RU1799378C - Method of alkanesulfonylanilide derivatives or theirs pharmaceutically acceptable salts synthesis - Google Patents

Description

NMR spectrum (.5): 2.52 (ZN, s.). 3.12 (3H, s.), 7.0-7.8 (7H, m.).

Example 17. The process described in Example 1 was carried out to give 4-acetyl-2 - (2,6-dichlorophenoxy) methanesulfonanilide. .;. ::.

Melting point 155-156 ° C.

IR (Nuyol): 3220, 1675, 1605, 1500cm 1.V.

Nuclear Magnetic Resonance Spectrum (CpCIs, 5): 2.49 (3H, s), 3.12 (3H, s), 7.0-7.9 (7.H, m).

Mass spectrum (t / e): 373 (M4), 259.

Example 18. A process was carried out as described in Example 1, obtained. 4-acetyl-2 - (2-bromophenoxy) methanesulfonanilide. -....: -.... ....

Melting point 95-9b ° C.

IR (Nujol): 3200, 1670, 1610, 1580, 1500cm 1.

NMR spectrum Oaz..sO.O.Z, (ZN, s.), 7, (8H, m.).

Mass spectrum (t / e): 383 (M4), 225.

Example 19. The process was carried out as described in Example .1 to give 4-acetyl-2. - (2-methoxyphenoxy) meta. Sulfosanilide.

Melting point 160 161 ° C.

IR (Nujol): 3280, 1675, 1605, 1500cm 1,

NMR spectrum (СОС1з, 5): 2.48 (ЗН, s.), 3.02 (ЗН, s.), 3.78 (ЗН, m.), 6.8-7.8 (7Н, m.) .

Mass spectrum (t / e): 385 (M +), 225.

Example 20. By carrying out the process as described in Example 1, 4-acetyl-2 - (2-chloro-4-fluorophenoxy) methanesulphonanilide is obtained.

Melting point 96-98 ° C.

Y-spectrum (Nuyol): 3230, 1680, 1605, 1580, 1515 cm 1.

NMR spectrum (CDCI3, b): 2.50 (ZN, s.), 3.13 (ZN, s.), 7.0-7.8 (7-Nm),

Mass spectrum (t / e): 357 (M4), 342.243.

Example 21, The process was carried out. As described in Example 1, 4-cyano-2- (2,4-dichlorophenoxy) methanesulfonanilide was obtained.

Melting point 164-165 ° C.

IR (Nujol): 3320, 2230, 1610, 1510cm 1.

-NMR spectrum (CDCI3, b): 3.14 (Z. s.), 6.8-7.9 (7N.m.).

Mass spectrum (t / e): 356 (M, 242 ...

Example 22. A mixture of 4-amino-3- (2,4-difluorophenyxy) benzophenone (2.1 g) and methanesulfenyl chloride (0.77 g) in pyridine (10 ml) was stirred overnight at room temperature. Pyridine was evaporated under reduced pressure. And the residual evaporation product was dissolved in ethyl acetate, washed with dilute hydrochloric acid and water in a sequential order, dried and evaporated under reduced pressure, the residual evaporation product (2 g) was dissolved in methanol (20 ml ) and treated with sodium hydroxide (0.2 g). The mixture was evaporated under reduced pressure and the residual product was solidified from ethanol. The result is a pale yellow powder of the 2- (2,4-difluorophenoxy) -4-benzoylmethanesulfonanilide sodium salt (1.5 g).

Melting point 160-170 ° C (with decomposition); IR (Nujol): 3450 (wide), 1640, 1590, 1500cm 1.:

Nuclear Magnetic Resonance Spectrum (D20, b): 2.94 (3H, s), 6.6-7.4 (11H, m).

Example 23. By carrying out the process as described in Example 1, 4-acetyl-2 - (3-chlorophenoxy) methanesulfonan-ylide was obtained in the form of an oil. This oil (2.4 g) was solidified in an aqueous solution of sodium hydroxide (10%, 20 ml), and as a result, the sodium salt powder of 4 - acetyl-2 - (3-chlorophenoxy) methanesulfonanilide (2.3 g) was obtained )

Melting point 290-300 ° C (decomposed).

IR (Nujol): 1660.1590, 1550cm:: -:;

Nuclear Magnetic Resonance Spectrum (dimethyl sulfoxide - de, b): 2.34 (3H, s.), 2.52 (3H, m.), 6.7-7.8 (7H, m.).

Example 24. Carried out the process as described in examples 1 and 23 ,. 4-acetyl-2 - (2,3-dichloro-phenoxy) -methanesulphonanilide sodium salt is obtained.

Melting point 162-170 ° C (decomposed). :.

IR (Nujol): 1665, 1590, 1550,

15oohm 1 ..::. .- ;.

NMR spectrum (dimethyl sulfoxide - de, b): 2.40 (3H, s), 2.55 (3H, s), 6.55 (1H, dd, 5 6.5 Hz), 7, 7-7.8 (5H, m) ...- .:

. # .-

PRI me R 25. Carried out the process as described in the example. 1, 4-acetyl-2 - (2,4-.dichlorophenoxy) methanesulfonanilide is obtained.

Melting point 199 201 ° C. IR (Nujol): 3370, 1680, 1610,

1510CM 1.. . . :.-.- ...

Spectrum NMR. (СОС1з, (3): 2.50 (ЗН, s.), 3.12 (ЗН, s.), 7.0-7.9 (4Н, m.), 7.43 (2Н. S.).

Mass spectrum (t / e); 407 (M). 392.293. Example 26. By carrying out the process as described in Example 1, 4-acetyl-2 - (2-methylthiophenoxy) methanesulfono-ananilide was obtained. ;

Melting point 122-125 ° C.

PC spectrum (СОС1з, d): 2.43 (ЗН, s.), 2.50 (ЗН, s.), 3.02 (ЗН, s.), 6.9-7.8 (8Н, m.) .

Mass spectrum (t / e): 351 (M), 225, 148.

Example 27. The process was carried out in the same manner as described in Examples 1 and 23 to obtain the sodium salt of 4-acetyl-2- (2-methylphenoxy) methanesulfonamide. .:. Melting point 150-160 ° C (decomposed).

IR (Nujol): 3450, 1650, 1590, 1550, 1495.

NMR spectrum (DaO, d): 2.20 (ZN, s), 2.38 (ZN, s), 3.00 (ZN, s), 6.8-7.8 (7H, m. )

Example 28. Having carried out the process as described in Example 1, methoxy-3- (2,4-difluoromenoxy) -4- (methanesolphonamido) benzamide is obtained,

Melting point 125-127 ° C.

IR spec.ctr (Nuyol): 3150, 1635, 1580, 1500cm 1.

NMR spectrum (СОС1з, 5): 3.12 (ЗН, s.), 3.84 (ЗН, s.), 6.8-7.8 (8Н, m.).

Mass spectrum (t / e): 372 (M4), 342.326.

Example 29. A mixture of 4-amino-3-chloro-5- (2,4-difluorophenoxy) -acetophenone (2.4 g) and methanesulfonic anhydride (2.5 g) was stirred at 100 ° C. for 1 h. This mixture is evaporated to dryness. The residual evaporation product was dissolved in chloroform, washed with saturated aqueous sodium bicarbonate, dried and evaporated to give an oil (2.5 g). This oil is purified by passing it through a chromatographic column filled with silica gel (50 g), eluting with chloroform. The purified product (oil) was dissolved in a solution of sodium hydroxide (180 mg) in methanol (20 ml), and the solution was evaporated. The residual evaporation product is crystallized from ethyl acetate and the resulting powder is the sodium salt of 4-acetyl-2-chloro-6 - (2,4-difluorophenoxy) methanesulfonanilide (1.1 g) .:

Melting point 270-272 ° C.

IR (Nujol): 1665, 1585, 1545, 1.505cm 1.

NMR spectrum (CDCIs, d): 2.43 (3H, s), 2.92 (3H, s), 6.7-7.3 (4H, m), 7.77 (1 N. D ., L 2 Hz).

Example 30. By carrying out the process in the same manner as described in Example 1, 4-acetyl-2 (2,4-difluorophenoxy) -5-methylmethanesulfonanilide was obtained.

. Melting point 116-117 ° C.

IR (Nujol): 3260, 1680, 1670, 1610.1575,1505cm 1.

NMR spectrum (СОС1з, d): 2.40 (ЗН, s.), 2.51 (ЗН, s.), 3.10 (ЗН. S.), 6.8-7.4 (5Н, m. ), 7.56 (1H, s.).

Mass spectrum (t / e): 355 (M) .. 340.276.

Example 31. By carrying out the process as described in Example 1, 2- (2,4-difluorophenoxy) 4- (methylthio) methanesulfonononylide was obtained. ;

Melting point 76-78 ° C.

IR (Nujol): 3300, 1610, 1580, 1500cm 1.

Nuclear Magnetic Resonance Spectrum (. (3): 2.35 (ZN.s.), 3.00 (ZN, s.), 6.4-7.6 (7H, m).

These compounds were prepared following a process similar to the description of Example 1.

Example 32.4-cyano-2 - (2L-difluorophenoxy) -5-chloromethanesulfonanilide.

Mp 232-233 ° C.

IR (Nujol): 3240, 2240, 1605, 1575, 1510, 1490cm 1

HMP (DMSO-d6.5): 3.22 (3H, s), 6.9-7.6 (5H, m), 7.72 (1 H, s).

Mass (t / e): 358 (M), 279.

Example 33.5-acetyl-4-cyano-2 - (2,4-difluorophenoxy) methanesulfonanilide so pl. 174-1760C.

IR (Nujol): 3400, 2230, 1690, 1605.157575.1510cm 1.

NMR (DMSO-de d): 2.61 (ZN, s), 3.22 (ZN, s); 7.0-7.7 (5H, m.), 8.14 (1 H, s.). .

Mass (t / e): 366 (M, 351.

Example p .34. α-cyano-difluoro-phenoxy) methanesulfoninylide (15 g) was dissolved in a solution of sodium oxide hydrate (2 g) in water (70 ml). Insoluble material was separated by filtration and the filtrate was concentrated to dryness ... The residue was dissolved in ethyl acetate (100 ml) and the solution was filtered. The filtrate was stirred at room temperature and the precipitate was separated by filtration and washed with ethyl acetate, whereby colorless crystals of sodium salt of 41-cyano-2 - (2,4-difluorophenoxy) methanesulfonanilide were obtained. (14.8 g). Melting point: 267-268 ° C.

IR (Nuyol): 2240, 1600, 1500, 1336.1250.11120 cm 1.

NMR (CO3OOD): 2.89 (3H, singlet), 6.8-7.6 (6H, multiplet).

Example 35, cyanide-I-difluorophenoxy) methanesulfonanilide (50 g) was dissolved in ethyl acetate (1000 ml) at 50 ° C. and insoluble particles were removed by filtration. A 25% sodium hydroxide solution (27.2 g) was added to the filtrate. The resulting solution was concentrated to approximately 500 ml under reduced pressure and stirring at 30 ° C. for 4 hours. Precipitation was separated by filtration and washed with ethyl acetate (50 ml), whereby colorless crystals of 4-cyano-2 - sodium salt were obtained. 2,4-difluorophenoxy) methanesulfonanilide (48.2 g).

This target compound was identical to the target compound from example 34 when comparing the corresponding physical data.

Example 36. 4-cyano-2 - (2.4-difluorophenoxy) methanesulfonanyl; id (48.6 g) was dissolved in a solution of sodium hydroxide (12 g) in water (486 ml). The mixture was filtered and the filtrate was stirred at room temperature for 1 h. Precipitates were separated by filtration and washed with water (96 ml), whereby colorless crystals of sodium salt 4-cyan 2 - (2: 4-difluorophenoxy) methanesulfonanilide (46 g) were obtained .

This compound was identical to the target compound from Example 34, which was established by comparing physical data ...

Example 37. 4-cyano-2 - (2,4-difluorophenoxy) methanesulfonanilide (10 g) was dissolved in a 5% sodium hydroxide solution (100 ml). The solution was extracted with ethyl acetate (250 ml). The extract was concentrated to 100 ml and the resulting mixture was stirred at room temperature for 30 minutes. The precipitates were filtered and washed with ethyl acetate, whereby colorless crystals of the 4-cyano-2 - (2.4-difluorophenrxi) methanesulfonanilide sodium salt (6 g) were obtained.

This target compound was identical to the target compound as established by comparing the physical data.

Example 38. 2- (2,4-Difluorophenoxy) - 4X1 Oxyethyl) methanesulfonanilide (0.97 g), mp: 103-105 ° C.

IR Spectrum (Nujol): 3480.1615.15.1585.15500 see .... .. .; . . ::.

Nuclear Magnetic Resonance Spectrum (SOSGs): 1.37 (3H, d, 3-6 Hz), 2.10 (1H, d, 3-4 Hz), 3.00 (3H, s), 4.6-4, 9 (1H, m.). 6.7-7.7 (7H, m.).

Mass spectrum (t / e): 343 (M4), 328; 222.

PRI me R 39. 4-Acetyl-2 - (2-methyl-sulfinyl phenoxy) methanesulfonylphananilide (0.77 g), so pl. 113-116 ° C.

IR (Nujot): 1690.1610.1580.1505.

Nuclear Magnetic Resonance Spectrum (CDCb. D): 2. (3S, s), 2.98 (3s, s), 3.00 (3s, s), 6.8-7.9 (7H, m) 8.98 (1H, s.).

Mass spectrum (t / e): 367 (M), 27Q, 225.

Example 40. Semicarbazono-3 - {2.4-difluorophenoxy) -4-methanesulfonamidoacetophenone (1.1 g).

Melting point 187-189 ° C.

IR spectrum (Nujol): 3500.33200, 1710, 1580.1505cm1.

Nuclear Magnetic Resonance Spectrum (dimethyl sulfoxide - de. D): 2.10 (3H, s), 3.04 (3H, s), 6.33 (2H, s). 6.9-7.7 (6H, m.), 9.26 (1 H, s.). 9.43 (1.N. s.).

Mass spectrum (t / e): 398 (PRI me R 41. 5- (3- (2,4-difluorophenoxy) - 4-methanesulfonamidophenyl-3-ethylsulfonyl-1,2,4-oxadiazole,

Melting point 168-169 ° C. IR (Nujol): 3310.1615.15565.1510.

Nuclear Magnetic Resonance Spectrum (dimethylsulfrxide - de, 5): 1.30 (t, 3-7 Hz), 3.30 (ZN, s.). 3.6V (2H, q., 3 7 Hz). 7.2-8.0 (6H, m.), 10.15 (lH, s.).

Mass spectrum (t / e): 459 (M4), 367, 326. In order to illustrate the usefulness of compound (I), the pharmacological test data of a typical compound of formula (I) are given below.

Anti-inflammatory activity; Test 1.

The effect of this drug on stimulated arthritis ,, Method :,

Ten Sprague-PaWley female rats were used for each test group. By subcutaneous injection, microbacterium tuberculosis (Asuat strain B) was introduced into the hind right paw at a dose of 0.5 mg. suspended in 6.05 ml of liquid paraffin. Injection of a microbacterial agent caused local inflammatory lesions (primary lesions) and then after 10 days secondary lesions were observed as if injected; never on injectable legs. The difference in: the volume of both legs before and after the injection of the stimulator is considered as the degree of arthritis. This medicine was administered orally once a day, sequentially for 23 days, starting from the first day. The results are shown in table 1.

Analgesic activity.

Test 2.

Rating Writhing syndrome in mice caused by acetic acid.

Methodology:

For each test group, ten ddy male mice were used. Rating syndrome (Writhing) was achieved by administering intraperitoneal injection to mice with 20 ml / kg of 0.6% acetic acid. Mice were observed from 3 to 13 minutes after the injection of acetic acid and the total number of pain of the Rayting was recorded. The drug was administered orally 1 hour before the injection of acetic acid. The frequency of pain in the treated animals was compared with the frequency

Table T

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1799378

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Table b