Nitrate-n alkanolamines or imides, the retrieval method, n-alkanolamine or imides

 

(57) Abstract:

The invention relates to physiologically active compounds and relates to derivatives of succinic acid, specifically nitrate N-alkanolamines or imides, method of production thereof, and also N-alkanolamines or imides. The purpose of the invention is the synthesis of previously unknown nitrates N-alkanolamines or imides way of obtaining them, as well as the synthesis of N-alkanolamines or imides. The essence of the invention lies in the fact that the proposed compounds of General formula (I) listed in the description. Method for obtaining these compounds, namely, that N-alkanolamine or imides process nitrous agent at -5 - 45oC, followed by dilution of the reaction mixture with water and isolation of the target product. In addition, the proposed intermediate products of General formula (II) listed in the description. The invention can be used in medical practice. 3 S. and 6 C.p. f-crystals, 2 tab.

The invention relates to a derivative of succinic acid and concerns of nitrate-N alkanolamines or imides of General formula (I)

< / BR>
< / BR>
R=O2NOCH2CH2NHC(O)CH(OH)CH2C(O)NH-, n=2

R=O2NOCH2CH2NHC(O)CH(ONO2CH2NHC(O)CH2CH2C(O)NH-, n=3

R=H2NC(O)CH2CH2C(O)NH-, n=2

< / BR>
< / BR>
< / BR>
which can be used in medical practice, for example, as kardiologicheskii active compounds with koronrodilatatia effect, method of production thereof, and also N-alkanolamines or imides intermediate products for the synthesis of compounds of formula (I).

Nitrate-N alkanolamines or imides are not described in literature.

It is known that succinic acid is widely used in practice in therapeutic and prophylactic purposes [1-4] Particularly well proven succinic acid as a therapeutic agent in the case of disorders of the heart muscle [1]

Also known structural analogue of sodium salt of succinate chloramphenicol

< / BR>
which is widely used in the treatment of typhoid fever, dysentery, brucellosis [5]

Finally, the known structural analogue related to replaced succinimido - -ethyl- -- -methylsuccinimide:

< / BR>
which is used for the treatment of epilepsy [6]

Despite the fact that these structural analogues are used in medical practice, none of them has cardiac activity.

Another aim of the invention is to develop a method of obtaining nitrates N-alkanolamines or imides of formula (I).

This goal is achieved according to the method lies in the fact that N-alkanolamine or imides process nitrious agent at -5 - 45oC, followed by dilution of the reaction mixture with water and isolation of the target product.

The necessary and sufficient conditions for this reaction are:

1. Use as nitrouse agent is nitric acid, the concentration of 75-98% taken in the amount of about 2-6.h. 1 wt. including amide or imide. The use of less concentrated (75%) or more kontsentrirovaniya, and secondly, it entails the introduction of additional operations, for example, to produce nitric acid of a concentration above 98% of the required vacuum distillation.

2. Use as nitrouse agent mixture of nitric and sulfuric acids at their volumetric ratio of 1:(2 6) 1 wt.h. amide or imide. The process with a ratio less than 1:2, impedes mixing of the reaction mass and affects the heat sink. Using the volume ratio between nitric and sulphuric acids greater than 1:6, significantly increases the flow rate conc. sulfuric acid and, ultimately, costly process.

3. Use as nitrouse agent mixture of nitric acid and acetic anhydride at a molar ratio equal to 1:(1 to 3). The change of this ratio as downward and upward does not improve the yield of the target product.

4. Use as nitrouse agent 8-13% solutions of nitric acid in chloralkali, for example in methylene chloride, dichloroethane, chloroform. Carrying out the process in more concentrated solutions makes him dangerous from the point of view of ability to detonate. The use of mixtures of nitric acid product.

After diluting the reaction mass with water, the target product emit either by filtration or after dilution of the reaction mixture with water to carry out the neutralization and target product produce by extraction with an organic solvent, such as ethyl acetate.

The invention also concerns new N-alkanolamines or imides of formula (II)

< / BR>
< / BR>
R=HOCH2CH2NHC(O)CH(OH)CH2C(O)NH-, n=2 (13)

R=HOCH2CH2NHC(O)CH2CH2C(O)NH-, n=2 (14)

R=HOCH2CH2CH2NHC(O)CH2CH2C(O)NH-, n=3 (15)

R=H2NC(O)CH2CH2C(O)NH-, n=2 (16)

< / BR>
which are intermediate compounds for the synthesis on their basis of nitrates of the formula (I), as well as other compounds, for example galoidoproizvodnykh, esters of carboxylic acids, esters of substituted carboxylic acids and inorganic acids.

The new compounds of formula (II) is produced by heating succinic acid and its dialkylamino esters with ethanol or propanolamine in alcohol followed by cooling the reaction mixture to room temperature and isolation of the target product.

N, N'-bis-(2-oxyethyl)succinimide (14). A mixture of 17 g of diethyl ester of succinic acid, 20 ml asados, washed with alcohol, dried in the air. Received 15,91 g (79,9%) N,N'-bis-(2-oxyethyl)succinimide with so pl. 156-157oC (methanol). Found, C 47,00; H A 7.62; N 13,62. C8H16N2O4. Calculated C 47,06; H To 7.84; N 13,73.

The synthesis of compounds (11-13, 15-17) were performed similarly. In table. 1 shows the melting temperature, the output, and the data of IR spectroscopy of the synthesized N-alkanolamines and N-(3-oksipropil)succinimide.

N, N'-bis-(2-nitroxyethyl)succinimide (5). To a mixture of 28 ml of H2SO4and 14 ml of HNO3(d 1,51) at 0-5oC was added 7 g of N,N'-bis-(2-oxyethyl)succinimide. Then the reaction mixture was stood still 6 hours at 0-5oC and poured into 250 g of finely crushed ice and then neutralized with KOH and extracted with ethyl acetate (525 ml). The extracts were combined and dried over MgSO4; after the distillation of the ethyl acetate under reduced pressure obtained 6,82 g (68,1%) N,N'-bis-(2-nitroxyethyl)succinimide with so pl. 100-101,5oC (from chloroform). Found, C 32.50 To; H 4,82; N 19,16. C8H14N4O8. Calculated C 32,65; H Amounts To 4.76; N 19,04.

N, N'-bis-(3-nitrosopropane)succinimide (6). To 15 ml of HNO3(d 1,51) was added at -5oC 2,87 g N,N'-bis-(3-oksipropil)succinimide, the reaction mixture was stirred a further 1 hour at-5-0ooC. Found; C 37,07; H 5,67; N 17,14. C10H18N4O8. Calculated C 37,27; H 5,59; N 17,38.

N, N'-bis-(2-nitroxyethyl)oxysuccinimide (3). To 21 ml of 75% HNO318-20oC was added to 4.2 g of N,N'-bis-(2-oxyethyl)oxysuccinimide, the reaction mixture was stirred for another 1.5-2 hours at this temperature and was poured into ice water, then neutralized with caustic soda and extracted with ethyl acetate (515 ml). The extracts were combined and dried over MgSO4. After the usual processing of 3.3 g (55.9 percent) of N,N'-bis-(2-nitroxyethyl)oxysuccinimide with so pl. 90-91oC (from dichloromethane). Found, C 30,84; H Br4.61; N Is 18.11. C8H14N4O9. Calculated C 30,96; H To 4.52; N 18,06.

N-(Nitroxymethyl)succinimide (8). To a mixture of 1.1 ml of acetic anhydride and 0.5 ml of HNO3when 10-15oC was added 1 g of N-(oxymethyl)succinimide [7] the reaction mixture was stirred for another 1-1 .5 hours at this temperature and was poured into ice-cold water. Was filtered crystalline precipitate of N-(nitroxymethyl)succinimide, washed with water, dried in the air. Received of 0.91 g (66,8%) of compound (8) with so pl. 111,5-113oC. Found; C 34,44; H 3,42; N 16,12. C5H6N2SO4when-5-2oC was added 1 g of N-(3-oksipropil)succinimide, the reaction mixture was stirred for another 5 hours at this temperature and was neutralized with potash, and then was extracted with ethyl acetate (315 ml). The combined extracts were dried over MgSO4. After the usual processing of 0.91 g (65,5%) of N-(3-nitrosopropane)succinimide with so pl. 35-36oC. Found; C 41,38; H 4,82; N 13,91. C7H10N2O5. Calculated C 41,58; H Of 4.95; N 13,86.

N-(Nitroxymethyl)succinimide (8). To a solution of 13.4 ml of dichloroethane and 2 ml of HNO3(13% solution) at 43-45oC was added 1 g of N-(oxymethyl)succinimide, the reaction mixture was stirred for another 30 min and poured into ice-cold water. Separated the organic layer, washed with 2% solution of NaHCO3, dried MgSO4. After removal of the dichloromethane under vacuum obtained 0.9 g (66,7%) of N-(nitroxymethyl)succinimide with so pl. 112-113oC.

Other nitrates were obtained similarly. In table. 2 shows so pl. as well as IR and Yarm-spectra of compounds 1-10.

Thus, the use of the proposed method to achieve the purpose of the invention and to obtain previously unknown nitrates N-alkanolamines or imides.

Compounds 1-10 were tested in experiments on animals on b is that a 15% alcohol solution gray mice weighing 20 g The test results showed that the proposed objects are LD-50 (the dose that causes the death of 50% of the animals) at the level of 430-1150 mg/kg

Compounds 1-10 were studied on cardiac activity in the Soviet Union biological research centre for security biologically hazardous substances by introducing a dose of 10 mg/kg for white rats weighing 240 g was shown their cardiac activity, and three compounds (3, 8, and 9) the size of the necrosis zone (in the zone of ischemia) have values 38,24,1; 42,25,4; 45,75,3 respectively; i.e., the inventive preparations are almost the same cardiac activity as N-(2-nitroxyethyl)nicotinamide, which is a highly efficient medicine (commercial name nicorandil, sigmart) for the treatment of angina and heart failure [8, 9] which is considered as equivalent for the purpose.

Sources of information

1. B. I. Srebrodolsky. The amber. M. Nauka, 1984.

2. Concise encyclopedia of chemical. In Soviet encyclopedia, M. 1965, T. 5, 335.

3. Medicinal product. Directory of medicines chemical-pharmaceutical plant Akrikhin, Staraya Kupavna, 1990, 16.

4. USSR author's certificate N 706641 is. Medicinal product. M. Medicine, 1994, T. 1, 43.

7. Cherluliez, Sulzer, Helv. chim. Acta, 8, 568.

8. Proc. Seminar "New in Treatment of Hert Failure and Angina Pectoris", 27 October, 1987, San Fransisco, USA, Amer. J. Cardiology, 1989, No. 63, 1-85.

9. C. S. Lieberman, L. N. Yakhontov. Chem.-Pharm. journal, 1988, 1046.

1. Nitrate-N alkanolamines or imides of General formula I

R(CH2)nONO2,

where

< / BR>
R O2NOCH2CH2NHC(O)CH(OH)CH2C(O)NH-, n is 2;

R O2NOCH2CH2NHC(O)CH(ONO2)CH2C(O)NH-, n is 2;

R O2NOCH2CH2NHC(O)CH2CH2C(O)NH-, n is 2;

R O2NOCH2CH2CH2NHC(O)CH2CH2C(O)NH-, n is 3;

R H2NC(O)CH2CH2C(O)NH-, n is 2;

< / BR>
< / BR>
< / BR>
2. The method of obtaining N-alkanolamines or imides of General formula I

R(CH2)nONO2,

where

< / BR>
R O2NOCH2CH2NHC(O)CH(OH) CH2C(O)NH-, n is 2;

R O2NOCH2CH2NHC(O)CH(ONO2)CH2C(O)NH-, n is 2;

R O2NOCH2CH2NHC(O)CH2CH2C(O)NH-, n is 2;

R O2NOCH2CH2CH2NHC(O)CH2CH2C(O)NH-, n is 3;

R H2NC(O)CH2CH2C(O)NH-, n is 2;

< / BR>
< / BR>
< / BR>
characterized in that the N-alkanolamine or imides process of nirukta.

3. The method according to p. 2, characterized in that as nitrouse agent take 75 to 98% nitric acid at 2 to 6 rpm.h.1 wt.h. amide or imide.

4. The method according to p. 2, characterized in that as nitrouse agent take a mixture of nitric and sulphuric acids at their volumetric ratio of 1 (2 6) 1 wt.h. amide or imide.

5. The way of getting p. 2, characterized in that as nitrouse agent take a mixture of nitric acid and acetic anhydride when a molar ratio of 1 (1 3).

6. The way of getting p. 2, characterized in that as nitrouse agent take 8 13% solution of nitric acid in methylene chloride or dichloroethane, or chloroform.

7. The method according to p. 2, characterized in that after dilution of the reaction mixture with water target product are filtering.

8. The method according to p. 2, characterized in that after dilution of the reaction mixture with water to carry out the neutralization and target product produce by extraction with an organic solvent, such as ethyl acetate.

9. N-alkanolamine or imides of the General formula II

R(CH2)nOH,

where

< / BR>
R HOCH2CH2NHC(O)CH(OH)CH2C(O)NH-, n is 2;

R HOCH2CH2NHC(O)CHCH2C(O)NH-, n is 2;

and

 

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FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 3,4-diaryl(hetaryl)maleimides of the formula (I): wherein R means (C1-C4)-alkyl or benzyl, or phenyl; R1 means bromine atom (Br) or aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group; Ar means aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group with exception for 3,4-di-(2,5-dimethyl-3-thienyl)-1-butylmaleimide. Method involves interaction of aryl(hetaryl)boronic acid of the formula: ArB(OH)2 wherein Ar has abovementioned values with N-substituted 3,4-dibromomaleimide of the formula (III): or N-substituted 3-bromo-4-aryl(hetaryl)maleimide of the formula (IV) wherein R and Ar have abovementioned values and with using palladium catalyst in the presence of base in organic solvent medium. Also, invention to some new derivatives of 3,4-diaryl(hetaryl)maleimides that show photochrome properties.

EFFECT: improved preparing method.

7 cl, 2 dwg, 14 ex

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