The way the optical purification of enantiomerically enriched derivative of benzimidazole

 

(57) Abstract:

Method of optical clearing of derivatives of benzimidazole of the formula 1A-1D

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is that enantiomerically enriched preparation of compounds of any of formulas 1A-1D in favor of either ( + ) - or (-)-enantiomer is treated with a solvent which selectively precipitated the racemate of the above compounds. Besieged racemate is filtered, followed by removal of the solvent, obtaining a single enantiomer of high optical purity. The method does not require reactive processing of compounds 1A-1D and simple in execution. 18 C.p. f-crystals.

The present invention relates to a method of optical purification of enantiomerically enriched preparations of some derivatives of 2-(pyridinylmethyl)-1H-benzimidazole, as well as other structurally related sulfoxide.

Art

There are a large number of patents and patent applications that describe the various substituted 2-(pyridinylmethyl)-1H-benzimidazole and structurally related sulfoxidov. This class of compounds has properties that allow the use of these compounds as inhibitors of secretion Gelu the l] -1H-benzimidazole, having a trivial name for omeprazole and its therapeutically acceptable salts. Omeprazole and its alkali metal salts are effective inhibitors of gastric secretion of acid, and they are useful as antiulcer agents. Other effective inhibitors of secretion of gastric acid are also compounds: 2-[[[3-methyl-4-(2,2,2-triptoreline)-2-pyridinyl]methyl]sulfinil] -1H-benzimidazole, which has the trivial name lansoprazole (EP-A1-174726); 2-[[[4-(3-methoxypropane)-3-methyl-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole, which has the common name of ariprazole (EP 268956); 2-[[2-(N-isobutyl-N-methylamino)benzyl] sulfinil] -1H-benzimidazole, which has the common name of leminoprazole (GB 2163747) and 2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)sulfinil]-1H-benzimidazole (EP 434999).

All these links: omeprazole, lansoprazole, ariprazole and leminoprazole have a stereogenic center at the sulfur atom, and therefore exist as two stereoisomers (enantiomers). The compound 2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)sulfinil]-1H-benzimidazole has two stereogenic center, one center on the methine carbon atom adjacent to the sulfur atom and one sulfur atom. Thus, this connection sudest class of chiral sulfoxidov, including omeprazole, described in the scientific literature since the late seventies, there were still reports of effective method of asymmetric synthesis of single enantiomers. In recent years, due to improved pharmacokinetic and biological properties of single enantiomers of pharmacologically active compounds has generated a lot of interest. You need a method that could be used to obtain single enantiomers of omeprazole and other optically pure analogues of omeprazole in large scale. Typically, asymmetric methods of obtaining chiral sulfoxidov produce optically active sulfoxidov rather in enantiomerically enriched forms, than in pure single enantiomeric forms, if these methods are not enzymatic transformations or partitioning methods. Therefore, you need a method that could be used on a large scale to improve the optical purity enantiomeric enriched optically active drugs omeprazole and other optically active analogues of omeprazole.

The prior art (DE 4035455 and WO 94/27988) methods of separation of various substituted 2-(2-pyridinylmethyl)-1H-benzimidazolecarbamic substituted 2-(pyridinylmethyl)-1H-benzimidazole. The diastereomers are then separated, and the selected diastereoisomer finally converted into optically pure sulfoxide at a stage of hydrolysis. These methods of separation, including diastereomeric intermediate, suffer from at least three major drawbacks, namely:

1) before you can obtain single enantiomers of substituted 2-(2-pyridinylmethyl)-1H-benzimidazole as a racemic intermediate, must be additionally subjected to processing in a pair of reaction stages;

2) methods of separation include complex phase separation;

3) there is a large amount of waste of the pure material, when the undesired stereoisomer in the form opposite diastereoisomer throw.

Further, the prior art (Euro. J. Biochem. 166 (1987) 453-459), for example, enantioselective synthesis of a derivative of 2-(2-pyridinylmethyl)-1H-benzimidazole, namely: single enantiomers sulfoxide agent (5,7-dihydro-2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl] -sulfinil] - 5,5,7,7-tetramethylbenzene-[5,6-d] imidazole-6-(1H)-it). This method is based on the enantioselective oxidation of the corresponding prehiring sulfide to the above sulfoxide. The authors argue that the key pure sulfoxide [(e.e.)>95%] with several stages of crystallization. However, the outputs and the number of stages of crystallization are not reported. This proposed method of crystallization is not suitable for a class of compounds of formula Ia-Ia of this application.

Brief description of the invention

The present invention is to provide a new method of improving the optical purity (enantiomeric excess, e.e.) enantiomeric enriched preparations of omeprazole, lansoprazole, ariprazole, leminoprazole and 2-[(4-methoxy-6,7,8,9-tetrahydro-5H - cyclohepta[b] pyridin-9-yl)sulfinil] -1H-benzimidazole. Unexpectedly, but the racemates of these compounds with a high degree of selectivity precipitate from the solvent to obtain single enantiomers with high optical purity.

The method according to the invention determined in paragraph 1 and later in PP. 2-9 disclose preferred embodiments of the invention. Preferred compounds obtained by the new method, determine in PP. 10-19.

Detailed description of the invention

The method of the present invention different stages of processing enantiomerically enriched preparation of optically active omeprazole of formula Ia

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or optically active lansoprazole formula IB

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or optical and optically active 2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)sulfinil]-1H-benzimidazole of the formula Ia

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the solvent from which the racemate selectively precipitates. The precipitated derivative of benzimidazole in the form of the racemate or in the form of a racemate with a small amount of the desired enantiomer is filtered off, and single enantiomer of a derivative of benzimidazole or (-)-enantiomer or in the form of its (+)-enantiomer, with sharply higher optical purity is obtained by removal of solvent from the filtrate. The solvent is preferably removed by evaporation. Substituted 2-(2-pyridinylmethyl)-1H-benzimidazole, which is suitable for processing preferably is omeprazole.

The deposition is carried out in a proton or not proton solvent. The solvent promotes crystallization and necessary for the separation. The choice of solvent, from which the racemate precipitates, is not essential for the process. The solvent is preferably an organic solvent. Suitable organic solvent may be a ketone, such as acetone or 2-butanone, or ester, such as ethyl acetate, or an alcohol, such as ethanol, or a nitrile, such as acetonitrile, or hydrocarbons, such as toluene. The solvent may also be a simple ether, and the precipitate. The solvent may also be a mixture of various organic solvents or a mixture of water and an organic solvent. The solvent is preferably selected from acetone, toluene or acetonitrile.

Temperature is not critical for the method according to the invention. However, if the temperature is too high, the solubility increases, the selectivity decreases and the compound decomposes. Therefore, preferred is room temperature, but also suitable are temperatures below room temperature.

Thus, a preferred feature of the method according to the invention is that the racemates of compounds of formula Ia-Ia unexpectedly very selectively crystallized from an organic solvent. A sharp increase in the enantiomeric excess of (-)-enantiomer or (+)-enantiomer of the compounds according to the invention receive in the mother liquor (filtrate), even just after one crystallization of the racemate. Therefore, the method is highly effective. In the single enantiomers can be obtained with very high enantiomeric excess even of not optically pure drugs. This means that the high enantioselectivity is not essential for asymmetric is prehiring sulfide. Thus, a wider range of synthesis methods can be considered when selecting the most appropriate methods of asymmetric synthesis for the preparation of compounds of formula Ia-Ia. For example, chemical yield, cost of reagents, reaction time and the degree of hazard handling reagents can thus be as important as the enantioselectivity, when choosing the method of synthesis.

More in detail the invention is illustrated by the following examples 1-16. Examples 7-9 illustrate the invention, together with the asymmetric synthesis.

Examples

The value of the enantiomeric excess in each example below shows the relative amount of each enantiomer. Value is defined as the difference between the relative percentages for the two enantiomers. For example, when the percentage of (-)-enantiomer of the sulfoxide is 97.5%, and the percentage of (+)-enantiomer is 2.5%, then the enantiomeric excess of (-)-enantiomer is 95%.

The enantiomeric composition of each sulfoxide define chiral HPLC (high performance liquid chromatography) or Chiralpak AD column, or Chiral AGP column under the following conditions:

The compound of formula Ia

Column - Chiralpak AD h,6 mm;

The wavelength of 302 nm;

Retention time for (-)-enantiomer is 4.0 min;

Retention time for (+)-enantiomer and 5.8 minutes

The compound of formula IB

Column - Chiral AGP h,0 mm;

Eluent Buffer solution of sodium phosphate (pH 7.0), I=0,025 (500 ml) and acetonitrile (70 ml);

A flow rate of 0.5 ml/min;

Injection volume 20 μl;

The wavelength was 210 nm;

Retention time for (+)-enantiomer - 6.2 min;

Retention time for (-)-enantiomer is 7.2 minutes

The compound of formula IB

Column - Chiral AGP h,0 mm;

Eluent Buffer solution of sodium phosphate (pH 7.0), I=0,025 (430 ml) and acetonitrile (70 ml);

A flow rate of 0.5 ml/min;

Injection volume 20 μl;

The wavelength was 210 nm;

Retention time for (+)-enantiomer of 4.1 min;

Retention time for (-)-enantiomer is 6.8 minutes

The compound of formula Iك

Column - Chiralpak AD h,6 mm;

Eluent - ISO-hexane (200 ml), ethanol (10 ml);

A flow rate of 0.5 ml/min;

The injected volume of 50 ál;

The wavelength of 285 nm;

Retention time for (-)-enantiomer, and 9.0 min;

Retention time for (+)-enantiomer is 9.8 minutes

The compound of formula Ia

Column - Chiralpak AD h,6 mm;

Eluent - ISO-hexane (150 ml), 2-propanol (50 ml);

antimere of diastereoisomer A - 6,9 min;

Retention time for (+)-enantiomer of diastereoisomer A and 8.1 min;

Retention time for (+)-enantiomer of diastereoisomer B was 8.8 min;

Retention time for (-)-enantiomer of diastereoisomer B - 11,0 minutes

The first diastereoisomer of the compound (Ia), suirvey on direct phase (achiral silica gel, see below) is named diastereoisomer A, and the second diastereoisomer B.

Example 1. Increasing the optical purity of from 60% e.e. to 98.4% e.e. for (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil] - 1H-benzimidazole, (-)-(Ia)

2.35 g of a Mixture of enantiomers of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl - 2-pyridinyl)methyl] sulfinil]-1H-benzimidazole (60% e.e. (-)-enantiomer) as a yellow syrup was dissolved in 20 ml of acetonitrile. Almost immediately in the form of a solid substance appears racemate, and after soaking for 30 min in the refrigerator, this white solid is filtered off. The solvent of the filtrate is evaporated with the formation of 1.2 g of (-)-enantiomer of omeprazole in the form of a yellow syrup with an optical purity of 98.4% of e.e.

Example 2. Increasing the optical purity of from 20% e.e. up to 91.4% e.e. for (-)-5-methoxy-2-[[(4-methoxy-3.5-dimethyl-2 - pyridinyl)-methyl] sulfinil]-1H-benzimidazole, (-)-(Ia)

2.35 g of a Mixture of enantiomers of 5-methoxy-2-[[(4-methoxy-3,5-d is ml 2-butanone. Almost immediately in the form of a solid substance appears racemate, and after soaking in the refrigerator for one hour this white solid is filtered off. The solvent of the filtrate is evaporated with the formation of 0.48 g of (-)-enantiomer of omeprazole in the form of a yellow syrup with an optical purity 91,4% e.e.

Example 3. Increasing the optical purity of 50% of the E. I. to 97.3% I. E. for (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil]-1H-benzimidazole, (-)-(Ia)

2.35 g of a Mixture of enantiomers of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl - 2-pyridinyl)methyl] sulfinil]-1H-benzimidazole (50% e.e. (-)-enantiomer) as a yellow syrup was dissolved in 20 ml of acetone. Almost immediately in the form of a solid substance appears racemate, and after soaking for one hour in the refrigerator, this white solid is filtered off. The solvent of the filtrate is evaporated with the formation of 1.0 g of (-)-enantiomer of omeprazole in the form of a yellow syrup with an optical purity of 97.3% e.e.

Example 4. Increasing the optical purity of 80% e.e. to 95.4% e.e. for (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil] - 1H-benzimidazole, (+)-(Ia)

2.35 g of a Mixture of enantiomers of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil] -1H-benzimidazole (80% e.e. (+)-enantiomer) at and after soaking for one hour in the refrigerator, this white solid is filtered off. The solvent of the filtrate is evaporated with the formation of 1.7 g of (+)-enantiomer of omeprazole in the form of a yellow syrup with an optical purity of 95.4% e.e.

Example 5. Increasing the optical purity of from 40% e.e. up to 88.7% e.e. for (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil]-1H-benzimidazole, (+)-(Ia)

2.35 g of a Mixture of enantiomers of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil] -1H-benzimidazole (40% e.e. (+)-enantiomer) as a yellow syrup was dissolved in 20 ml of ethanol. Almost immediately in the form of a solid substance appears racemate, and after soaking for one hour in the refrigerator, this white solid is filtered off. The solvent of the filtrate is evaporated with the formation of 1.0 g of (+)-enantiomer of omeprazole in the form of a yellow syrup with an optical purity of 88.7% of e.e.

Example 6. Increasing the optical purity of from 30% e.e. to 97,0% e.e. for (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil]-1H-benzimidazole, (+)-(Ia)

2.35 g of a Mixture of enantiomers of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil] -1H-benzimidazole (30% e.e. (+)-enantiomer) as a yellow syrup was dissolved in 20 ml of toluene. Almost immediately in ardoe substance is filtered off. The solvent of the filtrate is evaporated with the formation of 0.62 g of (+)-enantiomer of omeprazole in the form of a yellow syrup with an optical purity 97,0% e.e.

Example 7. Asymmetric synthesis with subsequent optical purification of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil]-1H-benzimidazole, (+)-(Ia)

A mixture of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole (0,47 g of 1.46 mmol), (3'S, 2R)-(-)-N-(phenylsulfonyl)-(3,3-dichloropropyl)oxaziridine (0.55 g, of 1.46 mmol), triethylamine (of 0.07 ml, 0.5 mmol) and carbon tetrachloride (20 ml) is stirred for 96 hours at ambient temperature. After removal of solvent the residue is dissolved in methylene chloride (25 ml). The mixture is extracted with two portions of aqueous solutions of sodium hydroxide (0.1 M, 15 ml). The combined aqueous solutions are neutralized with an aqueous solution of ammonium chloride in the presence of methylene chloride. The phases are separated, and the aqueous solution extracted with two portions of methylene chloride. The combined organic solutions are dried over sodium sulfate, and then remove the solvent. The residue (200 mg, 40% e.e.) dissolved in 2-butanone (3 ml), and the resulting solid is filtered off. The solvent of the filtrate is evaporated with the formation of 0.11 g (22%) ukazannoj the optical purification of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil] -1H-benzimidazole, (-)-(Ia)

1.6 kg (5.0 mol) of 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2 - pyridinyl)-methyl] -thio]-1H-benzimidazole was dissolved in 5.0 l of ethyl acetate. To the solution was added 31 ml (1.7 mol) of water. At room temperature, to the mixture 856 ml (5.0 mol) of (-)-diethyl D-tartrate, 744 ml (2.5 mol) of isopropoxide titanium (IV) and 435 ml (2.5 mol) of diisopropylethylamine. Then when the 30oC add 830 ml (4.5 mol) of gidroperekisi cumene. After stirring for one hour at 30oC the reaction is complete. Chiral and achiral chromatographic analyses show that the mixture consists of 71,4% sulfoxide with enantiomeric excess (e. e. ) to 72.9%. The mixture is cooled to 10oC, and after the addition of 1.7 l of isooctane product three times extracted with 12% aqueous ammonia solution total volume of 10 L. the combined aqueous phase is neutralized with 1.5 l of concentrated acetic acid in the presence of ethyl acetate (3 l). The phases are separated, and the aqueous phase extracted with ethyl acetate (3 l). The solvent of the combined organic solutions are removed, and at the end of the evaporation add acetonitrile (1.5 l) to facilitate the removal of solvent. Add acetone (2.5 l) to precipitate the racemate omeprazole, which is filtered off (254 g). HPLC-analyses (achiral and chiral columns) Pricesbuy purity increase from 72.9% e.e. to 96.3% e.e. the only precipitation of racemic omeprazole. Further, analysis of the composition of the filtrate (HPLC) shows that the output is 0.8 kg (46%). (-)-Enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] -sulfinil] -1H-benzimidazole do not emit in the neutral form and process further to the corresponding sodium salt.

Example 9. Asymmetric synthesis with subsequent optical purification of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil]-1H-benzimidazole, (+)-(Ia)

1.6 kg (5.0 mol) of 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole are dissolved in 7.5 liters of ethyl acetate. To the solution was added 31 ml (1.7 mol) of water. At room temperature, to the mixture 856 ml (5.0 mol) of (+)-diethyl L-tartrate, 744 ml (2.5 mol) of isopropoxide titanium (IV) and 436 ml (2.5 mol) of diisopropylethylamine. Then when the 30oC add 830 ml (4.5 mol) of gidroperekisi cumene. After stirring for one hour at 30oC the reaction is complete. Chiral and achiral chromatographic analyses show that the mixture contains 75% of the sulfoxide with enantiomeric excess (e.e.) 80%. The mixture is cooled to 10oC, and after addition of 1.5 l of isooctane and 0.5 l of ethyl acetate the product three times extracted with 12% water is islote in the presence of ethyl acetate (4 l). The phases are separated, and the aqueous phase extracted with ethyl acetate (4 l). The solvent of the combined organic solutions are removed. Add acetone (3.0 l) to precipitate the racemate omeprazole, which is then filtered. HPLC-analyses (achiral and chiral columns) of the filtrate show that this solution contains 90% of the sulfoxide with an optical purity of 95% e.e., and thus, the optical purity increase from 80% e.e. up to 95% e.e. the only precipitation of the racemate omeprazole. Further, analysis of the composition of the filtrate (HPLC) shows that the output is 1.0 kg (58%). (+)-Enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil] -1H-benzimidazole do not emit in the neutral form and process further to the corresponding sodium salt.

The source material in the form of enantiomerically enriched preparations of any of the compounds of formula IB, IB, Iك or Ia intended for optical treatment, receive, as described in examples 8 and 9.

Example 10. Increasing the optical purity of the two stereoisomers of 2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b] pyridin-9-yl)sulfinil] -1H-benzimidazole, (Ia)

In the following example, the first diastereoisomer specified in the title compound, suirvey on direct phase (silica gel)I in the raw mixture in the form of syrup (0.25 g) the following: the ratio of the diastereoisomers A:B is 4:3, optical purity of (-)-enantiomer of diastereoisomer A is 76% e.e., and optical purity of (+)-enantiomer of diastereoisomer B is 68% e.e.

Separation of diastereomers: chromatography (methanol-methylene chloride from 0 to 5%) leads to the separation of the two diastereomers. Thus, (-)-enantiomer of diastereoisomer A get in syrup (0,145 g) with an optical purity of 77% e.e. Also get in syrup (of 0.085 g) with an optical purity of 68% e.e. (+)- enantiomer of diastereoisomer B, however, diastereoisomer B contaminated with approximately 10% of diastereoisomer A.

Optical cleaning: the optical purity of (-)-enantiomer of diastereoisomer A boost by adding approximately 2 ml of acetonitrile to enantiomerically enriched preparation of diastereoisomer A (0,145 g). After stirring over night the precipitate (almost racemic diastereoisomer A) is filtered, and the solvent of the filtrate is removed film evaporation. Thus obtain 85 mg of (-)-enantiomer of diastereoisomer A syrup with an optical purity of 88% e.e. Similarly improve the optical purity of (+)-enantiomer of diastereoisomer B. So, by adding acetonitrile (2 ml) to enantiomerically enriched preparation of diastereoisomer B (0,085 mg), followed by stirring creamer B with an optical purity of 95% e.e.

Example 11. Increasing the optical purity(-)-2-[[[3-methyl-4-(2,2,2-triptoreline)-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole, (-)-(IB)

1.2 g of the Crude mixture indicated in the title compound with 55% enantiomeric excess (e. e.) treated with acetonitrile (a few ml) and receive the precipitate, which is removed by filtration. Evaporation of the filtrate results in the formation of oil with high optical purity. Repeat this procedure twice gives to 0.63 g of the desired compound in the form of an oil with an optical purity of 99.5% e.e.

Example 12. Increasing the optical purity(+)-2-[[[3-methyl-4-(2,2,2-triptoreline)-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole, (+)-(IB)

0,85 g of the Crude mixture indicated in the title compound with 46% enantiomeric excess (e. e.) treated with acetonitrile (a few ml) and receive the precipitate, which is removed by filtration. Evaporation of the filtrate results in the formation of oil with high optical purity. Repeat this procedure twice gives 0.31 g of the desired compound in the form of an oil with an optical purity of 99.6% of e.e.

Example 13. Increasing the optical purity(-)-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole, (-)-(Ie)

of 1.62 g of the Crude mixture ukazannoj is up sediment, which can be removed by filtration. Concentration of the filtrate gives 1,36 g specified in the title compound in the form of an oil with an optical purity of 91.5% e.e.

Example 14. Increasing the optical purity(+)-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole, (+)-(Ie)

1.63 g of the Crude mixture indicated in the title compound with 91% enantiomeric excess (e. e.) treated with acetonitrile (a few ml) and receive a precipitate which can be removed by filtration. Concentration of the filtrate gives 1.1 g specified in the title compound in the form of an oil with an optical purity 96,0% e.e.

Example 15. Increasing the optical purity(-)-2-[2-(N-isobutyl-N-methylamino)-benzylsuccinic]benzimidazole, (-)-(Iك)

In order to increase the optical purity, 1.6 g of the crude mixture indicated in the title compound with 92% enantiomeric excess (e.e.) handle a small amount of acetonitrile. The formed precipitate is removed by filtration. The solvent of the filtrate is removed film evaporation and obtain 1.2 g of the desired compound in the form of oil. According to chiral HPLC optical purity of the material is 96% e.e.

Example 16. Increasing the optical purity(+)-2-[2-[N-isobutyl-N-me (91% e.e.), polluted (-)-diethyl D-tartrate, dissolved in 40 ml of a mixture of ethyl acetate and hexane (10% EtOAc). The resulting residue (140 mg) removed by filtration. The solvent of the filtrate is removed film evaporation, and the residue is purified column chromatography (silica gel, EtOAc/hexane 15:85). Obtain 0.95 g specified in the title compound with an optical purity of 96% e.e. according to chiral HPLC.

1. The way the optical purification of enantiomerically enriched preparations of one of the compounds of formulas Ia, IB, IC, Iك and Ia

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characterized in that from enantiomerically enriched preparation of compounds of any of formulas Ia - Ia in favor of either ( + ) - or (-)-enantiomer is selectively precipitated the racemate of the above compounds by adding one organic solvent or a mixture of such solvents, and besieged the racemate is filtered, followed by removal of the solvent, obtaining a single enantiomer of the corresponding compounds of formula Ia - Ia of high optical purity.

2. The method according to p. 1, characterized in that the receive (-)-enantiomer of compounds of formula Ia with high optical cleaning.

3. The method according to p. 1, characterized in that the receive (+)-enantiomer compounds flaut by evaporation.

5. The method according to p. 1, wherein the enantiomerically enriched preparation process one organic solvent.

6. The method according to p. 1, wherein the enantiomerically enriched preparation is treated with a mixture of organic solvents.

7. The method according to p. 1, wherein the enantiomerically enriched preparation is treated with a mixture of water and one or more than one organic solvent.

8. The method according to p. 7, characterized in that the mixture of water and one or more than one organic solvent contains 50% of water.

9. The method according to p. 1, wherein the organic solvent is acetone, acetonitrile or toluene.

10. The method according to any of paragraphs.1 to 9, characterized in that the resulting product is a (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-sulfinil]-1H-benzimidazole.

11. The method according to any of paragraphs.1 to 9, characterized in that the resulting product is a (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-sulfinil]-1H-benzimidazole.

12. The method according to any of paragraphs. 1 to 9, characterized in that the resulting product is a(-)-2-[[[3-methyl-4-(-2,2,2-triptoreline)-2-pyridinyl]-methyl]-sulfi is to place a(+)-2-[[[3-methyl-4-(-2,2,2-triptoreline)-2-pyridinyl]-methyl]-sulfinil]-1H-benzimidazole.

14. The method according to any of paragraphs. 1 to 9, characterized in that the resulting product is a(-)-[[[4-(3-methoxypropane)-3-methyl-2-pyridinyl] -methyl]sulfinil]-1H-benzimidazole.

15. The method according to any of paragraphs. 1 to 9, characterized in that the resulting product is a(+)-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridinyl]-methyl]-sulfinil]-1H-benzimidazole.

16. The method according to any of paragraphs. 1 to 9, characterized in that the resulting product is a(-)-2-[2-(N-isobutyl-N-methylamino)benzylmorphine]-benzimidazole.

17. The method according to any of paragraphs. 1 to 9, characterized in that the resulting product is a(+)-2-[2-(N-isobutyl-N-methylamino)benzylmorphine]-benzimidazole.

18. The method according to any of paragraphs. 1 to 9, characterized in that the resulting product represents one of the single enantiomers more lipophilic diastereoisomer of 2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-sulfinil]-1H-benzimidazole.

19. The method according to any of paragraphs.1 to 9, characterized in that the resulting product represents one of the single enantiomers less lipophilic diastereoisomer of 2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b] pyridin-9-yl)-sulfinil]-1H-benzimidazole.

 

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The invention relates to compounds intended for use in the pharmaceutical industry as active ingredients in the manufacture of medicines

The invention relates to new pyrazole derivative and its salts, method of its production and pharmaceutical compositions based on it

The invention relates to a new benzodiazepine derivative of the formula I given in the text of the description, which are useful as medicines, which have an antagonistic effect against gastrin and/or CCK receptor-and their reception, where R1refers to a group-CH2CH(OH)(CH2)aR4or ketone group,- CH2CO(CH2)aR5where a = 0 or 1; R4- C1-C7-alkyl straight or branched chain or C3-C8-cycloalkyl; R5- C1-C8-alkyl, C3-C8-cycloalkyl,3-C8-cycloalkyl-C1-C8-alkyl, C1-C8-alkyl-C3-C8-cycloalkyl, pyrrolidyl, possibly substituted C1-C8-acyl, carbamoyl,1-C8-alkylamino-C1-C8-alkyl, or adamantylidene; R2is phenyl, substituted C1-C8-alkyl, C1-C8-alkoxyl, nitro, cyano, amino, halogen, C1-C8-alkylaminocarbonyl, di-(C1-C8-alkylaminocarbonyl, carboxy, C1-C8-allmineral, carboxyhemoglobin, carboxy(C1-C8)alkyl, or pyridylethyl, possibly substituted C1-C8-alkyl; R3- peloid in the 7-position of the benzodiazepine ring; W is hydrogen or C1-C8the alkyl in the 8-position of the benzodiazepine ring, or its pharmaceutically acceptable salt

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention proposes two variants of the improved method for preparing anti-ulcerous therapeutic agents of the formula (I): wherein radicals R1-R6 have values given in cl. 1 and cl. 2 of the invention claim. Method involves interaction of corresponding sulfides with m-chloroperoxybenzoic acid in acetone or a mixture acetone/water as a solvent. According to the first variant pH value of the reaction mixture is increased to the value above 7 after the reaction interaction and solvent is removed and crystals of compound of the formula (I) are separated. According to the second variant the interaction is carried out at pH ≥ 7.0 followed by addition of water if necessary and compound of the formula (I) crystals are separated. Invention is directed for preparing omeprazole or pantoprazole preferably. Invention provides preparing the end products of high purity and with high yield.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compound: N-[2-hydroxy-3(1-piperidinyl)-propoxy]-pyridine-1-oxyde-3-carboxyimidoyl chloride, stereoisomers thereof acid additional salts useful in treatment of pathological insulin resistance.

EFFECT: new compound useful in medicine.

5 cl, 10 tbl, 10 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new heterocyclic compounds corresponding to general formulas: (I) , (II) , (Ia) and (Ib) wherein substitutes have values given in the description. Such compounds are reversible inhibitors of cathepsins S, K, F, L and B. Also, invention relates to a method for preparing these compounds, pharmaceutical composition eliciting inhibitory activity with respect to cysteine proteases and to a method for modulation of autoimmune diseases, treatment of Alzheimer's disease and osteoporosis.

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

42 cl, 106 ex

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