UA75582C2 - Crystalline form of (s)-2 ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl} ethoxy] phenyl) propanoic acid, process for preparation thereof and use in medicine (variants) - Google Patents

Abstract

The present invention relates to a novel crystalline form of the compound (S)-2-ethoxy-3-(4-(2-(4-methanesulfony-loxyphenyl}ethoxy)phenyl] propanoic acid, shown by formula (I), or a pharmaceutically-acceptable salt thereof, and solvates thereof. The invention also concerns methods of treating one or more metabolic disease conditions, particularly those associated with Insulin Resistance Syndrome, and the use of a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for use in one or more of said conditions. The invention further concerns pharmaceutical compositions containing a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof, as active ingredient, as well as processes for the manufacture of a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof. (I)

Description

Description of the invention

The invention relates to the crystalline form of the compound 2 (5)-2-ethoxy-3-I4-(2--4-methanesulfonyloxyphenyl)ethoxy)phenyl| of propanoic acid, represented by the formula: и их и 4 g |. r M, : tya and 0 . Ж ne НВ и -й ня Sho Ж: р и и Я 7 n-. Yai z" Ob () s (8) s so

IC) or its pharmaceutically acceptable salt and solvate. The invention also relates to methods of treating one or more states of metabolic diseases, in particular those associated with insulin resistance syndrome, which involves the use of a crystalline form of a compound or its pharmaceutically acceptable salt or solvate in the production of therapeutic drugs for one or more metabolic diseases .

The invention also relates to pharmaceutical compositions that contain a crystalline form of the compound or its pharmaceutically acceptable salt or solvate as an active ingredient, as well as methods of manufacturing the crystalline form of the compound or its pharmaceutically acceptable salt or solvate. - c When forming medicinal compositions, it is important that the medicinal substance has such a form that would allow easy use and processing. This is important not only in view of the achievement of a viable manufacturing method under industrial "» conditions, but also in view of the subsequent manufacture of pharmaceutical compositions containing an active compound.

Chemical stability, solid state stability and shelf life of active ingredients are also important factors. The medicinal substance and the compositions containing it must have the ability to be effectively stored for a considerable period of time without significant changes in the physical and chemical properties of the active component (chemical composition, density, hygroscopicity and solubility). c In addition, it is important to obtain the drug in the most chemically pure form.

In view of this, significant problems can be created by amorphous materials. For example, unlike bo crystalline material, it is usually more difficult to formulate and work with them due to unreliable solubility,

With instability and chemical impurities.

Those skilled in the art will understand that this problem will be solved when it is possible to easily obtain a stable crystalline form.

Thus, it is desirable that commercially viable and pharmaceutically acceptable medicinal compositions, according to

Possibilities, had a substantially crystalline, stable medicinal form.

It should be noted that it is not always possible to achieve this goal. Indeed, it is not possible to predict the crystalline behavior of the structure of a compound based only on the molecular structure, since this is possible only empirically. име) The compound according to the invention is intended for therapeutic use in the syndrome of insulin resistance associated with a set of manifestations, including insulin resistance accompanied by hyperinsulinemia, possible type 2 diabetes, arterial hypertension, central (visceral) obesity, dyslipidemia in the form of disturbed lipoprotein levels, which are typically characterized by increased LDNH (very low-density lipoproteins) and decreased LDL (high-density lipoproteins), as well as reduced fibrinolysis.

As a recent epidemiological study showed, individuals resistant to insulin are at increased risk of 65 cardiovascular diseases and mortality, especially those who have suffered a myocardial infarction or stroke.

Atherosclerosis associated with type 2 diabetes is responsible for nearly 8,095 deaths.

As for clinical medicine, they also realize the need to increase insulin sensitivity in people suffering from insulin resistance syndrome and, accordingly, to eliminate dyslipidemia, which is considered the cause of the accelerated development of atherosclerosis. However, today such a disease is not clearly defined.

This invention relates to a solid crystalline form of a compound of formula I. Significant advantages can arise from the isolation of a crystalline form of a compound of formula I, for example, when obtaining a compound of such levels of purity and homogeneity as are required by the standards and such as to facilitate the manufacture of the composition.

The compound of formula I was isolated as a solid crystalline substance. The particular crystalline form that is isolated exists in a form that is essentially solvent-free ("anhydrous form"). On the other hand, it is possible to obtain the compound in a solvated form, for example, hydrated.

The invention is represented by the crystalline form of compound I or its solvate. A variant of the invention is a crystalline form of a pharmaceutically acceptable salt of compound I or its solvate.

The term "solvated" also includes "hydrated". By the term "crystalline form" should be understood every possible crystalline form of the compound of formula I, preferably in anhydrous form.

The crystalline form of the compound of the formula | can be determined by its melting point, powder X-ray diffraction, and single crystal X-ray diffraction.

The melting point of the crystalline form of the compound of formula I, as a rule, depends on the level of purity and can be determined by known conventional methods, for example, differential scanning calorimetry (DSC).

Of course, the anhydrous form has a melting point between 822C and 922C, for example around 8520-8990,

According to powder X-ray diffraction, the anhydrous form has characteristic peaks of high intensity at 6.2, 4.47, and 4.15 A. Additional to the first specific peaks of lower relative intensity have values of 4.69, 3.64, 3.60, and 3.45 A.

The crystalline form of the compound of the formula | can be obtained from a non-crystalline form of a compound of the formula by crystallization from a suitable solvent (including organic solvents, their aqueous solutions and co-mixtures) such as toluene and ethyl acetate, or a mixture of such solvents as a mixture of ethanol/water, isopropanol/water or toluene/isooctane. To initiate crystallization, it may be necessary to introduce a crystalline substance of the compound of formula I. The compound can be crystallized from the corresponding solvent system by supersaturation, for example, by cooling, evaporating the solvent and/or adding an antisolvent, i.e., a solvent in which the compound of the substance | poorly soluble, for example, heptane and isooctane). The temperature and time of gas crystallization depend on the concentration of the compound of formula I in the solution, on the solvent system used and the method of crystallization. co

The crystalline form of the compound of formula I can be isolated by known methods, for example, decantation, filtration and centrifugation. The crystalline form can be dried.

The same or a different solvent system can be used during recrystallization to reduce the content of impurities such as amorphous material, chemical impurities, or to convert the crystalline form to a solvated/hydrated or anhydrous form.

Crystallization is preferably carried out directly from the reaction solution. Crystallization can also be carried out from the subsequent solution.

The invention also relates to the method of obtaining the crystalline form of the compound of formula I, which consists in "70 Crystallization of the compound of formula I. shshc The term "anhydrous form" does not exclude the presence of a certain amount of solvent, including water, in the crystal lattice. The solvent, including water, may be outside the crystal lattice. "" The invention also relates to the crystalline form of the compound of formula I, which is described above, for use in medical therapy.

Another object of the invention is a pharmaceutical composition containing a crystalline form of a compound of formula I described above in combination with a pharmaceutically acceptable diluent or carrier. The crystalline form of the compound of formula I, which is described above, is used in the manufacture of a pharmaceutical composition by combining the crystalline form of the compound of formula I and a pharmaceutically acceptable diluent or carrier. "sl The composition may have a form for oral administration, for example, a tablet, capsule, solution in water or in oil, suspension or emulsion; for local purpose, for example, cream, ointment, gel, aqueous or oily solution or suspension; nasal administration, for example medicinal powder for inhalation Through the nose, nasal spray or

ГЯ6) drops; vaginal or rectal administration, for example, a suppository; for inhalation administration, for example, in the form of fine powder, dry powder, microcrystalline form or liquid aerosol; sublingual or buccal administration, for example, a tablet or capsule; or parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular, or infusion) such as a sterile aqueous or oily solution or suspension. iF) In general, the composition can be prepared in a traditional way, using traditional excipients. The amount of the crystalline form of the compound of formula I described above to be combined with one or more excipients to form a single dosage form will necessarily vary depending on the patient and the route of administration.

For example, a composition intended for oral administration to a person, as a rule, will contain from 0.001mg to 5Omg of the active substance in combination with an appropriate and standard amount of excipients, the mass fraction of which can vary from 1095 to 99.999990% of the total weight of the composition.

The invention also relates to the use of the crystalline compound according to the invention, which is described above, for the manufacture of a medicament intended for: (I) treatment of dyslipidemia;

(ii) treatment of type 2 diabetes; (ii) treatment of hyperglycemia; (im) treatment of hyperinsulinemia; (M) treatment of hyperlipidemia; (mi) treatment of arterial hypertension; and/or (my) treatment of abdominal obesity.

The invention also relates to a method of obtaining an effect as described above, or treating a disease or disorder, which consists in administering to a warm-blooded animal, preferably a human, in need of such treatment, an effective 7/0. Quantities of the crystalline form of the compound of formula I described above.

The amount of dosage of the crystalline form of the compound of formula I for therapeutic or prophylactic purposes will of course vary depending on the type and complexity of the medical condition, the age and sex of the animal or patient requiring treatment, and the method of administration, in accordance with known principles of medicine.

Appropriate daily doses of the compounds according to the invention for the therapeutic treatment of humans are approximately 0.001-5 Ω/kg of body weight, preferably 0.01-10 mg/kg of body weight.

The crystalline form of the compound of the formula | can be prescribed as a single means of treatment or together with other pharmacologically active agents such as antidiabetic, antihypertensive, diuretic or antihyperlipidemic.

The crystalline forms obtained according to the Examples below exhibited substantially the same X-ray powder diffraction pattern and/or differential scanning calorimetry thermogram. By comparing the corresponding diffraction patterns/thermograms (allowing for experimental error) it became apparent that the same crystalline form was formed. The initial temperature of differential scanning calorimetry can vary within 59 (for example, 223), and the remote values of X-ray diffraction on the powder can vary within 5 smaller decimal places.

Abbreviation of

ЕУАСс - ethyl acetate

NRI C - high-performance liquid chromatography

I-'PrOAc- isopropyl acetate Ge

MMP-M-methyl-2-pyrrolidinone

TNE- tetrahydrofuran so

Synthesis of (5)-2-ethoxy-3-I(4-(2--4-methanesulfonyloxyphenyl) ethoxy) phenyl propanoic acid 1) Ethyl (5)-2-ethoxy-3-(4-hydroxyphenyl) propanoate a) Production of ethyl 2-ethoxyethanoate o

A solution of 2-chloroacetic acid (50g, 529mmol, 1.0eq.) in pure ethanol (11Oml, 2.206.(o06. hereinafter means h- volume equivalent)) was introduced into an ethanolic solution of sodium ethoxide (494ml, 90g, 1.32mmol, 2.506.). During the introduction, the temperature was maintained at 15-252 C. After the introduction was completed, the temperature was increased to 502. The reaction mixture was cooled to 152 C after reaching 29595 conversion. Then NCI "(g) was added until the pH of the mixture was reached "1. When the conversion reached 29595, the suspension was cooled to 159 and neutralized with a solution of sodium ethoxide (approximately 5-2095 of the initially introduced amount) to pH 5-7. After o) with neutralization, the suspension was cooled to 59C and ethyl acetate (150 ml, See.) was added. The sodium chloride formed during the reaction was filtered and washed with ethyl acetate. After that, the solution was evaporated. The maximum mass fraction of ethanol was 2095. The total yield of the compound was 5895 of the theoretical (loss during evaporation). Chemical purity was 299905. b) Production of ethyl 2-ethoxy-3-(4-methoxyphenyl)propenoate.

N-4-Methoxybenzaldehyde (100g, 734mmol, 1.00eq.) and ethyl 2-extoxyethanoate (116g, 881mmol, 1.2eq.) were dissolved in tetrahydrofuran (bbOml, b.b.) under a nitrogen atmosphere. The solution was cooled to -202C. A solution of potassium tert-butoxide (98.8 g, mmol 1.2 equiv.) in tetrahydrofuran (704 ml, i.e. 7.106., relative to potassium tert-butoxide) was slowly added to the obtained solution, maintaining the temperature below -102C. After the addition was (ee) 50 complete, the reaction mixture was stirred for one hour at a temperature from -159C to -1096, "with maintaining the temperature "nbeC, to the suspension was added glacial acetic acid (53g, 1.24mol, 1.7eq .). The tetrahydrofuran was then evaporated until about 1/3 remained. Toluene (824 mL, 8.2406.) was added, and the remaining tetrahydrofuran was evaporated. Water (200 mL, 206.) and methanesulfonic acid (50 mL, 0.506.) were added to 5 suspension of toluene to obtain a water layer, the pH of which would be 2-3. The water layer was separated. The toluene layer was evaporated to remove the remaining water. To the toluene solution was added methanesulfonic acid (2.11g, 22mmol,

GF) O, OZeq.). The toluene solution was refluxed with a Dean-Stark nozzle until

Ge achieved full conversion. The solution was cooled to 259 and washed with sodium hydroxide (aq, 4895) (1.83Gg, 22mmol, 0.0Seq) diluted with water (1bml). The total yield of the compound was approximately 5295 of the theoretical value. c) Preparation of 2-ethoxy-3-(4-methoxyphenyl) propenoic acid.

Mayon (aqueous, 48905) (122 g, 1.4 mmol, 2.0 equiv.), water (244 ml, 2.4406.) and EUN (9 O ml, 0.906.) were added to a toluene solution of ethyl 2-ethoxy-3-(4- methoxyphenyl) propenoate (approximately 96g, 382mmol, 0.52eq). The reaction mixture was heated to 50°C and stirred until complete conversion. After completion of the reaction, the toluene layer 65 was separated, and the water layer was washed with toluene (100 ml, 106.). After separation of toluene, the water layer was cooled to 592 and acidified with concentrated NH (approximately 17 mL, 2.1 mmol, 2.9 eq.). By adding acid, the temperature was maintained below 102C. Ethyl acetate (10 Oml, 106.) was added to the acidic aqueous suspension. After extraction, the phases were separated. The ethyl acetate solution was evaporated and toluene (288 ml, See).

A seed of 2-ethoxy-3-(4-methoxyphenyl)propenoic acid was introduced into the toluene solution and cooled to 09b. After crystallization, the material was filtered. The wet substance was used without drying in the subsequent operation.

The total yield of the compound was approximately 4295 theoretical for operations b) and c) combined. Chemical purity was 99.795. d) Preparation of 2-ethoxy-3-(4-methoskyphenyl)propanoic acid. 70 Palladium on carbon (595, 6095 wetted with water) (13.2 g, 0.26 g Ra, 2.44 mmol Ra, 0.0054 equiv.) was added to a solution of 2-ethoxy-3-(4-methoxyphenyl)propenoic acid (100 g, 45O0mmol, 1.0eq.) in ethanol (80Oml, 806.) under nitrogen. Hydrogen was then injected into the vessel to achieve a total pressure of 400 kPa (4 bar).

Hydrogenation was carried out until full conversion was achieved. The catalyst was filtered off, and the ethanol was evaporated under vacuum. Toluene (500 ml, 5 vol.) was added, and then evaporated. The residue was dissolved in toluene (500 ml, Bob.) and 75 was evaporated to a volume of 26 bO0 ml. The solution was heated to 50°C and isooctane (800ml, 80°C) was added. The solution was cooled to 359C, after which a seed of 2-ethoxy-3-(4-methoxyphenyl) propanoic acid was introduced.

The temperature was maintained at 359 for 30 minutes. The diluted suspension was cooled at a rate of 1022; for an hour to a temperature of 52C, which was maintained overnight. After that, the crystals were filtered and washed in isooctane (22Oml, 2.206.). The crystals were dried in a vacuum at a temperature of 3020.

The yield of this compound was 8895 from the theoretical. Chemical purity was 99.895. e) Preparation of (15)-1-(1-naphthyl)-1-ethanammonium (25)-2-ethoxy-3-(4-methoxyphenyl) propanoate.

A solution of 2-ethoxy-3-(4-methoxyphenyl)propionic acid (100g, 44bmmol, 1.0eq.) in isopropyl acetate (200Oml, 2006.) was stirred at 0-59С0 in a nitrogen atmosphere. (5)-1-(1-naphthyl)ethanamine (45.8 g, 268 mmol, O0, equiv.) was added to the obtained solution. The resulting suspension was heated to 7590-8022 to dissolve all the particles, thus obtaining a solution. After that, the solution was cooled and a seed (3) of (5)-1-«1--aphthyl)ethylammonium salt (25)-2-ethoxy-3-(4-methoxyphenyl) propanoic acid was introduced. The desired diastereomer of the salt was selected by filtration. The crystals were washed with isopropyl acetate.

The obtained salt of (15)-1-"1-aphthyl)ethylammonium (25)-2-ethoxy-3-(4-methoxyphenyl)propanoic acid (b7g, 169 mmol, 1.eq.) was dissolved by heating to 7520-8092 in isopropyl acetate (1340ml, 2006). The resulting product was collected by filtration, washed in isopropyl acetate and dried in a vacuum at a temperature of 409C to a constant weight.

The total output for two crystallization operations was 7495 theoretical. Chemical purity was "9996".

The enantiomeric excess was (excluding errors) 97.890. t) f) Preparation of (5)-2-ethoxy-3-(4-methoxyphenyl) propanoic acid. chn

A suspension of (15)-1--1--aphthyl)ethylammonium (5)-2-ethoxy-3-(4-methoxyphenyl)propanoic acid salt (100g, 253mmol, 1.Eq.) in toluene was prepared. Next, the mixture was purified with the help of Ma OH (11.1 g, 278 mmol, 1.Eq.) in water (280 ml, 5 vol.6). The upper layer of toluene containing chiral amine was separated. The lower aqueous layer was washed with two more portions of toluene (280 ml, 5006.). Next, in order to obtain pH-1, the lower aqueous layer was acidified with 3795% aqueous solution of NOI (30 g, 304 mmol, 1.2 equiv.). An aqueous solution containing (5)-2-ethoxy-3-(4-methoxyphenyl) propanoic acid was extracted with two portions of ethyl acetate (280 ml, 506.). The combined extract was washed with one portion of water (280 ml, 5 vol.). The solvent was replaced with M-methylpyrrolidone under reduced pressure. :z» Mahon (granules) (45.5g, 1.14mmol, 4.eq.) and octanethiol (129g, 154ml, 884mmol, 3.eq.) were added to the solution of (5)-2-ethoxy-3-(4 -methoxyphenyl) of propanoic acid (approximately 56.bg, 25Zmmol, 1.Eq.) In

M-methylpyrrolidone (68Oml, 1206.) in a nitrogen atmosphere. The reaction mixture was heated to 12023 and maintained at a temperature of 11590-1252C until the completion of the reaction, which was determined by high-performance liquid chromatography.

The reaction mixture was cooled to 602C, as well as with water. With the help of concentrated NSI, the pH was adjusted to 2-3. The temperature was maintained at 602C -702C. Two layers were formed, with the upper one containing predominantly c-octanethiol and the corresponding methyl ether (formed in the reaction). The layers were separated, and the layer containing water and so 50 M-methylpyrrolidone was concentrated to 3-4 volumes in a vacuum at an internal temperature of 8020-1002.

The residue was extracted with a mixture of NaOH:EuAc. Then the ethyl acetate solution was washed three times with 1595 solution

Ko) masses.

The ethyl acetate was evaporated and the residue was used directly in the next step or, it can also be crystallized from toluene to give a white solid.

After crystallization, the yield was 5295, 9096 using only evaporation. Chemical purity was about 99.895. The enantiomeric excess was (excluding errors) 97.895. g) Preparation of ethyl (5)-2-ethoxy-3-(4-hydroxyphenyl) propanoate. ime) (5)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid (874g, 4.1bmmol, 1.0eq.) was dissolved in ethyl acetate (1250ml). Ethanol (300 Oml) and HCl (3795, aqueous) (40 ml, 0.48 mmol, 0.12 eq.) were added to this solution. The solution was heated to boiling (approximately 722), and the water/vbIIUAsS/EUN (2000 ml) was distilled off. Another portion of EUN (2000 ml) was added and another 2000 ml was driven off. This procedure was repeated one more time. Approximately 9,595 conversions were achieved at this stage. Next, EN (99.595, 1000 ml) was added and evaporated. All this was repeated until the conversion of 297.5905 took place. Then the solution was concentrated to a volume of 1700-2000 ml in a vacuum and cooled to 2096.

A solution of ethyl acetate containing ethyl (5)-2-ethoxy-3-(4-hydroxyphenyl) propanoate was added slowly (30-40 minutes) with intensive stirring to the solution of ManSO»z (mass fraction 7906, 3500 ml). After a few minutes, crystallization took place. Following the addition, the suspension was cooled to 0920-59 and stirred for at least an hour, maintaining the same temperature. The crystals were filtered off and dried under vacuum.

The yield was approximately 9395. The chemical purity was 29995. The enantiomeric excess was (excluding errors) 297.8905. 2) 2-(4(methanesulfonyloxyphenyl)ethyl methanesulfonate 2-(4-hydroxyphenyl)ethanol (356 g, 2.58 mmol, 1.0 equiv.) was dissolved in methylene chloride (3500 ml) and triethylamine (653 g, 6.44 mmol, 2.5 equiv.) . The mixture was cooled to -202 C. Methanesulfonyl chloride (657 g, 5.74 mmol, 2.2 eq.) was then added, maintaining the temperature at -2590 to -159 C. When the conversion reached 29596, the salt formed during the reaction 70 was filtered and washed with methylene chloride (b0 O ml) First, the organic layer was washed with a saturated solution of sodium hydrogen carbonate (70Oml) at a temperature of 202C, and then with water (70O0ml). The methylene chloride was evaporated and replaced with acetonitrile. At the next stage, an acetonitrile solution was used.

C) Ethyl (5)-2-ethoxy-3-(4-(2--4-methanesulfonyloxyphenyl)ethoxy)phenyl|propanoate

Ethyl (5)-2-ethoxy-3-I(I4-hydroxyphenyl)iopropanoate (325g, 1.34mmol, 1.00eq.) was dissolved in acetonitrile 75 (2600ml). When a homogeneous solution was formed, potassium carbonate (560g, 4.05mmol, 3.Eq.) and magnesium sulfate (100g, (0.2g/g K»CO»5)) were added. An acetonitrile solution of 2-(4-methanesulfonyloxyphenyl)ethyl methanesulfonate (total volume of approximately 205 Oml (0.3 g/ml, 2.21 mmol, 1.65 beq.)) was poured into the reaction vessel and the reaction mixture was refluxed at a temperature of 829 for 24 hours, intensively stirring and maintaining the volume by constantly adding portions of acetonitrile. When the conversion reached 29595, the reaction mixture was cooled to room temperature. The remaining salts were filtered off and washed with acetonitrile (800 mL).

The filtrate was evaporated to dryness. The remainder was used in the next step. 4) (5)-2-ethoxy-3-(4-(2--4-methanesulfonyloxyphenyl)ethoxy)phenyl| propanoic acid

To the oil ethyl (5)-2-ethoxy-3-I(4--2--4-methanesulfonyloxyphenyl)ethoxy)phenyl| of propanoate (723g, (71.290 test), 1.18mmol, 1.0eq.) was added tetrahydrofuran (3900ml). When a homogeneous solution was formed, water (900 ml) was added. The mixture was cooled to 41020. After one hour, lithium hydroxide solution (39Oml, 4M, 1.32 eq.) was added. (5)

Then the temperature was raised to 3092, the reaction was carried out at this temperature for 2-3 hours. When the conversion reached 29995, the reaction was stopped. Ethyl acetate (500 ml) was added, and the mixture was cooled to room temperature. The solution was stirred for about 30 minutes and tetrahydrofuran was evaporated. When approximately 8095-9095 of tetrahydrofuran had evaporated, water (1900 ml) was added. Evaporation was continued until no tetrahydrofuran remained in the mixture. Next, the alkaline aqueous solution was washed with a solution of ethyl acetate (100 Oml, 2 x 1250 ml and 9500 ml). pH of an aqueous solution of (5)-2-ethoxy-3-I4-(2--4-methanesulfonyloxyphenylethoxy)phenyl| of propanoic acid was brought to 2.0-2.5 with the help of NSI (aqueous) (550 ml, 3.0 M). Ethyl acetate (2500 mL) was added and the phases were separated. Ethyl acetate solution of MU (5)-2-ethoxy-3-I4-(2--4-methanesulfonyloxyphenyl)ethoxy)phenyl| of propanoic acid was washed with water (700 ml), and 3 o after separation was evaporated to dryness. The remaining oil was used in further crystallization. -

Crystallization of (5)-2-ethoxy-3-I(4-(-2--4-methanesulfonyloxyphenyl)ethoxy)phenyl propanoic acid

Crude material from three portions of (5)-2-ethoxy-3-I4-(-2--4-methanesulfonyloxyphenylethoxy)phenyl| of propanoic acid (1871 g total weight, 1262 g compound, 3.09 mmol, 1.0 equiv.), containing ethyl acetate (500 ml) was dissolved in toluene (500 O0 ml) at a temperature of 509C. After a clear solution was obtained, it was evaporated to reduce the amount of ethyl acetate present. The volume before evaporation was 6750 ml. Another portion of C toluene (2500) was added, after addition the volume was 7750 ml, evaporation was continued. Then added to the solution

From the third portion of toluene (2500 ml), the volume before addition was 6300 ml, after addition the volume was 8800 ml.

Evaporation was continued until an opaque solution with a volume of 8200 ml was formed. Isooctane (1000ml) was added to the solution, which was heated to 402C. Crystallization was started by introducing the seed at 402C. Mixture 75 was vigorously stirred until a suspension was formed. The mixing intensity was increased. The suspension was left overnight for crystallization. Next, the suspension was filtered and washed with toluene:isooctane 5:1 (1800 mL). After that, the crystals were dried under reduced pressure at a temperature of 4026 °C. -I(4-(2--4-methanesulfonyloxyphenyl)ethoxy)phenyl| propanoic acid (1040g (96.495 test), (ee) 50 2.45mmol, 1.0eq.) was dissolved in toluene (7/000ml) at a temperature of 602. After obtaining a clear

KZ solution, isooctane (1720 ml) was added to it. The solution was filtered through silica gel 60. The solution was cooled from 502С to 459С, at this temperature crystallization took place. The suspension was cooled to 202C. The solid was filtered and washed with toluene:isooctane 5:1 (1500 mL). After that, the crystals were dried under reduced pressure at a temperature of 4026.

Determination of melting point

F) Differential scanning calorimetry (DSC) was carried out on a Meshsheg 05C820 device, according to traditional methods, such as those described in Noppe, (.MU. ei ai. (1996), Oiyegepiia! Zsappipu Saiogiteigu,

Zrhipdeg, Vepiip. DSC of the anhydrous form gave an endotherm with an extrapolated onset of melting at a temperature of about 872C (about 102J/g).

Determination of the diffraction pattern of X-ray radiation on powder

X-ray diffractograms on the powder were determined using an X-ray diffractometer

Zietepz 05000 or/ha РПийрз Х'Реги МРО. Determination of the diffraction pattern of X-ray radiation on the powder was performed on samples obtained by traditional methods, for example, those described (in 65 Ziasomallo, S. eyi a). (1995). OepKip5, K. Ta

Zpudeg, K.G. (1996). Vipp, SLU.

(1948), Spetis! Sguziaodgarpu, Siagepdop Rgevzz5, Iopdop; or Kishd, N.R. and AiIehapaeg, G.E. (1974), Kh-Kau riytasiop Rgosedigev, doyp UMieu apa Bopv, Mem/ Hogki).

X-ray diffractograms on the powder of a typical sample of the anhydrous crystalline form of the compound of formula I are shown in Fig.1.

Anhydrous crystals were analyzed by powder X-ray diffraction, the results obtained are shown in Table 1 (where VI is the relative intensity), and are also shown in Fig.1.

The diffractogram was obtained by measuring with variable slits and without an internal standard. The intensity is based on the intensity observed when measuring the slit variables without subtracting the background 7/0 Emission. Relative intensity is less reliable, therefore, instead of numerical values, the following definitions are used:

Fo Relative Intensity Definition 25-1400 de (very strong) 10-25 s (strong) 3-0 ser (medium) 1-3 sl (weak)

Some additional weak or very weak peaks detected by the diffractogram were not presented in Table 1. of X-ray radiation on the powder for the anhydrous form of the crystalline form of the compound of formula I, shown in Fig. 1c

With peremetoiA | Ви пемети | 8 s-paremetviA VI. o r r zlv 600250 sl sh zo so yu yu zv m « z zva -; with own month) ;" It is clear that the d-parameter of X-ray diffraction patterns on powder will vary slightly depending on one or another device, so the given values should not be taken as unconditional.

It is reasonable to assume that the crystalline form of the compound of formula I described herein has α-values such that -i are within the 45 lower decimal place, especially within the 42 lower decimal place. sl Determination of the diffraction pattern of X-ray radiation on a separate crystal

The elementary cell was determined according to X-ray data on a separate crystal 1 of the anhydrous form. It turned out to be orthorhombic with Р2 42424 symmetry, 7-4, and had the following indicators: со 20 ахб,762 А, р-14,426 А, с-24,785 А, dr-у-909 and M-2060,2 АЗ,

Co.)

Claims (10)

The formula of the invention 1. The crystalline form of the compound (5)-2-ethoxy-3-I4-(-2--4-methanesulfonyloxyphenyl)ethoxy)phenyl| propanoic o acid, represented by the formula -- ю я о - (U vymy bo dnyakh - -- ОН о. g 7 o 9 bo which is characterized by the fact that it has an X-ray diffraction pattern on the powder, which has characteristic peaks of high relative intensity at 6 ,2, 4,47 and 4154A. 2. The crystalline form according to claim 1, which is characterized by the fact that it essentially does not contain a solvent. C. The crystalline form of claim 2, characterized in that it has a melting point of 82-9290. 4. The crystalline form according to claim 1, which differs in that the diffraction pattern of X-ray radiation on the powder has additional characteristic peaks of lower relative intensity at 4.69, 3.64, 3.60 and 3.45 A compared to the first peaks. 5. The crystalline form of the compound of formula I according to any of claims 1-4, which differs in that it is used as a medicine. 6. A pharmaceutical composition, which is characterized by the fact that it contains a crystalline form of the compound of formula I! according to 70 any of claims 1-4 and a pharmaceutically acceptable adjuvant, diluent or carrier. 7. Application of the crystalline form of the compound of formula I according to any of claims 1-4 in the manufacture of a medication for the treatment or prevention of conditions associated with reduced sensitivity of patients to insulin. 8. Use of the substance according to any of claims 1-4 in the manufacture of a medication for the treatment of metabolic disorders. 9. Use of the crystalline form of the compound of formula I according to any of claims 1-4 in the manufacture of a medication for the treatment or prevention of dyslipidemia, type 2 diabetes, hyperglycemia, hyperinsulinemia, arterial hypertension and/or abdominal obesity. 10. The method of manufacturing the crystalline form of the compound of formula I according to claim 1 from the non-crystalline form, which includes dissolving the non-crystalline compound in the appropriate solvent system, after which the non-crystalline compound is crystallized in the solvent system due to supersaturation, evaporation of the solvent and/or addition of an anti-solvent. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 5, 15.05.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. o c (ee) iv) iv) and - - and? -i 1 1 (ee) Ko) ime) 60 b5