SU1432983A1 - Method of producing arylamides of substituted arginine - Google Patents

Abstract

The invention relates to amides of carboxylic acids, in particular to the preparation of arylanides of β-protected arginine, which are used in the synthesis of peptides. The goal is to simplify the process, increase the output and expand the range of target products. They are obtained from N-protected arginine in the form of a salt with a strong acid and arylamine in the presence of a condensing agent, di-tert-butyl pyrocarbonate and prnadine, in dimethylformamide medium. The method allows to increase the yield up to 64-78% and to obtain arginine arylamides containing protective groups of acid-and-strong compounds.

Description

: 11U 32983

 The invention relates to the improved method of obtaining N-saBjitmenHOro arginine, which can be used as substrates of proteolytic enzymes and as intermediates for the synthesis of peptides.

The purpose of the invention is to simplify the process, increase the yield and expand the range of target products.

Example 1. p-Nitroanilide - tert-butyloxycarbopyl-b-arginine (1).

Mix 3.1 g (10.0 mmol) of hydro-5 rohdoride N-tert-butyloxycarbonyl-b-arppin, 1.5 g (11.0 mmol) of p-pitroaniline and 0.8 ml of pyridine in .30 ml of mixture D 1 methyl forms and toluene (1: 2) and toluene are distilled in a vacuum. The residue (sweetened to 10 ° C, / was added 2.7 ml (12.0 mmol) of di-tert-butyl pyrocarbonate. The reaction mixture was then stirred for 1 hour, gradually brought the temperature of the reaction mixture to room temperature). The mixture is stirred for 16 h, 50 ml of ether are added and the mixture is stirred for another 5-10 minutes. The oily precipitate formed is separated from the solution by decantation, washed with ether and diluted with 4.0 ml of a mixture of chloroform and n-propyl alcohol (3: 1). the solution is washed with water, 5% citric acid solution, 3% ammonia solution, water, saturated solution rum sodium chloride, dried over magnesium sulfate and evaporated. The residue is mixed with toluene and again evaporated. The residue is triturated in a mixture of ether and ethyl acetate and placed in a refrigerator. The precipitate formed is filtered off, washed with ether and dried.

A total of 2.8 g (64%) of compound I, m.p. 178-180 ° C, R.J. 0.51 (with Kieselgel UV-254 (Merck) chloroform, methanol and ice on acetic acid 8: 2: 1 (A)), 0.30 (n-butanol and 10% amhak 3: 1 (B)) M5-11, b (C 1, ethanol) J UV spectrum (water 0 315 named after (11820). 2. Podrochloride p-nit30

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40

An cm cm ka kashi in still about d sm cm sl l l y and c k t in l 4 sh

45

ethanol) Example

roanilide N-benzyl-ox, icarbonyl-b- arginine (II).

3, Gg (10.0 mmol) of N -benzyloxycarbonyl-b-arginine, 2.2 g (11.0 mmol) of quinoline-8-sulfH- acid, 1.5 g (11.0 mmol) of p-nitro55 are mixed.

.g

aniline and 0.8 ml of pyridine-in 30 ml of a mixture of dimethylformamide and t.toluene (1; 2). The toluene is distilled off in vacuo, the residue is cooled to 10 ° C, and I 2.7 P1 (12 miol) di-tert-butyl pyrocarbonate is added. The reaction mixture is stirred for 1 hour at 10 ° C, the temperature of the reaction mixture is gradually brought to room temperature, stirred for 16 hours, 50 ml of ether are added and another 5-10 Mini are stirred. The resulting oil-like precipitate is separated from the solution by decantation, triturated in 20 ml of 1 M solution, dissolved in 40 ml of a mixture of chloroform and i-propanol (3: 1). The organic solution is separated and successively washed with water, with a mixture of 10 ml of saturated sodium chloride solution with 2 ml of concentrated hydrochloric acid, filtered and dried. are evaporated over magnesium sulphate and evaporated. The residue is mixed with 15 ml of toluene and left again. The residue is mixed with ether, triturated, the resulting crystalline precipitate is filtered off, washed with ether and dried. The resulting product is dissolved in methanol, 1 ml of concentrated hydrochloric acid is added to the resulting solution, and the mixture is concentrated in vacuo to 10-15 ml. The solution is placed in cold water, the resulting crystalline precipitate is filtered off and dried under vacuum.

In the end, 3.0 g (64%) of compound 11 is obtained, m.p. 180-181 ° C, Ri 0.51 (A) i 0.30 (B); Mo 12.0 (with 1i ethanol).

Example 3. N-benzyloxycarbonyl-b-arginine (III) hydrochloride 4-methyl 1-coumaryl-7-amide.

ot

Mix 3.1 g (10.0 mmol)

To -benzyloxycarbonyl-L-argyine, 2.1 g (10.5 imol) quinoline-8-sulfonic acid, 0.8 ml pyridine, 2.0 g (11.0 mmol) of 7-amino-4-methylcoumarin in 30 ml of a mixture of dimethylformamide and toluene (1: 2) and toluene are distilled off in vacuo. The residue is cooled to 10 ° C, 3 ml (13.0 mmol) of di-tert-butyl pyrocarbonate are added and stirred for 16 hours. Then 50 MP ether is poured into the reaction mixture, stirred for 5 minutes, the solution is poured, the residue is triturated with 20 ml of 1 M NaOH, by adding K1T to 40 ml of a mixture of chloroform and n-propanol. (3: 1), the organic layer is separated, washed with water and evaporated to dryness.

The residue is dissolved in 20 ml of methanol, added to a solution of 2 ml of hydrochloric acid and placed in a refrigerator. The crystallized precipitate is filtered off with S, washed with methanol, ether and dried.

A total of 4.9 g (73.0%) of the compound III. Mp. 209-210 s. Ri 0.51 (A); 0.30 (B), 6 (t, dimetapformamide).

Pr and mer, and. Salt of 4-methylcoumaryl-7-amide s -beityloxycarbonyl-b- arginine with quinoline-8-sulfonic acid (IV)

3.1 g (10.0 siol) of N -benzyloxycarbonyl-b-arginine, 2.1 g (10.5 mmol) of quinrlin-8-sulphonic acid, 0.8 ml of pyridine, 2.0 g (11, 0 mmol) of 7-amino-4-methylcoumarin in 30 ml of a mixture of dimethylformamide and toluene (1: 2) and the toluene is distilled off in vacuo. The residue is cooled to, add 3.0 (mmol) of di-tert-butyl pyrocarbonate and stir for 16 hours. Then 50 ml of ether are poured into the reaction mixture, stirred for 5 minutes, the solution is poured, the residue is dissolved in chloroform and (3: 1). The resulting solution is sequentially washed with water, 5% solution of molten acid, 3% ammonia solution, water, high concentrations.

Example 6. Hydrochloride of 4-phenylaoanilide N-benzyloxycarbonyl-L-arginine (VI). . Hang 3.1 g (10.0 mmol)

with sodium chloride solution, dried over magnesium sulphate and evaporated. L-benzyloxycarbonyl-b-arginine. The residue is mixed with toluene and again 2.2 g (mmol) of quinoline-8-sulfo-evaporated. The residue is triturated in warm isopropanol, placed in a refrigerator.

acids, 2.0 g (10.0 mmol) of am-azobenzene, b, 8 ml of pyridine in 30 ml of a mixture of dimethylformamide and toluene (1: 2) and toluene. Distilled. The residue is cooled to, add 3.0 ml (13.0 mmol) of di-tert-butyl carbonate, stirred for 16 h. Then the reaction mixture is treated similarly

The precipitate formed is filtered off, washed with isopropanol, ether and dried.

A total of 5.2 g (78%) of compound IV was obtained with a mp. 105-1U C. The resulting product is recrystallized

from a mixture of acetic acid and methanol

The result is a compound IV so pl. 132-133 ° C, Rf 0.51 (A),

WD (lV methanol). Elemental analysis: Found, Z: N 12.0} S 4.7

4 jH54N60eS Calculated,% N 12.4, S 4.7.

Primer p. 5. Salt of 4-methylcum aryl-7-amide N-tert-butyloxycarb onyl-b-arginine with quinoline-8-sulfonic acid (V).

2.7 g (10.0 mmol) of N-tert-butyloxycarbonyl-b-arginium are mixed.

2.1 g (to, 5 mmol) of hiioli11-8-sulphonic acid, 0.8 ml of pyridine and 1.8 g (10.0 mmol) of 7-amino-4-meth11 lcoumarin

in 30 ml of dimethylnornamide and toluene (t: 2) and toluene are removed in vacuo. The residue is cooled to 10 ° C, 3.0 ml (13.0 kmol) di-tl) butylpyr6carboyate are added and stirred for 16 hours, 50 ml of ether are added, the mixture is stirred for 5 minutes, the solution is poured, the residue is dissolved in 40 ml chloroform and n-propanol (3: 1). The resulting solution is washed sequentially.

water, an OX solution of ammonia, 5% citric acid solution, a saturated solution of sodium chloride, dried over magnesium sulfate, and evaporated. The residue is ground in

mixtures of isopropanol with acetone, the crystalline precipitate is washed off, washed with ether and dried.

In total, 4.2 g (66%) of compound V are obtained, m.p. 164-165 Cj

Ri 0.50 (A), 0.31 (B) 14.9 ° (C 1; methanol).

Elemental analysis:

Found: C 56.5; H 5, b: n,

C eHjeMeS

Calculated,%: C 56.2 H N 13.1.,

Example 6. Hydrochloride of 4-phenylaoanilide N-benzyloxycarbonyl-L-arginine (VI). . Hang 3.1 g (10.0 mmol)

N-benzyloxycarbonyl-b-arginine, 2.2 g (mmol) quinoline-8-sulfo

N-benzyloxycarbonyl-b-arginine, 2.2 g (mmol) quinoline-8-sulfo

acids, 2.0 g (10.0 mmol) of am-azobenzene, b, 8 ml of pyridine in 30 ml of a mixture of dimethylformamide and toluene (1: 2) and toluene. Distilled. The residue is cooled to, add 3.0 ml (13.0 mmol) of di-tert-butyl carbonate, stirred for 16 h. Then the reaction mixture is treated similarly

0

five

In the end, get 3.5 g (67%). Dinoeni VI, so pl. 154-155 ° C; R 0.51 (A), 0.30 (B) -I 13.5 (c 1, methanol) ....

Elemental analysis:

Found,% g C 59.3 j H 4.7; N 19.0; SG7.0.

S bN chN Oz-NS

Calculated,%: C 59.6 - H 5.0; N 18.7V s Cl 6.8.

Example 7. Hydrochloride of 4-phenylazoanilide N, tert-butnloxycar-, boinyl-b-arginine (VII).

1.7 g (5.0 mmol) of gndro chlornd hydrate H t-tert-butsyuksi-karoshsh-b-argn inpa, 1.0 g (5.1 mnol vmiz1oazo-benzene and 0.3 ml of pnrpdnna in 20 MP mixed dimethylformanide and toluene (1 3) and toluene is an evaporation. The residue is oh / gated to 10 ° C, 1.5 ml (6.7 mmol) of di-treg-6ut11ppprocaronate is added, mixed with reaction CMfict 4; when and treated as in Example 1,

 In the end, get 1.6 jv (65%) VII, T.1Sh. 197-198 ° C. R4 0.50 (A) -; MD 1A, 8. (C 1i ethanol).

Elemental analysis.

Found,%: H 19.3; C1 7.5

C ,, 5Из, N, 0, .HC1

Calculated,%: H 20.0} .C1 7.2.

As can be seen from the above examples, the proposed method allows to significantly simplify the process of obtaining the N-protected argishsharshshadop by using a stable condensing agent, produced in the previous one. scale, and by carrying out the process at

lower energy costs due to the higher temperature of the reaction mixture.

Crone TOrOj the proposed method

allows to increase the yield up to 64-78% and expand the range of target products, since it allows to obtain arginine aryl amides containing

labile protective groups.

Claims (1)

Invention Formula fJ The method of obtaining aryl amides of N-protected arginine by the interaction of N-protected arginine, taken as a salt with a strong acid, with aryl aryl in the presence of a condensing agent and niridine in an organic solvent. and in order to simplify the process, to achieve the yield and expansion of the assortment of target () Gx products, di-tert-butyl pyrocarbonate is used as a condensing agent and the process is carried out at a temperature from 10 ° C to room in dimethylformamide.