SU1709904A3 - Method of hydroximic acid derivatives synthesis - Google Patents

Abstract

This invention relates to the preparation of hydroxamose acid derivatives; you are fflc CH = C

Description

sodium, dried over magnesium sulphate and stripped to an aldol product. The last solution was dissolved in 100 ml of toluene, 1 g of p-toluenesulfonic acid was added to it.  The mixture was kept in a steam bath for 1 hour, cooled, washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and stripped.  Obtain 39.0 g of the desired product, B).   (3 Phenoxyphenyl) -Butene-3 onoxime.  10.0 g of the product from step A and 7 g of hydroxylamine hydrochloride are dissolved in 50 ml of methanol, 15 ml of pyridine are added to the solution.  The mixture was stirred for 1 hour, stripped and redissolved in diethyl ether, washed with 2N aqueous hydrochloric acid and with saturated aqueous sodium chloride solution, dried over magnesium sulfate and stripped.  Obtain 10.2 g of the desired product c).  1-Methyl-3- (3 Phenoxyphenyl) -prop-2-enyl | -a. Cetolidroxamic acid. The product from step B (7.0 g) is dissolved in 50 ml of glacial acetic acid Ki4C LOTA. To the solution is added 2 g cyanboron sodium hydride.  The mixture is stirred at room temperature for 2 hours. An additional portion (0.75 g) of sodium cisnoborohydride is added to it and stirred at room temperature for another 2 hours. 10 ml of acetic anhydride is added to the mixture and stirred for 3 / - h, then the mixture is stripped.  The residue was dissolved in diethyl ether, washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and stripped.  Get S, K-diacetyl derivative.  The derivative is dissolved in 60 ml of methanol.  3 g of anhydrous potassium carbonate is added to the solution.  The mixture was stirred for 0.5 m and water was added thereto, followed by 10 ml of a 0% (w / v) aqueous solution of sodium hydroxide.  The mixture is washed with diethyl ether, poured into 2M hydrochloric acid solution and subjected to an extraction treatment with diethyl ether.  The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and stripped.  The residue is recrystallized from a mixture of diethyl ether and petroleum ether in a 1: 1 ratio. 2.1 g of the expected product is obtained, t, mp, 90-91 ° C, d). Possible enantiomeric separation (+} l-methyl-3- ( 3-phenoxyphenyl) -prop-2-enyl-acetohydrox MO8OI acid.  For separation, chiral KClO is used for liquid chromatography with high resolution of the chiral type 06, equipped with a UV detector with a wavelength of nm, in which the mobile phase is a mixture of methanol with water and acetic acid in the ratio 65: 35: 0.1, containing oxalic acid acid at a concentration of 0.5 mm.  A solution of a concentration of 1 mg / ml of the product of stage B is prepared in a mixture that serves as a sub-phase, and aliquots of 5 µl are introduced into the column.  The two enantiomers are separated with a retention time of 37 min (isomer I, levorotatory) and 3 min (isomer II, dextrorot; i), Example 2, Preparation of (- (-) - j - N-I -methyl -3- (3-phenjsilonyl) -prop 2-yl-acetohydroxamic acid and (-) -N-p-methyl-3- (3-cyoxyphenyl) -prop-2-enyl 2-acetohydroxamic acid.  A), () -1- (3-phenoxyphenyl) -buten-3-one.  The process is carried out analogously to stage A in example 1, B), (+) - () - 1 - (3-phenoxyphenyl) but-1-en-3-one.  11.9 g of the product from step A is dissolved in 100 ml of methanol.  The solution is cooled to -78 C.  Sodium borohydride is added to the solution.  The mixture is stirred for 3 hours. 2 g of NaBHij is additionally added to the mixture.  and stirred for 5 hours, after which the mixture was allowed to warm to room temperature.  After standing overnight, the mixture is stripped, the residue is partitioned between diethyl ether and water (15 ml each), the organic phase is separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and stripped.  51 Get 12.01, g of the desired product c).  () - () -1 (3-phenoxyphenyl) -but-1-en-3 ylchloroacetate.  12.01 g of the product from Step B and 5 chloroacetic acid are dissolved in methylene chloride.  15 g of 1,3-di | diclohexylcarbodiyimid are added to the solution.  The mixture is stirred for 5 minutes.  Then 0.5 g of dimethylaminopyridine is added.  Bring the mixture to a boil and mix for 1 hour.  200 ml of diethyl ether are added to the mixture and filtered.  The filter is washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and stripped.  The residue is dissolved in 100 ml of a mixture of diethyl ether and petroleum ether in a ratio of 1: 1, filtered and stripped.  Obtain 15.7 g of the desired product g).  (4-) - (3-phenoxyphenyl) -but-1-en-3-ol and (-) (3-phenoxyphenyl) -but-1-en-3-ol.  9.5 g of the product from step B are dissolved in 250 ml of a 0.1 M aqueous solution of phosphate buffer at pH 7 in a stream of nitrogen and 150 mg of lipase is added.  In the course of the reaction, a 1 M aqueous solution of sodium hydroxide was added, maintaining the pH at 7 (1.5 ml was added over a period of 27 hours).  After 27 hours, 250 ml of methyl chloride are added, the mixture is dried over magnesium sulfate and stripped.  The residue was eluted through a silica gel column using diethyl ether.  The eluate was monitored by thin layer liquid chromatography and identical fractions were combined and stripped.  3.7 g of (+) (3-phenok syphenyl) -but-1-en-3-ol, e (J-f8, (c.  2.72, ethanol) and 3.7 g of chiral bJ-1- (3-phenoxyphenyl) -but-1-ene-3-yl chloroacetate.  The latter compound is dissolved in 50 ml of methanol, and 1 g of anhydrous potassium carbonate is added to it.  The mixture is stirred for 0.5 h and then stripped.  The residue is partitioned between diethyl ether and water.  The organic layer is separated, washed with a saturated aqueous solution of sodium chloride and stripped.   2.7 g of (-) - eZ-1- (3-phenoxyphenyl) -but-1-en-3-ol are obtained,.  -11.0 (s.  2.82, ethanol).  D).  Chiral O, 0-bis- (tert-butoxycarbonyl) -N-fl-methyl-3 (3-phenoxyphenyl) -prop-2-en 1-yl} -hydroxylamine.  2.6 g of (-) (3-phenoxyphenyl) -but-1-en-3-ol from step D, 2.65 g of N, 0-bis- (tert-butoxycarbonyl) -hydroxylamine and 25 g of triphenylphosphine are dissolved in 30 ml of toluene and cool the solution to -78 ° C in a stream of nitrogen.  A solution of 2.9 g of diethyl azodicarboxylate in 10 ml of toluene is added.  The mixture is allowed to warm to room temperature.  60 ml of petroleum ether 0/60 are added to the mixture, precipitated as a dark resinous mass Pu-P 0.  The mother liquor is decanted and otparivat, getting reddish brown-orange butter-like product, which is passed. through a column of silica gel eluting with methylene chloride.  The eluate is stripped to obtain a pale yellow oil-like product, which is passed through a second column of silica gel, eluting with a mixture of diethyl ether and methylene chloride and petroleum ether 4Q / 60 and in a ratio of 1: (1-8).  Eluate is cleaned.  1.97 g of the expected product is obtained in the form of a colorless butter-like material, which is previously dried in a high vacuum.  E): (+) - J-N-1-ethyl-3- (3-phenoxyphenyl) -prop-2-enyl-3-anhydroxamic acid (isomer and).  1.97 g of the product from step D are dissolved in 12 ml of methylene chloride and 3 ml of trifluoroacetic acid are added under a stream of nitrogen.  The mixture is stirred for 1 hour at room temperature and then stripped to give hydroxylamine as a viscous, reddish-brown-red oil, which is dissolved in 5 ml of methylene chloride.  A solution of 5 ml of pyridine in 10 ml of methylene chloride is cooled to -10 ° C in a stream of nitrogen for 2 minutes and 2 ml of acetyl chloride is added.  Then a solution of a reddish-brown-red butter-like substance is added and the mixture is stirred for 1 hour at 0 ° C, after which it is poured out (mass / volume) citric acid solution (100 ml) and subjected to extraction treatment in 3 100 ml portions diethyl ether.  The combined extracts are washed with a saturated aqueous solution of sodium bicarbonate (50 ml) and 2 portions of 500 ml of water each, dried over sodium sulfate and stripped to obtain a pale yellow gum-like mass.  The gummy mass is dissolved in 25 ml of methanol. 1.1 g of potassium carbonate is added to the solution. The mixture is stirred for 0.5 h, then stripped.  The residue is partitioned between 100 ml of diethyl ether and 100 ml of water.  The organic phase is separated and extracted with a 1M aqueous solution of sodium hydroxide (100 ml).  The basic solvent was acidified with an excess of citric acid and extracted by extraction in 2 portions of 100 ml each of diethyl ether.  The combined extracts are washed with 100 ml of water, dried over sodium sulfate and stripped to give a tan resin-like mass, which is dissolved in a mixture of ethyl acetate and C0 / 6 petroleum ether in a 1: 2 ratio, initiating partial crystallization.  The solid formed is filtered off, recrystallized from a mixture of ethyl acetate and petroleum ether in a ratio of 1: 2, and dried under vacuum.  0.17 g of a pale cream solid is obtained with a melting point of 83-85 ° C, s (° C + 1.3 ° cement material).  The filtrate from the initial crystallization operation is stripped off.  The residue is passed through a silica gel column, eluting with diethyl ether.  The eluate is stripped off.  Get the target product in the form of a pale yellow resinous mass, which is dried in a high vacuum to obtain 0.32 g of product, E, Q ° (c.  1.00, ethanol).  An analysis of the product with a chiral liquid chromatographic method with high resolution (stage d) showed the presence of an enantiomeric excess of 90 (the ratio between isomer II and isomer I 95: 5) In accordance with the procedures in steps A and E (+) (3- phenoxyphenyl) -but-1-en-3-ol from stage G through 17 is the conversion to {-) - j-M-1-methyl-3- (3-phenoxyphenyl) -prop-2-enyl-acetohydroxamic acid (isomer I), ml -98.7 °, enantiomeric excess (the ratio between isomer I and isomer II is 93: 2).  PRI me R 3.  Getting b.  -1-methyl-3 3- (4-chlorophenoxy) -phenyl-prrp-2-enyl-acetohydroxamic acid.  BUT) . g, J 01 (-Chlorphenoxy) -phenyl} -buten-3-one.  2 ml 10 n.  an aqueous solution of sodium hydroxide is added to a solution of 3- (α-chlorophenoxy) -benzaldehyde (23.3 g) in 150 ml of acetone and vigorously stirred.  After a few minutes of stirring, the temperature is raised to. The mixture is left for 5 minutes and then poured into 600 ml of a 2M aqueous solution of hydrochloric acid and subjected to extraction treatment with 200 ml of a mixture of diethyl ether and petroleum ether in a 1: 1 ratio. The extract is washed with water and saturated solution sodium chloride, dried over magnesium sulphate and stripped.  An aldol product is obtained which is dissolved in 300 ml of toluene.  1 g of p-toluenesulfonic acid is added to the solution.  The mixture was kept at an elevated temperature for 1 hour, cooled, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried over magnesium sulfate and stripped.  The residue is passed through a column of silica gel, eluting with a mixture of methylene chloride and petroleum ether 0/60 (in a 1: 1 ratio first, and then 3: 1).  The eluate is stripped off.  19 g of the expected product are obtained.  B).   -1 - C-C-Chlorophenoxy) -phenyl-buten-3-onoxime.  19 g of the product from step A and 6.9 g of hydroxylamine hydrochloride are dissolved in 100 ml of methanol. 20 ml of pyridine are added to the solution.  The mixture is stirred for 1 h, stripped, again dissolved in 200 ml of diethyl ether, washed with 2N.  an aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and stripped.  20.3 g of the desired product B) are obtained.  E-K- (1-Methyl-3- 3- (4-chlorophenoxy) -phenyl-prop-2-enyl-acetohydroxamic acid.  20 g of the product from step B are dissolved in 100 ml of glacial acetic acid.  22 g of sodium cyanoborohydride are added to the solution (in separate portions and in a stream of nitrogen for 1.5. The mixture is stirred for another 1.5 h, and then added, an additional portion (2 g) of sodium cyanoborohydride. The mixture is stirred in for another 0.5 h, 25 ml of acetic anhydride are added to it and stirred for 21 h and stripped.  The residue is dissolved in 300 ml of diethyl ether, washed with 2 portions of 250 ml of water each time, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and stripped.  An H, M-diacetyl derivative is obtained, which is dissolved with 8,100 ml of methanol, 10 g of anhydrous potassium carbonate is added to it.  The mixture is stirred for 0.5 h and stripped.  The residue is dissolved with 8,250 ml of a 2M aqueous solution of sodium hydroxide and washed with 2 portions of 250 ml of diethyl ether. The basic solution is cooled with ice, its pH is adjusted to 3.0 by addition of concentrated hydrochloric acid and extracted with too ml of diethyl the ether.  The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and stripped.  13 g of the expected product are obtained, which is recrystallized from a mixture of diethyl ether and petroleum ether to obtain 1 g of the substance, t. square  86-87 ° C.  An example.  Preparation of -methyl-3-3- (4-fluorophenoxy) -phenyl-prop-2-enyl-7-acetohydroxanoic acid.  BUT).  3- (5-Fluorophenoxy) -toluene.  1.80 g of sodium hydride is suspended in 51.3 g of 3-bromotolurla.  While stirring, 8.40 g of 4-fluorophenol is added to the suspension during 0.25 hours.  The mixture is kept at 45 ° C until the bubbling stops (after 0.5 hT. After cooling, 3.75 g of cuprous chloride is added, and then with further cooling, 12 g of tris (3,6-dioxaheptyl) are added over 10 minutes -amine  The mixture is maintained at a nitrogen flow for 4 hours.  After cooling, the mixture is treated with 100 ml of 2M aqueous hydrochloric acid solution and extracted with diethyl ether.  The extract is washed with 2 portions of 100 ml of 2M aqueous hydrochloric acid solution, 2M aqueous solution of sodium hydroxide solution and 2 portions of 100 ml of water each, then treated with charcoal, filtered through a Kaiflo filter and stripped.  The residue is distilled under reduced pressure. The desired product is obtained c.   .  t. kip  130-135 ° C at a residual pressure of 10 mm Hg. Art.  B).  1-Dibromomethyl-3- (4-fluorophenoxy) benzene, A mixture of 9.0 g of the product of stage A and 17.45 N-bromosuccinimide (NBS) in 100 ml of fourXX carbon chloride is refluxed for 3 hours in the presence of UV -lamps.  The mixture is treated with 50 mg of azoisobutyronitrile (AIBN) at the beginning of the boil, and then after 3/4 h and 1.5 h.  The mixture is cooled, an additional 2.44 g of NBS and 50 mg of AIBN are added to it, heated, irradiated at elevated temperature for 1.5 h, cooled and filtered.  The residue is washed with carbon tetrachloride.  The filtrate and washings are combined and stripped.  An orange-brown butter-like product is obtained, which is dried under high vacuum, resulting in a yield of 17.97 g of the expected product.  I c).  3- (4-fluorophenoxy) -benzaldehyde.  A solution of 16.04 g of the product of stage B in a mixture of 100 ml of ethanol and 25 ml of water is treated with 13.37 g of precipitated calcium carbonate.  The mixture is heated under reflux for 20 hours.  After cooling, the mixture is filtered.  The filtrate is stripped.  The residue is dissolved in 100 ml of a 2M aqueous solution of hydrochloric acid. followed by extraction treatment with 200 ml of diethyl ether.  The extract is washed with 100 ml of water, dried over sodium sulfate and stripped to give an ice-yellow oil-like material, which is distilled under reduced adhesion.  17 8.90 g of the expected product are obtained with the ton.  kip  lOO-IBO C floor residual pressure.  0.2 mmHg  Art.  D).  B1 - W-C-Fluorophenoxy) -phenyl-buten-3-one.  A mixture of 8.9 g of the product from step B with 6.8 g of dimethylacetylmethylphosphine 6 (Nata, 11.37 g of anhydrous potassium carbonate and 100 ml of dry THF is kept in a stream of nitrogen at 50-55 ° C for 20 h.  The mixture is then cooled and filtered.  The residue was washed with THF. The filtrate and the washing liquid were combined and stripped to give a pale orange oil-like material, which was passed through a silica gel column, eluting the mixture of diethyl ether and petroleum ether in a ratio. 1: 2.  The eluate is stripped and dried under high vacuum.  5.59 g of product is obtained in the form of a very pale yellow oily viscous substance.  D) 3 3 - (+ Fluorophenoxy) -phenyl-buten-3-onoxime.  5.59 g of the product of stage G and 2.28 g of hydroxylamine hydrochloride are dissolved in 75 ml of methanol, 5.28 ml of pyridine is added over 0.5 h and the mixture is stirred for a further 0.75 h.  Next is the mixture. Stripped, re-dissolved in diethyl ether, washed with 2 portions of 100 ml of 2M aqueous hydrochloric acid and 200 ml of water, dried over sodium sulfate, stripped and dried under high vacuum.  5.97 g of the expected product are obtained in the form of a very pale yellow, viscous, oil-like material, which even partially crystallizes.  E).  And -M- {1- 3 - (- Fluorophenoxy) -phenyl-but-1-ene-3-yl-hydroxylamine 5.92 g of the product from step D and 9.83 g of oxalic acid are dissolved in 50 ml of methanol.  In a stream of nitrogen, 2.74 g of sodium cyanorbide acid is added over 1 hour.  The mixture is stirred for another 3.5 hours  Then, 1.37 g of sodium cyanoborohydride is added to it.  The mixture is stirred for 18 hours.  Another 1.37 g of sodium cyanorbide reed is then added.  The mixture is stirred in -.  for 3 hours and steam off.  The remainder.  treated with 10% (by volume) aqueous sodium bicarbonate solution and subjected to extraction treatment in 3 portions of 150 ml of diethyl ether.  The combined extracts are washed (w / v) with an aqueous solution of sodium bicarbonate and 2 portions of 100 ml each of water, dried over sodium sulfate, stripped and dried under high vacuum.  5.83 g of the expected product are obtained.  g)  E —Y — b-Methyl-3-C-C-fluorophenoxy) -phenyl-prop-2-enyl V-acetohydroxamic acid.  5.83 g of the product from step E and 3.71 g of pyridine are dissolved in 75 ml of dichloromethane.  3.89 g of acetyl chloride is added to the solution over 5 minutes.  The mixture is stirred for 2 hours, diluted with 150 ml of diethyl ether, washed with 3 portions of 100 ml of 2m aqueous aqueous hydrochloric acid, 2 portions of 200 ml of saturated aqueous sodium bicarbonate and 200 ml of water, dried over sodium sulfate and stripped.  Prepared as a pale yellow butter-like material N, an H-diacetyl derivative, which is dissolved in 75 ml of methanol, 5.91 g of anhydrous potassium carbonate is added to it.  The mixture is stirred for 0.5 h and filtered.  The filtrate is stripped.  A tan oil is obtained which is dissolved in 200 ml of diethyl ether, washed with 150 ml of water and subjected to extraction with 100 ml of a 2M aqueous solution of sodium hydroxide.  The aqueous washings and extracts are combined and acidified, and then subjected to extraction with 3 portions of 100 ml of diethyl ether.  The extracts are washed with 150 ml of water, dried over sodium sulfate, and stripped to obtain a pale yellow, oil-like product.  The latter crystallizes upon standing overnight at a temperature in the presence of a mixture of petroleum ether 40/60 with ethyl acetate.  The crystals are filtered, washed with a mixture of petroleum ether +0/60 with ethyl acetate, recrystallized from a mixture of diethyl ether and petroleum ether "O / bO and dried in air.  3.30 g of product are obtained with m. square  81-83 S.  In order to prove the advantages of 0 (-alkylated compounds proposed in comparison with non-alkylated analogs, the tests were carried out using

COAST

and as the proposed - connection,,

The test results are shown in the table.

The results of the study of toxicity within 1 day for oral administration of the proposed compounds (l) in rats.

Compounds (l) were administered orally to rats of the Wistar group at dosages of 50 and 500 mg / kg live weight / day, respectively. With a lower dosage, no clinical signs appeared, with higher dosage over the entire dosing period, animals showed minimal fur and mustache shearing at the end of the 14-day study period and a noticeable decrease in weight gain, followed by reduced intake

food, and, in addition, an increase in liver mass, accompanied by some histopathological and clinical chemical changes associated with the known properties of these compounds that affect the microsomal liver enzyme.

Thus, the proposed method allows to obtain compounds that are highly effective in inhibiting lipoxygenase and cyclooxygenase.

Claims (1)

Invention Formula The method of obtaining derivatives guide. roxamic acid of general formula 6 0 Ar-0-V-CH CH-CH-N (OH) COR W where is ag  phenyl which can be substituted by halogen, W R C-Cd-alkyl, -C-C-alkyl, distinguished by / i and s so that the connection is common formulas -Ag-O-CH CH-CH-N (OH) H;  W where Ar and W - have the indicated meanings and are reacted with an acylating reagent in an organic solvent medium. maximum dose, h Morska More than 6 3.7 The time at which the concentration of LTB4 in in vivo rises to 50 from the initial value (orally), h % reduction in P1P caused by treatment with OA aerosol {10 mg / ml for 5 seconds 6 hours after dosing per dose In vitro inhibition of UK 50, μM: 5-lipoxygenase cyclooxygenase 3.8 More than 8 eleven 52 0.06 0.08 1.0 1.0