The method of obtaining the individual stereoisomers of 4-substituted diprosone glutamic acid

 

(57) Abstract:

A method of obtaining an individual stereoisomers of 4-alkylthio - and 4-genericcialisviagra glutamic acid, based on the reaction of individual stereoisomer derived 4-blaglutinous acid salts of mercaptans in a ratio 1 : (2,5 - 3) in an atmosphere of inert gas or nitrogen in a mixture of ethanol and benzene.

The invention relates to organic chemistry, in particular to a method of obtaining an individual stereoisomers of 4-diprosone glutamic acid of General formula

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ALK is a lower alkyl.

From among 4-diprosone glutamic acid hitherto synthesized only 4-mitigationa acid (1 g) [1] as an intermediate product in the synthesis of analogs of the anticancer drug methotrexate, but the individual stereoisomers of this compound is not obtained. It is known that the biological activity of the compounds significantly depends on their stereoconfiguration [2] and the allocation of individual stereoisomers is complex synthetic task.

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Known methods for producing individual stereoisomers C4-derived Glu
They are time consuming, require significant consumption of solvents, they are distinguished by the duration separating pure isomers. In addition, it is not always possible to find a solvent system for the separation of diastereoisomers.

The closest in technical essence is a way of obtaining an individual stereoisomers dimethyl ether 4-arinaminpathy glutamic acid, used as intermediates for the synthesis of compounds with biological activity [4] the prototype. It consists in boiling dimethyl ether (2S, 4RS)-N-phthaloyl-4-blaglutinous acid (2) with an excess of arylamine for 10 to 11 hours in acetonitrile or ethanol, with subsequent separation of diastereoisomers.

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tree:

R CH3O (3), OH (4), CH3(5),

H (6), NHCOCH3(7),

I (8), Cl (9), Br (10).

Erythro:

R CH3O (11), CH3(12).

In the reaction of threo-isomers formed in larger quantities than the corresponding Erythro-isomers. For selection of createstatement (3 7) are repeated recrystallization of the product obtained by conducting the reaction in ethanol. Erythro-diastereoisomer (11, 12) are obtained by separation of the mixture on silica gel, followed now chromatography.

The disadvantage of this method is to conduct the process at a high temperature, its duration, the need for separation of the resulting reaction stereoisomers methods of preparative chromatography and repeated crystallization, which is time consuming, expensive solvents. The total yield of stereoisomers is 47-63% in Addition, separation of the diastereomers by crystallization method is not universal and requires the selection of solvents in the case of each individual connection.

The objective of the invention to develop a method ensuring receipt of halogen derivatives of glutamic acid of the individual stereoisomers of 4-alkylthio - or 4-genericcialisviagra glutamic acid high degree diastereoisomeric purity.

The problem is solved by obtaining mercaptide potassium from the corresponding mercaptan and potassium hydroxide in ethanol, its interaction with individual stereoisomer derived 4-blaglutinous acid at their molar ratio (2.5 to 3) 1 in the atmosphere of inert gas or nitrogen. The reaction leads to a mixture of benzene and ethanol, with subsequent distillation of the solvent is SS="ptx2">

The use of individual stereoisomer for the synthesis of 4-alkylthio - or 4-genericcialisviagra glutamic acid in the conditions for reaction with the address configuration allows without additional purification to obtain pure diastereoisomer directly during the reaction. When the molar ratio mercaptide potassium derivative of 4-blaglutinous acid is less than (2.5 to 3) 1 go side processes, which significantly reduces the yield of the target products. When the molar ratio mercaptide potassium derivative of 4-blaglutinous acid greater than (2.5 to 3) 1 does not increase the yield of the target product, and a further increase in consumption mercaptide potassium is impractical.

The use of a solvent mixture of benzene and ethanol eliminates the transformation of the original stereoisomer dimethyl ether N-phthaloyl-4-nonglutinous acid in the other stereoisomer. Any stereoisomer derived 4-blaglutinous acid is dissolved in benzene at room temperature, whereas the reaction in ethanol (prototype) it is necessary to heat the alcohol solution to 45-50oC to dissolve the derived 4-blaglutinous acid. Vhodnu, therefore, the reaction is carried out in inert gas or nitrogen.

The method is as follows.

To a solution of potassium hydroxide in absolute ethanol was added the appropriate mercaptan and is passed through a solution of an inert gas such as argon or nitrogen. To the resulting solution mercaptide potassium was added a benzene solution of individual diastereoisomer derived 4-blaglutinous acid in the ratio of mercaptide potassium stereoisomer (2.5 to 3):1. The reaction is carried out under stirring on a magnetic stirrer at room temperature for 45-60 min in an inert gas, for example argon or nitrogen. Remove the solvents under reduced pressure, the residue is dissolved in an organic solvent, mainly ethyl acetate, washed it with a solution of Na2CO3and water and dried with MgSO4. Remove the solvent in vacuo, get the target products with the release of 81-99% and with high stereoisomeric purity (93-97%), as determined by HPLC on device "milikhrom" (sorbent Silsor C18, column 643 mm, mobile phase hexane-ISO-propanol in the ratio 160:1 for compounds 16, 40:1 for 17 and 5:1 for 18).

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The composition and structure of the obtained compounds is uniquely characterized by d the isomers.

Elemental analysis of the obtained compounds made on isolamento analyzer CHNS-0 Model EA-1108. IR spectra were taken on a UR-20 instrument in the paste in vaseline oil.

UV spectra were taken on a Specord in an alcohol solution.

1H-NMR-spectra are taken on the device Tesla BS-567A (100 MHz) with TMS as internal standard.

The proposed method allows us to simplify the process of obtaining individual stereoisomers of 4-alkylthio - and 4-genericcialisviagra glutamic acid by eliminating operations repeated recrystallization and column chromatography, to reduce the process time and to be heated up.

All this makes it more affordable to obtain the enantiomers of the target compounds, which are potentially biologically active substances.

Example 1. Dimethyl (2S,4R)-N-phthaloyl-4-deleteoperation acid.

To a solution of 0,221 g (0,00390 mol) of KOH in 15 ml of absolute ethanol under stirring on a magnetic stirrer at room temperature was added 0,84 ml (0,0041 mol) of decelerating. Through a solution of miss argon. To the resulting solution was added a solution of 0.5 g (0,0013 mol) dimethyl (2S, 4S)-N-phthaloyl-4-blaglutinous kilotonnes temperature, the precipitate is filtered off KBr. The mother liquor is evaporated and the residue oil is light yellow in color dissolved in 30 ml of ethyl acetate. An ethyl acetate layer is washed with a solution of Na2CO3(410 ml), water and dried with MgSO4. The solvent is evaporated in vacuum, get a colorless mobile oil.

Rf(chloroform: benzene: methanol 12:10:1): 0,86.

UV (nm): 220,292 (N-calolina group).

IR (cm-1): 1725, 1765 (C= 0 calolina group); 1750 (C=0 ester groups); 1610 (Valens. the vibrations. ring); 660 (C-S).

PMR in CDCl3(TMS, M. D.): 0,86 (s, 3H, CH3s - decyl); of 1.26 (s, 16H, (CH2)8s - decyl); 2,33 - 2,62 (m, 2H, s-CH2the decyl); 2,77 (m, 2H, CH2the remainder of glut. to you); of 3.32 (dd, 1H, CH ); to 3.73 (s, 6H, CH3ester groups); 5,04 (dd, 1H, CH ); 7,92 to 7.68 (m, 4H, falorni group).

C25H35NO6S

Found (%): 62,71 H 7,25 N 3,07 S 7,02.

Calculated (%): C 62,89 H 7,34 N 2,94 S Of 6.71.

The output of 0.61 g of 98.5

Example 2. Dimethyl (2S,4R)-N-phthaloyl-4-(pyridyl - -2'-thio)glutamic acid.

To a solution 0,22 g (0,00390 mol) of KOH in 15 ml of absolute ethanol under stirring on a magnetic stirrer at room temperature was added 0,46 g (0,0041 mol) of 2-mercaptopyridine. The reaction of lead in the atmosphere of nitrogen. To Pol of absolute benzene. (The ratio of mercaptan/ connection 15 3:1). The mixture is stirred for 45 min at room temperature, the precipitate is filtered off KBr. The mother liquor is evaporated, and the residue is dissolved in 30 ml ethyl acetate and washed with a solution of Na2CO3(2x20 ml) and then water, dried achiasmatic layer MgSO4. The solvent is evaporated under reduced pressure, get the oil bright yellow color.

Rf(chloroform: benzene: methanol 12:10:1): 0,61.

UV (nm): 220, 290 (N-calolina group).

IR (cm-1): 1725, 1765 (C=0 calolina group); 1730 (C=0 ester groups; 1475, 1550, 1570 (pyridine ring); 640 (C-S).

PMR in CDCl3(TMS, M. D.): 2,53 up 3.22 (m, 2H, CH2); 3,70 and 3,72 (two s, 6H, CH3ester groups); at 4.75 (dd, 1H, CH ); 5,12 (dd, 1H, CH ); 6,9 7,3 (m, 3H pyridyl); 7,69 7,88 (m, 4H, falorni group); 7,92 to 8.0 (m, 1H pyridyl).

C20H18N2O6S

Found (%): C 58,11 H Of 4.44 6,67 N S 7,50.

Calculated (%): C 57,97 H 4,35 N 6,76 S 7,73.

Yield 0.52 g, 96,5

Example 3. Dimethyl (2S, 4R)-N-phthaloyl-4-(pyrimidinyl - 2'- thio)glutamic acid.

To a solution of 0.182 g (0,0033 mol) of KOH in 15 ml of absolute ethanol under stirring on a magnetic stirrer at room temperature was added 0,38 g (0,0034 mol is amylovora ether (2S, 4S)-N-phthaloyl-4 - blaglutinous acid in 15 ml of absolute benzene. (The ratio of mercaptan/ connection 15 of 2.5:1). The mixture is stirred for 60 min at room temperature, the precipitation is filtered off KBr. The mother liquor is evaporated, and the residue is dissolved in 30 ml ethyl acetate and washed with a solution of Na2CO3(2x20 ml), then water. Dried an ethyl acetate layer MgSO4. The solvent is evaporated in vacuum, get the oil light yellow color.

Rf(chloroform: benzene: methanol 12:10:1): 0,50.

UV (nm): 220, 290 (N-calolina group).

IR (cm-1): 1715, 1770 (C= 0 calolina group); 1740 (C=0 ester groups); 1555 (pyridine ring); 660 (C-S).

PMR in CDCl3(TMS, M. D.): 2,59 of 3.27 (m, 2H, CH2); to 3.73 (s, 6H, CH3ester groups); 4,59 (dd, 1H, CH ); 5,11 (dd, 1H, CH); 6.89 in (t, 1H, 5ththe proton of pyrimidine); 7,70 - to 7.93 (m, 4H, falorni group); of 8.27 (d, 2H, 4thand 6ththe protons of pyrimidine).

C19H17N3O6S

Found (%): C 54,71 H 4,06 N 10,26 S 7,89.

Calculated (%): C 54,96 H 4,10 N 10,12 S 7,71.

The yield of 0.44 g, 81.3%of

The method of obtaining the individual stereoisomers of 4-substituted diprosone glutamic acid formula

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where AIk lower alike potassium hydroxide corresponding mercaptan, subjected to interaction with an individual stereoisomer dialkylamide ether N phthaloyl-4-blaglutinous acid at a molar ratio of 2,5 3 1 in a mixture of ethanol and benzene in the atmosphere of inert gas or nitrogen.

 

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