RU1807986C - 5-(@@@-nitro-@@@-tert-butyloxycarbonyl)arginylamino-naphthalene-1-sulfamides as intermediates for the preparation of 5-arginyl-1-aminonaphthalene sulfamides - Google Patents

Abstract

Usage: as intermediates for the preparation of 5-arginyl-1-aminophthalenesulfonamides. SUMMARY OF THE INVENTION: products of the formula (N02NH) (NH) CNH- (CH2) 3CH (NHC (-0) -0-C- (CH3) cC (0) IH- (naphthalyl) S02NR1R2, where,, Ca.Hs. ,., SbNc, CeHi, cyclohexyl, --CH2-SbNb or the group - NRiRa means - N (CH3) 2, -M (C2H5) 2, -M (CzH7) C. -N (C4H9) 2.-M (IEO -C4He) 2.or.-NCH2CH2QCH2CH2. -NCH2CH2CH2CH2CH2, -NCH2CH2CH2CH2CH2CH2, reagent 1: Ms-nitro-M1-tert-butyloxycarbonylarginine Reagent 2: 5-aminonaphthalen-l-1-sulfamide; -butylpyrocarbonate, dry dioxane. 4 tab.

Description

The invention relates to the field of organic chemistry, specifically to the new derivatives of 5- (N-HHTpo-N-tert-butyloxycarbonyl) arginylaminonaphthalene-1-sul to the names of the general formula

 : nm:;: - L; . -®. CNHtCHjUCHCHN O about 0, NHN, „. v., .. / rL v, / Kl

S02 (2

(CH COCNH fa-c o

where RI H; R2 CH3; CaN z. C4 He, i-C / iHg, t-C Ne. С5Н11, С8Н17 (1а-ж), А (1з),

 (1 and); NRiR2 N (CH3) 2 (1 k), N (C2H5) 2 (1 L), M (C3H7) 2 (1 m), N (C4H9) 2 (1H), N-n- (C4H9) 2 (1 °);

O (1p); O {1p) -O (1s)

as intermediate products, for the preparation of derivatives of 5-argynylamino-naphthalene-1-sulfamides used in biotechnology for the synthesis of artificial peptide substrates and as chromogenic and fluorogenic substrates in determining the enzymatic activity of the prosthesis.

The purpose of the invention is the search for a series of substituted aminonaphthalene sulfamides of new substances that, when used as intermediates, provide the desired products in high yield and using more affordable reagents.

The goal is achieved by the new derivatives of 5- (N4-HHTpo-NL-TpeT-6yrnflOKCHKap6onyl) arginylaminononaphthalene-1-sulfamides of the formula I.

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5- (Mn-nitro-M1-tert-butyloxycarbonyl) arginylaminonaphthalene-1-sulfes, yields (1a-c) are obtained by condensation of Uc-nitromocret-butyloxycarbonylarginine with 5-aminonaphthalene-1-sulfamides using a di-tert condensing agent -butyl pyrocarbonate in dry dioxane. After removing the block by catalytic hydrogenation, useful substances are obtained - 5-arginylaminonaphthalene-1-sulfamides dihydrochlorides.

Example 1. 5 PMh-nitro-Y-tert-butyloxycarbonyl) arginylaminonaphthalene-1-methylsulfamide (la).

3.2 g (0.01 mol) of (M-nitro-M-tert-butyloxycarbonyl) arginine, 0.8 ml of dry pyridine and 2.4 ml of di-tert-butyl pyrocarbonate are stirred in 10 ml of dry dioxane at 20 ° C. over 1.5 hours. 2.36 g of 5-aminonaphthalene-1-methylsulfamide are added in small portions over the course of 50 minutes to the resulting solution. The reaction mixture was stirred for 4 hours at 20 ° C., an additional 1.6 ml of di-tert-butyl pyrocarbonate was added and stirred for 17 hours. After that, the dioxane was evaporated under reduced pressure, the masked residue was dissolved in acetone and the solution was passed through a chromatographic column. with alumina, elute with ethyl acetate-methanol (1: 1). Unreacted sulfamide is isolated from fractions containing 5-aminonaphthalen-1-methylsulfamide. Fractions containing the desired product were combined, boiled for 0.5 hours with activated carbon, filtered off, and the filtrate was evaporated. The oily residue was triturated with dry diethyl ether, the precipitate formed was filtered off and dried (in air). 3.82 g (71%) of chromatographic and analytically pure product are obtained, mp. 126-131 ° C, Rf 0.51 (ethyl acetate-methanol 19: 1), ph20 - 7.3 (C1; acetone)

Found,%: C 49.31; H 5.96; N 18.03: S

5.63. C22H31N7S07.

Calculated,%: 49.15; H 5.81: N, 18.24; S 5.96.

PRI me R 2. 5- (N4-HHTpo-NL-TpeT-6yTH-Loxycarbonyl) arginylaminonaphthalene-1-pentamethylsulfamide (le).

Obtain analogously to example 1 of 2.9 g of 5-aminonaphthalene-1-pentamethylsensulfate. Yield 3.73 g (63%).

Other examples of the synthesis of compounds (1a-c) by this method are collected e tab. 1. mp. Rf. Elemental analysis and 1 H NMR for compounds (1a-c) are given in Table. 2.

PRI me R 3. Dihydrochloride 5-arginylaminonaphthalene-1-pentamethylene sulfides yes (He).

5.92 g (5-Nq-HHTpo-N-tert-butyloxycarbonyl) arginylaminonaphthalene-1-penta methylene sulfamide are dissolved in 150 ml of dry methanol, 10 ml of 4.4 N HCI in methanol and 2 g of catalyst are added (10 % PdC). Stirred in a stream of hydrogen for 25 hours at 0 to 20 ° C. another 2.5 g of catalyst and 4.5 ml of HCI in methanol are added, stirred for another 23 hours in a stream of hydrogen. After this, the reaction mixture was filtered, the filtrate was evaporated, the oily residue was triturated with 5 dry diethyl ether, filtered and washed with ether. Obtain 4.73 g (91%) of the target product, so pl. 141-145 ° C, Rf 0.40 (n-butanol-acetic acid-water 4: 1: 2) Mo20 + 6.3 (CI; CHzOH). NMR (DMSO): 0 1.38 (CH3), 3.06 (CH2).

Found,%: C 48.76; H 6.45; N, 15.94; - S 5.46; CI 13.24.,

Calculated,%: C 48.55; 6.21; N, 16.18; S 6.17; CI 13.65.- ..:. 5 S21Nz2M650zS12:

Other examples of synthesis by this technique are collected in table. 3. The data of elemental analysis are given in table. 4..

Example 4.5-Arginylaminonaphthalene-0 1-pentamethylene sulfamide, 5.2 g (0.01 mol) of dihydrochloride 5-arginylaminonaphthalene-1-pentamethylene sulfamide was dissolved in 50 ml of water, 200 ml of n was added to the solution in a separatory funnel. -butanol and (in portions - 5 mi of 20 ml., shaking after each portion) 5% aqueous NaHCOs to pH 7 (aqueous layer). The organic layer was washed with water twice in 20 ml and evaporated to 10-15 ml. The residue was triturated with 150 ml of dry 0 ether, filtered off, washed with ether, and dried. 4.15 g (93%) of the expected product are obtained. Mp 138-1430C, Rf 0.40 (the same system), + 6.9 (CI; CHzOH).

Found,%: C 56.24; H 6.77; N, 18.85; S 5 6.54.

C21H30N6S03 .. Calculated,%: 56.48; H 6.77; N, 18.82; S 7.18.

Thus, the use of 5- {Nq- 0 HHTpo-NL-TpeT-6yTHflokCHKap6oHHfl) ap-vinylaminonaphthaline in-1-sulfamides as intermediates for the synthesis of substituted 5-aminonaphthalene-1-sulfamides allowed 5

It is possible to obtain the target products using more accessible reagents and with a yield of 62-84% versus 35-40% when using known intermediates.

physico-chemical properties of 5- (M-nitro-I-tert. butyloxycarboiip) arginipaninone “phtvlim-1-sulfamide obpei Formula 1a-c.

 (,, / -BOCXArgUH -JO).

T - 6 l and 2

 Etipatsvt "t-met" zero (19: O; silufol;

Htt, acetone

  Table 3 Preparation of 5-arginylaminononaphthalene-1-sulfamides dihydrochlorides of the formula II according to the example, - .--

Solvent: methanol, 150 ml. ;. Medium: 4.4 N, HCI in CHzOH, 14.5 ml.

Catalyst: 10% Pd / C, 4.5 g. Reaction time: 48 hours. Temperature 20 ° C.

..., -; / .... : ..,,:, /,: -. ;. . . ;. - V; - v / - V -. ;: ..,. -. .T E 6 L I C E 4

Elemental analysis of 5-arginylaminonaphthalene-1-sulfamides 1a-o |

 ArgNH-®о

: -so

@ -50gn

,

Continuation of table 4