LT3910B - Proess for preparing 5-arginylaminonaphthalene-1-sulphamides - Google Patents

Abstract

Invention is intended for the improvement of arginyl derivatives containing aminonaphthalene sulfamides. Compounds described by the invention are used in biotechnology as chrome and fluorogenic substrates for establishing protease ferment activity using the new analysis method (ANSA). Material output makes only 35-40 percent, when they are produced by using known methods in rough conditions, when many intermediary stages and toxic materials such as dicyclohexylcarbodiimide are present and at the same time forming benzyl bromide as a by-product. The aim of the invention is to increase the output and simplify the process is achieved by the reduction of a number of stages, declining from use of hard to obtain toxic reagents, avoiding by-product formation. The process is executed: (N<q>-nitro-N<α>-tert butyloxycarbonyl)arginine is condensed in pyridine with 5-aminonaphthalene-1-sulfamide in dioxane at a presence of di-tert butylpyrocarbonate further using chromatography and cleaning the reaction mix up to a analytically pure product. N<q>-nitro-N<α>-tert butyloxycarbonyl groups are split off by hydrogen hydrogenation, in HCl methanol solution participating Pd/C as a catalyst. The produced di-hydrochloride is treated by NaHCO3. Output amounts to 64.8-79.4 percent.

Description

The present invention relates to the field of bioorganic chemistry, in particular to arginyl derivatives containing aminonaphthalenesulfamides of the general formula:

ArgNH

where = H, R ₂ = CH ₃ , C ₂ H _5> n -, i C ₃ H ₇ , n -, i -, t C ₄ H ₉

C ₅ H ₁₁ , C ₈ H ₁₇ ,, CH _Z or R -) = R ₂ = CH ₃ , C ₂ H 5, C ₃ K ₇ , n -, i C ₄ H ₉ ;

Arg - arginine residue or NR ₁ R ₂ = NO, n

N

for improving the way of receiving. The compounds described are used in biotechnology as chromo- and fluorogenic substrates for the determination of the enzymatic activity of proteases and for the analysis of their complex mixtures, and may be used for the synthesis of other derivatives, their bases and their application for the same purposes. WITH COPYRIGHT No. No. 1822563 by Application No. 4019225 /.

The closest route of preparation is the synthesis of 5-arginylaminonaphthalene-1-pentamethylenesulfamide / Baoopr. xhm. No. 4, vol. 15, c. 444-451 /. In this way, ^a N -karbobenzoksiarginino hydrochloride is mixed with N-hydroxybenzotriazole (OBT) dimetilforamide (DMF) and condensed with 5-aminonaphthalene-lpentametilensulfamido hydrobromide in the presence of dicyclohexylcarbodiimide. The N '-substituted arginyl-ANSA * HBr salt is cleaved (ANSA * - aminonaphthalene-1-sulfamide residue) and the substitution carbobenzoxy group is removed with hydrogen bromide in glacial acetic acid, the arginyl-ANSA HBr salt is liberated, and the free base is isolated. , yields 40%.

The disadvantage of the prototype method is the production of the final product in a low yield (-40% based on starting material) using a number of intermediate steps. In addition, the process uses a strong allergen dicyclohexylcarbodiimide, a non-industrial reagent hydrobromic acid in glacial acetic acid, a by-product, a hardly utilizable lacrimator benzyl bromide. It is not expedient to isolate the end products with HBr salts and to continue their intended use due to the reactivity of HBr which results in the instability of these salts (HBr can reduce the sulfamide group and the Br2 may oxidize other labile groups).

The object of the invention is to increase the yield of the final products.

The object is achieved by a process comprising obtaining the N-substituted 5-arginylaminonaphthalene-1-sulfamide, deprotecting and isolating the final product. In this method, starting materials used in the free base - 5 aminonaftalen-l-sulfamidas which is acylated ^q N -nitro-N-dioxane -tret.butiloksikarbonilargininu pyridine medium in the presence of di-tret.butilpirokarbonatui to form 5 ^(q N -nitro-N ^a - tert-butyloxycarbonyl) for arginyl-aminonaphthalene-1-sulfamide. The protecting group is deprotected by hydrogenation with hydrogen in a solution of hydrogen chloride in methanol using a carbon-palladium catalyst to form 5-arginylaminonaphthalene-lsulfamide dihydrochloride.

The distinguishing features of the process of the invention are, first of all, the use of certain starting materials, as well as the modification of the reagents and the actions to obtain a positive effect in comparison with the known method.

The whole of the proposed operations makes it possible to obtain purer intermediates, reduce the number of intermediate steps, and increase the yield of the product (49.0-62.7%) based on the amount of N ⁹ -nitro-N tert -butyloxycarbonylarginine used in the reaction (see Table 7). . In addition, the compounds were obtained 2. HCl in the form of arginyl-ANSA salts is convenient for long-term storage, as it is stable and, if desired, can be cleaved to free bases in high yields.

The invention is illustrated by the following examples. For purposes of comparing the conditions and results, examples of the method-prototype are provided in parallel with the method of the invention.

Example 1. 5-Arginylaminonaphthalene-1-pentamethylenesulfamide (by known method).

A solution of 3.5 g (10 mmol) of N '-carbobenzoxy-arginine hydrochloride in 20 ml of dimethylformamide was stirred at -4 ° C, added to a solution of 1.33 g of N-hydroxybenzotriazole in 10 ml of dimethylformamide, 2.1 g of dicyclohexylcarbodiimide was added and stirred for 40 min. At 0 ° C. To the resulting solution was added 3.7 g (10 mmol) of 5-aminonaphthalene-1-pentamethylenesulfamide hydrobromide and 2.8 mL of triethylamine. The mixture is stirred for 48 hours, filtered, 60 ml of ethyl acetate and 120 ml of hexane are added to the filtrate, decanted, the residue is washed with ethyl acetate-hexane, dissolved in butanol-water, the supernatant is separated, the aqueous extracted with butanol, the combined > 3 and aqueous KHSO4, aqueous and dry evaporated. The resulting product (R _f = 0.75, butanol-acetic acid-water 4: 1: 2) is not crystallized and is used in another synthesis.

4 g of the resulting N ^a -pavaduoto derivative 2.5 was stirred with 40 ml of 2N HBr in acetic acid at 20 ° C with stirring and poured into 600 ml of ether, the precipitate is filtered, dissolved in 200 ml of water and extracted with ethyl acetate and the aqueous layer was evaporated to dryness and the residue dissolved in butanol / CHsCOOH-water (4: 1: 2) and chromatographed on a column (5 × 15 cm) filled with silica gel using the same system. The blue fluorescence zone is collected, evaporated to dryness, dissolved in 200 ml of water, stirred at 50 ° C with 0.5 g of activated carbon, filtered, 1 g of NaBr is added to the filtrate, evaporated to 20 ml and basified to pH 7.8 with Na ₂ CO3 and left at 4 ° C. The precipitate was separated, dried in vacuo. Yield: 2.1 g (40%). Rf = 0.28 (same system, on siluffl plates). The thin-layer chromatogram is highlighted with ninhydrin under UV light and exhibits blue (λ = 440 nm) fluorescence.

Example 2. 5- (N ^q -nitro-N '- tert -butyloxycarbonyl) arginylaminonaphthalene-1-pentamethylenesulfamide.

3.2 g of (N ^q -nitro-N '- tert -butyloxycarbonyl) arginine, 0.8 ml of dry pyridine and

2.4 ml of di-tert-butylpyrocarbonate are stirred for 1.5 hours. 10 ml of dry dioxane at 20 ° C. To the resulting solution within 50 min. 2.9 g of 5-aminonaphthalene-1-pentamethylenesulfamide are added in small amounts. The reaction mixture was stirred for 4 hours, another 1.6 ml of di-tert-butylpyrocarbonate was added and stirred for 17 hours. The dioxane is then evaporated off under reduced pressure, the oily residue is dissolved in acetone, and the solution is passed through a chromatography column filled with alumina, eluting with ethyl acetate-methanol (1: 1). The fraction containing the final product is ethyl acetate-methanol (1: 1). The fraction containing the final product is boiled with activated carbon 0.5, filtered, and the filtrate is evaporated. The oily residue is removed in dry diethyl ether, the resulting residue is filtered and air dried. 3.73 g (63%) of pure product are obtained, m.p. 117-121 ° C, Rf = 0.70 on silica plates (ethyl acetate-methanol 19: 1), / a / ² ° D - 5.8 (Cl, acetone).

Found: C, 52.77; H, 6.51; N, 16.71; S, 4.83.

Calculated for C 52.78 H 6.30 N 16.58 S 5.42. C26H37N7SO7.

Similarly, other N-substituted 5-arginylaminonaphthalene-l-sulfamides were obtained. Their yields are given in Table 1 and the physicochemical properties in Table 2.

Example 3. 5-Arginylaminonaphthalene-1-pentamethylenesulfamide dihydrochloride.

5.92 g of 5- (N -nitro-N ^q -tret.butiloksikarbonil ^a) arginilaminonaftalen lpentametilensulfamido-dissolved in 150 ml of dry methanol was added 10 ml of 4.4 N HCl in methanol and 2 g of catalyst (10% Pd / C). Stir in a stream of hydrogen for 25 hours. At 20 [deg.] C., another 2.5 g of catalyst and 4.5 ml of HCl in methanol are added and the mixture is stirred under a stream of hydrogen for a further 23 hours. The reaction mixture is then filtered, the filtrate is evaporated, and the oily residue is taken up in dry diethyl ether, filtered and washed with ether. 4.73 g (91%) of the final product are obtained, m.p. 141-145 [deg.] C., Rf = 0.40 (butanol-acetic acid-water 4: 1: 2 on a siluffole plate), [alpha] ²⁰ D + 6.3 (Cl, CH3OH). NMR (DMSO), δ, md: 1.38 (CH ₂ ); 3.06 (CH ₂ ).

Found: C, 48.76; H, 6.45; N, 15.94; S, 5.46; Cl, 13.24.

Calculated: 48.55 6.21 16.18 6.17 13.65. C ₂ iH3 ₂ N6SO3C1 ₂ .

The protecting groups of other N-substituted arginylaminonaphthalenesulfamides are similarly removed. The yields of the corresponding dihydrochlorides are shown in Table 3 and their physicochemical properties are shown in Table 4.

Example 4. 5-Arginylaminonaphthalene-1-pentamethylenesulfamide.

5.2 g (0.01 mole) of 5-L-arginilaminonaftalen pentametilensulfamido dihydrochloride was dissolved in 50 ml of water to the solution through the distribution funnel was added 200 ml of butanol, and (20 ml portions, shaking each time) by 5% NaHCO ₃ in water to pH > 7 (water layer). The organic layer is washed twice with 20 ml and evaporated to 10-15 ml. The residue is taken up in 150 ml of dry ether, filtered, washed with ether and dried. 4.15 g (93%) of the final product are obtained. Melting point 138-143 ° C, R f = 40 (same system),? / ² ° d + 6.9 (Cl; CH ₃ OH).

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

Calculated: 56.48 6.77 18.82 7.18. C21H30N6SO3.

Other 5-arginylaminonaphthalene-1-sulfamides were obtained according to Example 4. Their yields are given in Table 5 and the physicochemical properties in Table 6.

The yields of the final products are shown in Table 7, based on the amount of the starting compound (N ^q -nitro-N '-tert-butyloxycarbonyl) arginine (3.2 g). The examples above and Table 7 show that the proposed method raises the yield of the final product from 40% to 49.0-62.7%). An additional technological advantage of the proposed process is the ability to isolate stable intermediates, arginylaminonaphthalenesulphamides dihydrochlorides, which, unlike (N '-carbobenzoxy) arginylaminonaphthalenesulphamides, arginylaminonaphthalenesulphamides and their hydrobromides, can be stored for long periods and used directly in peptide synthesis as required.

Utilization of the invention enables the production of arginyl-ANSA in industrial quantities from available raw materials and in high yields.

table

5- (N -nitro-N ^q -tret.butiloksikarbonil ^a) arginilaminonaftalen-l-sulfonamide according to Example 2 Obtaining

HN ^> CNH (CH ₂ ) ₃ CHCOHN

° 2 ^NHN (CH 2

Added amount of substituted arginine: 3.2 g.

Condensing agent: di-tert-butylpyrocarbonate (4 ml) pyridine (0.8 ml) Solvent: dioxane (10 ml)

Reaction time: 21 hours. Temperature: 20 ° C

Yesterday No. Ri r ₂ Accompanied by ANSA *, g Yield, g,% 1 2 3 4 5 1. H ch ₃ 2.36 3.82 (71) 2. H c ₂ h ₅ 2.50 3.42 (62) 3. H C ₃ H ₇ 2.64 3.62 (64) 4. H iC ₃ H ₇ 2.64 3.79 (67) 5. H C ₄ H ₉ 2.78 3.65 (63) 6th H 1-C4H9 2.78 3.59 (62) 7th H TC4H9 2.78 3.77 (65) 8th H C ₅ Hn 2.92 3.68 (62) 9th H c ₈ h ₁₇ 3.34 3.31 (52) 10th H n 3.04 4.12 (68) 11th H "I" <O 3.11 4.11 (67)

Ί Continuation of the table

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* 5-Aminonaphthalene-1-sulfamides

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Preparation of 5-Arginylaminonaphthalene-1-sulfamides dihydrochlorides according to Example 3

2-HCl-ArgNH - / ^R <0 / ^s ° ^NNx

Solvent: methanol (150 mL).

Medium: 4.4 NHCl and 14.5 mL CH ₃ OH.

Catalyst: 10% Pd / C (4.5 g).

Response time: 48 hours. Temperature: 20 ° C.

Yesterday No. Ri r ₂ Amount of N-substituted compound, g Product yield, g (%) 1 2 3 4 5 1. H ch ₃ 5.38 4.33 (93) 2. H c ₂ h ₅ 5.52 4.36 (91) 3. H C ₃ H ₇ 5.66 4.34 (88) 4. H iC ₃ H ₇ 5.66 4.44 (90) 5. H C ₄ H ₉ 5.80 4.67 (92) 6th H 1-C4H9 5.80 4.62 (91) 7th H t-C4H9 5.80 4.52 (89) 8th H CjHu 5.94 4.54 (87) 9th H n 6.06 4.96 (93) 10th ch ₃ ch ₃ 5.52 4.31 (90)

continuation of the table

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table

Physico-chemical characteristics and elemental analysis of 5-Arginylaminonaphthalene-l-sulfamides dihydrochlorides

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, _; Table 5

Preparation of 5-Arginylaminonaphthalene-1-sulfamides

ArgNH— (Q)

Starting compound: 5-arginylaminonaphthalene-1-sulfamides dihydrochloride. Solvent: water (50 ml).

Medium: Butanol (200 mL).

Neutralization: 5% NaHCO _{3 in} water to pH> 7 (aqueous layer)

Yesterday No. Ri r ₂ Of dihydrochloride quantity, g Product yield, 8th % 1 2 3 4 5 1. H ch ₃ 4.28 3.72 95 2. H c ₂ h ₅ 4.43 3.79 93 3. H C ₃ H ₇ 4.57 3.87 92 4. H iC ₃ H ₇ 4.57 3.83 91 5. H C4H9 4.72 4.13 95 6th H 1-C4H9 4.72 4.17 96 7th H t-C4H9 4.72 4.05 93 8th H C ₅ Hn 4.86 4.27 95 9th H n 4.98 4.33 94 10th ch ₃ ch ₃ 4.44 3.83 94 11th C ₂ H ₅ C ₂ H 5 4.72 4.04 93

continuation of the table

1 2 3 5 12th N 0 4.85 4.31 96 13th O 5.20 4.15 93 14th o 4.98 4.33 94

table

Elemental analysis of 5-Arginylaminonaphthalene-l-sulfamides i · ArgNH— (Tj)

Yesterday No. Ri r ₂ Empirical formula Elemental analysis data,% Found / Calculated C H N S 1 2 3 4 5 1. H ch ₃ C ₁₇ H ₂ 4N ₆ SO ₃ 52.22 52.03 6.06 6.16 21.18 21.41 7.74 8.14 2. H c ₂ h ₅ Ci ₈ H ₂₈ NeSO ₃ 53.10 53.18 6.72 6.45 20.49 20.67 7.22 7.89 3. H C ₃ H ₇ C ₁₉ H ₂₈ N ₆ SO ₃ 53.95 54.27 6.87 6.71 19.84 19.98 6.80 7.62 4. H iC ₃ H ₇ Ci ₉ H ₂₈ N ₆ SO ₃ 54.01 54.27 6.42 6.71 20.31 19.98 7.11 7.62 5. H C ₄ H ₉ C ₂ oH ₃ oNeS0 ₃ 55.41 55.28 6.85 6.96 19.48 19.34 6.84 7.38 6th H i-CįHg C ₂ oH ₃₀ N ₆ S0 ₃ 55.26 55.28 7.00 6.96 19.17 19.34 6.69 7.38 7th H t-C4H ₉ C ₂ oH ₃ oNeS0 ₃ 55.07 55.28 7.12 6.96 19.21 19.34 6.53 7.38 8th H CsHn C ₂ iH ₃₂ N ₆ SO ₃ 56.29 56.23 7.00 7.19 18.84 18.73 7.25 7.15 9th H n C ₂₂ H ₃₂ N6SO ₃ 57.18 57.37 7.14 7.00 18.07 18.25 6.28 6.96 10th ch ₃ ch ₃ Ci ₈ H ₂₆ N ₆ SO ₃ 53.36 53.18 6.64 6.45 20.91 20.67 7.10 7.89

continuation of the table

1 2 3  '4 5 c ₂ h ₅ c ₂ h ₅ C ₂₀ H ₃₀ N ₆ SO ₃ 54.93 6.85 19.70 7.61 55.28 6.96 10.34 7.3 12th N \ \> c ₂₀ h ₂₈ n ₆ so ₄ 53.72 6.39 18.92 6.89 53.56 6.29 18.74 7.15 13th Ό C ₂ iH ₃₀ N ₆ SO ₃ 56.24 6.77 18.85 6.54 56.48 6.77 18.82 7.18 14th O c ₂₂ h ₃₂ n ₆ so ₃ 57.61 6.86 18.43 6.54 57.37 7.00 18.25 6.96

table

Yield of final product 5-arginylaminonaphthalene-1-sulfamides, calculated from the yield of N ^q -nitro-N ^£ -trert.butyloxycarbonylarginine (3.2 g)

ArgNH—

O ^S ° ^{! N} \ r '' - / «2

Yesterday No. Ri r ₂ ANSA content, g Product yield, g % 1 2 3 '4 5 1. H ch ₃ 2.36 2.46 76.12 2. H c ₂ h ₅ 2.50 2.14 64.82 3. H C ₃ H ₇ 2.64 2.18 72.14 4. H iC ₃ H ₇ 2.64 2.22 67.79 5. H C ₄ H ₉ 2.78 2.40 77.6 6th H iC ₄ H ₉ 2.78 2.36 79.2 7th H tC ₄ H ₉ 2.78 2.34 74.0 8th H C ₅ Hn 2.92 2.30 77.76 9th H -o 3.04 2.74 76.26 10th ch ₃ ch ₃ 2.50 2.14 75.63 11th c ₂ h ₅ c ₂ h ₅ 2.78 2.26 73.49 12th 2.93 2.50 79.47 N o 13th O 2.90 2.38 72.26 14th r 3.04 2.59 71.74 N J

Intermediate and final product yields

Yesterday No. Ri, r ₂ Yield 1 stages,% Yield 2 stages,% Yield 3 stages, % Yield 1-3,% 1 2 3 4 5 6th 1. H ch ₃ 71 93 95 62.73 2. H c ₂ h ₅ 62 91 93 52.47 3. H nC ₃ H ₇ 64 88 92 51.81 4. H i-C ₃ H ₇ 67 90 91 54. 87 5. H nC ₄ H ₉ 63 92 95 55.6 6th H i-C ₄ H ₉ 62 91 96 54.16 7th H t-C4H9 65 89 93 53.80 8th H C5H11 62 87 95 51.24 9th H c ₈ h ₁₇ 68 93 94 59.45 10th ch ₃ ch ₃ 58 90 94 49.7 11th c ₂ h ₅ c ₂ h ₅ 62 ' 91 93 52.47 12th N 0 65 89 96 55.54 13th Ό 63 91 93 53.32 14th O 65 92 94 56.21

Claims (1)

DEFINITION OF INVENTION 5-Arginylaminonaphthalene-l-sulfamides of general formula I: ArgNH Wherein R j = H, R ₂ = CH ₃ , C ₂ H ₅ , n -, i C ₃ H ₇ , n -, i -, t C ₄ H _g , C5Ū11. CgHiy, ^ch 2- <O ^; or R ₁ = R ₂ = CH ₃ , C ₄ S, C ₃ H ₅ , n-, i C ₄ H ₉ ; or NRiR ₂ = A process for the preparation of Arg - the arginine residue comprising the interaction of N-substituted arginine with the corresponding aminonaphthalenesulfamide in an organic solvent in the presence of a condensing agent, to obtain the N-substituted 5-arginylaminonaphthalene-1-sulfamide, its deprotection and isolation. to increase product yield as N-sat arginine use N ^q N ^ nitro--tret.butiloksikarbonilargininą which interacts with the base 5 aminonaftalen-l-sulfamidu using a solvent of pyridine and dioxane and di-condensing agent to produce an N-tret.butilpirokarbonatą sat 5arginylaminonaphthalene-1-sulfamide of general formula II: MM O Wherein R 1 and R 2 are as defined above and deprotecting with hydrogen in methanolic hydrogen chloride as palladium on carbon catalyst.