Methods for preparing simvastatin of high purity degree and semi-synthetic statins

FIELD: pharmacy, chemical technology.

SUBSTANCE: invention relates to methods for preparing simvastatin of high purity degree from lovastatin by the following stages: (a) opening lactone ring in addition of lovastatin in reaction with amine for formation of amide; (b) protection of 1,3-diol moiety by a protecting group; (c) removal of 2-methylbutyryl group joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining of 2,2-dimethylbutyrate group by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and lactone ring closure resulting to formation of simvastatin. Semi-synthetic statin is prepared from statin by carrying out the following steps: (a) opening lactone ring by reaction of statin with amine resulting to formation of amide; (b) protection of 1,3-diol moiety by using the protecting group; (c) removal of group R1 joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining group R2 by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and (g) lactone ring closure with formation of semi-synthetic statin. Invention provides enhancing purity degree of the product.

EFFECT: improved preparing methods of statins.

17 cl, 19 ex

 

The technical field to which the present invention

The present invention relates to a method for producing semi-synthetic statins, to intermediate compounds produced during the implementation of this method, and to a method for producing simvastatin high degree of purification.

The background to the present invention

Based medicines statins are currently the most effective means for lowering low-density lipoprotein in the blood of the patient, prone to cardiovascular diseases. To this class of drugs include lovastatin (lovastatin), simvastatin (simvastatin), pravastatin (pravastatin), compactin (compactin), fluvastatin (fluvastatin) and atrovastatin (atrovastatin).

Simvastatin is the common medical name for a chemical compound, which is called Botanical,2,2-dimethyl-1,2,3,7,8,8A-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl)-ethyl]-1-naphthaleneacetic, [1S*[1A,3A,7b,8b(2S*,4S),-8b]] (No. 79902-63-9 in the Registry CAS). Structural molecular formula of simvastatin below, with the atoms marked with numbers.

Lovastatin is the common medical name for a chemical compound, which is called [1S-[1α(R*),3α,7β(2S*4S*),8αβ]]-1,2,3,7,a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl)-ethyl]-1-naphthalenyl 2 methylbutanoate (No. 75330-75-5 in the Registry CAS). Structural molecular formula lovastatin below, with the atoms marked with numbers.

The lovastatin molecule at position 8 of the ring system hexahydronaphthalen has a side chain 2-methylbutyryl ether. In contrast, the molecule simvastatin in position 8 of the ring system hexahydronaphthalen has a side chain 2,2-dimethylbutyryl. It is known that simvastatin as a means of lowering low-density lipoprotein in the blood is more effective than lovastatin.

In the prior art disclosed methods of conversion of lovastatin to simvastatin. In U.S. patent No. 4582915, which is incorporated into the present application by reference, describes methods for converting mevinolin (mevinolin), compactin and their dihydro and tetrahydropyrimidine more active inhibitors of HMG-CoA reductase by S-methylation natural side 2(S)-malibutique-chain with the formation of lateral 2,2-delivorias-chain.

In U.S. patent No. 5223415, which is incorporated into the present application by reference, discloses a method of enzymatic hydrolysis lovastatinsee acid by treatment lovastatin acid by a strain of microorganisms Clonostachys compactiuscula ATCC 38009 or ATSS 74178, or cell-free extract from them. The resulting product is an inhibitor of HMG-CoA reductase and, sledovatel is but applicable as antihypercholesterolemic funds. This product is also used as an intermediate product for other inhibitors of HMG-CoA reductase.

In U.S. patent No. 4293496, which is incorporated into the present application by reference, discloses a method of removing side 2-methylbutyryl chain by basic hydrolysis of ester lovastatin using a hydroxide of an alkali metal, preferably lithium hydroxide (LiOH). The resulting products are suitable for synthesis antihypercholesterolemic funds.

In U.S. patent No. 4444784, which is incorporated into the present application by reference, discloses a method of introducing a molecule hydrolyzed lovastatin new side chain.

In U.S. patent No. 5159104, which is incorporated into the present application by reference, discloses a method of producing simvastatin by sequential acylation of directon (diollactone) with the formation of double-acylated intermediate product with subsequent selective diallylammonium and circuit lactoovo ring with the formation of simvastatin.

A brief description of the invention

The closest analogue of the present invention is a technical solution for U.S. patent No. 5159104.

A method of obtaining a statin described in the mentioned patent, it is not possible to get simvastatin high degree of purification, almost the Eski pure simvastatin.

The aim of the invention is to obtain practically pure simvastatin containing less than about 0.1% (by weight) simva-oxalate (simva-oxolactone).

Another aim of the invention is to obtain practically pure simvastatin containing less than about 0.1% (by weight) of anhydrovinblastine (anhydrosimvastatin).

Another aim of the invention is to obtain practically pure simvastatin containing less than about 0.1% (by weight) of simvastatin dimer.

Another aim of the invention is to obtain practically pure simvastatin containing less than about 0.1% (by weight) of digidrokvercetina (dihydrosimvastatin).

Another aim of the invention is to obtain practically pure simvastatin containing less than about 0.1% (by weight) of at least one of the compounds from the following list: Simba-oxalate, anhydrovinblastine, simvastatin dimer, digidrokwertitin.

The present invention relates to a method for producing simvastatin high degree of purification of lovastatin, comprising the following stages: trip lactoovo ring by casting lovastatina in the reaction with the amine to obtain amide; protection of 1,3-Volovoi part of the protective group; UD is of 2-methylbutyryl group, attached with a complex of essential communication through the oxygen at position 8 hexahydronaphthalen ring; join 2,2-dimethylbutylamino group by formation of a complex of essential links to the hydroxyl at position 8; removing the protective group; conversion of amide to acid salt; and circuit lactoovo ring with the formation of simvastatin.

According to another aspect of the present invention relates to a method for producing semi-synthetic statin, having a molecular structural formula shown below (Formula I):

from statin that has the following molecular structural formula (Formula II):

contains the following stages: trip lactoovo ring by casting statin, having a molecular structural formula of Formula II in the reaction with the amine to obtain amide; protection of 1,3-Volovoi part of the protective group; 2 removal of methylbutyryl group, attached through a complex of essential communication through the oxygen at position 8 hexahydronaphthalen ring; join 2,2-dimethylbutylamino group by formation of a complex of essential links to the hydroxyl at position 8; removing the protective group; conversion of amide to acid salt; and circuit lactoovo ring with the formation of polysynthetic the ski statin, having a molecular structural formula of Formula I, where R1and R2- acyl group attached to the oxygen through a complex of essential communication, and R3and R4groups independently selected from the following list: -H, -OH, -C1-10alkyl, -C6-14aryl, C6-14aryl-C1-3.

Detailed description of the invention

The object of the invention is a method of obtaining a practically pure simvastatin containing less than about 0.1% (by weight) simva-oxalate (simva-oxolactone).

Another object of the invention is a method of obtaining a practically pure simvastatin containing less than about 0.1% (by weight) of anhydrovinblastine (anhydrosimvastatin).

Another object of the invention is a method of obtaining a practically pure simvastatin containing less than about 0.1% (by weight) of simvastatin dimer.

Another object of the invention is a method of obtaining a practically pure simvastatin containing less than about 0.1% (by weight) of digidrokvercetina (dihydrosimvastatin).

Another object of the invention is a method of obtaining a practically pure simvastatin containing less than about 0.1% (by weight) of at least one of the connection the settings from the following list: Simba-oxalate, anhydrogalactose, simvastatin dimer, digidrokwertitin.

The way to get simvastatin high degree of purification

According to the first aspect of the present invention relates to a method for producing simvastatin high degree of purification of lovastatin, containing the following stages: trip lactoovo ring by casting lovastatina in the reaction with the amine to obtain amide; protection of 1,3-Volovoi part of the protective group; 2 removal of methylbutyryl group, attached through a complex of essential communication through the oxygen at position 8 hexahydronaphthalen ring; join 2,2-dimethylbutylamino group by formation of a complex of essential links to the hydroxyl at position 8; removing the protective group; conversion of amide to acid salt; and circuit lactoovo ring with the formation of simvastatin.

The transformation of lovastatin to simvastatin according to the method of the present invention are shown in the following Scheme I:

In preferred variants of the method according to the invention, the stage of breaking lactoovo rings perform by reduction of the lactone in the reaction with ammonia, primary amine or secondary amine. When performing phase tripping lactoovo ring by reduction of the lactone in the reaction with the amine in predpochtitel the different variants of the method according to the invention, the amine is chosen from the following list: n-butylamine, cyclohexylamine, piperidine, pyrrolidine.

Impurities, which may be formed during the synthesis of simvastatin, shown in the following Scheme II:

In preferred embodiments of the proposed invention is almost pure simvastatin obtained by the method according to the invention contains less than about 0.1% (by weight) of sambaaccount (simva-oxolactone).

In preferred embodiments of the proposed invention is almost pure simvastatin obtained by the method according to the invention contains less than about 0.1% (by weight) of anhydrovinblastine.

In preferred embodiments of the proposed invention is almost pure simvastatin obtained by the method according to the invention contains less than about 0.1% (by weight) of digidrokvercetina.

In addition, when applying the present invention provides the almost pure simvastatin, which contains less than 0.1% (by weight) of simvastatin dimer.

Optionally, the method according to the invention, practically pure simvastatin can be synthesized from contaminated lovastatin containing up to about 30% of impurities.

A method of obtaining a statin high degree of sight of the TCA

According to another aspect, the present invention relates to a method for producing semi-synthetic statin, having a molecular structural formula shown below (Formula I):

from statin that has the following molecular structural formula (Formula II):

contains the following stages: trip lactoovo ring by casting statin, having a molecular structural formula of Formula II in the reaction with the amine to obtain amide; protection of 1,3-Volovoi part of the protective group; 2 removal of methylbutyryl group, attached through a complex of essential communication through the oxygen at position 8 hexahydronaphthalen ring; join 2,2-dimethylbutylamino group by formation of a complex of essential links to the hydroxyl at position 8; removing the protective group; conversion of amide to acid salt; and circuit lactoovo ring with the formation of semi-synthetic statin, having the structural molecular formula Formula I, in which R1and R2- acyl group attached to the oxygen through a complex of essential communication, and R3and R4groups independently selected from the following list: -H, -OH, -C1-10alkyl, -C6-14aryl, C6-14aryl-C1-3.

The chemical transformation is soedineniya, having a molecular structural formula of Formula II, a chemical compound having a molecular structural formula of Formula I by the method according to the present invention are shown in the following Scheme III:

In preferred embodiments of the proposed invention is a semi-synthetic statin, having a molecular structural formula of Formula I is synthesized by the method according to the present invention contains less than about 0.1% impurities.

Optionally, the method according to the invention, semi-synthetic statin, having a molecular structural formula of Formula I may be synthesized from contaminated statin, having a molecular structural formula of Formula II containing up to about 30% of impurities.

In preferred embodiments of the proposed invention R1is the acyl group of the following form:

where Ω is oxygen, which is the Deputy hexahydro-naphthalene rings in position 8, R5is a group selected from the following list:- 1-15alkyl, - -C3-15cycloalkyl, -C2-15alkenyl, -C2-15quinil, -phenyl, -panels1-6alkyl, and a is a substituent R5selected from the following list: hydrogen, halogen, C1-6Ala is l, With1-6alkoxy, C6-14aryl.

In preferred embodiments of the proposed invention R2is the acyl group of the following form:

where Ω is oxygen, which is the Deputy hexahydro-naphthalene rings in position 8, R6is a group selected from the following list:- 1-15alkyl, --C3-15cycloalkyl, -C2-15alkenyl, -C2-15quinil, -phenyl, -panels1-6alkyl, and b is a substituent R6selected from the following list: hydrogen, halogen, C1-6alkyl, C1-6alkoxy, C6-14aryl.

Dashed lines indicated in the structural molecular formula of Formula I and Formula II letters X, Y and Z shows a possible double bonds, these double bonds when they are present, or are in positions X and Z simultaneously, or only one of the positions X, Y, or Z.

In preferred variants of the method according to the invention, the stage of breaking lactoovo rings perform by bringing lactoovo rings in the reaction with ammonia, primary amine or secondary amine. Stage opening lactoovo ring can be performed by bringing lactoovo rings react with an amine, selected from the following list: n-butylamine, cyclohexylamine, piperidine, pyrrolidine.

In preference the sustained fashion variants of the method according to the invention, the opening lactoovo ring is performed in an organic solvent. This organic solvent may be selected from the following list: toluene, cyclohexane, tetrahydrofuran, acetonitrile.

In preferred variants of the method according to the invention, the stage of breaking lactoovo rings perform at temperatures above the ambient temperature. In preferred variants of the method according to the invention, stage opening lactoovo ring can be performed at a temperature of about 60°C.

In preferred variants of the method according to the invention, stage opening lactoovo ring includes removal of unreacted amine after the formation of the amide. In a number of ways to remove unreacted amine comprises removing amine by evaporation and/or washing the organic solution with amide, using diluted acid.

The method according to the present invention also includes the stage of protection of 1,3-Volovoi part of the protective group. Ways to protect hydroxyl groups are well known in the industry, they are disclosed, for example, in U.S. patent No. 6100407 and 6252091, in European patent number EP 299656 and in International patent application WO 95/13283 included in the present application by reference. The protective group may be selected from the following list: acetal, ketal, cyclic is Ulfat, cyclic phosphate, borate group.

In one of the embodiments of the present invention as a protective group used ketal. In this embodiment, the stage of protection of 1,3-Volovoi part can be performed by obtaining Catala using ketone. Getting Catala preferably performed in an organic solvent. This organic solvent may be selected from the following list: toluene, cyclohexane, tetrahydrofuran, acetonitrile, ethyl acetate.

In another embodiment of the method according to the invention as a protective group used acetal. In this embodiment, the stage of protection of 1,3-Volovoi part can be performed by obtaining acetal using aldehyde. Getting acetal preferably performed in an organic solvent. This organic solvent may be selected from the following list: toluene, cyclohexane, tetrahydrofuran, acetonitrile, ethyl acetate.

In another embodiment of the method according to the invention, protection of 1,3-Volovoi part can be done by obtaining dioxin part, whereby the protection of 1,3-Volovoi part is as shown below in Scheme IV:

In another embodiment of the method according to the invention, protection of 1,3-Volovoi part of what may be accomplished by obtaining acetal, having the following structure:

where the group RWithcan be selected from the following list: hydrogen, halogen, C1-6alkyl, C1-6alkoxy, C6-14aryl, such as phenyl or an aromatic heterocycle, a m and n independently from each other can take values from 0 to 10.

In addition, in the method according to the present invention also provides the use of other protective groups, such as:

(1) cyclic sulfate

(2) cyclic phosphate

(3) the cyclic borate

In preferred variants of the method according to the invention, the stage of protection of 1,3-Volovoi parts perform at a temperature of from about 5°50°C. In more preferred embodiments, the stage of protection is performed at a temperature of from about 20°With up to about 25°C.

In preferred variants of the method according to the invention, the stage of protection of 1,3-Volovoi parts perform in the presence of catalytic reagent. As such catalytic reagent is preferable to use acid. This acid may be selected from the following list: p-toluene acid, sulphuric acid is.

In one embodiment of the method according to the invention, the stage of removal of R1includes the recovery of a statin with structural molecular formula of Formula III with a reducing agent. This reducing agent may be selected from the following list: alumaguard lithium aluminum hydride, the hydride diisobutylaluminum. In preferred embodiments, the recovery phase is performed in an inert solvent. This inert solvent may be selected from the following list: toluene, tetrahydrofuran. In addition, the recovery phase may optionally include the neutralization of the residual reducing agent with water.

In preferred variants of the method according to the invention, the stage of restoration performed at a temperature of from about 0°With up to about 30°C. In more preferred embodiments, the stage of protection is performed at a temperature of from about 5°With up to approximately 10°C.

In one embodiment of the method according to the invention, the stage of removal of R1includes conversion of a statin with structural molecular formula of Formula III in the reaction with the ORGANOMETALLIC reagent in an inert solvent.

As the ORGANOMETALLIC reagent can be used reagent is a Grignard reagent is (mineralogical). The temperature at which the statin with the structural molecular formula "Formula III" lead in the reaction with the Grignard reagent, preferably is in the range from about -10°With up to about 20°C. a more preferred temperature range of the reaction statin with structural molecular formula of Formula III with a Grignard reagent is from about -5°With up to approximately 10°C.

Alternatively, as the ORGANOMETALLIC reagent can be used derived alkylate. In the preferred embodiment, is derived alkylate is an n-utillity. The preferred temperature range of the reaction statin with structural molecular formula of Formula III with the derived alkylate ranges from approximately -70°C to about -20°C.

In one embodiment of the method according to the invention, the stage of removal of R1includes conversion of a statin with structural molecular formula of Formula III in the reaction with the amine. In preferred embodiments, this amine is an ammonia or a primary amine. The molar ratio of amine to the statin with the structural molecular formula of Formula III preferably is 1:1.

Stage of removal of R1can be performed in the presence of water. Also what about the, stage of removal of R1can be performed in the presence of an organic solvent.

In preferred variants of the method according to the invention, the stage of removal of R1performed at a temperature of from about 100°With up to approximately 250°C. In more preferred embodiments, the stage of removal of R1performed at a temperature of from about 130°C to about 200°C.

In preferred variants of the method according to the invention, the stage of removal of R1perform at a pressure above atmospheric.

In preferred variants of the method according to the invention, the stage of accession R2includes acylation of oxygen, who is Deputy hexahydronaphthalen ring in position 8. Phase acylation may include conversion of a statin with structural molecular formula Formula IV in a reaction with the acid chloride of the acid. Alternatively, phase acylation may include conversion of a statin with structural molecular formula Formula IV in a reaction with the free acid in the presence of carbodiimide. As such carbodiimide can be used 1,3-dicyclohexylcarbodiimide. In another alternative embodiment, phase acylation may include bringing Tatin with structural molecular formula Formula IV in a reaction with the symmetrical anhydride in the presence of an organic solvent and catalyst. In a preferred embodiment, the catalyst used 4-dimethylaminopyridine.

In preferred variants of the method according to the invention, the stage of acylation performed at a temperature of from about 20°With up to approximately 110°C. In more preferred embodiments, the stage of removal of R1performed at a temperature of from about 80°With up to approximately 110°C.

In those embodiments of the method according to the invention, which provide for the protection of hydroxyl groups-O1H and O2H, the method according to the present invention may additionally include removing the protective groups after the addition step R2. In preferred embodiments, the stage of removal of the protective groups include hydrolysis in the environment of a mixture of water and an organic solvent in the presence of a catalyst. In preferred embodiments, this organic solvent is tetrahydrofuran. As a catalyst may be used an acid catalyst. In preferred embodiments, this acid catalyst used one of the compounds from the following list: hydrogen chloride, sulfuric acid, p-toluene acid.

In preferred variants of the method in the proposed izaberete the s stage of removal of the protective groups is carried out at a temperature of from about 20° With up to approximately 100°C. In more preferred embodiments, the stage of removal of R1performed at a temperature of from about 30°With up to about 70°C.

In preferred variants of the method according to the invention, phase transformations amide in acid salt includes hydrolysis. This hydrolysis can be performed in the environment of a solution containing a base, water and an organic solvent. In preferred embodiments, the base is selected from the following list: sodium hydroxide, potassium hydroxide. In preferred embodiments, the organic solvent is selected from the following list: methyl alcohol, ethyl alcohol, toluene, tetrahydrofuran.

In preferred variants of the method according to the invention, phase transformations amide in acid salt includes the formation of a salt with a pharmaceutically acceptable counterion. Salt with a pharmaceutically acceptable counterion is preferably ammonium salt.

In preferred variants of the method according to the invention, stage circuit lactoovo ring involves the formation of lactate in the medium of organic solvent. In preferred embodiments, the organic solvent is selected from the following list: toluene, ethyl acetate, cyclohexane. In preferred embodiments, the stadiums, the circuit lactone ring perform at elevated temperatures. This temperature is in the range from about 60°With up to approximately 110°C. a more preferred temperature range is from about 80°C to approximately 110°C.

In one alternative implementation of the method according to the present invention are provided by a stage of isolation of a statin with a molecular structural formula of Formula I by crystallization.

Simvastatin high degree of purification obtained by the method according to the present invention, in combination with at least one pharmaceutically acceptable inert filler, can be used for the production of pharmaceutical compositions. Such pharmaceutical compositions suitable for the reception of mammals patients in the form of dosage forms.

These dosage forms can contain almost pure simvastatin, or, alternatively, they can contain almost pure simvastatin as part of a pharmaceutical composition. As in pure form and in pharmaceutical compositions, almost pure simvastatin may be taken in the form of powder, granules, aggregation, or any other solid form. Such pharmaceutical composition may include a composition for tableting. Depending on the applied method of a tablet is the way, the desired product yield and other factors, these pharmaceutical tableting composition may have more or fewer components. Such pharmaceutical compositions may contain diluents, as which can be used, for example, such derivatives of cellulose, as powdered cellulose, microcrystalline cellulose, ultrafine cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, salts of carboxymethylcellulose and other substituted and unsubstituted derivatives of cellulose; starch; pre gelatinizing starch; inorganic diluents like calcium carbonate and calcium diphosphate and other diluents, are well known to the average expert in the field. Among the diluents suitable for use in the pharmaceutical compositions according to the invention, also includes substances such as waxes, sugars (e.g. lactose) and "sugar" (setiathome aliphatic) alcohols (such as mannitol and sorbitol), polymers and copolymers of acrylates, as well as pectin, dextrin and gelatin.

Other inert fillers include binders, such as Arabian gum, pre-gelatinizing starch, sodium alginate, glucose and other binding substances is STV, used for wet and dry granulation and when pelletizing mucem direct compression; leavening agents, such as chromalveolata sodium, crosspovidone, nizkozameshhennoj hydroxypropylcellulose, etc.; lubricating agents such as magnesium stearate and calcium and sodium fumarate; flavoring agents; sweeteners; preservatives; pharmaceutically acceptable dyes and agents, giving the tablet a slide, for example silicon dioxide.

The dosage form may be adapted for oral, transbukkalno, parenteral, ophthalmic, rectal or percutaneous administration. To dosage forms for oral administration include tablets, pills, capsules, pellets, sachets, suspensions, powders, lozenges, elixirs, etc. Simvastatin high degree of purification disclosed in the present invention, may be made in the form of suppositories, ophthalmic ointments and suspensions, and parenteral suspensions imposed by other means. The most preferred method of administration of simvastatin, obtained according to the invention is oral.

Encapsulated dose may contain solid pharmaceutical composition contained within the capsule, which may have a coating of gelatin. Tablets and powders may also be covered intersolubility Obol is ccoi. Powder form with intersolubility sheath may be in the composition of the shell such substances as teleocichla cellulose acetate, phthalate of hydroxypropylmethylcellulose, phthalate polyvinyl alcohol, karboksimetiltselljuloza, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and of methyl methacrylate and similar substances, which, if desired, can be used in conjunction with suitable plasticizers and/or fillers. Coated tablets may be a surface membrane or tablet may consist of particles of a powder or granules, supplied intersolubility shell.

Currently simvastatin is sold in the form of tablets, 5 mg, 10 mg, 20 mg, 40 mg and 80 mg, which include the following inert excipients: magnesium stearate, starch, talc, titanium dioxide and other ingredients. As preservative used butylhydroxyanisole.

Lovastatin delivered on the market in the form of tablets 10 mg, 20 mg and 40 mg for oral administration. In addition to the active ingredient, such as lovastatin, these tablets contain the following inert excipients: cellulose, lactose, magnesium stearate, starch. As preservative used butylhydroxyanisole.

Features and benefits of these and other embodiments featur is imago of the invention will be more fully understood after studying the examples, considered below. It should be noted that the purpose of these examples is to illustrate the advantages of the present invention, and not to cover the entire scope of the invention.

Examples

The conditions of the experiment

Analysis by the method of liquid chromatography high resolution was carried out as described in the source Ahawk and others (A.Houck et al.), Talanta, vol 40(4), 491-494 (1993), "Liquid-chromatographic distribution of known impurities present in bulk lovastatin in small quantities: application of chromatography high and low levels" ("Liquid Chromatographic determination of the known low level impurities in lovastatin bulk drug: an application of high-low chromatography").

Equipment for liquid chromatography high resolution:

Pump/injector Alliance Waters;

Diode matrix M Waters;

The data processing system Millennium Waters;

- Column: Prodigy 5 C8 250×4.6 mm (phenomenex).

Conditions:

the applied volume: 10 μl;

the gradient profile flow (linear);

A=acetonitrile;

In=0,1% orthophosphoric acid (H3PO4).

time (minutes)Flow (ml/min)%%
01,56040
11,56040
51,58020
81,59010
161,59010
201.56040

The column temperature: 30°C.

Definition at wavelengths of 200 nm and 237 nm.

The samples were podpisyvalisj to acetonitrile at a concentration of 1.5 mg/mg.

Retention time:

digidrokwertitin8,10 min (200 nm);
simvastatina acid5,77 min (237 nm);
lovastatin6,34;
simvastatin7,11;
anhydrogalactose8,90;
dimer simvastatin15,36.

Example 1

Getting piperidylamine lovastatin:

A mixture containing 1 g (2.5 mmol) of lovastatin, 10 ml (0.1 mol) of piperidine, 100 mg (0.82 mmol) of N,N-dimethylaminopyridine and 30 ml of toluene was subjected to reflux distilled within 36 hours. Then the mixture was cooled to room temperature and washed twice with 2 N hydrochloric acid (HCl), taken both times in volume of 30 ml, and washed twice with water, taken twice in a volume of 20 ml Organic layer was dried with sodium sulfate, filtered and Aparan. The residue was mixed with hexane and the resulting precipitate was filtered, the result of which was obtained 0.87 g of piperidine lovastatina in a solid white color.

Example 2

The reaction butylamide lovastatin with thionyl chloride

To a solution containing 1.2 g (2.5 mmol) of butylamine lovastatin in 20 ml of toluene, was added 0,76 g (7.5 mmol) of triethylamine. Then dropwise was added 0.45 g (3.7 mmol) of thionyl chloride. After exposure for 1 hour at room temperature the reaction mixture was washed with water, dried (using sodium sulfate), filtered and evaporated, the resulting oily substance is brown.

Example 3

The reaction butylamide lovastatin with phosphorylchloride

To a solution containing 1.2 g (2.5 mmol) of butylamine lovastatin in 20 ml of toluene, was added 0,76 g (7.5 mmol) of triethylamine. Then was added dropwise 0,58 g (3.8 mmol) of phosphorylchloride. After exposure for 1 hour at room temperature the reaction mixture was washed with water, dried (using sodium sulfate), filtered and evaporated, the resulting oily substance is brown.

Example 4

A. Obtaining acetonide of butylamide lovastatin

A mixture containing 40 g (98 mmol) of lovastatin and 60 ml of n-butylamine was subjected Deleg is the key for 1 hour, evaporated, and then evaporated twice with toluene, taken up in 100 ml of the crude amide was dissolved in 500 ml of acetone, after which the solution was added 3 g of p-TsOH. A clear solution was subjected to stirring at room temperature for two hours, and during this time occurred the formation of a solid phase. Then the mixture was cooled down to -10°C, which was maintained for three hours, then the solid phase was isolated and dried to obtain 45 g (88%) of amide/acetonide in a solid white color. Another 5 g was obtained from the mother liquor by partial evaporation of the solution.

C. Alkylation of amide/acetonide obtained at the stage And as an intermediate product:

Amide/acetonide in the amount of 19.5 g (of 37.6 mmol) in a mixture of tetrahydrofuran and cyclohexane (in the ratio 4:1), taken in the volume of 280 ml, was cooled to a temperature of -40°C, after which it was added 113 ml of 1 M of laimiroheline (obtained from pyrrolidine and n-utility at a temperature of -15° (C)while the temperature was maintained below -30°C. After this solution for two hours under stirring at a temperature of -35°With, and to it was added 5 ml of MeI in one piece. Then the solution was subjected to stirring at a temperature of -30°C for one hour, after which it was allowed temperature rise to -10° C. thereafter, to the solution was added 300 ml of 1 N hydrochloric acid (HCl), and the resulting mixture was subjected to delegirovano within one hour. Then to the reaction mixture was added ethyl acetate in the amount of 300 ml, and then the organic layer was washed with 3 N hydrochloric acid (HCl), taken in a volume of 100 ml, and evaporated. To the obtained residue were added 300 ml of methanol and 125 ml of 2 N sodium hydroxide solution (NaOH). The resulting mixture was subjected to delegirovano within 12 hours, resulting in the evaporation of the greater part of methyl alcohol. Then to the reaction mixture was added 120 ml of water and 300 ml of ethyl acetate, and the value of pH was brought to 5 with 3 N hydrochloric acid (HCl). Then the organic layer was added 60 ml of methyl alcohol and 25 ml of a mixture of ammonium hydroxide (NH4OH) and methyl alcohol (1:3 ratio). The resulting mixture was subjected to stirring at room temperature for one hour, after which it was cooled to a temperature of 10°C. the Obtained solid was collected and dried. The result was obtained 13.5 g (80%) ammonium salt simvastatinum acid.

Example 5

The way to get simvastatin from lovastatin by recovery of the ester group R1

A. Receiving AC is tanida of butylamide lovastatin

A mixture of lovastatin, taken in an amount of 40.5 g (100 mmol), and n-butylamine, taken in a volume of 75 ml, was subjected to heating at delegirovano for 2 hours. The excess amine was evaporated and the reaction mixture was subjected to evaporation together with toluene, taken up in a volume of 100 ml For the crude amide was added 400 ml of acetone and 5 g of p-TsOH. The resulting mixture was subjected to stirring at room temperature for 2 hours, and then subjected to cooling in a bath of ice/water for 2 hours. The obtained solid substance was collected by filtration and dried. Then from the mother liquor was received another dose of the product, the total output of which was 49 g (94-95%).

B1. The recovery of the intermediate product obtained at stage A, by means of lithium aluminum hydride

Chemical compound obtained in stage A, in the amount of 45 g (87 mmol) was dissolved in 200 ml of tetrahydrofuran, and the resulting solution was added dropwise to a suspension of 7 g (2.1 equivalents) of lithium aluminum hydride (LiAlH4) in 100 ml of tetrahydrofuran at a temperature of 10-15°C for approximately 20 minutes. Then the resulting mixture was subjected to stirring for 30 minutes. After the reaction mixture was processed for 20%aqueous solution of potassium hydroxide (KOH) (exothermic reaction). Obtained the salts were separated by filtration and washed with tetrahydrofuran, taken in a volume of 200 ml. Combined filtrates were evaporated to a syrupy substance, the amount of which amounted to 35.5,

B2. The recovery of the intermediate product obtained at stage A, using chloromethylene (Grignard reagent)

A solution of 2 g (3.9 mmol) of chemical compounds obtained in stage A, in 20 ml of tetrahydrofuran was cooled to a temperature of 0°. Then to him for 20 minutes was added dropwise 12 ml of 3 M chloromethylene. After incubation for 18 hours at room temperature was achieved complete metamorphosis acetonide n-butylamide lovastatin.

B3. The recovery of the intermediate product obtained at stage A, using n-utility

A solution of 91 g (1.9 mmol) of chemical compounds obtained in stage A, in 25 ml of tetrahydrofuran was cooled to a temperature of -50°. Then to him for 10 minutes was added dropwise 2,47 ml of 2.5 M chloromethylene. After incubation for 18 hours at room temperature was obtained alcohol intermediate product.

C. Acylation of the intermediate product obtained at stage B, and obtaining the ammonium salt of simvastatin

4-dimethylaminopyridine in the amount of 3 g dissolved in 300 ml of pyridine, was added to a solution of 25 g (57 mmol) of the intermediate product obtained at stage B, and placenames was heated to a temperature of 50-55° With, preferably to a temperature of 50°C. Then cooled mixture in one portion was added chloride 2,2-dimethylmaleic acid in a quantity of 50 ml, after which the resulting mixture was subjected to stirring for 40 hours (analysis by the method of liquid chromatography high resolution showed complete conversion). To the reaction mixture were added 400 ml of water and 400 ml of ethyl acetate (EtOAc). Then the organic layer was twice washed with 10%-s ' solution of sodium bicarbonate (NaHCO3), taken in a volume of 400 ml of water taken in a volume of 400 ml, and 10%hydrochloric acid (HCl), taken in a volume of 400 ml Organic layer was subjected to evaporation and dissolved in 200 ml of tetrahydrofuran, after which the resulting solution was added 200 ml of water, and then 10 g of p-TsOH. Then the resulting mixture was subjected to delegirovano within 2 hours. Then to the reaction mixture were added 400 ml of ethyl acetate (EtOAc), and then 300 ml of water. The organic layer was twice washed with 10%-s ' solution of sodium bicarbonate (NaHCO3), taken in a volume of 400 ml, and then subjected to evaporation. The obtained residue was subjected to dissolution in 300 ml of methyl alcohol (Meon), then to the solution was added 170 ml of a 2 N solution of sodium hydroxide (NaOH). The resulting mixture was subjected to delegirovano for 3 hours at room temperature, resulting in h is th go evaporation of the greater part of methyl alcohol (Meon). Then to the reaction mixture was added 120 ml of water and the pH was brought to 7 with 3 N hydrochloric acid (HCl), after which was added 300 ml of ethyl acetate (EtOAc). Then the value of pH was brought to 4, and the layers were subjected to separation. To the organic layer was added 100 ml of ethyl acetate (EtOAc), and then 40 ml of a mixture of ammonium hydroxide (NH4OH) and methyl alcohol (Meon) (in the ratio 1:3). The resulting mixture was subjected to stirring at a temperature of -10°C for 2 hours, after which the solid was collected and washed with ethyl acetate (EtOAc) and ethyl alcohol (EtOH) (cold). The product yield was 16 g (62%), analysis by the method of liquid chromatography high resolution showed the contents of ammonia salt of simvastatin 98,9%.

D. the transformation of the ammonium salt of simvastatin in simvastatin

A suspension of 9 g of ammonium salt of simvastatin, obtained in stage C in 250 ml of toluene was heated to a temperature of 100°C, which was maintained for 6 hours. Then the suspension was subjected to deleverage for 30 minutes, then filtered and evaporated. To the residue was added 100 ml of cyclohexane, and the resulting solution was again subjected to evaporation. Of the approximately 150 ml of cyclohexane solution crystallized crude simvastatin in Targovishte white. The product yield was 85%, the analysis by the method of liquid chromatography high resolution showed the contents of simvastatin to 98.4%.

Example 6

The way to get simvastatin from lovastatin by recovery of the ester group R1

A. Obtaining acetonide of butylamide lovastatin

A mixture of lovastatin, is taken in the amount of 950 g (2.4 mol), toluene, taken up in a volume of 8 l, and n-butylamine, taken in a volume of 500 ml (5 mol), was heated to a temperature of 85°C in nitrogen atmosphere. The resulting solution was maintained at a temperature of 85°C-95°C for 2 hours, then was cooled to room temperature. Then to the solution was added 5 l of 4 N solution of sulfuric acid, after which the resulting mixture was subjected to stirring for 5 minutes. The bottom layer was removed and the upper layer was added 1.5 l (12 mol) of 2,2-dimethoxypropane. Then the solution was subjected to stirring at room temperature for 30 minutes, after which the mixture was subjected to concentration by evaporation in a vacuum at a temperature of 55-60°to obtain a concentrate in the amount of 5.4 kg

C. Recovering the intermediate product obtained at stage A, by means of lithium aluminum hydride

the 5.8 l (5.5 kg, which corresponds to 2.4 mol of the intermediate product obtained in stage A) of the concentrate obtained at the stage And was smiling is about 2 l of toluene. The resulting mixture was cooled down to 0°C in nitrogen atmosphere. Then within 75 minutes, to the mixture was added to 6 l of 1 N solution of lithium aluminum hydride (LiAlH4) in toluene (6 mol of lithium aluminum hydride), the temperature of the reaction mixture was maintained below 8°C. the resulting mixture was subjected to stirring at a temperature of 5-10°C for 3 hours, then for 100 minutes, to the mixture was added to 5.3 liters of water, the temperature of the mixture was maintained below 10-15°C. Then, to the mixture (suspension) was added to 5 l of 4 N solution of sulfuric acid, after which the mixture was subjected to stirring for 15 minutes. After that, the mixture was left alone for the deposition of layers. Then lower milk white layer was removed and the upper layer was washed with water, taken up in a volume of 6 liters, and aqueous 1 N sodium hydroxide solution. Then 6 l of the upper layer was removed by evaporation in vacuum (pressure of from 150 to 300 mm of mercury) at a temperature of 50-60°C.

C. Acylation of the intermediate product obtained at stage B, 2,2-dimethylbutyramide

To the obtained at the stage In the alcohol solution of the intermediate product, in toluene, in which the mentioned intermediate product contained in the amount of 2.4 mol, was added 250 ml of toluene solution containing 35 g (0.29 mol) of 4-(N,N-dimethylamino)pyridine and 1.6 liters to(11.4 mol) of triethylamine and 1.5 kg (11 mol) of 2,2-dimethylbutyramide. The resulting solution was heated to a temperature of 105-110°and subjected to stirring at this temperature for 10 hours in nitrogen atmosphere. Then the resulting suspension was cooled to room temperature, and then thereto was added 3 l of 4 N solution of sulfuric acid. The resulting mixture was subjected to stirring for 5 minutes, after which she was left alone to separate the layers. After the lower layer was removed, and the upper layer was washed with 4 N solution of sulphuric acid taken in the quantity of 2 liters

D. Obtaining ammonium salt of simvastatin

The reaction mixture obtained in stage (approximately 11 l)was mixed with 4.5 l of 4 N solution of sulfuric acid. The resulting mixture was heated to a temperature of 70-75°C for 3 hours, through a mixture of nitrogen was passed. Then the mixture was left alone to cool it to room temperature, after which it was removed the bottom layer. Then the top layer was cooled down to 5°and washed With 2 N sodium hydroxide solution taken in a volume of 2.5 L. the removal of the bottom layer was added to 6 l of 2 N sulfuric acid solution, and the mixture was subjected to stirring at first for 3 hours at room temperature and then for 3 hours at a temperature of 45-55°C. Then the obtained suspension was cooled to a temperature which s 5-10° With, after which it was added to 2.75 l of 4 N solution of sulfuric acid, the temperature of the suspension was maintained below 10°C. the lower layer was removed and to the residue was added a concentrated solution of ammonium hydroxide (NH4OH). Then the mixture was subjected to concentration by evaporation in a vacuum at a temperature of 50-60°With removal of the toluene and water. Then to the residue was added 3 l of ethyl acetate, and the mixture was subjected to stirring at a temperature of 50°C for 30 minutes, the result was obtained homogeneous suspension. This suspension was cooled to room temperature and filtered under vacuum. The resulting cake (the residue on the filter was washed with ethyl acetate, taken in a volume of 1 l, and then subjected to suspendirovanie environment ethyl acetate, taken in a volume of 4 l, and the obtained suspension was heated to a temperature of 50°C, which was maintained for 90 minutes. After that, the hot suspension was filtered and the resulting cake (the residue on the filter was washed with ethyl acetate. The result was obtained crystalline ammonium salt of simvastatin in the number 891,

E. Receiving simvastatin

Obtained in stage D of crystalline ammonium salt of simvastatin in the amount of 570 g was subjected to suspendirovanie in the environment of toluene, taken up in a volume of 13 liters ZAT is m to the suspension was added 2 l of water, and the value of pH was brought to 3 by addition of 4 N solution of sulfuric acid. The resulting mixture was subjected to stirring for 30 minutes, then was removed the bottom layer. The upper layer was washed with water, taken in an amount of 2 l, and then subjected to concentration by evaporation of 4 l of toluene at a temperature of 50-60°With vacuum. The remaining solution was subjected to heating and was maintained at a temperature 85-92°C in nitrogen atmosphere for 2.5 hours. Then the solution was cooled to a temperature of 15°With, to it was added 3 l of water, and the pH value of the mixture was brought to 8-8,5 by adding 1 N sodium hydroxide (NaOH). After this was removed the bottom layer and the top layer was added 3 l of water, after which the pH value of the mixture was brought to 6 by addition of 6 N sulfuric acid solution. Then the bottom layer was removed and the upper layer was subjected to concentration to a volume of 1 l by evaporation in a vacuum at a temperature of 50-60°C. then, to the obtained concentrate for 1 hour at a temperature of 50-60°C was added n-hexane in the amount of 350 ml and the resulting mixture was subjected to stirring at a temperature of 50-60°C for 30 minutes, after which it within 2 hours was subjected to slow cooling to a temperature of 15°C. the Obtained crystals were tfilter the Vanir and washed with a mixture of n-hexane and toluene (5:1 ratio), taken in the amount of 350 ml. Output simvastatin amounted to 440,

Example 7

Way to obtain the ammonium salt of simvastatin by recovery of the ester group R1lovastatin

A. Obtaining cyclohexanamine lovastatin

A mixture of lovastatin, taken in an amount of 5 g (0.012 mol), cyclohexylamine, taken in an amount of 6 ml (0,052 mol), and toluene, taken up in a volume of 50 ml, were delegirovano within 6 hours. Then the reaction mixture was cooled to room temperature, and then thereto was added 20 ml of ethyl acetate. After that, the mixture was twice washed with 2 N hydrochloric acid (HCl), both times taken in a volume of 30 ml, and water, both times taken in a volume of 20 ml Organic layer was dried with sodium sulfate, filtered and subjected to thickening up to a volume of 15 ml by evaporation. Then, to the obtained concentrate was added 50 ml of hexane, the precipitate was filtered, resulting in 5.5 g of cyclohexanamine lovastatina in the form of white powder.

C. Obtaining the acetonide of cyclohexanamine lovastatin

To a solution of 5 g (10 mol) of cyclohexanamine lovastatin in 25 ml of acetone was added 300 mg (1.6 mmol) of p-TsOH. The resulting mixture was subjected to stirring at room temperature for 18 hours, after which it was merged in a mixture consisting of 50 ml of ethyl acetate and 0 ml of 10%aqueous solution of sodium bicarbonate, the resulting mixture was dried with sodium sulfate, filtered and subjected to evaporation. The obtained residue was dissolved in toluene and the resulting solution was then evaporated, the result of which was obtained 4.9 g of the acetonide of cyclohexanamine lovastatin.

C. Obtaining ammonium salt of simvastatin

Suspension 836 mg (22 mmol) of lithium aluminum hydride in an environment of 15 ml of tetrahydrofuran was cooled to a temperature of 0°and within 15 minutes was added dropwise a solution is 4.93 g (9.1 mmol) of chemical compounds obtained in stage b In 20 ml of tetrahydrofuran. The resulting reaction mixture was aged for 18 hours at room temperature, after which it was cooled down to 0°C, after which it was added 0.1 ml of water and 10%aqueous solution of potassium hydroxide. After that, the mixture was filtered through celite, and then was evaporated tetrahydrofuran, in the result there were obtained 4.3 g (9 mmol) of the alcohol intermediate product.

D. Obtaining ammonium salt of simvastatin

A mixture of 4.3 g (9 mmol) of the alcohol intermediate product obtained in stage C, 40 ml of pyridine, 200 mg of N,N-dimethylamino-pyridine and 7.2 g (54 mmol) of acid chloride of 2,2-dimethylmaleic acid, was subjected to stirring at a temperature of 65°C for 72 hours. Then received MES was cooled, and to it was added 100 ml of toluene, after which the mixture was twice washed with 10%solution of sodium bicarbonate, both times taken in a volume of 50 ml, and brine, taken in a volume of 30 ml. After that, the toluene layer was dried with sodium sulfate, the mixture was filtered and evaporated. Then the residue was dissolved in 100 ml of toluene, which was then evaporated. After that, the residue was dissolved in 20 ml of tetrahydrofuran and 20 ml of water. Then to the resulting solution were added 2 g of p-TsOH, after which the solution was subjected to delegirovano for 5 hours. After this, the solution was infused into the mixture consisting of 70 ml of toluene and 50 ml of 10%aqueous solution of sodium bicarbonate. The organic layer was separated and washed with 10%solution of sodium bicarbonate, taken in an amount of 30 ml then the organic solution was dried, filtered and subjected to evaporation, the result was obtained, the balance in the amount of 4.8 G. of This residue was dissolved in 70 ml of methanol and 40 ml of 2 M solution of sodium hydroxide (NaOH). The reaction mixture (solution) was subjected to delegirovano within 72 hours. Methyl alcohol was evaporated, and the aqueous layer was cooled down to 0°C. Then the aqueous layer was acidified, namely, the value of pH of the aqueous layer was brought to 5 with 2 N hydrochloric acid (HCl). After this the to the reaction mixture was added 75 ml of ethyl acetate, and was separated organic layer. The ethyl acetate was added 5 ml of 25%ammonia solution. Then the precipitate was filtered, the result of which was obtained 1.1 g ammonium salt of simvastatin, the total output of which of the acetonide of cyclohexanamine lovastatin was 27%.

Example 8

Getting decelerating of butylamide lovastatin

A. Introduction to butylamide lovastatin silyl group

According to the method described in the literature (Askin, D.; Verhoeven, T.R.; Liu, M.-H.; Shinkai, I., J. Org. Chem., 1991, 56, 4929), was obtained t-butyl-dimethylsiloxy butylamide lovastatin, the output of which amounted to 68% (crude product), as defined by the method of liquid chromatography high-resolution factor mobility Rfwas 12,87.

Century Restoration of t-butyldimethylsilyl of butylamide lovastatin

A solution of t-butyldimethylsilyl of butylamide lovastatin taken in the amount of 1.65 g (2.34 mmol) in 30 ml of tetrahydrofuran (THF)was added to 6 ml (2.5 equivalent) 2 M solution of complex alumoweld lithium - tetrahydrofuran (LiAlH4·2THF) in toluene at a temperature of 0°C. the resulting reaction mixture was subjected to stirring for 2 hours, after which it to stop gassing was added to wet sulfate sodium (Na2SO4·nH2O). Attempts to filter the suspension through a glass Raven is u (P2) with a layer of celite did not succeed. The reaction mixture was infused in dilute (<1 N) hydrochloric acid (HCl). The aqueous layer was removed using diethyl ether. The organic layer was washed with brine, dried with sodium sulfate (Na2SO4) and evaporated. The yield of product amounted to 1.07 g (89%). Defined by the method of liquid chromatography high-resolution factor mobility Rfwas 9,27.

C. Acylation t-butylcyclohexanol lovastatinsee alcohol

To the solution obtained as an intermediate product at the stage In lovastatinsee alcohol, taken in an amount of 360 mg (of 0.58 mmol) and triethylamine taken in the volume of 0.32 ml, in 10 ml of toluene was added 0.31 g (4 equivalents) of 2,2-dimethylbutyramide. The resulting reaction mixture was heated to reflux for 10 hours (standard procedure). Analysis by the method of liquid chromatography high resolution showed the presence of a mixture of chemical compounds, among which were present and desired Vallromanes product, factor mobility Rfwhich was 15,81. Removal of protective groups was carried out according to the method described in the literature (Askin, D.; Verhoeven, T.R.; Liu, M.-H.; Shinkai, I., J. Org. Chem., 1991, 56, 4929), resulting in a yield of 68% (crude product), as defined by the method of liquid chromatography the raffia high-resolution factor mobility R fwas 12,87.

Example 9

Getting diacetylbenzene derived lovastatin

A. Obtaining benzylidene derived butylamide lovastatin

Butylamide lovastatin taken in the amount of 4.77 g (10 mmol), was dissolved in 50 ml of toluene. Then to the resulting solution was added 10.6 g (10 equivalents) of benzaldehyde and 500 mg of p-TsOH, after which the resulting mixture was subjected to stirring at room temperature for 16 hours. Then to the reaction mixture was added saturated aqueous solution of sodium bicarbonate (NaHCO3), and then were split layers. Then the toluene layer was washed with saturated aqueous sodium bicarbonate (NaHCO3), a saturated aqueous solution of hydrochloric acid (HCl), dried with sodium sulfate (Na2SO4) and evaporated. After that, the residue was subjected to purification using chromatography on a column (SiO2) /n-hexane/ethyl acetate, resulting in the final product, the output of which amounted to 2.6 g (46%).

Century Restoration benzylidene derived

Benzylidene derived compound in the amount of 2.6 g was dissolved in 50 ml of toluene, and the resulting solution was cooled down to 0°C. Then to the cooled solution dropwise was added 11.5 ml of 1 M solution of complex alumoweld lithium - tetrahydrofuran (LiAlH 4·2THF) in toluene, the temperature of the reaction mixture was maintained at 10°C. the resulting solution was subjected to stirring at a temperature of 0-5°C. Then the solution was added to 1.8 ml of 30%aqueous solution of sodium hydroxide (NaOH), and the resulting mixture for 16 hours under stirring at room temperature. Then the mixture was filtered through celite, washed with toluene, taken up in a volume of 50 ml, and subjected to concentration to a volume of about 50 ml.

C. Obtaining benzylidene derived simvastatin

To the reaction mixture obtained in stage B, was added to 1.9 g (4.1 equivalents) of triethylamine, 2.5 g (4 equivalents) dimethylsilanol acid and 50 mg of dimethylaminopyridine, after which the mixture was subjected to delegirovano for 16 hours. Then the mixture was infused into the system water/ethyl acetate, and was subjected to separation into layers. After that, the organic layer was washed first with water then with a saturated solution of sodium chloride, then dried with sodium sulfate and evaporated, resulting in a 3.3 g of the crude product. Further transformation of the obtained product in the simvastatin is performed according to the procedures described in Example 5, stage C and stage D, the second part.

Example 10

Lovastatinsee restore azeto the IDA of pyrrolidinone lovastatin

To a solution of the acetonide of pyrrolidine of butamide lovastatin obtained by the method described in Example 3 by reaction between lovastatin and pyrrolidino, taken in an amount of 1 g (1.94 mmol) in 20 ml of tetrahydrofuran at a temperature of 0°was added 40 mg (1.1 mmol) of lithium aluminum hydride. After 18 hours at room temperature the conversion was 50%.

Example 11

Restoring butylamide lovastatin

To a suspension of 400 mg (10.5 mmol) of lithium aluminum hydride (LiAlH4) in 50 ml of tetrahydrofuran at a temperature of 0°C was added a solution of butylamine lovastatin taken in the amount of 2.25 g (5 mmol), in tetrahydrofuran taken in a volume of 25 ml of the resulting mixture was subjected to stirring at ambient temperature for 16 hours, after which it to stop gassing was added to wet sulfate sodium (Na2SO4·nH2O), analogue of Glauber's layers. Then to the mixture was added dry sodium sulfate (Na2SO4). Then the suspension was filtered through a glass filter, and the filtrate was evaporated under reduced pressure until dry, the result was obtained the crude product as a thick oily liquid brown, the output of which amounted to 1.03 g (53%). Defined by the method of liquid chromatography high RA the solution the coefficient of mobility of this crude product R fwas 12,87 (source material - 5,79).

Example 12

Selective allerease effect on nitrogen alcohol acetonide of butylamide lovastatin, after which it can be implemented acylation of hydroxyl (OH) groups

To the alcoholic solution of the acetonide of butylamide lovastatin, taken in an amount of 2.1 g (5 mmol), and triethylamine, taken in an amount of 0.8 ml (5.5 mmol)in 50 ml of toluene at a temperature of 0°was added 1.1 equivalent of 0.64 ml, 5.5 mmol) of benzoyl chloride. Then the reaction mixture was subjected to stirring at room temperature for 16 hours. The sample subjected to analysis by the method of liquid chromatography high resolution, showed the main peak value of the mobility ratios Rf=6,16 (source material) and Rf=9,13. After 21 hours appeared peak value of Rf=6,67. Analysis by the method of nuclear magnetic resonance showed a small peak of NH and three other peaks in the region of 6.5-5 parts per million, indicating that the amide allerban.

Example 13

The reaction of lovastatin with ammonia

A suspension of 0.25 g (0.6 mmol) of lovastatin in 15 ml of methanol was cooled to a temperature of 5°in a bath of ice/water. Then methyl alcohol was saturated with ammonia (gas), after which the reaction mixture was subjected to heat treatment at a temperature of 130°With over 40 hours in Zapadno the glass tube. Analysis by the method of liquid chromatography high resolution showed that the resulting reaction mixture contains 43% of the respective decelerating product.

Example 14

The reaction lovastatin n-butylamide

A solution of 0.5 g (1.2 mmol) of lovastatin in 15 ml of n-butylamide was subjected to heat treatment at a temperature of 150°With over 40 hours in a sealed vessel. Analysis by the method of liquid chromatography high resolution showed that the resulting reaction mixture contains 12.3% of the corresponding decelerating product. Structure decelerating of butylamide was confirmed by the formation of the corresponding acetonide by reaction with p-TsOH and acetone and comparison of the acetonide with another sample acetonide obtained as described in Example 5, the second part of stage A.

Example 15

The reaction lovastatin n-heptylamine

A solution of 0.5 g (1.2 mmol) of lovastatin in 10 ml of heptylamine been delegirovano for 70 hours. Analysis by the method of liquid chromatography high resolution showed that the resulting reaction mixture contains 17% of the respective decelerating product.

Example 16

All three decelerating chemical compounds obtained in Examples 13, 14 and 15, were converted into corresponding azeto the IDA (by ring closure) adding to each of them 400 ml of acetone and 5 g of p-TsOH. The resulting mixture was subjected to stirring at room temperature for 1 hour, then cooled in ice water for 2 hours. The obtained solid substance was collected by suction and dried.

Example 17

Three acetonide obtained in Example 16, were each individually transformed simvastatin by acylation and from the reactions of transformation of ammonium salts as described in Example 5, stage C and D.

Example 18

Recrystallization of simvastatin from the system toluene/n-hexane

The crude simvastatin in the amount of 35 g was dissolved in 140 ml of toluene under stirring at a temperature of 60°C. and Then slowly added n-hexane under stirring and gradual lowering of temperature to 0-5°C. After stirring for 1 hour at the above temperature was collected precipitate, which was then washed with a mixture of toluene and n-hexane (1:4 ratio by volume) and dried, the result of which was obtained recrystallizing product number 33,

Example 19

Recrystallization of simvastatin from the system methyl alcohol/water

Recrystallizing simvastatin in the amount of 33 g was dissolved in 300 ml of methyl alcohol at room temperature, after which the resulting solution was subjected to a treatment with activated charcoal. Then exhaust the tree is hydrated coal was removed by filtration, and the product was precipitated by adding 450 ml of water. The suspension was cooled to a temperature of 5-10°and the product was collected, washed with a mixture of methanol and water (in the ratio 1:2 by volume) and dried, the result of which was obtained recrystallizing product number 31,

1. The way to get simvastatin high degree of purification of lovastatin, containing the following stages:

a) opening lactoovo ring with the introduction of lovastatin in the reaction with the amine for the formation of amide,

(b) protection of 1,3-Volovoi part of the protective group,

c) removing 2-methylbutyryl group, attached through a complex of essential communication through the oxygen at position 8 hexahydronaphthalen rings,

d) attaching 2,2-dimethylbutylamino group by formation of a complex of essential links to the hydroxyl at position 8,

e) removing the protective group,

f) conversion of amide to acid salt,

(g) circuit lactoovo ring with the formation of simvastatin.

2. The method according to claim 1, in which stage opening lactoovo ring is carried out by bringing the lactone in a reaction with at least one chemical compound selected from the following list: ammonia, primary amine, secondary amine.

3. The method according to claim 1, in which stage opening lactoovo rings done is make by reduction of the lactone in a reaction with at least one amine, selected from the following list: n-butylamine, cyclohexylamine, piperidine, pyrrolidine.

4. The method according to claim 1, in which the protective group selected from the following list: acetal, ketal, cyclic sulfate, cyclic phosphate, borate group.

5. The method according to claim 1, wherein in the received simvastatin contents simva-okalona less than approximately 0.1%.

6. The method according to claim 1, wherein in the received simvastatin content anhydrovinblastine less than approximately 0.1%.

7. The method according to claim 1, wherein in the received simvastatin content digidrokvercetina less than approximately 0.1%.

8. The method according to claim 1, in which lovastatin was contained in a mixture in which the content of impurities is approximately 30%.

9. The method of obtaining synthetic statin having a molecular structural formula I

from statin that has the following molecular structural formula II

contains the following stages:

a) opening lactoovo ring by casting statin, having the structural molecular formula II in the reaction with the amine to obtain amide,

(b) protection of 1,3-Volovoi part of the protective group,

c) removing the group R1attached with complex EPE is Noah communication through the oxygen at position 8 hexahydronaphthalen rings,

d) joining the group R2through the formation of a complex of essential links to the hydroxyl at position 8,

e) removing the protective group,

f) conversion of amide to acid salt,

(g) circuit lactoovo ring with the formation of semi-synthetic statin, having a molecular structural formula I,

where R1and R2- acyl group attached to the oxygen through a complex of essential communications;

R3and R4groups independently selected from the following list: -H, -OH, -C1-10alkyl, -C1-10aryl, C6-14aryl-C1-3.

10. The method according to claim 9, wherein the content of impurities in the statin, having a molecular structural formula I, less than about 0.1%.

11. The method according to claim 9, wherein the statin, having a molecular structural formula II is contained in a mixture in which the content of impurities is approximately 30%.

12. The method according to claim 9, in which the protective group selected from the following list: acetal, ketal, cyclic sulfate, cyclic phosphate, borate group.

13. The method according to claim 9, in which R1- acyl group that resembles the following:

where Ω is the oxygen that is Deputy hexahydronaphthalen ring at position 8;

R5group selected from the following is the first list: 1-15alkyl, -C3-15cycloalkyl, -C2-15alkenyl, -C2-15quinil, -phenyl, -panels1-6alkyl;

A - substituent R5selected from the following list: hydrogen, halogen, C1-6alkyl, C1-6alkoxy, C6-14aryl.

14. The method according to claim 9, in which R2- acyl group of the following form

where Ω is the oxygen that is Deputy hexahydronaphthalen ring at position 8;

R6group selected from the following list:1-15alkyl, -C3-15cycloalkyl, -C2-15alkenyl, -C2-15quinil, -phenyl, -panels1-6alkyl;

In the substituent R6selected from the following list, hydrogen, halogen, C1-6alkyl, C1-6alkoxy, C6-14aryl.

15. The method according to claim 9, in which the dotted lines indicated in structural molecular formulas I and II letters X, Y and Z shows a possible double bonds, which may be located on or in the positions of X and Z at the same time, or only in one of the positions X, Y, or Z.

16. The method according to claim 9, in which the stage opening lactoovo ring is carried out by bringing the lactone in the reaction with ammonia, a primary amine, or secondary amine.

17. The method according to claim 9, in which the stage opening lactoovo ring is carried out by bringing the lactone in a reaction with an amine, selected the output from the following list: n-butylamine, cyclohexylamine, piperidine, pyrrolidine.



 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing derivatives of 2-(6-substituted-1,2-dioxane-4-yl)-acetic acid of the formula (1) or its salt, or acid wherein X means halogen atom, tosylate, mesylate, acyloxy-group, aryloxy- or nitro-substituted benzenesulfonyl group; each R1, R2 and R3 means independently (C1-C3)-alkyl group from compound of the formula (2):

wherein X has abovementioned values by using a suitable acetylation agent in the presence of acidic catalyst and its following conversion, if necessary, to the corresponding salt or acid. These compounds are intermediate substances in synthesis of statins that represent inhibitors of HNG-CoA-reductase. Also, invention relates to new parent compounds of the formula (2) in (4R,6S)-forms and new compounds of the formula (1b) given in the description. Invention provides preparing a valuable intermediate substance with high yield.

EFFECT: improved preparing method.

11 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: biotechnology, organic chemistry, microbiology, pharmacy.

SUBSTANCE: invention describes a new highly productive strain of fungus Aspergillus terreus № 44-62 that is deposited in the Collection of the company Metkinen Oy, Littoinen, Finland, producing lovastatin. Also, invention relates to a method for isolation of lovastatin and a method for lactonization of statins, such as lovastatin and simvastatin. Method for isolation of lovastatin involves its extraction from raw obtained in culturing the above said fungus-producer, concentrating extract, lactonization of lovastatin in the absence of solvent, clearing and crystallization of the end product. The lactonization process of statins carrying out in the absence of solvent provides preparing their lactones in crystalline form directly and practically without impurities of dimmers and acid form. Invention provides highly profitable manufacturing lovastatin and allows preparing the end product corresponding to Pharmacopoeia purity, higher yield (above 70%) and low cost.

EFFECT: improved preparing method and enhanced quality of product.

48 cl, 2 dwg, 10 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to the production of carbonyl compounds, which are used as primary intermediates and fine organic synthesis

The invention relates to the production of lactones, which are used as corrosion inhibitors of metals to produce antioxidants for hydrocarbon fuels and lubricants

The invention relates to an improved method of lactonization when receiving statins, for example inhibitors of HMG-COA reductase inhibitor lovastatin and simvastatin, in particular, relates to a method for obtaining compounds of formula (I) where R represents the radical of the formula (III), where R1represents N or CH3that includes (a) treatment of compounds of formula (II), where Z is hydrogen, a metal cation or NH4and R is as defined above, is a weak organic acid in the absence of a strong acid as catalyst and water at a temperature below 55oWith, and (b) adding antibacterial, which causes the precipitation of the compounds of formula (I) in the form of a crystalline product

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to arylated amides of furan and thiophene carboxylic acids of the formulae (Ia) and (Ib) wherein W means oxygen or sulfur atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x means 0, 1, 2 or 3; R(14) means phenyl, and to their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition and using proposed compounds a medicinal agents. Compounds can be used as anti-arrhythmic biologically active substances and especially in treatment and prophylaxis of atrium arrhythmia.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 29 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes valsartan salts chosen from the group involving monosodium, monopotassium, disodium, dipotassium, magnesium, calcium, bis-diethyl (or dipropyl, or dibutyl)-ammonium salts or their hydrates, and mixtures of these salts also. Also, invention relates to a method for their preparing and a pharmaceutical composition comprising thereof. Proposed salts can be in crystalline, partially crystalline, amorphous or polymorphous form. Prepared salts show high quality of crystalline lattices that is a base for chemical and physical stability of new compounds.

EFFECT: improved preparing method, improved and valuable properties of salts.

11 cl, 11 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

FIELD: medicine.

SUBSTANCE: method involves additionally administering vitamins B6, B12 and folic acid to patients receiving anticoagulation therapy. Protein content is limited in daily food allowance to 0.8-1.1 g/kg of body weight and cysteine content is increased to 400-500 mg/day.

EFFECT: enhanced effectiveness of treatment; eliminated homocysteine link in pathogenesis.

FIELD: medicine.

SUBSTANCE: method involves administering Clonidine (Clophelinum). The drug is introduced intramuscularly, intravenously or as pills on the background of neurotropic therapy at a dose of 2.5-3.0 mcg/kg of body weight during the first hours of posttraumatic period within 7-10 days.

EFFECT: accelerated and simplified treatment course.

1 dwg, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used for stabilization of homeostasis and arresting pathological processes in the body. Invention proposes a pharmaceutical composition as powder with particles size from 250 to 400 mcm comprising the following components by the first variant, wt.-%: carbon, 10.01-53.02; oxygen, 30.10-53.10; potassium, 0.26-1.99, and calcium, 0.20-31.37, and comprising the following components by the second variant, wt.-%: calcium, 0.35-31.20; carbon, 10.99-50.21; oxygen, 34.55-51.03; sulfur, 0.73-14.81, and phosphorus, 0.08-3.30. Invention provides compensation of trace elements unbalance that causes and accompanies many diseases, possibility for stabilization of trace element homeostasis and arresting pathological processes of different etiology.

EFFECT: improved and valuable medicinal properties of composition.

12 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 5-amidino-2-hydroxybenzenesulfonamide of the general formula (I): wherein R2 means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (A): wherein (A) means -COORA, -CONRBRC, 3-7-membered monocyclic heterocycloalkyl group comprising one or two heteroatom in ring chosen from atoms N, O, S that can comprise oxo-group and 5-6-membered monocyclic aromatic heterocyclic group comprising one-three heteroatoms in ring chosen from atoms N, O, S that can comprise oxo-group or lower alkyl wherein RA means hydrogen atom (H), 3-7-membered monocyclic aliphatic alkyl group, lower alkyl that can comprises a substitute chosen from the group (i) wherein (i) means -COORA1 wherein RA1 means hydrogen atom (H), -OCORA2 wherein RA2 means lower alkyl group, -OCOORA3 wherein RA3 means lower alkyl, -ORA4 wherein RA4 means hydrogen atom (H), lower alkyl -CONRA5RA6 wherein RA5 and RA6 mean independently hydrogen atom (H), lower alkyl, or -NRA5RA6 forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; wherein RB and RC mean independently hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (ii), or -NRBRC forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; (ii) means -COORB1 wherein RB1 means hydrogen atom (H), lower alkyl; T means oxygen atom (O), sulfonyl group; or TR1 means -SO2NRB3RC3 wherein RB3 and RC3 means independently hydrogen atom (H), lower alkyl; R2 means lower alkyl, phenyl that can comprise one-three substitutes chosen from the group (B) wherein (B) means halogen atom, -COORE, sulfamoyl, lower alkylsulfonyl wherein RE means lower alkyl; Q means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (D) wherein (D) means 5-6-membered monocyclic aromatic heterocyclic group that can comprise one-three heteroatom chosen from atoms N, O, S that can comprise a substitute chosen from the group (iv) wherein (iv) means oxo-group, lower alkyl; Z means hydrogen atom (H), hydroxyl group (OH), -COORN wherein RN means lower alkyl that can comprise a substitute chosen from the group (viii) wherein (viii) means -OCOR5 wherein RN5 means lower alkyl that can comprise -OCORN51 wherein RN51 means lower alkyl; or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit activated factor X in blood coagulation system that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and compositions.

12 cl, 5 tbl

FIELD: medicine, cardiology.

SUBSTANCE: invention proposes an agent for correction of abdominal complications in acute period in myocardium infarction. Proposed agent represents ondansetron or domperidone. Agent reduces frequency of hyperemia occurring, improved indices of intestine contractions, promotes to declining lethality in acute period in myocardium infarction.

EFFECT: improved and valuable medicinal properties of agent.

4 tbl, 6 dwg

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical preparation based on angiotensin-converting enzyme inhibitor, its using in prophylaxis of insult, diabetes and/or congestive cardiac insufficiency and corresponding methods for its using in patient with maintenance heart function and subjected for risk of cardiovascular attack due to previous history of ischemic disease, insult or peripheral arterial disease. In particular, inhibitor of angiotensin-converting enzyme can be chosen from ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Invention promotes to reducing the total lethality of patients group in case of cardiovascular diseases, cardiac attacks and insults, the necessity for carrying out procedures for revascularization (such as surgery operation for coronary shunt, angioplasty with using balloon and so on) and diabetic complication are diminished.

EFFECT: improved and valuable medicinal properties of preparations.

19 cl, 1 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: method involves administration of amlodipine in the dose 5 mg, once in the same time and metformin in the dose 500 mg, 2 times per 24 h in patients at the background of individually selected hypocaloric diet. Treatment is carried out for 8 weeks, not less. Method provides optimization of intravascular activity of platelets due to correction of primary homeostasis and the level of their antioxidant protection. Invention can be used for rapid optimization of functions of platelets at metabolic syndrome.

EFFECT: improved and enhanced method for optimization.

2 ex

FIELD: medicine, pharmacology, biochemistry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition that comprises a medicine orlistat and sucrose fatty acid ester wherein fatty acid moiety in fatty acid di-, tri- or tetra-ester means a mixture of two or some fatty acids. Also, invention relates to a method for treatment of obesity by using the claimed composition. Invention provides enhancing effectiveness of treatment.

EFFECT: enhanced and valuable properties of composition.

36 cl, 5 dwg, 7 tbl, 19 ex

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