The method of obtaining fluorinated nitrogen-containing heterocyclic compounds

 

(57) Abstract:

Method for obtaining nitrogen-containing heterocyclic compounds having at least one fluorine-substituent in the heterocyclic ring, which includes the stage of interaction of nitrogen-containing heterocyclic compounds with gaseous elemental fluorine in the presence of at least one of chlorine, bromine, iodine or interhalogens connection. The reaction can be carried out in the presence of a base. As the source can be used heterocyclic compound includes preferably five - or six-membered heterocyclic ring, which may contain optional substituents, such as, for example, pyridine, pyrimidine, pyridazine, pyrazin, triazine, quinoline, isoquinoline, cinoxacin, hinzelin and biperiden. The technical result - direct selective fluorination of heterocyclic rings. 8 C. p. F.-ly, 2 Il.

The present invention relates to the production of halogenated compounds, in particular halogenated heterocyclic compounds. More specifically, the invention relates to the fluorination of heterocyclic compounds.

Obtaining halogenated heterocycles on the e substrates, for example, in the pharmaceutical industry, in the industry of plant protection products and dyes.

There are few ways of introduction of a fluorine atom in position 2 and/or 6 of the pyridine. Traditionally, methods of obtaining 2-herperidin was based on a multistage decomposition type Balza-Shiman (Balz-Schieman) tetrafluoroborate salts pyridinethione. The methods of exchange of halogen, including the interaction of the source of fluoride ion, such as SbF5, KF, HF, etc. with chlorinated pyridine at elevated temperatures, often used to obtain herperidin. Electrochemical fluorination of pyridine in the presence of a source of fluoride ion gives 2-herperidin only with the release of 22%. Differed xenon in the reaction with pyridine gives a mixture of herperidin and peroxosulfates cesium reacts with pyridine in ether at room temperature, giving 2-herperidin with the release of 61%.

Obtaining related fluorine-containing heterocycles, such as 2-ftorhinolon, can be carried out by similar methods, i.e. methods of sharing halogen, forcedisable etc.

The method of direct fluorination of organic compounds disclosed in U.S. patent N 2013030. However, the method is aimed mainly at nheterocyclic products is usually low, and the resulting materials have a low degree of purity. Methods of obtaining 2-herperidin direct reaction with elemental fluorine has been disclosed in U.S. patent N 4786733. In this case, the reaction is kinetically compete with fluoridation of the side chain and, therefore, the outputs of the target 2-herperidin again are low. In addition, the reaction of elemental fluorine with quinoline leads to the most prevalent fluoridation condensed aromatic rings and the spatial fragmentation of heterokonta. Surprisingly, but now found that heterocyclic compounds can be selectively fluorinated elementary fluorine, if another halogen is present in the reaction medium.

According to the present invention, a method for obtaining a heterocyclic organic compounds having at least one fluorine-substituent in the heterocyclic ring, and the method includes the stage of interaction of heterocyclic compounds with elemental fluorine in the presence of at least one of chlorine, bromine, iodine and interhalogens connection.

Examples interhalogen compounds are monobromide iodine and monochloride iodine.

Heterocyclic compound is eroticlinks connection may include five - or six-membered ring, which may contain optional substituents. The ring may be attached or fused with another one or more rings, which may or may not be heterocyclic. Preferably the ring is attached to or condensed with a benzene ring with one or more other aromatic rings.

Heterocyclic compound preferably includes a six-membered aromatic ring containing one or more nitrogen atoms, such as pyridine, or related heterocycle, such as a pyrimidine, pyridazine or triazine, or related heterocycle condensed with benzene ring, such as quinoline, isoquinoline, cinoxacin or hinzelin, or bi - or polycyclic compound, such as biperiden.

The provisions of the ring or rings heterocyclic compounds, fluorinated according to the method of the present invention, which are not occupied by heteroatoms, can bear substituents. Thus, if the heterocycle is pyridine, it can be substituted by from one to five with the provisions of the ring. If the heterocycle is pyrimidine, it can be substituted by from one to four provisions of the ring. If the heterocycle is a quinoline or isoquinoline, it can biterate optional substituents can be independently selected from alkyl, alkoxygroup, halogen, -CN, -OH, -NO2-NH2, NH, -N(alkyl)2, -NHCO-Coulcil, -COOH, -Soaltee, -CONH2, -CONH(alkyl), CON(alkyl)2, -COY, -CY13and SO2Y2in which

Y represents-H, -F, -Cl, -Br, alkyl, -OH or-Alkyl;

Y1is-F or-Cl;

Y2is-F, -Cl, -Br, -NH2, -NH or-N(alkyl)2.

In each of these substituents, the alkyl is preferably C1-C4-alkyl, alkoxygroup is preferably C1-C4-alkoxygroup and halogen is preferably F or Cl.

When the aromatic compound is pyridine, it is preferably unsubstituted, monosubstituted or disubstituted. If pyridine is monosubstituted, it is preferably substituted in position 4. If pyridine Disaese, it is preferably substituted in positions 2 and 4.

Preferred substituents for the heterocyclic compounds are selected from-OH, -CN, -NO2, -NHCOCH3, -OCH3, -COOCH3, -COOH, COCH3, -CH3, -F, -Cl, Br, CF3and-CONH3and combinations thereof.

All the hydrogens on the carbon atoms associated with the heteroatom may be replaced by fluorine example, pyridine gave 2,6-giftability when using two equivalents each of fluorine and halogen. In this way cinoxacin gave 2,3-diphthongisation and pyrimidine gave dipteronia pyrimidines.

In a preferred method of the present invention to the reaction medium type base. The base can be an organic base such as triethylamine, or an inorganic base, such as sodium fluoride. Surprisingly, it was found that this addition of base in the reaction medium results in a significantly higher conversion of the original heterocycle in fluorinated products at the specified time.

Examples of ftorirovanie that you can perform the method of the present invention, given in Fig. 1 of the accompanying drawings. Group R1-R4independently selected from hydrogen and substituents for hydrogen as defined above.

Fig. 2 of the accompanying drawings gives examples of ftorirovanie method of the present invention, in which the heterocycle introduce two atoms of fluorine. Again the group R1-R4independently selected from hydrogen and substituents for hydrogen as defined above.

Examples of organic bases that can be are sodium fluoride and potassium fluoride.

The ratio of the base to the heterocyclic compound may vary within wide limits, although preferably the molar ratio is in the range of 0.2 to 8.0:1, especially from 1.0 to 1.4:1 (base: heterocyclic compound).

The method according to the present invention can be carried out by passing gaseous fluorine in a liquid containing heterocyclic compound, halogen and, if used, the base. The reaction can be carried out in a vessel which contains the liquid, or, alternatively, the fluid flow can enter into contact with a stream of fluorine gas counterflow method. The liquid may contain conventional inert organic solvent, such as acetonitrile or fluorinated organic liquid such as fluorinated alkane (for example, CF2ClCFCl2), perftoran, perpendicular, fluorinated simple ether, perforated simple ester or partially fluorinated alkane.

The method can be carried out at a temperature of from -20 to 80oC, preferably at a temperature of from -10 to 30oC and especially at a temperature of from -5 to 25oC.

Gaseous fluorine is preferably diluted before use by mixing with an inert gas, toobanna 5-15% vol.

The ratio of fluorine to the heterocyclic compound may vary within wide limits, although preferably the molar ratio of fluorine to aromatic compound is from 0.5:1 to 6:1 and especially from 1:1 to 4:1. The use of a higher ratio of fluorine to heterocyclic connection ensures that more than one fluorine atom can be selectively entered in the heterocyclic compound.

After fluorination fluorinated products can be distinguished by blowing the reaction mixture with nitrogen to remove any residual gaseous fluorine with subsequent dilution with excess water and neutralization, followed by extraction in a suitable solvent, followed by distillation. Fluorinated heterocyclic products can be separated by fractional distillation, chromatography or crystallization from a suitable solvent.

The method according to the present invention offers a simple and convenient way to obtain fluorinated heterocycles directly from the parent heterocycle and elemental fluorine, therefore, in the method of the present invention is not required to obtain chlorinated heterocycles for exchange reactions of halogen or aminirovanie the heterocycle is method of obtaining fluorinated heterocycles.

Introduction the base in the reaction mixture ensures rapid conversion of starting material into the product and therefore, is particularly useful variant of the present invention.

The method of the present invention is further illustrated by the following examples.

Example 1. Getting 2-herperidin.

The solution containing pyridine (9.5 g, 120 mmol) and iodine (30.0 g, 118 mmol) in Arklone (Trade mark) (CFCl2CFCl2) (150 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (165 mmol) in a 10% mixture in a dry nitrogen is then passed through the stirred solution using a tube with a narrow bore diameter of the polytetrafluoroethylene (PTFE) at a rate of approximately 40 ml/min After adding fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (300 ml), neutralized with solid sodium bicarbonate and continuously extracted with dichloromethane. The organic extracts are dried and evaporated to condition yellow oil, identified as 2-herperidin (6.5 g, 56%) with a purity > 95% according to GC;

H(200 MHz, CDCl3, Me4Si) 6,9 M. D. (1H, m), 7,2 (1H, m), and 7.8 (1H, m), and 8.2 (1H, m), (C(50 MHz, CDCl3, Me4Si) 109,4 is,5, 6-C), 163,5 (d1JC-F237,4, 2-C); (F(235 MHz, CDCl3, CFCl3)-67,9 memorial plaques (s, 2 F); m/z (E1+) 97, (M+, 100%), 70 (68), 69 (12), 57 (18), 50 (29), 39 (22).

Example 2. Getting 2-fluoro-4,7-dichlorohydrin without the use of reason.

The solution containing 4,7-dichlorohydrin (1.0 g, 5 mmol) and iodine (1.28 g, 5 mmol) in CF2ClCFCl2(30 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (7 mmol) in 10% vol. mix in dry nitrogen is then passed through the stirred solution using a PTFE tube inner diameter at a rate of approximately 15 ml/min After adding fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (30 ml) and extracted with dichloromethane. The organic extracts are dried and evaporated to oil condition (0,98 g). GC/MS analysis showed a 34% conversion of the starting material. Column chromatography on silica gel with dichloromethane as eluent gave 2-fluoro-4,7-dichlorohydrin (0.33 g, 87%) as white crystals; other data were identical to those described in subsequent reactions.

Example 3. Fluoridation 4,7-dichlorohydrin using Foundation.

The solution containing 4,7-dichlorohydrin (1.0 g, 5 IMO nobunny drying tube filled with sodium lime. Elemental fluorine (7 mmol) as a 10% mixture in a dry nitrogen is then passed through the stirred solution using a PTFE tube inner diameter at a rate of approximately 15 ml/min After adding fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (30 ml) and extracted with dichloromethane. The organic extracts are dried and evaporated to state a brown oil (1.06 g). GC/MS analysis showed a 69% conversion of the starting material. Column chromatography on silica gel with dichloromethane as eluent gave 2-fluoro-4,7-dichlorohydrin (0.66 g, 88%) as white crystals: I. pl. 105-106oC (sublimation in vacuum at an oil bath, 60oC/ < 1 mm RT.CT.); RF0,72; (Found: C, 49,7; H, 1,7; N, 6,3. C9H4Cl2FN requires: C, 50,0; H, 1,85; N, 6.5 per cent);H(400 MHz, CDCl3, Me4Si) 7,20 M. D. (1H, d, JH3,F2,4, H-3), 7,58 (1H, DD, JHS,H6, 9,0, JH6,H82,2, H-6), of 7.95 (1H, d, JH6,H82,0, (H-8), 8,13 (1H, d, JH5,H69,2, H-5);F(235 MHz, CDCl3, Me4Si) -60,0 M. D. (C);C(100 MHz, CDCl3, Me4Si) 110,38 (d2J 45,8, C-3), 123,6 (d4J 2,3, C-4a), output reached 125.5 (s, C-6), uniforms, 127.6 (d,5J 1,2, C-5), 128,1 (d4J 2,6, C-8), 137, 9 (s, C-7), 146,4 (d3J 24,6, C-4), 146,6 (d3J 18,5, C-8a), 160,9 (measures 4. Fluoridation of 3-brainline using Foundation.

A solution containing 3-bromohydrin (1.0 g, 4.8 mmol), iodine (1.22 g, 4.8 mmol) and triethylamine (of 0.48 g, 4.8 mmol) in CF2ClCFCl2(30 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (5 mmol) in a 10% mixture in a dry nitrogen is then passed through the stirred solution using a PTFE tube inner diameter at a rate of approximately 15 ml/min After adding fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (30 ml) and extracted with dichloromethane. The organic extracts are dried and evaporated to state a brown oil (0.95 g). GC/MS analysis showed 56% conversion of the starting material. Column chromatography on silica gel with dichloromethane as eluent gave 2-fluoro-3-bromohydrin (0.52 g, 85%) as white needles: so pl. 75-76oC (sublimation in vacuum at an oil bath 50oC/ < 1 mm RT.CT.);

RF0,69 (CH2Cl2); (Found: C, And 47.5; H, 2,1; N, 6,2. C9H5NBrF requires: C, to 47.8; H, 2,2; N, 6.2 per cent); H(400 MHz, CDCl3, Me4Si) of 7.55 M. D. (1H, DD, JH5,H6, = JH6,H78,0, H-6), 7,74 (1H, DDD, JH7,H88,4, JH6,H77,2, JH5,H71,2 H-7), 7,76 (1H, d, JH5,H68,0, SUP>2J 43,2, C-3), 126,6 (s, C-6), 127,0 (d4J 2.7, and C-8), USD 128.0 (d,5J 1,9, C-5) USD 128.0 (d,4J 2,2, C-4a), 130,9 (d5J 1,1, C-7), 143,5 (d3J 3,7, C-4), 144,2 (d3J 15,1, C-8a), 157,3 (d1J 238,1, C-2);F(235 MHz, CDCl3, CFCl3)-60,8 M. D. (C); m/z (E1+225 (M+, 100%), 227 (M+, 74), 146 (56), 126 (23), 101 (18), 75 (14).

Example 5. Fluorination of 4-chlorhydrin.

A solution containing 4-chlorhydrin (1.0 g, 6 mmol), iodine (1.55 g, 6 mmol) and triethylamine (0,60 g, 6 mmol) in CF2ClCFCl2(30 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (7 mmol) as a 10% mixture in a dry nitrogen is then passed through the stirred solution at room temperature tube PTFE inner diameter at a rate of approximately 20 ml/min After adding fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (30 ml) and extracted with dichloromethane. The organic extracts are dried and evaporated to state a brown oil (1.01 g). GC/MS analysis showed a 76% conversion of the starting material. Column chromatography on silica gel with dichloromethane as eluent gave 2-fluoro-4-chlorhydrin (0,76 g, 90%) as white needles: so pl. 60-61oC (sublimation in vacuum on the oil is of Buet: C, OF 59.5; H, 2,75; N, 7.7 PER CENT); H(400 MHz, CDCl3, Me4Si) 7,20 M. D. (1H, d, JH3,F2,4, H-3), a 7.62 (1H, DDD, JH5,H6= JH6,H77,4, JH6,H81,2, H-6), 7,78 (1H, DDD, JH6,H7= JH7,H87,8, JH5,H71,2, H-7), of 7.96 (1H, d, JH7,H8and 8.4, H-8), 8,19 (1H, d, JH5,H6AND 8.4, H-5);F(235 MHz, CDCl3, CFCl3)-61,5 M. D. (c)C(100 MHz, CDCl3, Me4Si) 110,2 M. D. (d 2J 45,8, C-3), to 124.2 (d,5J 0,8, C-5), 125,1 (d4J 2,6, C-4a), 127,0 (d6J 2.7, and C-6), 128,5 (d4J 1,5, C-8), humidity 131.6 (s, C-7), 145,9 (d3J 18, C-8a), 146,6 (d3J 12,5, C-4), 160,2 (d1J 242,3, C-2); m/z (E1+) 183 (M+, 26%), 181 (M+, 100%), 146 (35), 126 (15), 75 (12), 50 (11).

Example 6. Fluoridation 6-chlorhydrin.

A solution containing 6-chlorhydrin (1.0 g, 6.1 mmol), iodine (1.55 g, 6.1 mmol) and triethylamine (0,62 g, 6.2 mmol) in CF2ClCFCl2(30 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (7 mmol) as a 10% mixture in a dry nitrogen is then passed through the stirred solution using a PTFE tube inner diameter at a rate of approximately 15 ml/min After adding fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (30 ml) and extracted with dichloromethane. The organic extracts are dried and evaporated to with what I chromatography on silica gel with dichloromethane as eluent gave 2-fluoro-6-chlorhydrin (0,82 g, 93%), RF0,78 (CH2Cl2); H(400 MHz, CDCl3, Me4Si) 7,12 M. D. (1H, DD, JH3,H48,8, JH3,F2,8, H-3), to 7.67 (1H, DD, JH7,H89,2, JH5,H72,4, H-7), of 7.82 (1H, d, JH5,H72,4, H-5), 7,87 (1H, d, JH7,H89,0, H-8), 8,16 (1H, DD, JH3,H4= JH4,F8,8, N-4);C(100 MHz, CDCl3, Me4Si) 111,1 M. D. (d2J 42,3, C-3), 126,3 (s, C-5), RUB 127.3 (s, C-4a), of 129.6 (s, C-8), to 131.4 (s, C-7), 131,9 (s, C-6), 141,0 (d3J 9,9, C-4), 144,1 (d3J 16,8, C-8a), 161,2 (d1J 243,8, C-2);F(235 MHz, CDCl3, CFCl3)-61,5 M. D. (c); m/z (E1+) 181 (M+, 100%), 183 (M+32%), 146 (34), 126 (11).

Example 7. Fluoridation of phenanthridine using Foundation.

The solution containing the phenanthridine (1.0 g, 5.6 mmol), iodine (1.4 g, 5.6 mmol) and triethylamine (0.56 g, 5.6 mmol) in CF2ClCFCl2(30 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (7 mmol) as a 10% mixture in a dry nitrogen is then passed through the stirred solution using a PTFE tube inner diameter at a rate of approximately 15 ml/min After adding fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (30 ml) and extracted with dichloromethane. The organic extracts are dried and evaporated to a state brown m what chlormethine as eluent gave 6-fortunantely (0.39 g, 67%). RF0,78 (CH2Cl2);H(400 MHz, CDCl3, Me4Si) to 7.61 M. D. (1H, DDD, JH1,H2= JH2,H3= 7,8, JH2,H41,2, N-2), of 7.69 (2H, m, H-3 and H-9), 7,88 (1H, DDD, JH7,H88,4, JH8,H97,2, JH8,H101,4, H-8), of 7.97 (1H, DD, JH3,H48,0, JH2,H41,2, H-4), 8,21 (1H, DD, JH9,H108,0, JH8,H101,4, H-10), to 8.45 (1H, DD, JH1,H28,0, JH1,H30,8, H-1), charged 8.52 (1H, DD, JH7,H88,4, JH7,H91,2, H-7);F(376 MHz, CDCl3, CFCl3), 68,2, M. D. (c);C(100 MHz, CDCl3, Me4Si) 117,3 M. D. (d3J 35,1, C-6a), 122,2 (d3J 3,8, C-7), 122,2 (s, C-1), 123,9 (d4J 1,9, C-10b), to 124.2 (s, C-10), 126,5 (d6J 2,3, C-2), to 127.9 (s, C-9), 128,7 (d4J 1,6, C-4), 129,4 (s, C-3), 132,1 (s, C-8), to 136.5 (d,3J 7,2, C-10a), 141,5 (d3J 17,9, C-4a), 158,1 (d1J 248,7, C-6); m/z (E1+) 197 (M+, 100%).

Example 8. Fluorination of 4-ethylpyridine.

A solution containing 4-ethylpyridine (12.8 g, 120 mmol) and iodine (30.5 g, 120 mmol) in CF2ClCFCl2(150 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (165 mmol) in a 10% mixture in a dry nitrogen is then passed through the stirred solution using a PTFE tube inner diameter at a rate of approximately 40 ml/min After adding fluoride solution was poured into 10% aqueous solution meskie extracts are dried and evaporated to condition yellow oil (9,54 g), which contained ethylpyridine (78% conversion), 2-herperidin and minor amounts of other products according to GC/MS analysis. Oil re-dissolved in dichloromethane and washed with a solution of 2H HCl, dried (MgSO4) and evaporated to a state of a clear oil with obtaining 2-fluoro-4-ethylpyridine with a purity > 95% (6.3 g, 54%, based on the conversion of 78%);H(200 MHz, CDCl3Me4Si) 1,26 M. D. (3H, t, J 7,6, CH3), 2,69 (2H, K, J 7,6, CH2), to 6.75 (1H, s, H-3), 7,02 (1H, DM, J 5,1, H-5), of 8.09 (1H, d, J 5,1, H-6);C(50 MHz, CDCl3, Me4Si) 14,1 M. D. (CH3), 28,2 (d4JC-F2,7, CH2), 108,5 (d2JC-F36,5, C-3), 121,3 (d4JC-F3,9, C-5), 147,3 (d3JC-F15,2, C-6), 159,3 (d3JC-F7,8, C-4), 164,2 (d1JC-F236,3, C-2);F(235 MHz, CDCl3, CFCl3) 69,9 M. D. (c); m/z (E1+) 125 (M+, 100%), 110 (47), 97 (15), 83 (13).

Example 9. Fluoridation of quinoline.

The solution containing quinoline (10.6 g, of 82.5 mmol) and iodine (21,0 g of 82.5 mmol) in CF2ClCFCl2(150 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (165 mmol) in a 10% mixture in a dry nitrogen is then passed through the stirred solution using a tube made of PTFE narrow inner divita sodium (300 ml), neutralized with sodium bicarbonate and extracted with dichloromethane. The organic extracts are dried (MgSO4) and evaporated to a oil (7.2 g). Distillation gave 2-ftorhinolon (6.5 g, 54%) as a pale yellow oil: so Kip. 134-136oC/ 30 mm RT.article (lit., 133oC/ 30 mm RT. Art.)H(400 MHz, CDCl3, Me4Si) 7,05 M. D. (1H, DD, JH3,H48,8 JH3,F2,8, H-3), 7,51 (1H, DDD, JH5,H68,0, JH6,H76,8, JH6,H80,8 H-6), 7,71 (1H, DDD, JH7,H88,0, JH6,H77,6, JH5,H71,2, H-7), 7,81 (1H, d, JH5,H68,0, H-5), 7,94 (1H, d, JH7,H8and 8.4, H-8), to 8.20 (1H, DD, JH3,H4= JH4,FAND 8.4, H-4);F(250 MHz, CDCl3, Me4Si)-63,2 memorial plaques;C(100 MHz, CDCl3, Me4Si) 110,0 M. D. (d2J 42,1, C-3), 126,1 (d4J 2,6, C-8), to 126.8 (d,4J 1,9, C-4a), of 127.5 (s, C-6), USD 128.0 (d,5J 1,2, C-5), to 130.6 (d,5J 0,8, C-7), 141,9 (d3J 9,9, C-4), to 145.7 (d3J 16,7, C-8a), owed 161.1 (d1J to 240.5, C - 2); m/z (E1+) 147 (M+, 100%).

Example 10. Fluoridation of 3-brainline without using Foundation.

A solution containing 3-bromohydrin (1.0 g, 4.8 mmol) and iodine (1.22 g, 4.8 mmol) in CF2ClCFCl2(30 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (5 mmol) in a 10% mixture in a dry nitrogen is then passed through peremeci the e add fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (30 ml) and extracted with dichloromethane. The organic extracts are dried and evaporated to state a brown oil (0,92 g). GC/MS analysis showed a 43% conversion of the starting material. Column chromatography on silica gel with dichloromethane as eluent gave 2-fluoro-3-bromohydrin (0.35 g, 74%) as white needles: so pl. 75-76oC (sublimation in vacuum at an oil bath 50oC/ < 1 mm RT.CT.); RF0,69 (CH2Cl2); (Found: C, And 47.5; H, 2,1; N, 6,2. C9H5NBrF requires: C, to 47.8; H, 2,2; N, 6.2 per cent);H(400 MHz, CDCl3, Me4Si) of 7.55 M. D. (1H, DD, JH5,H6= JH6,H78,0, H-6), 7,74 (1H, DDD, JH7,H88,4, JH6,H77,2, JH5,H71,2 H-7), 7,76 (1H, d, JH5,H68,0, H-5), to $ 7.91 (1H, DD, JH7,H88,4, JH6,H80,8, H-8), 8,42 (1H, d, JH4,FAND 8.4, H-4);C(100 MHz, CDCl3, Me4Si) 104,0 (d2J 43,2, C-3), 126,6 (s, C-6), 127,0 (d4J 2.7, and C-8), USD 128.0 (d,5J 1,9, C-5), USD 128.0 (d,4J 2,2, C-4a), 130,9 (d5J 1,1, C-7), 143,5 (d3J 3,7, C-4), 144,2 (d3J 15,1, C-8a), 157,3 (d1J 238,1, C-2);F(235 MHz, CDCl3, CFCl3)-60,8 M. D. (C); m/z (E1+) 225 (M+, 100%), 227 (M+, 74), 146 (56), 126 (23), 101 (18), 75 (14).

Example 11. Fluoridation of 4-chloro-7-triptoreline.

A solution containing 4-chloro-7-trifloromethyl (1.0 g, 4.3 mmol) and iodine (1.1 g, 4.3 mmol) in CF2ClCFCl2(30 ml), placed in a fluorination apparatus, SN is Hom nitrogen is then passed through the stirred solution using a PTFE tube inner diameter at a rate of approximately 15 ml/min After adding fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (30 ml), neutralized with solid sodium bicarbonate and extracted with dichloromethane. The organic extracts are dried and evaporated to condition yellow solid (1,09 g). GC/MS analysis showed a 5% conversion of the starting material. Column chromatography on silica gel with dichloromethane as eluent gave 2-fluoro-4-chloro-7-trifloromethyl (0.05 g, 86%) as white needles: so pl. 94-95oC (sublimation in vacuum at an oil bath 50oC/ < 1 mm RT. Art.); RF0,69 (CH2Cl2); (Found: C, While 47.7; H, 1,3, N, 5,5. Cl10H4NClF4requires: C, 48,1; H, 1,6; N, 5.6 per cent)H(400 MHz, CDCl3, Me4Si) 7,32 M. D. (1H, d, JH,F2,4, H-3), 7,79 (1H, DD, JH5,H68,8, JH6,H81,6, H-6), 8,23 (1H, m, H-8), 8,32 (1H, d, JH5,H68,8, N-5);C(50 MHz, CDCl3, Me4Si) 112,3 M. D. (D2JC-F45,5, C-2), 122,9 (m, C-6), 123,4 (K1JC-F272,7, CF3), 125,6 (s, C-5), 126,2 (m, C-8), a 126.7 (c, C-4a), 133,4 (K2JC-F33,2, C-7), 145, 2mm (d3JC-F18,7, C-8a), 146,7 (d 3JC-F12,9, C-4), 160,9 (d1JC-F245,3, C-2);F(235 MHz, CDCl3, CFCl3)-55,0 M. D. (1F, s, F-2), -59,2 (3F, C, CF3); m/z (E1+) 249 (M+, 100%), 251 (M+, 33), 230 (26), 214 (18), 201 (11), 199 (33), 194 (12), 145 (26), 99 (19).

Prong, 5.6 mmol) and iodine (1.4 g, 5.6 mmol) in CF2ClCFCl2(30 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (7 mmol) as a 10% mixture in a dry nitrogen is then passed through the stirred solution using a PTFE tube inner diameter at a rate of approximately 15 ml/min After adding fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (30 ml) and extracted with dichloromethane. The organic extracts are dried and evaporated to condition orange oil (0,91 g). GC/MS analysis showed 17% conversion of the starting material. Column chromatography on silica gel with dichloromethane as eluent gave 6-fortunantely (0.09 g, 48%); RF0,78 (CH2Cl2);H(400 MHz, CDCl3, Me4Si) to 7.61 M. D. (1H, DDD, JH1,H2= JH2,H3= 7,8, JH2,H41,2, N-2), of 7.69 (2H, m, H-3 and H-9), 7,88 (1H, DDD, JH7,H88,4, JH8,H97,2, JH8,H101,4, H-8), of 7.97 (1H, DD, JH3,H48,0, JH2,H41,2, H-4), 8,21 (1H, DD, JH9,H108,0, JH8,H101,4, H-10), to 8.45 (1H, DD, JH1,H28,0, JH1,H30,8, N-1), charged 8.52 (1H, DD, JH7,H88,4, JH7,H91,2, H-7);F(376 MHz, CDCl3, CFCl3), -68,2 M. D. ();C(100 MHz, CDCl3, Me4Si) 117,3 M. D. (d2J 35,1, C-6a), 122,2 (d3J 3,8, C-7), 122,2 (s, CP>3J 7,2, C-10a), 141,5 (d3J 17,9, C-4a), 158,1 (d1J 248,7, C-6); m/z (E1+) 197 (M+, 100%).

Example 13. Fluoridation of cinoxacin.

The solution containing cinoxacin (15.6 g, 120 mmol) and iodine (30.5 g, 120 mmol) in CF2ClCFCl2(150 ml), placed in a fluorination apparatus fitted with a drying tube filled with sodium lime. Elemental fluorine (165 mmol) in a 10% mixture in a dry nitrogen is then passed through the stirred solution using a PTFE tube inner diameter at a rate of approximately 40 ml/min After adding fluoride solution was poured into 10% aqueous solution of sodium metabisulfite (300 ml), neutralized with sodium bicarbonate and continuously extracted with dichloromethane for 24 hours. The organic extracts are dried and evaporated to oil condition (13,6 g). GC/MS analysis showed 49% conversion of cinoxacin. The oil is purified column chromatography on silica gel using dichloromethane as eluent to obtain pure 2-forination in the form of a pale yellow oil (5.30 g, 62%, based on 49% conversion); RF0,53;H(200 MHz, CDCl3, Me4Si) 7,7 M. D. (2H, m), and 7.9 (1H, m) and 8.1 (1H, m), 8,67 (1H, d, JH,F7,9, H-3);F(250 MHz, CDCl3, Me4Si) - 75,1 M. D. ();C(50,3 MHz, CDCl33JC,F10,9, C-8a), 141,52 (d4JC,F1,8, C-4a), 156,74 (d1JC-F, 256,0, C-2); m/z (E1+) 148 (M+, 100), 129 (20), 121 (12), 103 (17), 76 (24), 50 (17); and 2,3-divergenceline (0.27 g, 3%) as pale yellow solids; RF0,75;H/(400 MHz, CDCl3, Me4Si) 7,79 M. D. (2H, m, Ar-H), to 7.99 (2H, m, Ar-H);C(50 MHz, CDCl3, Me4Si) 127,8 (s, C-8), 130,4 (s, C-7), 138,4 (DD,3JC-F5,4, C-4a), 146,1 (DD,1JC-F261,3,2JC-F39,5, C-2);F(235 MHz, CDCl3, CFCl3)-82,8 M. D. (C); m/z (E1+) 166 (M+, 100%), 139 (11).

1. The method of obtaining fluorinated nitrogen-containing heterocyclic compounds having at least one fortuntately in the heterocyclic ring, wherein the stage includes the interaction of nitrogen-containing heterocyclic compounds with gaseous elemental fluorine in the presence of at least one of chlorine, bromine, iodine or interhalogens connection.

2. The method according to p. 1, characterized in that the heterocyclic compound includes a five - or six-membered heterocyclic ring, which may contain optional substituents selected from alkyl, alkoxy, halogen, -CN, -OH, -NO2, -NH2-N, -N(alkyl)2, NHCO, -soo is which Y represents-H, -F, -Cl, -Br, alkyl, HE or Alkyl; Y1is-F or-Cl; Y2is-F, -Cl, -Br, -NH2The N or-N(alkyl)2.

3. The method according to p. 1 or 2, characterized in that the heterocyclic compound includes a six-membered aromatic ring containing one or more nitrogen atoms, the ring which is optionally condensed with one or 2 benzene rings or attached to another aromatic ring.

4. The method according to p. 3, characterized in that the heterocyclic compound is selected from pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, cinoxacin, hinzelin and bipyridine.

5. The method according to PP.1 to 4, characterized in that the gaseous fluorine diluted before use by mixing with inert gas.

6. The method according to PP.1 to 5, characterized in that it is carried out by passing gaseous fluoride in an organic solvent containing heterocyclic compound and at least one of chlorine, bromine, iodine and interhalogens connection.

7. The method according to PP.1 - 6, characterized in that the organic solvent is a fluorinated organic solvent.

8. The method according to PP.1 to 7, characterized in that the indicate of triethylamine, tributylamine, N-methylpiperidine sodium fluoride and potassium fluoride.

 

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< / BR>
in which Z represents C or N, provided that two Z are nitrogen atoms; R1is:

< / BR>
in whichisor, R6represents H or alkyl, and R7and R8are each H, alkyl, nitro or phenyl, or alternatively, R7and R8taken together, represent butadiene or 1,4-butylene; R2and R3are each H, F, cyano, acyl, nitro, alkyl, morpholino or one of the above definitions for R1; R4and R5are each H, hydroxyl, alkyl, cycloalkyl, heterocycle, phenyl, or Y-substituted alkyl; Y represents a hydroxyl, acyloxy, F - substituted methyl, cycloalkyl, tetrahydrofuranyl, carboxyl, alkoxycarbonyl or

The invention relates to new chemical compounds having valuable properties, in particular derivatives of dihydropyridines of General formula (I)

< / BR>
where R1aryl with 6-10 carbon atoms, unsubstituted or once-three times substituted by identical or different substituents from the group comprising halogen atom, a nitro-group, cyano, trifluoromethyl, cryptometer and triptoreline,

or substituted unbranched or branched alkyl with 1-8 carbon atoms, which is not substituted or substituted aryl with 6-10 carbon atoms, or substituted unbranched or branched alkoxygroup or alkoxycarbonyl with 1-8 carbon atoms, carboxypropyl, an amino group or a group of the formula-NR4R5in which

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or thienyl,

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R3a hydrogen atom or an unbranched or branched alkyl with 1-8 carbon atoms,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerable salts

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The invention relates to a derivative of a simple ester, application and intermediate compounds used for their production

FIELD: organic chemistry, chemical technology, insecticides.

SUBSTANCE: invention describes new compounds of the formula (X): wherein R1 means -CH2-Het; R means unsubstituted (C1-C20)-alkyl or (C1-C20)-alkyl that is substituted with one or some phenyls, or it means unsubstituted phenyl or phenyl substituted with (C1-C6)-alkyl, or it means (C1-C6)-alkyl that is substituted with cyclohexyl or means unsubstituted (C3-C7)- cyclohexyl or substituted with one or some substitutes taken among the group including halogen atom and (C1-C6)-alkyl, or it means biphenyl, or phenoxyphenyl; T and U each means independently from one another (C1-C6)-alkyl; R2, R'2 mean hydrogen atom; Het means pyridyl that is substituted with halogen atom. Also, invention describes a method for preparing compound of the formula (X) by interaction of compound of the formula (XX) with acid R-COOH and isolation of the end product from reaction mixture wherein substitutes R, R1, R2, R'2, T and U have values indicated for the formula (X); Hal means halogen atom. Also, invention describes a parasiticidal composition for control of blood-sucking insects. Invention provides preparing compounds eliciting parasiticidal activity with expressed prolonged effect.

EFFECT: improved preparing method, valuable properties of compounds and composition.

11 cl, 8 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: organic chemistry, chemical technology, fungicides.

SUBSTANCE: invention describes derivative of benzoylpyridine of the formula (I) or its salt:

wherein X represents halogen atom, (C1-C6)-alkoxy-group optionally substituted with a substitute taken among halogen atom, phenyl, methoxy-, methylthio-, dimethylamino-group, vinyl or ethynyl; phenoxy-group, (C3-C6)-cycloalkoxy-group, hydroxyl group, (C1-C6)-alkyl group, (C2-C6)-alkenyl group, CF3, (C1-C6)-alkylthio-group, (C1-C6)-alkoxycarbonyl group, (C1-C6)-dialkylaminocarbonyl group, (C1-C6)-alkylcarbonyloxy-group, (C1-C6)-alkylcarbonyl group, amino-group, (C1-C4)-alkylamino-group or di-(C1-C4)-alkylamino-group; n represents 1, 2, 3 or 4; R1 represents (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group, (C1-C6)-alkoxy-group optionally substituted with phenyl, phenoxy-group, (C3-C10)-cycloalkyloxy-group or hydroxyl group; m = 1, 2 or 3 under condition that if m = 2 then R2 can form ring -OCH2O- (with exception when pyridine ring is substituted with benzoyl group at 2-position; pyridine ring is substituted with (C1-C6)-alkoxy-group, hydroxyl group or benzyloxy-group; n = 1; m = 1 or 2). Also, invention describes fungicide comprising compound of the formula (I) or it salt as an active component, methods for preparing derivatives of benzoylpyridine, phenylpyridylmethanol that is an intermediate compounds used for synthesis of compound of the formula (I). Invention provides fungicide properties of compound of the formula (I) or its salt.

EFFECT: improved method for preparing, valuable properties of compounds.

17 cl, 36 tbl, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved methods for preparing compounds of the formulae (I) and (II) or their salts wherein X represents halogen atom; Y represents halogen atom, halogenalkyl, alkoxycarbonyl or alkylsulfonyl; n = 0-3. Method for preparing compound of the formula (I) involves catalytic hydrogenation of compound of the formula (II) in the presence of a catalyst, such as palladium in solvent medium at temperature from 0°C to 60°C. Method provides preparing the end compounds with high yields (95-97%) and high purity degree due to minimization of by-side dehalogenation reaction of the parent reagents. Method for preparing compound of the formula (II) involves treatment of the corresponding derivative of 2-fluoro-derivative with the cyanide source in the presence of a catalyst, such as tetraalkyl ammonium salt in an aqueous solvent or without solvent at temperature from 10°C to 60°C. Method provides preparing the end compounds with high yields (80-90%), high purity (98%) at moderate temperatures.

EFFECT: improved preparing methods.

23 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing tetrachloropicolinic acid. Method involves interaction of 2-cyanopyridine with chlorine in presence of catalysts wherein phosphorus chlorides are used in the amount 2-60 weight % of the initial load of 2-cyanopyridine, and phosphorus oxychlorides also. The chlorination process is carried out in the melt at temperature 120-200°C and under pressure up to 0.6 MPa followed by dosing the reaction mass into a mixture of water with sulfuric acid, and then hydrolysis is carried out in the presence of phosphoric acid formed after hydrolysis of phosphorus chlorides. The end product is isolated by the known procedures. Method provides simplifying the process by using the standard equipment, improving ecological indices and reducing energy consumptions.

EFFECT: improved preparing method.

2 cl, 6 ex

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