Method of producing 2,4,6,8-tetraazbicyclo[3,3,0]octane-3,7-dione

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (glycoluril). The reaction takes place at 80°C for 60 minutes, where concentrated sulphuric acid is used in an aqueous medium and reagents are taken in the following molar ratios: glyoxal 2.0; urea 4.0; sulphuric acid 0.4; water 12, and the freshly prepared glyoxal solution is added while stirring for 20 minutes, after which the mixture is stirred for 40 more minutes.

EFFECT: novel method of producing glycoluril, which increases output of the end product and is simpler.

1 cl, 1 tbl, 1 dwg

 

The invention relates to a method for 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (glycoluril), which is a precursor for the production of explosives, bleaching activators of funds, and is also used as fertilizer of prolonged action.

A method of obtaining 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (glycoluril) condensation of urea and glyoxal in sulfuric acid medium at boiling [1]. When the reactants are taken in the following molar ratios: glyoxal:urea:sulfuric acid:water- 2(4,4-5,0)(0,4-0,5)(26-30).

The disadvantages of this method include: carrying out the reaction at a very high temperature, which leads to the formation of byproducts, partial polymerization of glyoxal (a speed which increases with increasing temperature), which reduces the output of glycoluril during the process of condensation of glyoxal with urea.

Closest to the present invention is a method of obtaining glycoluril by condensation of an aqueous solution of glyoxal (30% wt.) with urea at 85-90°C for 20-30 minutes [2]. The condensation is carried out in acidic medium, maintaining the pH level of 1.5-2.0, and to maintain the pH using hydrochloric acid. The yield of the target product - 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (glycoluril) after recrystallization and drying is 52-55%.

To weeks is the action of this method are the low yield of the target product 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (glycoluril), as well as the use as a catalyst bat hydrochloric acid, which requires constant monitoring of pH of the reaction mixture and the periodic addition of catalyst as it evaporates at the reaction temperature (85-90°C).

New technical problem - simplification of the method and increase the yield of the target product.

To solve the problem in the method of obtaining 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione, comprising the condensation of urea with glyoxal when heated in the presence of a mineral acid in aqueous medium, the reaction is carried out at 80°C. for 60 minutes, and as a mineral acid using concentrated sulfuric acid, the reactants are taken in the following molar proportions:

Glyoxal2,0
Urea4,0
Sulfuric acid0,4
Water12

and freshly prepared aqueous solution of glyoxal was added dropwise under stirring for 20 minutes, after which the mixture is stirred for 40 minutes.

One of the distinguishing features of the proposed method is used in isawanya as the mineral acid is concentrated sulfuric acid. Sulfuric acid is less volatile, which contributes to more stable to maintain the pH of the reaction medium without the use of additional reagents, as well as to maintain the desired temperature.

During the process it is necessary to strictly adhere to the proposed limits of the molar ratios of Regents. The proposed ratio selected on the basis of experimental studies, the results of which are shown in Table 1, which shows that the optimal molar ratio of the reagents are as follows: glyoxal - 2,0; water - 12,0; urea - 4,0; sulfuric acid is 0.4. The optimum temperature synthesis - 80°C.

Using the molar amount of sulfuric acid in the amount of more than 0.4 mol to 2 mol of glyoxal is impractical due to cost increase, and adding in the amount of less than 0.4 mol ineffective due to the decrease of the yield of the target product - 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione(glycoluril).

The use of water in the amount of 12 mol to 2 mol of glyoxal can increase the reaction rate by increasing the concentration of the reactants and does not lead to a significant increase in the viscosity of the reaction medium and, as a consequence, the decrease of the yield of the target product. The use of large quantities of water (more than 12 mol) helps reduce the concentration of the purpose of the reactants and increase the time of synthesis of the target product.

Synthesis at 80°C is due to the fact that higher synthesis temperature (90°C and above) lead to boiling of the reaction mixture and its release from the reactor vessel, and smaller - at 70°C to yield the target product.

In addition, to increase the output 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (glycoluril) you want to apply a freshly prepared solution of glyoxal, because during long-term storage polymerized glyoxal, which ultimately contributes to lowering the yield of the target product - 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (glycoluril). The solution of glyoxal was added dropwise under stirring for 20 minutes, after which the mixture is stirred for further 40 minutes. Glyoxal was added dropwise as the reaction is exothermic and sharp adding glyoxal is violent boiling of the reaction mixture and the discharge from the reaction vessel. Mixing within 20-40 minutes is required for complete reaction.

Optimal synthesis time is 60 minutes, of which 20 minutes is spent on the addition of glyoxal with stirring and then 40 minutes of further stirring the reaction mixture. A further increase in synthesis time does not enhance the yield of the target product.

Thus, the use of the proposed conditions for the synthesis of 2,4,6,8-tetraaza is yclo[3.3.0]octane-3,7-dione (glycoluril) allows to increase the yield of the target product to 91-94%. In addition, no additional purification of the target product.

Further the method is illustrated with an example.

EXAMPLE. Getting 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (glycoluril).

In the reactor sequentially load 201,28 g of water; 217,24 g urea; 43,10 g of the technical solution of sulfuric acid (ρ=1.84 g/cm3), the mixture is stirred. Heating of the mixture is 55-60°C, then heated forced and added dropwise 260,27 g of an aqueous solution of glyoxal (ρ=the 1.265 g/cm3, ω=36 wt.%). Prolonged heating of the reaction mixture is not required, because the reaction of glyoxal to urea is an exothermic process. Glyoxal was added dropwise within 20 minutes and after stirred for another 20-40 minutes. The reaction mixture is cooled to room temperature, the precipitate is filtered off, washed with water and dried. Get 214,98 g of white crystalline powder that is 93.7% of theoretical.

The IR spectrum of glycoluril in the Annex to the drawing, 1 is the reference sample, 2 - sample of the product obtained by the proposed method.

The IR spectrum of glycoluril

1685 cm-1-ν(C=O)

3209 cm-1-ν(N-H)

Thus, the application of the proposed method can improve the yield of the target product when you simplify the method.

Sources of information

1. Patent RU 2063970 C1. publ. 20.07.1996.

2. Slezak F.., Hirsch A., Rosen I.J. Org. Chem. - 1960. -V.25. - P.660-661 (prototype).

Table 1
№ p/pThe ratio of reactants, the moleTemperature, °COutput %
WaterUreaH2SO4
1to 12.04,00,49093,6
2to 12.04,00,48093,7
3to 12.04,00,47081,2
4to 12.04,00,59092,9
5to 12.04,00,690 of 92.7
6to 12.04,50,490br93.1
7to 12.04,50,48088,4
8to 12.04,50,590to 92.1
9to 12.04,50,58089,2
10to 12.05,00,490of 92.7
11to 12.05,00,48089,0
12to 12.05,00,59092,5
13 to 12.05,00,58082,7
1430,04,00,49089,0

The method of obtaining 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione by condensation of urea with glyoxal when heated in the presence of concentrated sulfuric acid in an aqueous medium, characterized in that the reaction is carried out at 80°C for 60 min, and reagents take in the following molar ratios:

Glyoxal2,0
Urea4,0
Sulfuric acid0,4
Water12,

and freshly prepared aqueous solution of glyoxal was added dropwise under stirring for 20 min, after which the mixture is stirred for further 40 minutes



 

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33 cl, 448 ex, 1 tbl

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(IVa)

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20 cl, 6 tbl, 192 ex

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14 cl, 1 tbl, 119 ex

FIELD: organic chemistry.

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EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

FIELD: organic chemistry, pharmaceutical compositions.

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20 cl, 12 tbl, 8 ex

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EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

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