RU2383550C1 - Intermediate products - methyl 7-aryl-4, 9-diaroyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1, 7-diazaspiro[4,4]none-3, 8-diene-8-carboxylates; methyl 6, 9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3, 4,10-trioxo-7-oxa-2, 9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylates; method of producing methyl 6, 9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3, 4, 10-trioxo-7-oxa-2, 9-diazatricyclo [6.2.1.01,5]undec-5-ene-8-carboxylates; methyl 11-benzoyl-2-o-hydroxyphehyl-3, 4, 10-trioxo-9-p-tolyl-6-phenyl-7-oxa-2, 9-diazatricyclo [6.2.1.01,5]undec-5-ene-8-carboxylate having antimicrobial activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel intermediate compounds - methyl 7-aryl-4,9-diaroyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]none-3,8-diene-8-carboxylates of formula III

Ar¹=Ar²=Ph, Ar³=C₆H₄Me-n (IIIa); and Ar¹=C₆H₄Br-n, Ar²=C₆H₄OEt-n, Ar³=C₆H₄Me-n (IIIb), for synthesis of methyl 6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.0^1,5]undec-6-ene-8-carboxylates of formula IV

where Ar¹=Ar²=Ph, Ar³=C₆H₄Me-n (IVa); Ar¹=C₆H₄Br-n Ar²=C₆H₄OEt-n, Ar³=C₆H₄Me-n (IVb), which exhibit antimicrobial activity and are used as precursors for synthesis of novel heterocyclic systems, and a method for synthesis of said compounds.

EFFECT: compounds have high effectiveness.

5 cl, 1 tbl, 5 ex

Description

"Intermediates - methyl 7-aryl-4,9-diaroyl-3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-1,7-diazaspiro [4.4] nona-3,8-diene-8 β-carboxylates; Methyl 6,9-diaryl-1 1-aroyl-2- (o-hydroxyphenyl) -3,4,10-trioxo-7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undec-5-ene -8-carboxylates; The method of obtaining methyl 6,9-diaryl-11-aroyl-2- (o-hydroxyphenyl) -3,4,10-trioxo-7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undec-5- en-8-carboxylates; Methyl 11-benzoyl-2-o-hydroxyphenyl-3,4,10-trioxo-9-p-tolyl-6-phenyl-7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undec-5- en-8-carboxylate with antimicrobial activity. "

Technical field

The invention relates to the field of organic chemistry, namely to the synthesis and isolation of intermediate products (individual compounds) of 1,7-diazaspiro [4.4] non-3,8-diene-8-carboxylates having antimicrobial activity, to the synthesis of individual compounds with functionalized bridging heterocyclic system of 7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undecane having antimicrobial activity, which can be used as starting materials for the synthesis of new heterocyclic systems.

State of the art

Structural analogues of the claimed compounds are known (5-methyl-2-oxo-1-phenyl-4-ethoxycarbonyl-2,3-dihydro-1H-pyrrole-3-spiro-2- (3-benzoyl-4-hydroxy-1-o -hydroxyphenyl-5-oxo-2,5-dihydropyrroles) obtained by the reaction of 3-aroyl-2,4-dihydro-1H-pyrrolo [2,1-c] [1,4] benzoxazine-1,2,4-trion with ethyl 3-arylamino-2-butenoates (ethyl esters of 3-arylamino-2-butenoic acids) (RF Patent for the invention No. 2294330, priority 11.10.05, application 2005131264, registered in the State Register of the Russian Federation on February 27, 2007).

The disadvantages of this method include the impossibility of obtaining methyl 7-aryl-4,9-diaroyl- (3-hydroxyphenyl) -2,6-dioxo-1,7-diazaspiro [4.4] nona-3,8-diene-8-carboxylates, which are an intermediate product for the synthesis of a more complex bridging heterocyclic system of 7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undecane with antimicrobial activity.

Structural analogs of the claimed compounds are known (7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undecane) obtained by the reaction of 3-aroyl-5-phenyl-1,2,4,5-tetrahydro-1H-pyrrolo [ 2,1-a] quinoxaline-1,2,4-triones with 3-amino and 3-benzylamino-5,5-dimethyl-2-cyclohexen-1-ones (RF Patent for the invention No. 2257386, priority 05.05.04 , application 2004113761, registered in the State Register of the Russian Federation on July 27, 2005). The synthesis of structural analogues is carried out according to the following scheme:

The disadvantages of this method include the impossibility of producing methyl 6,9-diaryl-11-aroyl-2- (o-hydroxyphenyl) -3,4,10-trioxo-7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undec-5-en-8-carboxylic acid. Structural analogues have weak antimicrobial activity. Compound (IIIa) has a minimum inhibitory concentration against E. coli E. coli M ₁₇ stamp 1000 μg / ml and Staphylococcus aureus P-209 1000 μg / ml.

Disclosure of invention

The objective of the invention is to develop a simple method for the synthesis of intermediate products of methyl 7-aryl-4,9-diaroyl-3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-1,7-diazaspiro [4.4] non-3, 8-diene-8-carboxylates and the development of a synthesis method from these intermediates — methyl 6,9-diaryl-11-aroyl-2- (o-hydroxyphenyl) -3,4,10-trioxo-7-oxa-2,9 -diazatritsiklo [6.2.1.0 ^1,5] undec-5-ene-8-carboxylates exhibiting antimicrobial activity, which can be used as precursors for the synthesis of new heterocyclic systems find application in prakt Český health.

The task is carried out by boiling 3-aroyl-2,4-dihydro-1H-pyrrolo [2,1-s] [1,4] benzoxazine-1,2,4-triones with methyl 4-aryl-2-arylamino-4 -oxo-2-butenoates, taken in the ratio 1: 1, in an inert aprotic solvent to obtain intermediate products - substituted methyl

7-aryl-4,9-diaroyl-3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-1,7-diazaspiro [4.4] nona-3,8-diene-8-carboxylates, cyclized at recrystallization from ethyl acetate to methyl 6,9-diaryl-11-aroyl-2- (o-hydroxyphenyl) -3,4,10-trioxo-7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undec 5-en-8-carboxylates according to the scheme:

I, Ar ¹ = Ph (a), C ₆ H ₄ Br-p (b); II, Ar ² = Ph, Ar ³ = C ₆ H ₄ Me-p (a), Ar ² = C ₆ H ₄ OEt-p, Ar ³ = C ₆ H ₄ Me-p (b); III, IV, Ar ¹ = Ar ² = Ph, Ar ³ = C ₆ H ₄ Me-p (a), Ar ¹ = C ₆ H ₄ Br-p, Ar ² = C ₆ H ₄ OEt-p, Ar ³ = C ₆ H ₄ Me-p (b).

The process is carried out at a temperature of 79-80 ° C, and absolute benzene is used as a solvent. Ethyl acetate was used as a solvent for recrystallization.

From the patent and technical literature, methods have been identified for the preparation of methyl 7-aryl-4,9-diaroyl-3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-1,7-diazaspiro [4.4] non- 3,8-diene-8-carboxylates of the compounds, but using these methods, products are obtained that cannot be used for the synthesis of bridged heterocyclic systems.

From the patent and technical literature, no methods for the synthesis of methyl 6,9-diaryl-11-aroyl-2- (o-hydroxyphenyl) -3,4,10-trioxo-7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undec-5-ene-8-carboxylates having similar characteristics with the claimed method, namely, the starting products, solvents in which the reaction takes place, and the temperature range were not used, on the basis of which we can conclude that the claimed technical solution the criterion of "novelty" and "inventive step".

The invention is illustrated by the following examples.

Example 1 (intermediate). Methyl 4,9-dibenzoyl-3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-7-p-methoxyphenyl-1,7-diazaspiro [4.4] nona-3,8-diene-8-carboxylate (IIIa).

A solution of 1.0 mmol of 3-benzoyl-2,4-dihydro-1H-pyrrolo [2,1-s] [1,4] benzoxazine-1,2,4-trion (Ia) and 1.0 mmol of methyl (2E) -4- oxo-4-phenyl-2- (4-toluidine) -2-butenoate (IIa) in 10 ml of absolute benzene was boiled for 20 minutes (until bleaching), cooled, the precipitate was filtered off, washed 2 times with 1 ml of ethyl acetate and 5 ml of hexane . Yield 85%, mp. 184-185 ° C.

Compound (III a) C ₃₆ H ₂₆ N ₂ O ₈ .

Found%: C 70.32; H 4.16; N, 4.58.

Calculated%: C 70.35; H 4.26; N, 4.56.

Example 2 (intermediate). Methyl 4-p-bromobenzoyl-3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-7-p-methoxyphenyl-9-n-ethoxybenzoyl-1,7-diazaspiro [4.4] nona-3.8 diene-8-carboxylate (IIIb).

A solution of 1.0 mmol of 3-p-bromophenyl-2,4-dihydro-1H-pyrrolo [2,1-c] [1,4] benzoxazine-1,2,4-trion (1b) and 1.0 mmol of methyl (2E) - 4-oxo-2- (4-toluidine) - (4-ethoxyphenyl) -2-butenoate (IIb) in 10 ml of absolute benzene was boiled for 25 minutes (until discoloration), cooled, the precipitate was filtered off, washed 2 times with 1 ml of ethyl acetate and 5 ml of hexane. Yield 86%, mp. 209-210 ° C.

Compound (IIIb) C ₃₈ H ₂₉ BrN ₂ O ₉ .

Found,%: C 61.76; H 3.92; Br 10.84; N, 3.76.

Calculated,%: C 61.88; H 3.96; Br 10.83; N, 3.80.

Compounds (III a, b) - light yellow crystalline substances with high melting points, melting with decomposition, readily soluble in DMF and DMSO, insoluble in ordinary organic solvents, insoluble in alkanes and water, giving a positive test (cherry color) for the presence of enol and phenolic hydroxyls with an alcoholic solution of iron (III) chloride.

The IR spectra of compounds (III a, b) contain stretching vibrations of OH groups in the form of a broad peak in the region of 3150-3170 cm ^-1 , COOMe groups in the region of 1760-1770 cm ^-1 , and two lactam carbonyl groups in the form of two peaks in the region of 1723-1736 cm ^-1 , acetyl and aroyl carbonyl groups in the form of two peaks in the region of 1620-1675 cm ^-1 .

In the ¹ H NMR spectra of solutions of the spiro compounds (III a, b) in DMSO-d _6, in addition to signals of protons of aromatic rings and related groups, there is a singlet of protons of the methoxy group in the region of 3.23-3.30 ppm, a singlet of the proton of the phenolic OH group in the region of 9.83 -9.84 ppm, broadened singlet of a proton of the enol group of OH in the region of 12.50-12.60 ppm

The proposed method is quite simple to implement, one-stage and allows to obtain methyl 7-aryl-4,9-diaroyl-3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-1,7-diazaspiro not described in the literature [4.4 ] nona-3,8-diene-8-carboxylates, with practically quantitative yield, which can be used as starting materials for the synthesis of new heterocyclic systems.

Example 3. Methyl 11-benzoyl-2-o-hydroxyphenyl-3,4,10-trioxo-9-p-tolyl-6-phenyl-7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undec -5-en-8-carboxylate (IVa). A solution of 1.0 mmol methyl 4,9-dibenzoyl-3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-7-p-methoxyphenyl-1,7-diazaspiro [4.4] nona-3,8-diene- 8-carboxylate was recrystallized from 10 ml of ethyl acetate, cooled, the precipitate was filtered. Yield 90%, mp. 190-191 ° C (from ethyl acetate).

Compound (IVa) C ₃₆ H ₂₆ N ₂ O ₈ .

Found,%: C 70.28; H 4.21; N, 4.49.

Calculated,%: C 70.35; H 4.26; N, 4.56.

Example 4. Methyl 6-p-bromophenyl-2-o-hydroxyphenyl-3,4,10-trioxo-9-p-tolyl-11-p-ethoxybenzoyl-7-oxa-2,9-diazatricyclo [6.2.1.0 ^{1 , 5} ] undec-5-en-8-carboxylate (IV6).

A solution of 1.0 mmol methyl 4-p-bromobenzoyl-3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-7-p-methoxyphenyl-9-p-ethoxybenzoyl-1,7-diazaspiro [4.4] non- 3,8-diene-8-carboxylate was recrystallized from 10 ml of ethyl acetate, cooled, the precipitate was filtered off. Yield 93%, mp. 210-211 ° C (from ethyl acetate).

Compound (IV6) C ₃₈ H ₂₉ BrN ₂ O ₉ .

Found,%: C 61.85; H 3.94; Br 10.79; N, 3.82.

Calculated,%: C 61.88; H 3.96; Br 10.83; N, 3.80.

Compounds (IV a, b) are colorless crystalline substances with high decomposition temperatures, readily soluble in DMF and DMSO, insoluble in ordinary organic solvents, insoluble in alkanes and water, giving a positive test (cherry color) for the presence of phenolic hydroxyl with an alcoholic solution of iron chloride (III).

In the IR spectra of compounds (IV a, b), there are stretching vibrations of the OH group in the form of a wide peak in the region of 3220-3230 cm ^-1 , the COOMe group in the region of 1767-1770 cm ^-1 , two lactam and ketone carbonyl groups in position 4 in the form of one or two peaks in the region of 1721-1755 cm ^-1 , an aroyl carbonyl group in the region of 1700-1707 cm ^-1 .

In the NMR spectra of ¹ N solutions of compounds (IV a, b) in DMSO-d ₆ , in addition to signals of protons of aromatic rings and related groups, there is a singlet of protons of the OMe group in the region 3.23-3.34 ppm, a singlet of methine proton C ¹¹ H in the region of 5.15-5.25 ppm, the singlet of the proton of the phenolic OH group in the region of 9.91-10.01 ppm.

The ¹³ C NMR spectrum of the solution of the compound (IVb) in DMSO-d ₆ present the following signals carbon atoms (δS, ppm): 189.11 (CO C ₆ H ₄ OEt), 176.95 ⁽⁴ C = O), 167.87, 163.07 (С ¹⁰ = О, С ³ = О), 159.80 ( С ООСН ₃ ), 154.07 (С ⁵ ), 137.68-106.49 g.s. (С ^Ar ), 92.44 (С ⁸ ), 65.29 (С Spiro), 63.72 (C ¹¹ ), 53.76 (OCH ₂ ), 44.52 (OCH ₃ ), 20.49 (CH ₃ ), 14.40 (CH ₂ CH ₃ ).

Example 5

The study of the antimicrobial action of the claimed compounds was carried out on gram-positive microorganisms Staphylococcus aureus (strain 906) and E. coli (strain 1275), by the method of double serial dilutions in accordance with the methodology for studying the antimicrobial action of drugs [G.N. Pershin. Methods of experimental chemotherapy. - M., 1971 p. 100, 109-117].

For the cultivation of bacteria used meat peptone agar and broth (pH 7.2-7.4). Initial dilutions of microbial bodies were prepared according to the optical turbidity standard from daily agar culture. To determine the antimicrobial effect, the microbial load corresponded to 2.5 · 10 ⁵ microbial bodies in 1 ml of medium. Microbial suspension was added to the prepared diluted preparations in a nutrient medium. The results of the experiments were taken into account after a 20-hour (inhibitory effect) and 7-day (bactericidal action) thermostating at 37 ° C. Antimicrobial (bacteriostatic - MIC and bactericidal - MBK) activity was evaluated by the minimum effective concentration. The maximum tested concentration of the compounds was 1000.0 μg / ml. The reference standard was phenyl salicylate, known in medical practice (MD Mashkovsky “Medicines”. - M.: Medicine, 1993, v. 2 p. 472).

Studies have shown (see Table 1) that the claimed compound (IVa) exhibits antimicrobial properties against gram-positive and gram-negative bacteria, i.e. the inhibitory effect in relation to the culture of Staphylococcus aureus at a concentration of 125.0 μg / ml, which exceeds the average concentration of the standard phenyl salicylate by 6 times and in relation to Escherichia coli - 1000.0 μg / ml.

The bactericidal effect of compound (IVa) was observed in relation to Staphylococcus aureus at a concentration of 250.0 μg / ml, which exceeds the average concentration of the standard phenyl salicylate by 8 times.

Due to the fact that the proposed compound has a pronounced antimicrobial effect on gram-positive and gram-negative microflora and its activity against Staphylococcus aureus is 8 times higher than that of a structural analogue, it can find application in practical medicine.

Table 1 The study of the antimicrobial action of compounds Connection number E. coli Staphylococcus aureus MIC, μg / ml MBK, mcg / ml MIC, μg / ml MBK, mcg / ml Iva 1000,0 - 125.0 250,0 Reference standard - phenyl salicylate - - 750.0 2000.0

Claims (5)

1. Intermediates - methyl 7-aryl-4,9-diaroyl-3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-1,7-diazaspiro [4.4] nona-3,8-diene- 8-carboxylates of the general formula III:

where Ar ¹ and Ar ² means Ph, Ar ³ means C ₆ H ₄ Me-p (IIIa); Ar ¹ means C ₆ H ₄ Br-p, Ar ² means C ₆ H ₄ OEt-p, Ar ³ means C ₆ H ₄ Me-p (IIIb). 2. Methyl 6,9-diaryl-11-aroyl-2- (o-hydroxyphenyl) -3,4,10-trioxo-7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undec-5- en-8-carboxylates of the general formula IV:

where Ar ¹ and Ar ² means Ph, Ar ³ means C ₆ H ₄ Me-p (IVa); Ar ¹ means C ₆ H ₄ Br-p, Ar ² means C ₆ H ₄ OEt-p, Ar ³ means C ₆ H ₄ Me-p (IVb). 3. The method of obtaining methyl 6,9-diaryl-11-aroyl-2- (o-hydroxyphenyl) -3,4,10-trioxo-7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undec- 5-en-8-carboxylates IV a, b:

where Ar ¹ and Ar ² means Ph, Ar ³ means C ₆ H ₄ Me-p (IVa); Ar means C ₆ H ₄ Br-p, Ar ² means C ₆ H ₄ OEt-p, Ar ³ means C ₆ H ₄ Me-p (IVb), characterized in that methyl 7-aryl-4,9-diaroyl- 3-hydroxy-1- (2-hydroxyphenyl) -2,6-dioxo-1,7-diazaspiro [4.4] nona-3,8-diene-8 carboxylates of formula III a, b:

where Ar ¹ and Ar ² means Ph, Ar ³ means C ₆ H ₄ Me-p (IIIa); Ar ¹ means C ₆ H ₄ Br-p, Ar ² means C ₆ H ₄ OEt-p, Ar ³ means C ₆ H ₄ Me-p (IIIb), recrystallized from ethyl acetate, followed by isolation of the desired products. 4. The method according to claim 3, characterized in that ethyl acetate is used as a solvent. 5. Methyl 11-benzoyl-2-o-hydroxyphenyl-3,4,10-trioxo-9-n-tolyl-6-phenyl-7-oxa-2,9-diazatricyclo [6.2.1.0 ^1,5 ] undec 5-en-8-carboxylate with antimicrobial activity.