METHODS OF OBTAINING DL-HYDROX1-BENCENAMIDES BACKGROUND OF THE INVENTION The compounds DL-4-hydroxy-4-phenylalhexamide, DL-3-hydroxy-3-phenylamphenolide and DL-2-hydroxy-2-phenylbutyramide have a broad spectrum of anticonvulsant activity. They protect mice against attacks provoked by pentylenetetrazole, bicuculline, 4-aminopyridine, thiosemicarbazide and against maximum electric shock (Meza Toledo et al, Arzneim, Forsch, 40 (II), 1289 (1990)). They also protect cats and rats against hippocampal kindling (Solís et al, Arch. Neurocien. (Méx.) 1, 99 (1996)). In addition, DL-3-hydroxy-3-phenylpentanamide protects rats against Gamma-butyric acid withdrawal syndrome, a model of focal epilepsy which shows extraordinary resistance to classical antiepileptic drugs (Brailowsky et al, Epilepsy Res. 11 , 67 (1992)). DL-3-hydroxy-3-phenylpentanamide also produces a significant decrease in spike and spike discharges in a congenital epilepsy model of the Strasbourg rat (Brailowsky et al cited above). In order to increase the biological activity of the mentioned amides, a new series of DL-hydroxy-benzenamides was synthesized.
DESCRIPTION OF THE INVENTION 1. Synthesis of DL-2-hydroxy-2- (phenyl or 3 ', 4'-dichlorophenol) hexanamides Compounds 1 and 2 were prepared by a condensation between the respective ketones: valerophenone and 3', 4'-dichlorovalerophenone with trimethylsilyl cyanide, in the presence of zinc iodide, to form the corresponding cyanohydrins, which were partially hydrolysed in acid medium to form amides 1 and 2.
1. 1 Synthesis of DL-2-hydroxy-2-phenyl hexanamide (1) 37.5 g (0.2314 mol) of valerofenone, 1154 g (0.0036 g) were placed in a 500 ml round bottom flask with two nozzles. moles) of zinc iodide, 103 ml of methylene chloride and 26.79 g (0.2698 moles) of trimethylsilyl cyanide. The reaction was maintained with stirring at room temperature for 12 hours. Subsequently, the reaction mixture was concentrated, the residue was cooled, 50 ml of 37% HCl was added, saturated with HCl (g) and left to stand overnight. The solid formed was separated by filtration and recrystallized with benzene to obtain 14 g (29.2%) of 1 with a m.p. 83-84 ° C. IR (ATR): 1668, 3267, 3444 cm'1; 1 H-NMR, 300 MHz (CDCl 3) d: 0.89 (t, 3 H, He, J = 6.69 Hz), 1.32 (m, 2 H, H 5), 1.99 (m, 2 H, H 4), 2.17 (m, 2 H, H 3 ), 3.73 (s, 1H, -OH), 6.07 (sa, 1H, -NH2), 6.54 (sa, 1 H, -NH2), 7.44 (m, 5H,? 2 ·, 3 ·, 4 · .5 ·. 6 ·); 3 C NMR, 75 MHz (CDCl 3) d: 14.15 (C6), 22.98 (C5), 25.64 (C4), 39.02 (C3), 78.81 (C2), 125.59 (C3.5), 127.82 (C4), 128.50 ( 02 ·, 6 '), 142.61 (C), 177.55 (d).
1. 2 Synthesis of DL-2-hydroxy-2- (3'5 4'-dichlorophenyl) hexanamide (2) It was synthesized with the method described in 1.1 for compound 1. A reaction mixture containing: 11.55 g (0.05) was used. moles) of 3 ', 4'-dichlorovalerophenone, 248 mg (0.0007769 moles) of zinc iodide, 25 ml of methylene chloride and 5.8 g (0.0584 moles) of trimethylsilyl cyanide. After concentrating, hydrolyzing (15 ml HCl 37%), filtering and recrystallizing with benzene, 5 g (36.2%) of 2 were obtained with one m.p. 103-104 ° C. IR (ATR): 1671, 3257, 3467 crrf1; 1 H-NMR, 300 MHz (CDCl 3) & 0.86 (t, 3H, H6, J = 7.1 Hz), 1.28 (m, 2H, H5), 1.99 (m, 2H, H4), 2.15 (m, 2H, H3), 3.76 (s, 1H, -OH) , 6.08 (sa, 1 H, -NH2), 6.78 (sa, 1H, -IMH2), 7.39 (d, 1 H, H5-, J = 2 Hz), 7.43 (d, 1H, H6-, J = 2 Hz), 7.68 (s, 1H, Hy); NMR-13C, 75 MHz (CDCl 3) d: 14.34 (Ce), 23.10 (¾), 25.80 (C4), 39.57 (C3), 78.64 (C2), 125.49 (C5), 128.09 (C6), 130.56 (C? ), 132.18 (C3), 132.78 (C4), 143.08 (d), 176.91 (d). 2. Synthesis of DL-3-hydroxy-3- (3,5'-5'-bistrifluoromethylphenyl) pentanamide (3) and of DL-3-hydroxy-3-phenyl heptanamide (4) Compounds 3 and 4 were prepared by a condensation between 3 ', 5'-bistrifluoromethylpropiophenone and valerophenone with ethyl bromoacetate, in the presence of zinc, to form the corresponding hydroxyesters which were treated with ammonium hydroxide to produce amides 3 and 4.
Compound n i R2 3 1 CF3 CF3
2. 1 Synthesis of DL-3-hydroxy-3- (3 ', 5'-bistrifluoromethylphenyl) pentanamide (3)
2. 1.1 Synthesis of ethyl DL-3-idroxy-3- (3 ', 5'-bistrifluoromethylphenyl) pentanoate
To a stirred mixture containing: 38 g (0.1406 mol) of 3 ', 5'-bistrifluoromethylpropiophenone, 29.33 g (0.1757 mol) of ethyl bromoacetate, 30 ml of benzene and 9 ml of anhydrous ethyl ether, was added 14.70 g. (0.2248 moles) of activated zinc and refluxed for 3 hours. The reaction mixture was hydrolyzed with 126 ml of 10% H2SO4 and the organic layer was washed successively with 5% H2SO4 (49 ml), 10% Na2CO3 (18 ml), 5% H2SO4 (20 ml) and finally with water (2 x 50 ml). The benzene layer was saved and the combined acid solutions were extracted with ethyl ether (2 x 50 mL). The ether extracts and the initial benzene solution were combined, dried over anhydrous MgSO4, filtered and concentrated. The residue was distilled under reduced pressure to obtain 34.7 g (68.9%) of ethyl DL-3-hydroxy-3- (3 ', 5'-bistrifluoromethylphenyl) pentanoate which distilled at 151-152 ° C at 25 mm Hg. IR (ATR): 1714, 3491 cm'1; NMR-H, 300 MHz (CDCl 3) d: 0.77 (t, 3 H, H 5, J = 7.6 Hz), 1.09 (t, 3 H, -COOCH 2 -CH 3) J = 7.2 Hz), 1.85 (miAA'Xs), 2H , H4), 2.91 (m (AA '), 2H, H2), 4.04 (m, 2H, -COOCH2 e, J = 7 Hz), 4.55 (sa, 1 H, -OH), 7.76 (s, 1H, ? 4 ·), 7.88 (s, 2H,? 2 · .6); NMR-13C, 75 MHz (CDCb) 5: 7.53 (C5), 13.75 (CCH3), 35.75 (C4), 44.36 (C2), 61.14 (C-0CH2-). 75.04 (C3), 120.98 (C4-, 3.75 Hz), 123.20 (Wax-, 232.5 Hz), 125.52 (C2-, 6 ·, 3J1V9F = 2.8 Hz), 131.45 (C3-, 5 ·, 2J13C19F = 33 Hz) , 148.42 (Ci), 172.51 (d).
2. 1.2 Synthesis of DL-3-hydroxy-3- (3 \ 5'-bistrifluoromethylphenyl) pentanamide (3) A mixture containing 29.1 g (0.0812 mol) of DL-3-hydroxy-3- (3 ', 5'- bistrifluoromethylphenyl) ethyl pentanoate, 100 ml of ethanol and 100 ml of 28% NH 4 OH was cooled to 0 ° C and saturated with NH 3 < ¾ The flask was capped with a rubber stopper and kept at room temperature for 30 days. After the reaction mixture was cooled, 7 g of solid NaCl was added and extracted with ethyl ether (100 ml). The ether extract was concentrated and the residue was recrystallized from water to obtain 7 g (26.1%) of 3 with a m.p. 84-85 ° C. IR (ATR): 1672, 3196, 3359 cm-1; NMR-1H, 300 MHz (CDCb) d: 0.74 (t, 3H, H5, J = 7.40 Hz), 1.81 (m, 2H, H4), 2.72 (s, 1H, H2), 5.28 (s, 1 H, -OH), 5.84 (br s, 1H, -NH2), 6.17 (br s, 1 H, -NH2), 7.77 (s, 1H, H4-), 7.86 (s, 2H,? 2-, 6 ·); C-NMR, 75 MHz (CDCb) d: 7.83 (Cs), 35.92 (¾), 45.53 (C2), 75.71 (Cs), 121.33 (C * 3.75 Hz), 123.78 (CCF3, 1J13C19F = 270.75 Hz) , 125.75 ((¼ ·, ß ·, 3J1V r 4.9 Hz), 131.85 (¾, s, 33 Hz), 148.75 (Cr), 174.71 (Ci). 2.2 Synthesis of DL-3-hydroxy-3-phenyl- heptanamide (4) 2.2.1 Synthesis of ethyl DL-3-hydroxy-3-phenyl heptanoate It was synthesized with the method described in 2.1.1 for DL-3-hydroxy-3- (3 ', 5'-bistrifluoromethylphenyl) ethyl pentanoate A reaction mixture containing: 51.4 g (0.3172 moles) of valerophenone, 66.17 g (0.3965 moles) of ethyl bromoacetate, 66 ml of benzene, 20 ml of anhydrous ethyl ether and 32.40 g (0.4955 moles) was used. activated zinc After hydrolysis, extraction and distillation, 58.8 g (74.1%) of ethyl DL-3-hydroxy-3-phenyl heptanoate was obtained, which distilled at 154-155 ° C at 15 mm Hg. IR (ATR): 1712, 3499 cm'1; H-NMR 400 Hz (CDCIs) d: 0.81 (t, 3H, H7, J = 7.32 Hz), 1.08 (t, 3H, -COOCH2-CH3, J = 6.96 Hz), 1.23 (m, 4H, H5, 6), 1.77 (ddd, 2H, H4, J = 4, 4.6 Hz), 2.88 (m (AA '), 2H, H2), 4.01 (q, 2H, -COOCH2Me, J = 7 Hz) , 4.39 (s, 1H, -OH), 7.21 (d, d, 2H,? 4?, J = 2.4 Hz), 7.31 (dd, 2H,? 3?, 5-, J = 2, 4 Hz ), 7.41 (dd, 1H, H2-, 6-, J = 2.4 Hz); 3 C NMR, 100 MHz (CDCIs) S: 14.02 (C7), 14.05 (CCH3), 23.01 (C6), 25.59 (C5), 43.14 (C4), 45.47 (C2), 60.72 (C-0CH2-). 75.09 (C3), 125.13 (C3-, 5 '), 126.72 (C4, 128.32 (C2-, 6 ·), 2.2.2 Synthesis of DL-3-hydroxy-3-phenyl-heptanamide (4) A mixture containing : 57.8 g (0.2312 moles) of ethyl DL-3-hydroxy-3-phenyl heptanoate410 mL of absolute ethanol and 290 mL of 28% NH40H was cooled to 0 ° C and saturated with NH3 (g). The flask was capped with a rubber stopper and kept at room temperature for four weeks. After the reaction mixture was cooled, 20 g of solid NaCl was added and extracted with three 100-ml portions of ethyl ether each. The combined ether extracts were concentrated and the residue was recrystallized with water obtaining 27.5 g (53.8%) of 4 with a m.p. 93-94 ° C. IR (ATR): 1660, 3219, 3410 crrf1; NMR- ?, 300 MHz (CDCl 3) d: 0.80 (t, 3H, H7l J = 7.1 Hz), 0.99 (m, 2H, H6), 1.24 (m, 2H, H5), 1.77 (m, 2H, H4) , 2.67 (m (AAJ), 2H, H2), 5.13 (s, 1H, -OH), 5.84 (sa, 1H, -NH2), 6.03 (sa, H, -NH2), 7.28 (m, 5H,? 2 ·, 3 ·, 4 ·, 5 ·, 6-); NMR-13C, 75 MHz (CDCl 3) d: 13.90 (C7), 22.81 (Ce), 25.32 (C5), 42.90 (C4), 46.10 (C2), 75.26 (C3), 124.95 (C3-, 5.), 126.55 (C4-), 128.06 (C2, e-), 145.39 (C), 174.95 (d).
3. Synthesis of DL-4-hydroxy-4- (4'-trifluoromethyl-ethyl) -riexanamide (5) Compound 5 was obtained by a condensation between 4'-trifluoromethylpropiophenone with diethyl succinate, in the presence of sodium hydride to form the corresponding hemiesters which were decarboxylated in acid medium, to produce DL-5-ethyl-5- (4'-trifluoromethylphenii) butyrolactone. The treatment of the lactone with ammonium hydroxide led to the amide 5.
3. 1 Synthesis of DL-4-hydroxy-4- (4'-trifluoromethylphenyl) hexanamide (S) 3.1.1 Synthesis of DL-5-ethyl-5- (4'-trifluoromethylphenyl) butyrolactone A mixture containing: 25 g ( 0.1237 moles) of 4'-trifluoromethylpropiophenone, 115 ml of dry benzene, 64.57 g (0.37 1 mole) of diethyl succinate, 8.91 g (0.3712 mole) of sodium hydride and 1.8 ml of absolute ethanol was stirred for 3 hours in an atmosphere of nitrogen. It was then acidified with 26 ml of glacial CH3COOH, diluted with 112 ml of water and extracted with four 50 ml portions of ether each. The combined ether extracts were washed with two 100 ml portions of 5% Na 2 CO 3 and the ether phase was saved. The alkaline solution was acidified with 98% H2SO4 and extracted with two 50 ml portions of ether each. The ethereal fraction obtained from the acid phase was combined with that extracted from the alkaline phase, dried over anhydrous MgSO 4, filtered and concentrated. 69.6 g of a thick product were obtained, to which 99 ml of glacial CH3COOH, 66 ml of 48% HBr and 33 ml of water were added. The reaction mixture was refluxed for 24 hours, concentrated and extracted with four 50 ml portions of ethyl ether each. The combined organic phases were washed with a saturated solution of 5% NaHCO 3 and the ether phase was saved. The alkaline phase was acidified with 98% H2SO4, extracted with ether, the combined ether extracts were concentrated and the residue obtained was treated with 99 ml of glacial CH3COOH, 66 ml of 48% HBr, 33 ml of water and reflux for 40 hours. Subsequently, the obtained solution was treated as previously mentioned. The ethereal fraction of this second treatment was combined with the ethereal solution initially separated from the original reaction. These were washed with a saturated solution of NaCl and dried over anhydrous MgSO 4. Subsequently, it was filtered, concentrated and the residue fractionally distilled under vacuum obtaining 7.8 g (24.4%) of DL-5-etii-5- (4'-trifluoromethylphenyl) butyrolactone which distilled at 152-154 ° C at 30 mm. of Hg. IR (ATR): 1779 cm '; NMR- ?, 400 MHz (CDCIs) d: 0.74 (t, 3H, -CH3), 1.92 (q, 2H, -CH2Me), 2.39 (m, 4H, -CH2-CH2-), 7.47 (m, 4H, ? 2 ·, 3-, 5; «) -13C NMR, 10O MHz (CDCI3) d: 8.28 (C7), 29.85 (C6), 34.8 (C4), 35.26 (C3), 89.55 (C5), 118.78 (Wax) ), 125.75 (Cy.s), 125.92 (C2-, 6-), 129.49 (C4-), 147 (Cv), 1 6.58 (C2). 3.1.2 DL-4-hydroxy-4- (4'-trifluoromethylphenyl) hexanamide (5) A mixture containing: 3.9 g (0.0151 mol) of DL-5-etif-5- (4'-trifluoromethylphenyl) butyrolactone, 15 ml of absolute ethanoi and 15 ml of 28% NH4OH was cooled to 0 ° C and saturated with NH3 (g). The flask was capped with a rubber stopper and kept at room temperature for three weeks. After the reaction mixture was cooled, 1.5 g of solid NaCl was added and extracted with three 10 ml portions of ethyl ether each. The combined ether extracts were concentrated and the residue was recrystallized with water to obtain 1.0 g (24.1%) of 5 with a m.p. 129-130 ° C. IR (ATR): 1682, 3198, 3388 cirf1; 1 H NMR, 400 MHz (CDCl 3) d: 0.74 (t, 3 H, H 6 J = 7.48 Hz), 1.83 (q, 2 H, H 5, J = 7.52 Hz), 2.11 (m, 4 H, H 2, 3), 4.35 (s, 1 H, -OH), 5.63 (sa, 1 H, -NH2), 5.84 (sa, 1 H, -NH2), 7.55 (m (AA'BB '), 4H,? 2 ·, 3 · , HE-); 13 C-NMR, 100 MHz (CDCl 3) d: 7.80 (C6), 30.38 (C3), 36.61 (C5), 36.98 (Cj), 76.78 (C4), 124.6 (Wax), 125.12 (C3., 5.), 126.15 (C2-, 6 '), 128.7 (C4-), 149.94 (C1), 176.85 < Ci).