SU1010057A1 - Process for producing esters of n-(2-aminobenzhydryl)-alpha-,beta-,gamma-amino acids and dipeptides - Google Patents

Abstract

METHOD FOR OBTAINING ETHER N

Description

The known method is C / obtaining 25 liters to obtain 2-aminobenzchloride,

N- (2-aminobenzgidropyl) ethyl ester, which is reacted with

α-glycine, which consists in treating the k-S with a multiple excess of freshly distilled 2-zminobenzhydrol with glycine thionium ethyl ether according to Scheme 2

The disadvantage of these methods for obtaining M- (2-aminobenzhydryl) -glycine ethyl ester is the low yield (16-32) of the final product and the inability to obtain the compounds of the general formula (} using this method.

The aim of the invention is a new method of obtaining new 1M- (2A 4 esters of nobenzhydryl-d-, L-, J-au, and akisLO1 and dipeptides of the general form (u)).

.

where is r,

And have

h indicated

values, v.p khtsihs

intermediate G1r., auktania

synthesis biologist ich - with-inactive

substances with valuable pharmacological properties

The goal is achieved by describing a 1m method of producing compounds of general formula (1) (According to which 1 mole of 2-aminobenzhydrol of general formula

.NHg

sn-he

0 where R and R have the indicated meanings, they are reacted with, 01, 3 moles of trifluoroacetic anhydride in chloroform in the presence of 1,0t1, 36 moles of triethylamine at ({-20) ° C for. min, then add 1.0-1.3 mol ether of amino acids or dipeptide total fg 15mula

Н-Л-Я 3 where A and R have the indicated meanings in the form of free osno-ania or halide hydrate in the presence of 2-3 moles of triethylamine, and the reaction mixture is kept for –k hours at 20–22 ° С and Зг8 hours at i 0–60 s The progress of the reaction and the homogeneity of the final compounds are monitored by thin layer chromatography on Silufol plates in the following systems: I. Pyridine - acetic acid water (20: 11: 6) - ethyl acetate 1:19. II. Pyridine - acetic acid water (20: 11: 6) - ethyl acetate 1:38. III. Acetone - hexane 1: 2. IV. Acetone - hexane 2: 3 V. Acetone - benzene 1: 2 VI. Acetone - benzene 1: Acetone-i-xylene 1: 4, n-Butanol-acetic acid water-4: 1: 1 IX. Methanol-chloroform 1:19 X. Chloroform - methanol - acetic acid 17: 2: 1. PRI me R 1. Methyl ester of N- (2-amino-5-bromobenzgidril) - glycine (la}. To a solution of 13.9 g (0, C5 mol of 2-amino-5-bromobenzhydrol in 100 ml of chloroform added at minus 20 ° for 3-4 min. 9.1 ml (0.0b5 mol) of trifluoroacetic anhydride in 15 ml of chloroform, and then 9.5 ml (0.068 mol of triethylamine. The solution is stirred at minus 35 min. After this The reaction solution was added at minus 16 C to a solution of 8.2 g (o, O65 mol) glycine methyl ester hydrochloride in 60 ml of chloroform and 18.2 MP (0.13 mol) of triethylamine. The reaction mixture was stirred at 20-22 C 1. 4 and boil for 3 h. The reaction mixture is washed at iS-lS C, hydrochloric acid solution (ml 2), water (kO ml 2) Saturated aqueous sodium bicarbonate or ammonia is added to the aqueous acid solution to a pH of 7.8. The precipitate separated from the solution is filtered, washed with water until pH 7 and the first part of aa is obtained. The chloroform solution is washed with sodium bicarbonate or ammonia to a pH of 7.8, then with water to pH 7, dried over sodium sulfate and evaporated in vacuo. The residue is combined with the initial isolation of Ha, crystallized with 374z methonol or ethyl acetate a., Chloroorl a or their mixtures with hexane, petroleum ether (T ((sp, 30-70 ° C) and give 13.8 g of (methanol) ta. An additional solution of 2.4 g (from methanol) is then separated from the atomic solution. The yield of N- (2-a / i-5-bromobenzhydryl) -glycine methyl ester (1a is 16.2 g (92.5% 1) 24125:, Rf 0.31 (III), Rf 0.45 (IV). Found,%: C 55.14; H N 8.1 1. C, .Br. Calculated,%: C 55.03; H 4, SU N 8.02. IR spectrum: 1725 (); 1220 (C-0C), 3340 (| X – H) see. Similarly, M- (2-amino-2 -chloro-5-bromobenz hydr yl.) - glycine (1 b) Yield of Tr., 154155С, Rf 0.30 (ill); Rf 0.44 (IV) Found,%: C 50.12; H 4.96; N 7.36ad. Avgs. : C 50.59; H 4.90; N 7.30. IR spectrum: 1720 (); 1220 (C-OC), 3340, 3440 (NH) cm-1, .. M- (2- amino-4-chloro-5-bromobenzhydryl) -glycine (1c). Yield 90S; mp 93-94C; Rf 0.30 (lll); Rf 0.44 (IV). Found: C 50, 15; H 4.24; N 7.38. Cib H, NiOi, Calculated, I: C 50.99; H 4.20; N 7.30. IR spectrum: 1720 (); 1215 (C-0C), 3350, 3450 (N-H) cm-., M- (2-amino-4-chloro-5-bromo-benzhydryl) -glycine methyl ester (1c). Yield 90%; one". 93-94 with; Rf 0.30 (. III), Rf 0.44 (IV) Found,%: C 50.15; H 4.24; N 7.38, .. b1, g. Calculated,%: C 50.93; H 4.20; N 7.30. IR spectrum: 1720 (), 1215 (C-0C), 3350, 3450 (N-H) CM-i M- (2-amH-5-chloro-benzhydryl) -glycine methyl ester (ir). Output TP PO-1P ° C; Rf 0.45 (IV). Found,%: C 63.16; H 5.68; N 9.23. Calculated,%: C 63, On; H 5.62; N, 19. 7 10 Found, I: C 51.2; H A, 63; N 7, (Lg 2 ° 2VgS) Calculated, I: C 51, H, 56; N 7.04. IR spectrum: 1730 (), 1210 (C-0C), 3380, (NH) cm- ;: Methyl ester M- (2-amino-5-brombeizhydryl) -c /.- amino-butyric acid (lie) . Exit 841; LL 121-122 0, Rf 0.36 (III); Rf 0.50 (IV). Found,% -. C 57.40; H 5.68; N 7.50. . Calculated,%: C 57.30; H 5.61; N 7.43. IR spectrum: 1740 (), 1215 (C-0C), 3380-3420 (N-H) cm., N- (2-aMMHO-5-6pOMbenzhydryl) -valine methyl ester (HL). Exit 78, Tp 86-97S; Rf 0.34 (ill); Rf 0.42 (IV Found,%: C 58.51; H 5.97; N 7.24. Calculated: C 58.32; H 5.92; N 7.16. IR spectrum: 1730 (C -O), 1215 (C-0C), 3380-3410 (NH) CM-. M- (2-amino-5-bromobenzhydryl) -aspartic acid di-methyl ester (From). Output 821; T 78-794 ; Rf 0.34 (III). Found,: C 54, 27; H 5, Yu; N 6.71. Q, gHj, N B g Calculated, I: C 54.17; H 5.02; N 6 , 65. IR spectrum: 1735 (), 1200, 1240 (C-O-C), 3350-3360, 3430 - (NH) N- (2-amino-5-bromobenzhydryl) -glutamic acid di-methyl ester. (Ni) Yield 84%; Tp 84-85 ° C; Rf 0.40 (IV). Found: C 55.24; H 5.41; N 6.50. (Calculated,%: C 55, 18; H 5.33; N 6.44. IR spectrum: 1730 (), 1200, 1240 (C-O-C), 3360-3380, 3420-3440. M- (2-amino) methyl ester 5-methylbenzgidril) -glutamine oh acid (11k). Yield 81%; „, 71-72 C) Rf 0.32 (IV). Found,%: C $ 8, Gb; H 7.13; N 7.62. C2, H2, Nj, 04 578 Calculated,%; C 68.09; H 7.07; N 7.56. IR spectrum: 1730 (), 1200, 1260 (C-O-C), 3380-3 00, cm - Methyl ether N- (2-amino-5-orombenzhydryl) -glutamic acid. Yield, Rf 0.32 (V). Found,%: C 5.28; H 5.10; N 6,71СЖ О .Вг Calculated,%: C 54.17; And 5.92; N 6.65 Methyl ester of H- (2-amno-5-chlorobenzhydryl) -p-alanine (Sha), Yield 84; fi; M.p. 121-122С, - Rf 0.84 (Vlab Rf 0.41 (IV). Found,%; C 64.13; H 6.10; N 8.84. C H N O CI. Calculated,%: C 64.05; H 6.01; N 8.79; IR spectrum: 1720 (), 1245 (C-0) 3420, 3450 (NH) cm. Methyl ester M- (2-amino-2-chloro) 5 bromo-benzhydryl) -r-alanine (Shb). Yield 2%; Trl 78-79C, - Rf 0.79 (Vl), Rf 0.41 (IV). Found: C 51.42; H 4 , 60; N 7) 12, Calculated,%: C 51.34; H 4.5b; N 7.04, N- (2-amino-5-6-thrombenzhydryl) -Rgalanine methyl ester hydrochloride (SW). . Yield 86%; . IlB-lig C; Rf 0.75 (i), Rf 0.43 (X). Found,%: C 46,98; H 4.93; N 6.52 .. g, 2ЧС1 Calculated,%: 46.81; H 4.85; N 6,42, N- (2-amino-5-methyl-benzgi, aryl) methyl-p-alanine methyl ester (III) hydrochloride. M.p. 133-134s; Rf 0.38 (I); Rf 0.41 (X). Found,%; C 58.31; H 6.58; 7.60Va 0 2HC1 Calculated, I: C 58.23; H 6.51; N 7.54. N- (2-a 1Ho-2-chloro-5-bromo-benzhydryl) -aminomaspnic acid (iVa) methyl ester, Yield 79%; Tp, .10–107 ° C; Rf 0, 7b (V)); Rf 0.44 (IV). Found 2 ;: C 52.60; H 4.96 N 6.88QgH N O .BrCI Calculated, C 52.51; H 4.90; N 6.80. Methyl ester of M- (2-amino 5 methylbenzhydri) - sg-amiomaglic acid (IV6). Exit 821, - So. 88-89 Rf 0.29 (VI); Rf O.iig (IV). Finding% C 73.13; H 7 N 9, You Slen,: C 73.05; H 7, N 8.97 .. N- (-amino-5-bromo-6-benzhydryl) dG-inmin of a clear acid (iVe) methyl ester hydrochloride. Yield 86%, TPA. nO-nfc; Rf 0.80 (I), - Rf 6, AB (X). Found,%: C A8,13; H 5.2 (; N 6.31., NjOjBr.2HC1) Calculated: C + 8.02; H 5.15; N 6.22. N- (-no-5-chloro-benzhydryl methyl ester hydrochloride) - y-amine of glial acid (iVr) .Yout 86y; T.PA 122-123 C, - Rf 0,80 (|), 0,2 (X), Found, I: C 53.36; H 5.77; N 6.97 VLNjOa 2HCl Calculated: C 53.28; H 5.71; N6.90 Example 3. N- (5-bromobenzylhydryl) glycylglycine (1Xa) ethyl ester. To a solution of 13.9 g (0.03 mol) of 2-amino-5bromobenzhydrol in 100 ml of chloroform is added at minus, for 3- WH 7 ml (0.05 mol) of trifluoroacetic anhydride in 15 ml of chloroform, and then 7.3 ml (0.052 ml triethylamine. The solution is stirred at minus 0 to N. Then, at minus gchei, 9.8 g {0.05 about glycine glycine ethyl ester hydrochloride in 70 ml of chloroform and 1 4 ml (o, T mol) of triethylamine. The solution is stirred at 20-22 0 7 h and at 40 C for 8 h. The reaction mixture is washed at 16-17 ° С with hydrochloric acid ( 30), water (AO ml 1 2) sodium bicarbonate to pH 7 with water to pH 7. The chloroform solution is dehydrated with sodium sulfate, evaporated in vacuo, the residue is dissolved in diethyl ether, the same portion of hexane is added and left for 3 hours at about C. The precipitated precipitate is separated and discarded, the filtrate is evaporated in vacuo., the residue is washed with 710 ether (T, to p.ZO-70C) or hexane (AO 2 ml), dried and prepared v.vakuume 1Ha. In the presence of impurities detectable by fine chromatography, purification is performed by dissolving the substance in a mixture of diethyl ether - hexane (1: 1 L of evaporation of a part of the solvent in a vacuum before crystallization and keeping the solution until complete crystallization at minus. (2-amino-5-bromobenzhydryl) -glycyl-glycine (1Xa) 17.7 g (8A%), mp 127-128 ° C; Rf 0.36 (IV). GH. 1T5G1 (1G -. .- 1G IR. Spectrum: 1735, 1665 cm-MS 0), 1200 cM-t (COC), 3380-3 20). Found,%: C 5A, 38; H 5 FOR; N 10.08 ... Calculated,% C 5A, 30; H 5.28; N 10.00, N- (2-amino-5-bromobenzhydryl) -glycyl-glycine (V6) ethyl ester hydrochloride, hydrogen chloride in diethyl ether was added to the ether-hexane solution of 1Xa, the precipitate was separated, washed with ether, dried in vacuum over caustic soda for 6 h and get 1X6 (. g. H2S. Output Rf 0.60 (VIII), T. pl. iA-PZ C. IR spectrum: 1735, 1670 cm- (), 1210-1220 cm ( С-0С), 3320-3280, ЗЗБО-ЗААО CM- (NH). Found,; С А6.3b; Н А, 97: N 8.63., Ъ Calculated, I: С А6.27; ON , 90; N 8.52. Similarly, get: ethyl ester of N- (2-amino-5-chlorobenzhydryl) -glycyl-glycine (VB). The yield Tpl, 93-9AC; Rf 0, A2 (V), Rf 0, 35 Found., I: C 60.82; H 5.9 7; N 11; Calculated: C 60.72; H 5.90, N11.18 M- (2-amino-5-methyl-benzhydride) glycyl-gly.cin (Vr) ethyl ester. Output 8U; TP 91- 924; Rf 0, AA (V); Rf O, FOR (IV). C 67.6A and 7.16; Found, 11, c 67.58; H 7.09; calculated, N 11.83. Methyl ether N - (2-ag4 but-5-bromobenzhydryl) -glycyl-alanine, -)). П 1010 Exit 83/0; M.p. 107-1084, Rf 0.35 (VII); Rf 0.37 (IV). Found, I: C 5. About; H 5.32; N 10.08. Calculated Z: C 54.30; And 5.28; N 10.00. IR spectrum:, 1bb5 (), 1210 (C – O – C), 360–3380 (N – H) cm–. N- (2-amino-2-chloro-U-5-bromo-benzhydryl) -glycyl-alanine methyl ester (Ve). Exit 82, T 9b-97C, - RfO, 32 (VH); Rf 0.38 (IV). . Found: I: C 50.27; H 4.73; N 9.30. -5 C.N. AOvBrCi Calculated, I: C 50.18; H 4, b5; N 9.2it. IR spectrum: 1740, 1660 (), 1205 (C-O-C), 3380-3 0 (N-H) N- (2-amino-5-methyl-benzhydryl) -glycyl-alanine methyl ester (Vm). Exit TPK. 103-104 ° C; Rf 0.3b (VII); Rf 0.39 (IV). Found With 67.66; H 7.18.25 N 11, Calculated, I: .C 67.58; H 7.09; N 11.82. IR spectrum: 1740, 1660 (), 1220З (С-О-С), 3400-3450 (N-H) cmg Methyl ester of M- (2-amino-5-bromobenzhydryl) -apanyl glycine (V3). Exit TPA. 122-123 C; Rf 0.45; (Vll), Rf 0.36 (IV). Found,%: C 54.43, H 5.32; N 10.10. Included, o: C 54.30; H 5.28; N 10.10. I IR spectrum: 1740, 1bb5 (), 1210 (C-O-C), 3400-3440 (N-H) cm-. 5712 Y- (2-amino-5-methylbenzhydryl) -apanyl-glycine (Wee) methyl ester, Yield 765 ;; Mp 11b-P7C; Rf 0.7 (VII); Rf 0.37 (IV). Found,%: C 67, b7; H 7.18; N 11.89. C ,, 0 Calculated, I: C b7,58; H 7.08; N 11.82, IR spectrum:, 1b70 (), 1206 (C-O-C), 3380-3 20 (NH) see. N- (2-Amino-5-bromobenzhydryl) -glycyl-phenylalanine methyl ester ( VK). Output ".. 83-84 C; Rf 0, (vll); Rf 0.38 (IV). Found,%: C 60.57; H 5.36; N 8.53. C ,, Calculated, I: C 6Q, k9; H 5.28; N 8.46. IR spectrum: 1735, 1660 (), 1215 (C-O-C), 3380-3 40 (N-H) cm, N- (2-a methyl ester in but-5-methylbenzhydryl) -glycyl-phenylapanine ( Vl). Tf output. 90-91 C; Rf 0.46 (VII), Rf 0.39 (IV). Found,%: C 72.37; H 6.83; N 9.81, Calculation, eno,%: C, 72.37; H 6.77; N 9.74 IR spectrum: 1735, 1660 (), 1215 (C-O-C), 3380-3440 (N-H) cm. Methyl ester of M- (2-amino - $ - chlorobenzhydryl) -M-car6o6enzoxylysine (VM), Yield 85%, - T „. 66-6 / C; Rf. 0.43 (IV). Found,%: C 66.02; H 6.39; N 8.31С, D Ц04С1 Calculated,%: C 65.94; H 6.32; N 8.24 IR spectrum: 1730, 1710 (), 1200 (C-O-C), 3380, 3450 (N-H).

Claims (1)

METHOD FOR PRODUCING ETHERS? 1- (2-aminobenzhydryl) -o £ -, β> -, 0-AMINO ACIDS AND DIPEPTIDES OF THE GENERAL FORMULA X / ^R CH -A-P. 2 ό Pi where.-R is hydrogen, halogen or lower alkyl; R ^ is hydrogen, halogen in the ortho or para position; A Gly, Ala, p-Ala, Abu, Asp (R ^), Glu (Ri), Asp, G1u, Vai, Phe, Lys (Z),. . . tf-Abu, CP-Ph-fb-Ala, Gly-Gly, Gly-Ala, Ala-Gly, Gly-Phe, 'R ₂ - lower alkyl,' Z is benzyloxy carbonyl, characterized in that 1 mol of 2-aminobenzhydrol of the general formula wherein R and R ^ have the indicated meanings, are reacted with 1,0- 1.3 moles of trifluoroacetic anhydride in chloroform in the presence of 1.04-1.36 moles of triethylamine at (- 14) - (- 20) ®С for 35-40 minutes, then 1.0-1.3 moles of amino acid ester are added or dipeptide of the General formula HA-Ri., Where A and Rj have the indicated meanings, in the form of a free base or hydrochloric acid hydrate in the presence of 2-3 moles of triethylamine and the reaction mixture is kept for 1-4 hours at 20-22 ^ 0 and 3 ~ 8 hours at 4О 6O®C. SU .... 1010057