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

Abstract

METHOD OF OBTAINING H-ETHERS

Description

There is a known method for producing 25lom to obtain 2-aminobenzchloride,

ethyl ester of N-(2-aminobenzhydryl)-which enters into interaction with

-glycine, which consists of treating k-S multiple excess of freshly distilled 2-nitrobenzhydrol with thionyl chloride of ethyl glycine according to scheme 2

The disadvantage of the indicated methods for obtaining ethyl ester of N-(2-aminobenzhydryl)-glycine is the low yield (16-32) of the final product and the impossibility of obtaining the proposed compounds of the general formula (} by this method.

The aim of the invention is a new method for obtaining new esters of 1M-(2a,4-benzhydryl- d-, b-, J-anisyloxyl) and dipeptides of general formula ().

.

where R,

And they have

h , indicated

meanings, v.p. khtsikhs

intermediate G1p.,auctania

synthesis of biologically active substances

substances with valuable pharmacological properties,

The stated goal is achieved by the described method of obtaining compounds of the general formula (1) (According to which 1 mole of 2-aminobenzhydrol of the general formula

.NHg

sn-on

0 where R and R have the indicated values, are reacted with 1.01.3 mol of trifluoroacetic anhydride in chloroform in the presence of 1.0t1.36 mol of triethylamine at (-20)°C for min, then 1.0-1.3 mol of amino acid ester or dipeptide of total fg 15 ml are added.

H-L-Ya 3 where A and R have the indicated meanings in the form of a free base or halide hydrate in the presence of 2-3 moles of triethylamine, and the reaction mixture is kept for 10 hours at 20-22°C and for 3 to 8 hours at 0-60°C. The progress of the reaction and the chemical 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 - n-xylene 1:4, n-Butanol-acetic acid water - 4:1:1 IX. Methanol-chloroform 1:19 X. Chloroform - methanol - acetic acid 17:2:1. Example 1. Methyl ester of N-(2-amino-5-bromobenzhydryl)-glycine (la). To a solution of 13.9 g (0.065 mol) of 2-amino-5-bromobenzhydrol in 100 ml of chloroform are added at minus 20° over 3-4 min, and then 9.5 ml (0.068 mol) of triethylamine. The solution is stirred at minus 35 min. After this, a solution of 8.2 g (0.065 mol) of methyl ester of glycine hydrochloride in 60 ml of chloroform and 18.2 MP (0.13 mol) are added to the reaction solution at minus 16°C. triethylamine. The reaction mixture is stirred at 20-22 °C 1.4 and boiled for 3 h. The reaction mixture is washed at 40-40 °C with hydrochloric acid solution (20 ml x 2), water (10 ml x 2). Saturated aqueous sodium bicarbonate or ammonia is added to the aqueous acid solution until pH 7.8. The precipitate separated from the solution is filtered off, washed with water until pH 7, and the first part of Ia is obtained. The chloroform solution is washed with sodium bicarbonate or ammonia until pH 7.8, then with water until pH 7, dehydrated with sodium sulfate and evaporated in vacuo. The residue is combined with the initially isolated H2O, crystallized with 3743 methanol or ethyl acetate, chloroform or their mixtures with hexane, petroleum ether ( T((ip, 30-70 C) and obtain 13.8 g (from methanol) of Ta. An additional 2.4 g (from methanol)a are then isolated from the aqueous solution. The yield of methyl ester of N-(2-a/ino-5-bromobenzhydryl)-glycine (1a) is 16.2 g (92.5%). Mp. 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) cm . Similarly obtained Methyl ester of N-(2-amino-2-chloro-5-bromobenzhydryl)-glycine (1b). Yield TrX. 154155C, Rf 0.30 (ill); Rf 0.44 (IV). Found, .%: C 50.12; H 4.96; N 7.36ad .August. . Detected, %: C 50.59; H 4.90; N 7.30. IR spectrum: 1720 (); 1220 (C-OC), 3340, 3440 (N-H) cm-1 , .. Methyl ester of N-(2-amino-4-chloro-5-bromobenzhydryl)-glycine (1c). Yield 90S; mp 93-94C; Rf 0.30 (III); Rf 0.44 (IV). . . Found, %: C 50.15; H 4.24; N 7.38. Cib H,b NiOi, Calculated, I: C 50.99; H 4.20; N 7.30. IR spectrum: 1720 (); 1215 (C-0C ), 3350, 3450 (N-H) cm-., Methyl ester of N-(2-amino-4-chloro-5-bromo-benzhydryl )-glycine ( 1b). Yield 90%; 1„. 93-94 s; 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 Methyl ester of N-(2-aminomethyl-5-chloro-.benzhydryl)-glycine (ir). Yield Tp PO-11°C; Rf 0.45 (IV). Found, %: C 63.16; H 5.68; N 9.23. Calculated, %: C 63.16; H 5.62; N ,19. 7 10 Found, I: C 51.2; H A,63; N 7. (Ar 2°2BrC) Calculated, I: C 51, H ,56; N 7.04. IR spectrum: 1730 (), 1210 (C-0C), 3380, (N-H) cm-;: M-(2-amino-5-bromobeishydryl)-c/.-amino-butyric acid methyl ester (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-., Methyl ether N-(2-aMMHO-5-6pOMbenzhydryl)-valine (NH). Yield 78, Tp 86-97C; 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 (N-H) CM-. Dimethyl ester of N-(2-amino-5-bromobenzhydryl)-aspartic acid (Iz). Yield 821; T 78-794; Rf 0.34 (III). Found, : C 54 .27 ; H 5 , 10 ; N 6.71. Q,gHj,N В г Calculated, I: C 54.17; H 5.02; N 6.65. IR spectrum: 1735(), 1200, 1240 (C-O-C), 3350-3360, 3430 -(N-H) Dimethyl ester of N-(2-amino-5-bromobenzhydryl)-glutamic acid . (Ni) Yield 84%; Trd 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 . Dimethyl ester of N-(2-amino-5-methylbenzhydryl)-glutamic acid (11k). Yield 81%; „, 71-72 C) Rf 0.32 (IV). Found, %: C $8, G6 ; 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 ester N-(2-amino-5-orombenzhydryl)-glutamic acid.. Yield, Rf 0.32 (V). Found, %: C 5.28; H 5.10; N 6.71SJ O.Br Calculated, %: C 54.17; And 5.92; N 6.65 H-(2-amno-5-chlorobenzhydryl)-p-alanine methyl ester (Sha), Yield 84; fi; Tpl. 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 (N-H) cm-. Methyl ester of N-(2-amino-2-chloro-5-bromo-benzhydryl )-p-alanine (IIIb). Yield 2%; Trl 78-79C, - Rf 0.79(IVl), Rf 0.41 (IV). Found, %: C 51.42; H 4.60; N 7)12, Calculated, %: C 51.34; H 4.56; N 7.04, Methyl ester of N-(2-amino-5-6-romo-benzhydryl )-Pgalanine hydrochloride (IIIb). . 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, Methyl N-(2-amino-5-methyl-benzhydryl)-p-alanine hydrochloride (IIIa). Mp 133-134 s; 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. Methyl N-(2-a-1Ho-2-chloro-5-bromo-benzhydryl)-aminomasp ate (IVa), Yield 79%; mp ,.106107°C; Rf 0.76 (V)); Rf 0.44 (IV). Found, 2;: C 52.60; H 4.96 N 6.88QgH N O .BrCl Calculated, C 52.51; H 4.90; N 6.80. Methyl ester of N-(2-amino 5-methylbenzhydry d)--3-aminomagnesium acid (IV6). Yield 821.- Mp 88-89 Rf 0.29 (VI); Rf 0.10 (IV). Found, % C 73.13; H 7 N 9, Calculated, : C 73.05; H 7, N 8.97. Methyl ester hydrochloride of N-( -amino-5-bromo-6-benzhydryl)-dG-amine methyl ester (IVe). Yield 86%, TPA. nO-nfc; Rf 0.80 (I),- Rf 6,AO (X). Found, %: C A8.13; H 5.2(; N 6.31. ,NjOjBr.2HC1 Calculated, %: C +8.02; H 5.15; N 6.22 . Hydrochloride of methyl ester of N-(-ano-5-chloro-benzhydryl)--y-amine methyl ester (IVr). Yield 86%; TPA. 122-123 C,- Rf 0.80 (|), 0.2 (X), Found, I: C 53.36; H 5.77; N 6.97VLNjOa 2HCl Calculated, %: C 53.28; H 5.71; N6.90. Example 3. Ethyl ester of N-(5-bromobenzhydryl)glycylglycine (1Xa). To a solution of 13.9 g (0.03 mol) of 2-amino-5-bromobenzhydrol in 100 ml of chloroform are added at minus 3°C, followed by 7.3 ml (0.052 mole) of trifluoroacetic anhydride in 15 ml of chloroform, and then 7.3 ml (0.052 mole) of triethylamine. The solution is stirred at minus 0°C. Then 9.8 g (0.05 mole) of ethyl ester of glycineglycine hydrochloride in 70 ml are added at minus 3°C. chloroform and 1.4 ml (0.1 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 ° C with hydrochloric acid (30 ), water (10 ml), sodium bicarbonate to pH 7, and 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 h at 0 C. The precipitate that forms is separated and discarded, the filtrate is evaporated in vacuo, the residue is washed with 7-10 petroleum ether (bp 30-70 C) or hexane (20 ml), dried in vacuo, and 1Xa is obtained. In the presence of foreign impurities detected by fine chromatography, purification is carried out by dissolving the substance in a mixture of diethyl ether and hexane (1:1), evaporating part of the solvent in a vacuum until crystallization begins and keeping the solution until complete crystallization at minus. The yield of ethyl ester of N-(2-amino-5-bromobenzhydryl)-glycine-N-glycine (1Xa) is 17.7 g (8A%), mp 127-128C; Rf 0.36 (IV). ShG. . 1T5G1(1G -..- 1G IR spectrum: 1735, 1665 cm-MS 0), 1200 cm-t (C-O-C), 3380-320). Found, %: C 5A,38; H 5,3A; N 10.08... . Calculated, % C 5A.30; H 5.28; N 10.00, Ethyl N-(2-amino-5-bromobenzhydryl)-glycyl-glycine hydrochloride (V6), hydrogen chloride in diethyl ether is added to an ether-hexane solution of 1Xa, the precipitate is separated, washed with petroleum ether, dried in a vacuum over caustic soda for 6 hours and 1X6 (.g. X2HC) is obtained. Yield Rf 0.60 (VIII), mp ia-n3C. IR spectrum: 1735, 1670 cm-(), 1210-1220 cm (C-0C ), 3320-3280, 336O-3AAO CM-(N-H). Found, ; C A6.3b; H A,97: N 8.63. ,ъ -ь Calculated, I: C A6.27; HA,90; N 8.52. The following was obtained similarly: ethyl N-(2-amino-5-chlorobenzhydryl)-glycyl-glycine (VB). Yield Tm,93-9AC; Rf 0.A2 (V), Rf 0.35 Found, I: C 60.82; H 5.97; N 11, Calculated,: C 60.72; H 5.90, N11.18 Ethyl N-(2-amino-5-methyl-benzhydryl)-glycyl-glycine (Vr). Yield 8U; Tp 91-924; Rf 0.AA (V) ; Rf O,3A (IV). . C 67.6A I 7.16; Found, 11, s 67.58; H 7.09; calcd, N 11.83. Methyl ester of N-(2-a4-5-bromobenzhydryl)-glycyl-alanine,-) . II 1010 Yield 83/0; mp 107-1084, Rf 0.35 (VII); Rf 0.37 (IV). Found, I: C 5 .O; H 5.32 ; N 10.08. Calculated, Z: C 54.30; I 5.28; N 10.00. IR spectrum: , 165 (), 1210 (C-O-C), 360-3380 (N-H) see--. N-(2-amino-2-chloro-10-5-bromo-benzhydryl)-glycyl-alanine methyl ester (Ve). Yield 82, T 96-97C,- RfO,32 (VH); Rf 0.38 (IV). . , Found, I: C 50.27; H 4.73; N 9.30. -5 C.H AOvBrCi Calculated, I: C 50.18; H 4.65; N 9.2it. IR spectrum: 1740, 1660 () , 1205 (C-O-C), 3380-3 0 (N-H) N-(2-amino-5-methylbenzhydryl)-glycyl-alanine methyl ester (Vm). Yield Tpc. 103-104 C; Rf 0.36 (VII); Rf 0.39 (IV). Found, C 67.66; H 7.18,25 N 11, Calculated, I:.C 67.58; H 7.09; N 11.82. IR spectrum: 1740, 1660 () , 122030 (C-O-C), 3400-3450 (N-H) cm3 Methyl ester of N-(2-amino-5-bromobenzhydryl)-apanyL glycine (V3). Yield of TPA. 122-123 C; Rf 0.45; (Vll),Rf 0.36 (IV). Found, %: C 54.43, H 5.32; N 10.10. Calculated, o: C 54.30; H 5.28; N 10.10. I IR spectrum: 1740, 165 (), 1210 (C-O-C), 3400-3440 (N-H) cm-. 5712 Methyl ester of N-(2-amino-5-methylbenzhydryl)-apanyl-glycine (VII), Yield 765;; mp 116-117C; Rf 0.7 (VII); Rf 0.37 (IV). Found, %: C 67.67; H 7.18; N 11.89. C,,0 Calculated, I: C 67.58; H 7.08; N 11.82, IR spectrum: , 1670 (), 1206 (C-O-C) , 3380-3 20 (N-H) cm. N-(2-amino-5-bromobenzhydryl)-glycyl-phenylalanine methyl ester (VK). Yield „.. 83-84 C; 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-bno-5-methylbenzhydryl)-glycyl-phenylalanine methyl ester (VL). Yield Tf. 90-91 C; Rf 0.46 (VII), Rf 0.39 (IV). Found, %: C 72.37; H 6.83; N 9.81, Calculated, %: 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 N-(2-amino-$-chlorobenzhydryl)-N-carboxymethyl ester (VM), Yield 85%, - T„. 66-6/C; Rf. 0.43 (IV). Found, %: C 66.02; H 6.39; N 8.31C, D C04C1 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 OBTAINING ESTERS OF ?1-(2-AMINOBENZHYDRYL)-О£-, 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^ - 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 - benzyloxy carbonyl, characterized in that 1 mol of 2-aminobenzhydrol of the general formula where R and R^ have the indicated values, is introduced into interaction 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)®C for 35-40 min, then add 1.0-1.3 moles of an amino acid ester or dipeptide of the general formula H-A-Ri., where A and Rj have the indicated values, in the form of a free base or halide hydrate in the presence of 2-3 moles of triethylamine and the reaction mixture is maintained for 1-4 hours at 20-22°C and 3-8 hours at 40-60°C. SU .... 1010057