SU1189859A1 - Chiral derivatives of (s)-or (r)-2-n-(n'-benzylalkyl)-aminobenzophenone as reagent for producing optical isomers of alpha-aminoacids - Google Patents

Abstract

Chiral derivatives (S) or (K) -2-H- (K-benzyl alkyl) aminobenzophenone of the general formula (CH 2 N O CH-Cl H-) CH 2 C 0 Cn where n 3-4, as reagents for obtaining optical isomers with α-amino acids . 00 from 00 ate

Description

The invention relates to new compounds from the class of chiral peptides, namely to the chiral derivatives of (S) - or (K) -2-M- (s-benzylalkyl) aminobenzophenone of the general formula (CUlnn, CH-C-H where n 3- 4, which are used as a reagent for obtaining optical oi-amino acid isomers. The purpose of the invention is to find new compounds with enhanced stereospecificity in a number of chiral peptides. Example 1. C. place 2 mmol of o-aminobenzophenone, 25 ml of methylene chloride in a beaker and 50 ml of buffer solution with pH 7. This forms two layers Suspended liquids: upper - lower aqueous solution — organic. The resulting upper and lower layers are mixed separately. During separate mixing, a solution consisting of 3 mmol of hydrochloride hydrochloride is added dropwise to the lower layer (organic) during 3 minutes at room temperature. -H-benzyl-8-proline, dissolved in 2 ml of dry methylene chloride. Concentrated NaOH solution was temporarily added to the upper (aqueous) layer in such a way that the pH of the aqueous layer was maintained at 6-7. Then the upper (aqueous) and lower (the organic layers are continued to be mixed separately for another 45-60 minutes, then the pH of the upper (aqueous) layer is adjusted to 10, and then the lower (organic) layer is separated from the upper (aqueous) pH control solution This is carried out using a pH meter and a glass electrode and a reference electrode are used. The separated aqueous layer is washed three times with 15 ml of methylene chloride. The organic extracts obtained are combined with the separated organic layer. From the resulting solution is distilled off under the vacuum at iTr-uje solvent stripping, a resinous product is obtained, which is purified by liquid distribution chromatography. Silica gel of the grade 40/100 / is used as a fixed layer and placed in a 2.5-30 cm column. chloroform system: diethyl zfir; benzene: ethanol absolutized: acetic acid in 4: 4: 4: 1: 1 ratio. The control is carried out by thin layer chromatography on a Silufol and U-254 force box. Eluent (five component system) containing conductive purified product was distilled off, to the residue was added 25 ml of water and anhydrous sodium carbonate to establish in the resulting mixture, pH 9. The separated as a result of processing the product was extracted with chloroform. The extraction was carried out three times using 30 ml of chloroform. Dale: e chloroform is distilled off and (S) -2-N- (N-benzylpropyl) aminobenzophenone is obtained in the form of a slowly crystallizing oil (1.8 mmol, yield 60%), which is recrystallized from acetone and get crystals with m.p. . 95-96 C. Calculated,%: C 78.12; H 6.25; N 7.2 Found: C 78.04; H 6.22; N 7.33., .TcC -119.5 (CHCl3; 4.79 x mol / l). IR spectrum, (VKG): 1700 (C O, amide I); 1525 (NH, amide C); 1655 (CO benzophenone; 1587, 1495 (Ar); 760, 772 (Ar o-substituted); 705 (Ar monosubstituted); 1455, 32803100 (). NMR spectrum (G, MA): about 1.92 , 3 (multiplet, 4Н, CHj rings), 3.3 (multiplet, ЗН, oiH + СН at the N ring;) 3.61 „„ L CHj is benzyl. (J 14 Hz); 7.7 (multiplet, 12Н , aromatics); QV quartet of the AH system, fragment of o-aminobenzophenone, (J ... 10 Hz); 12.2 (C, 1H, -NH-). The resulting substance has the formula CH2.) N PH R) Example 2. The procedure is similar to Example 1, but instead of hydrochloride-L-benzyl-3-prolyl hydrochloride, the hydrochloride hydrate-H-benzyl-K-pipecolinic acid is injected into the lower organic layer and uchayut (R) -2-N- (N -benzilpipekolil) aminobenzophenone (0.6 mmol, yield 20%), m.p. 94-95C. Calculated,%: C 78.39; H 6.53; N 7.04. Found,%: C 78.41; H 6.52; N 7.06. 0 +99.0 (SNS; 5-1O mol IR spectrum, cm- (in KBr): 1700 {C O, amide I); 1520 (NH, amide II); 1660 (WITH benzophenone); 1585 149b (Ar); 760, 772 (Ar o-substituted), 705 (Ar monosubstituted); 1460 3280-3100 (). NMR spectrum (. SL, M.A.): c 1.0-2, (multiplet, -8H, CH, ppic); 2.84 (1H, o -H-ppic multiplet); 12.84 (broad signal, 1H, -N-H-C-); Quarter system AB of the benzyl group CHj (14 Hz); (. Quartet of the system AB H, H fragment of o-aminobenzophenone; 6.78-7.47 (multiplet 12Н Ar). The resulting substance has the formula / СН2 Н2С № Examples Concrete (S) -2-N- (N -benzylprolyl) aminobenzophenone for the preparation of optical isomers of n-acids are as follows: Example 1: Preparation of S-shaft from RS-valine, 1.1. Preparation of the complex. methanol, 0.33 mmol copper sulfate in water, 0.6 ml of 1N sodium methoxide in methanol and 0.33 mmol of RS-valine in 0.6 ml of 1N sodium methylag solution in meth The reaction mixture was stirred at room temperature for 8 hours. The end of the reaction was monitored by thin layer chromatography until the (S) -2-N- (N-benzylpropyl) aminobenzophenone agent disappeared in the reaction mixture. Then 30 ml of a mixture of water was added to the reaction mixture. chloroform in a ratio of 2: 1 and the complex formed is extracted with chloroform three times in 15 ml each time. The chloroform extracts are combined and the chloroform is distilled off. 1.2. The decomposition of the complex and the determination of o (α-amino acids. 0.2 mmol of the obtained complex is dissolved in 2 ml of methanol, 5 ml of 1N hydrochloric acid solution (pH 1) is added, the mixture is kept for 10-15 minutes, then evaporated the solution of concentrated ammonia is added to the dry residue, and the (S) -2-N- (N-benzsh1propyl) amino benzophenone is extracted and chloroform is extracted three times with 20 ml each time. After evaporation of the chloroform, 0.18 mmol of starting reagent (S) - is obtained. 2-N- (N-benzylpropyl) aminobenzophenone Ammonium solution remaining after extraction with chloroform The solution after the column is evaporated, the residue is dissolved in 10 ml of water and then the solution is passed through the resin KU-2 in the H-form. The resin is washed with 50 nl of water and sorbed on the resin about {-amino acid elute with 10% aqueous solution of ammonia. The eluate is evaporated. Obtain 0.184 mmol of valine containing an enantiomeric excess of S-form 50% (by a known method, get valine containing an enantiomeric excess of S-form 30%). Example 2. Getting S-valine from RS-valine. 2.1. The process is carried out analogously to example 1.1, but instead of copper sulphate, a solution of nickel chloride in methanol is taken. The reaction mixture is kept in a thermostat at 40-42 ° C for 8 hours. 2.2. The process is carried out as in Example 1.2, but 1 n is added. The solution of hydrochloric acid, heated to 50-60s, and holding the solution for 1 hour. Valine is obtained with an enantiomeric excess of S-form of 91% (known valine contains an enantiomeric excess of S-form 50). Example 3, Preparation of S-Leucine from R-Leucine. 3.1. The process is carried out similarly to Example 2.1, but instead of RS-valine, R-leucine is taken, the reaction mixture is kept in a thermostat at 40-42 0 for 4 hours. 3.2. The process is carried out analogously to example 2.2, a leucine containing an enantiomeric excess of the S-form of 81.8% is obtained (the known leucine contains an enantiomeric excess of 5-form 61.2%) Example 4. Preparation of S-phenylalanine from RS-phenylalanine. 4.1. The process is carried out similarly to Example 2.1, but instead of RS-valine, RS-phenylalanine is taken. 4.2. The process is carried out similarly to Example 2.2; phennalanine is obtained containing an enantiomeric excess of S-form of 96% (known phenylalanine contains an enantiomeric excess of S-form 80%). Example 5. Getting treoni on. The process is carried out analogously to example 2, but instead of RS-valine take 0.4 mmol of glycine. The resulting complex is then not decomposed, but taken in an amount of 0.2 mmol and dissolved in 2 ml of 0.1N. a solution of sodium methoxide in methanol, 20 mmol of acetaldehyde are added. The mixture is kept for 4 hours at room temperature. Then 5 ml of a 1N solution of hydrochloric acid heated to 30 ° -BOC are added to the mixture to decompose the complex. After 20 minutes, acetaldehyde is distilled off. Next, the process is conducted analog. Example 2.2. Receive threonine and allotreonin in a ratio of 20: 1. Enantiomeric excess of (R)-threonine 98% (by a known method, threonine and allotreonin are obtained in a ratio of 19: 1. Enantiomeric excess of (R)-threonine 97%). Example 6. Getting serine. Proceed as in Example 5, but 0.2 mmol of the complex is dissolved in 2 ml of 0.2 N. sodium methylate solution in methanol. Then 0.21 ml of 11 N is added. aldehyde forms aqueous solution. The mixture was incubated for 4 hours at room temperature, then acetic acid was added to pH 4-5. To remove excess formaldehyde, the reaction mixture is then evaporated to dryness under vacuum, the residue is dissolved in 2 ml of methanol, 5 ml of 1N is added. hydrochloric acid to decompose the complex. The mixture was incubated for 20 minutes Next prodess are analogous to example 2.2. A serine containing an enantiomeric excess of the R-form of 76% is obtained (the known serine contains an enantiomeric excess of the R-form of 58.6%). An example of the specific use of the obtained (R) -2-N- (N-benzylpipekolyl) aminobenzophenone reagent to obtain optical isomers of o-amino acids. Receive threonine as follows. The process is carried out analogously to example 5, but instead of (8) -2-N- (s-benzylprolyl) aminobenzophenone, take (R) -2-N- (N-benzylpipekolil) aminobenzophenone. Receive threonine and allotreonin in a ratio of 20: 1. Enantiomeric excess of (S) -Treonin is 94% (92% by a known method). The table shows the data characterizing the stereospecificity of chiral reagents by a known method (S) -2-N- (N - benzylprolyl) aminoacetophenone (t) and (S) -2-N- (N-benzylprolyl) aminobenzophenone (II), expressed through an enanthionic excess of the target isomer (S or R - H3OMepa oi-amino acids) obtained with the help of chiral reagents I and L from racemates of various oC-amino acids through an appropriate complex including a metal ion.

2 Cu Cu Ni Ni Ni Ni

3

four

38 (s)

88 (s)

30 (s)

50 (s)

60 (s)

94 (s)

50 (s)

91 (s)

80 (s)

96 (s)

8.6 (R)

76 (R)

Claims (1)

CHIRAL DERIVATIVES (S) - or (R) -2-N- (Ν'-ENZYLALKYL) AMINOBENZOPHENONE AS REAGENTS FOR OBTAINING OPTICAL ISOMERS d-AMINO ACIDS, (57) Chiral derivative (S) or (B) -2-P To ^t '-benzylalkyl) aminobenzophenone of the general formula where η = 3-4, as reagents for the production of optical isomers (/ -amino acids.