cool until the first crystals appear, in particular, the solution is allowed to cool to about 50 ° C, thereby providing the appearance of the first crystals, and then allowed to cool further, in particular to room temperature.

In accordance with another aspect, the present invention relates to a method for preparing Form B of a compound of formula (Ι-a) or a compound of formula (Ι-a) mainly in form B, the method comprising recrystallizing compound (Ι-a) from a suitable solvent at a temperature of 60 ° C or higher, in particular at 70 ° C or higher. Suitable solvents are, for example, lower alkanols, for example C3-4 alkanols and, in particular, propanol. Other suitable solvents are ethyl acetate or mixtures thereof with low boiling halogenated hydrocarbons such as dichloromethane.

The following examples disclose the invention in more detail and are intended to illustrate the invention, but not to limit it.

Examples

Preparation of (8) - (+) - 2- (2-chlorophenyl) -2-hydroxyethyl carbamate (compound (Ι-a)).

Example 1. Methyl ester of 8 - (+) - 2-chloro-mandelic acid (intermediate 1).

(8) - (+) - 2-Chlormindalic acid (100.0 g, 535.9 mmol) was dissolved at room temperature in methanol (553.0 g). After cooling to 10 ± 5 ° C, gaseous hydrogen chloride is fed to the solution surface for 30 minutes while maintaining the temperature below 25 ± 5 ° C. The progress of this reaction and subsequent reactions are monitored using HPLC. Trimethylorthoformate (62.6 g, 589.5 mmol) at a temperature of 20 ± 5 ° C is added to a light yellow solution until discoloration, which is stirred for 30 minutes at the same temperature. Then the solvent and gaseous hydrogen chloride are removed in vacuum (40 ± 5 ° C, 40 ± 10 mbar) as much as possible. The oily residue was diluted with toluene (130 g) and the solvent was again removed in vacuo as much as possible. Toluene (261 g) was added and the solution was cooled to 15 ± 5 ° C.

Example 2. The 2-Methoxy-1-propyl derivative of the methyl ester of (8) - (+) - 2-chloro-mandelic acid (intermediate 2).

Hydrogen chloride gas (0.55 g, 15 mmol) is fed to the surface of the solution (pH drops from 3 to 1-2). In a second flask, 2-methoxypropene (78.0 g, dissolved in toluene (120 g) at 20 ± 5 ° C.

- 9 007741

1081.7 mmol) and add the above-obtained solution of intermediate compound 1 at a temperature in the range of 25 ± 5 ° C (approximately 30 min). After complete addition, the mixture is stirred for 30 minutes. Triethylamine (14.0 g, 138.3 mmol) was added to the light yellow solution until it became colorless, it was stirred at room temperature for 5 min and diluted with toluene (402 g) (if pH> 8 was not reached, triethylamine was added). The mixture is washed with water (1x150 g), an aqueous solution of sodium bicarbonate (5%, 1x150 g) and an aqueous saturated solution of sodium chloride (1x150 g). Drying with sodium sulfate (approximately 65 g), filtration and removal of approximately 86 g of toluene in vacuo gave intermediate 2.

Example 3. 2- (2-Chlorophenyl) -2- (2- (2-methoxy) propyl) ethanol (intermediate 3).

First, Ueprige ™ ECB B (13.0 g) is added and then Ueirig ™ EC5 A (13.0 g) and the mixture is heated for 85 minutes to 85 ± 5 ° C. The appearance of the solution varies from clear to slightly cloudy. The UeirigE ™ EC5 C (73.9 g, approximately 1239.4 mmol) is added dropwise to the solution so that a temperature of 95 ± 5 ° C is established (approximately 45 minutes, the onset of the exothermic reaction may be delayed). The reaction ends 15 minutes after completion of the dropwise addition, which also shows the appearance in the mixture of a color change from milky to gray (due to zinc). If the above does not occur, 7.0 g of Ueirige ™ ECB B and 7.0 g of Ueirige ™ ECB A are directly added to the reaction mixture, and the whole mixture is heated until the conversion is complete. The solution was cooled to 15 ± 5 ° C and methanol (30 g) was added (hydrogen evolution occurred). An aqueous solution of sodium hydroxide (30%, 238.0 g) is added dropwise while maintaining the temperature below 20 ° C (approximately 30 min, above 25 ° C intense foaming is observed). After the addition is complete, the biphasic mixture is heated to 50 ± 5 ° C for 1 h and the previously formed precipitate is now dissolved. After cooling to room temperature, the phases were separated and the colorless organic phase was washed with water (1x200 g) and aqueous saturated sodium chloride solution (1x200 g). Drying with sodium sulfate (approximately 65 g), filtering and removing in vacuum about 180 g of solvent, a solution of intermediate 3 is obtained.

Example 4. 2- (2-Chlorophenyl) -2- (2- (2-methoxy) propyl) ethyl carbamate (intermediate 5).

To a solution obtained in Example 3, a suspension of 1,1'-carbonyldiimidazole (103.8 g, 641.4 mmol) in toluene (180 g) was added over 30 minutes at a temperature in the range of 25 ± 5 ° C. Then, the conversion to 1-imidazolyl-1 ′ - [2- (2-chlorophenyl) -2- (2- (2-methoxypropyl))] ethoxycarbonyl (intermediate 4) is completed. Toluene (200 g) and an aqueous solution of ammonium hydroxide (25%, 364 g) are added. After stirring vigorously at room temperature for 3 hours, the phases are separated and the organic phase containing intermediate 5 is washed with water (1x200 g) and an aqueous saturated sodium chloride solution (1x200 g).

Example 5. Obtaining compound (1-a).

Water (160 g) and a concentrated aqueous hydrochloric acid solution (39 g) were added to the organic phase containing intermediate 5, obtained as described above, giving a pH value <1.0. After stirring at room temperature for 5 minutes, precipitation of compound (Ι-a) begins. After 4 hours, the product is filtered off, the filter cake is washed with water (3x75 g) and toluene (3x44 g). After drying (50 ± 5 ° C, 40 + 10 mbar), 96.9 g of compound (Ι-a) are obtained (purity 99.8%, determined by HPLC analysis 99.0%, its (enant. Excess), determined by chiral HPLC,> 99.9%, 444.8 mmol, total yield 83.0%).

Example 6. Obtaining the compound (Ι-a) form A.

The product of the previous example was suspended in methanol (115 g) and, after heating to the distillation temperature, the resulting solution was filtered hot, cooled to room temperature and stirred at that temperature for 15-20 hours. Water (577 mg) containing concentrated hydrochloric acid was added. (approximately 13 mg, the pH of the solution is 3.7 ± 0.2). The mixture is cooled to 5 ± 5 ° C, stirred at the indicated temperature for 2 hours and then filtered. The filtered precipitate was washed with water (3x30 g). After drying (50 ± 5 ° C, 50 ± 10 mbar), 93.0 g of compound (Ι-a) of Form A are obtained (purity 100%, analysis 99.7%, its> 99.9%, 430.0 mmol , the total yield of 80.2%).

Example 7. Determination of the polymorphic form by x-ray powder diffractometry.

Sample preparation.

Approximately 0.5 g to 1 g of the sample is carefully pressed in the powder sample holder to obtain a clear, smooth surface.

Equipment.

Use a system based on a powder diffractometer ΑΡΌ 1700 (RNRK), computer-controlled, with automatic expansion of the slit and a secondary monochromator or equivalent equipment.

Registration terms.

Copper emission: Κ _α ι = 0.15406 and K _a2 = 0.15444 nm

Voltage: 40 kV

- 10 007741

Current: 30 mA

Slot Expansion: Automatic

Entrance Slit: 0.1 °

Graphite secondary monochromator for Si-K _a1 Xe proportional counter

The counting starts at 2θ 1.5 ° and is carried out in steps from 2θ 0.02 ° until 2θ 40 ° is reached. The counting time in the interval is 3 s and the total recording time is 2 h 50 min.

Form A of the compound of formula (Ι-a) can be characterized by its X-ray powder pattern, which includes the main peaks listed in table. 1 in the examples.

Table 1. Peaks of powder x-ray diffraction form A.

Form In the compounds of formula (ΙΙ) can be characterized by its powder x-ray, which includes the main peaks listed in table. 2.

Form A.

Angle Parameter ά Intensity oh oh 2-Theta ° Angstrom Cn 9,217 9.58681 4610 100.0 10,506 8,41395 108 2, 3 14,954 5,91952 986 21,4 17,375 5,09990 1501 32.6 18,435 4.80892 3287 71.3 20,028 4,42979 884 19,2 20,720 4.28343 286 6.2 21,045 4,21801 2535 55, 0 22,205 4,00026 80.1 1.7 23,257 3.82165 1248 27.1 24,954 3,56544 494 10.7 25,715 3.46166 1776 38.5 26, 093 3,41233 684 14.8 27,379 3.25489 3953 85.8 27,689 3.21908 954 20, 7 29,339 3.04172 163 3, 5 30,134 2.96333 517 11.2 31,480 2,83961 129 2,8 31,780 2,81347 310 6.7 32,139 2.78287 113 2,4 32,880 2.72180 318 6.9 33,097 2.70446 337 7.3 34,664 2,58570 479 10,4 35,170 2,54967 972 21.1 35,500 2,52667 464 10.1 35,995 2.49305 109 2,4 36, 700 2.44679 250 5,4 36,958 2,43029 374 8.1 37,314 2,40791 1034 22.4 38,349 2,34527 408 8.9 39,222 2.29508 161 3,5 39,683 2,26945 310 6.7

Example 8. Obtaining the form In the compound (Ι-a).

5.0 g (19.0 mmol) of crude K \. 1-333369 (polymorph A) was dissolved in 4.75 g of 2-propanol by heating to the distillation temperature. The resulting solution was cooled to room temperature over 30

- 11 007741 min, after which the substance crystallizes. After further stirring at 4 ° C for 1 h, the product is filtered off and dried at 80 ° C and 20 mbar for 8 h. Yield: 4.0 g (15.2 mmol, 80%), polymorph B.

2-Theta Parameter ά Intensity Relative intensity 9.13 9, 686 486,0 0.324 10.38 8.522 198.0 0,132 12.81 6, 910 334.0 0.223 15.04 5,890 507.0 0.338 15, 92 5,567 153.0 0.102 17.32 5,120 594.0 0.396 18.31 4,845 694.0 0.463 18.58 4,775 282.0 0.188 19.37 4,582 239, 0 0.159 20.04 4,431 326.0 0.217 20.81 4,268 864.0 0.576 21.72 4,092 324.0 0.216 22.15 4,013 1,500.0 1,000 23.25 3, 826 661.0 0, 441 24.94 3,57Ό 416, 0 0.277 25, 64 3,474 516.0 0.344 27,20 3,278 1044.0 0, 696 27.59 3,233 506, 0 0.337 28.23 3,161 216.0 0.144 28.56 3,125 221.0 0.147 29.44 3,034 208.0 0.139 30.34 2,946 328.0 0.219 30.83 2,900 314.0 0.209 31.77 2,816 259.0 0.173 32.13 2,786 200, 0 0.133 32.68 2,740 335.0 0.223 33.04 2,711 276.0 0.184 34.30 2,614 207.0 0.138 34.81 2,577 621.0 0.414 35.29 2,543 244.0 0.163 35, 91 2,501 243.0 0.162 36.36 2,471 189.0 0,126 37.08 2,424 412, 0 0.275 37.66 2,388 349.0 0.233 38.55 2,335 431.0 0.287 39.09 2,304 321.0 0.214

CLAIM

Claims (17)

1. A method of obtaining a compound of the formula where K is halogen; - 12 007741 K ¹ and K ² independently represent hydrogen or C _1-4 alkyl, comprising (a) reducing an ester of the formula wherein P is an appropriate protecting group for an alcohol; K ³ is C _1-4 alkyl; an appropriate reducing agent of the ester to alcohol to give an alcohol of formula (b) reacting an alcohol of formula (III) with a carbonyl compound of formula O X Υ (IV) where X and Υ are the corresponding deleted groups; and then with an amine of formula k ¹ n — 1 / \ ² (V) to thereby obtain a compound of formula (c) removing the protective group P to obtain a compound of formula I. 2. The method according to claim 1, in which K represents 2-chlorine, K ¹ and K ² represent hydrogen. 3. The method according to claim 1 or 2, in which the protective group for alcohol is selected from 2- (2-methoxy) propyl. 4. The method according to claim 1 or 2, wherein the carbonyl compound of formula (IV) is selected from diimidazolylcarbonyl, an aryl or substituted aryl haloformate. 5. The method according to claim 1 or 2, in which K ³ means methyl. 6. The method according to claim 1 or 2, in which the corresponding reducing agent of the ester to alcohol is a metal hydride or a metal hydride complex. 7. A compound of the formula wherein K, K ¹ and K ² are as defined in claim 1 or 2, and P is an ether type group. 8. The compound of claim 7, wherein the ether type group is selected from methoxymethyl ethers (MOM); tetrahydropyran ethers (THP esters); chloro-substituted tetrahydrofuranyl ethers derived from 2-chlorotetrahydrofuran; tetrahydrothiofuranyl ethers; - 13 007741 1-ethoxyethyl esters; 1-methyl-1-methoxyethyl esters; triphenyl ethers and their corresponding derivatives; benzyl esters and their corresponding derivatives; 4-methoxytetrahydropyranyl ethers; 4-methoxytetrahydrothiopyranyl ethers. 9. The compound according to any one of claims 7 or 8, wherein P is 2- (2-methoxy) propyl. 10. The compound of formula (1-a) characterized in that the compound of formula (Ι-a) is in monoclinic crystalline form. 11. The compound of formula (S-a), as defined in claim 10, having the following peaks of x-ray powder diffraction Angle 2-Theta ⁰ 9,217 10,506 14,954 17,375 18,435 20,028 20,720 21,045 22,205 23,257 24,954 25,715 26,093 27,379 27,689 29,339 30,134 31,480 31,780 32,139 32,880 33,097 34,664 35,170 35,500 35,995 36,700 36,958 37,314 38,349 39,222 39,683 Parameter ά Intensity % Angstrom Cn 9.58681 4610 100.0 8,41395 108 2,3 5,91952 986 21,4 5,09990 1501 32.6 4.80892 3287 71.3 4,42979 884 19,2 4.28343 286 6.2 4,21801 2535 55.0 4,00026 80.1 1.7 3.82165 1248 27.1 3,56544 494 10.7 3.46166 1776 38.5 3,41233 684 14.8 3.25489 3953 85.8 3.21908 954 20.7 3.04172 163 3,5 2.96333 517 11.2 2,83961 129 2,8 2,81347 310 6.7 2.78287 113 2,4 2.72180 318 6.9 2.70446 337 7.3 2,58570 479 10,4 2,54967 972 21.1 2,52667 464 10.1 2.49305 109 2,4 2.44679 250 5,4 2,43029 374 8.1 2,40791 1034 22.4 2,34527 408 8.9 2.29508 161 3,5 2,26945 310 6.7 - 14 007741 12. The compound of claim 10, essentially not containing other polymorphic forms of the compounds of formula (1-a). 13. The compound according to claim 11, essentially not containing other polymorphic forms of the compounds of formula (1-a). 14. The compound of formula (1-a) characterized in that the compound of formula (1-a) is in triclinic crystalline form. 15. The compound of formula (1-a) according to 14, having the following peaks of x-ray diffraction in powder: 2-Theta Parameter ά Intensity Relative intensity 9.13 9, 686 486.0 0.324 10.38 8.522 198.0 0,132 12.81 6, 910 334.0 0.223 15.04 5,890 507.0 0.338 15, 92 5,567 153.0 0.102 17.32 5,120 594.0 0.396 18.31 4,845 694.0 0.463 18.58 4,775 282.0 0.188 19.37 4,582 239.0 0.159 20.04 4,431 326.0 0.217 20.81 4,268 864.0 0.576 21.72 4,092 324.0 0.216 22.15 4,013 1,500.0 1,000 23.25 3, 826 661.0 0.441 24.94 3,570 416.0 0.277 25.64 3,474 516.0 0.344 27,20 3,278 1044.0 0, 696 27.59 3,233 506.0 0.337 - 15 007741 28.23 3,161 216.0 0.144 28.56 3,125 221.0 0.147 29, 44 3, 034 208.0 0.139 30.34 2,946 328.0 0.219 30.83 2,900 314.0 0.209 31.77 2,816 259, 0 0.173 32.13 2,786 200, 0 0.133 32, 68 2,740 335, 0 0.223 33, 04 2,711 276, 0 0.184 34.30 2, 614 207.0 0.138 34.81 2,577 621.0 0.414 35.29 2,543 244.0 0.163 35, 91 2,501 243.0 0.162 36.36 2,471 189, 0 0,126 37.08 2,424 412.0 0.275 37.66 2,388 349, 0 0.233 38.55 2,335 431.0 0.287 39, 09 2,304 321.0 0.214 16. The compound according to 14, essentially not containing other polymorphic forms of the compounds of formula (Σ-a). 17. The compound according to clause 15, essentially not containing other polymorphic forms of the compounds of formula (Σ-a).