CIVENTICHEM CV-4057

Laquinimod is a potent immunomodulator which prevents neurodegeneration and inflammation in the central nervous system.

[N-ETHYL-N-PHENVI-5-CHLORO-1, 2-DIHVDRO-4-HYDROXY-1-METHYL-2-OXO-QUINOLINE-3-CARBOXAMIDE] [5-CHLORO-1, ] [2-DIHYDRO-4-HYDROXY-L-METHYL-2-OXO-QUINOLINE-3-CARBOXYLIC] acid methyl ester (3.0 g), N-ethylaniline (2 eq. 2.88 ml), and heptane (60 ml) were heated and the volatiles, mainly heptane and formed methanol, (32 ml) distilled off during [6] hours and 35 minutes. After cooling to room temperature the crystalline suspension was filtered and the crystals were washed with heptane and dried in vacuum to yield the crude title compound (3.94 g, 98 percent) as white to off-white crystals.Example 3 [N-ETHYL-N-PHENYL-5-CHLORO-1, 2-DIHYDRO-4-HYDROXY-1-METHVL-2-OXO-QUINOLINE-3-CARBOXAMIDE] (reaction in toluene, not part of the invention) [5-CHLORO-1, ] [2-DIHYDRO-4-HYDROXY-L-METHYL-2-OXO-QUINOLINE-3-CARBOXYLIC] acid methyl ester (3.0 g), N-ethylaniline (2 eq. 2.88 ml), and toluene (60 ml) were heated and the volatiles, mainly toluene and formed methanol, (32 ml) were distilled off during 6 hours and 35 minutes. After cooling to room temperature and precipitation of the product with heptane (40 ml), the crystals were filtered and washed with heptane and dried in vacuum to yield the crude title compound (3.58 g, 90 percent yield) as off-white crystals. The crude products were analysed using HPLC and reference compounds, see table 1. Only two by-products were detected in the crude products. Peaks with area-percent below 0. [02percent] are not included.5-Chloro-1, 2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (3.0 g), N-ethylaniline (2 eq 2-2.88 ml), and heptaue (60 ml) were heated and the volatiles, mainly heptane and formed methanol, (32 ml) distilled off during 6 hours and 35 minutes. After cooling to room temperature the crystalline suspension was filtered and the crystals were washed with heptane and dried in vacuum to yield the crude title compound (3.94 g, 98percent) as white to off-white crystals.5-Chloro-1, 2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (3.0 g), N-ethylaniline (2 eq. 2.88 ml), and toluene (60 ml) were heated and the volatiles, mainly toluene and formed methanol, (32 ml) were distilled off during 6 hours and 35 minutes. After cooling to room temperature and precipitation of the product with heptane (40 ml), the crystals were filtered and washed with heptane and dried in vacuum to yield the crude title compound (3.58 g. 90percent yield) as off-white crystals.b) . To a stirred solution of (9) (10 mmol) in anhydrous THF (50 ml) was added sodium methoxide (3.6 mmol as 0.5 M in MeOH) portion-wise under NA mixture of 6 (5.00 g) and N-ethylaniline (5.0 g) in n-heptane (150 mL) was refluxed for 4.0 hours in a Soxhlet apparatus containing 4 A molecular sieves (22.9 g). After cooling the mix- ture the product was isolated as above to furnish 6.54 g (98 percent) of N-ethyl-N-phenyl-5-chloro- l, 2-dihydro-4-hydroxy-l-methyl-2-oxo-quinoline-3-carboxamide (B). 1H-NMR analysis on the isolated product revealed no impurities. Laquinimod acid was prepared according to the method described in U.S. Pat. No. 6, 875, 869: 5-Chloro-1, 2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (3.0 g), N-ethylaniline (2 eq 2-2.88 ml), and heptane (60 ml) were heated and the volatiles, mainly heptane and formed methanol, (32 ml) distilled off during 6 hours and 35 minutes. After cooling to room temperature the crystalline suspension was filtered and the crystals were washed with heptane and dried in vacuum to yield laquinimod acid (3.94 g, 98percent) as white to off-white crystals. Laquinimod acid was converted into laquinimod sodium using the method described in U.S. Pat. No. 6, 077, 851, A solution of 5 M sodium hydroxide was prepared by dilution of a 50percent by weight sodium hydroxide solution (10.0 g) with sterile water to the total volume of 25 ml. N-Ethyl-N-phenyl-1, 2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide (10.0 g) was suspended in ethanol (150 ml) and the previously prepared 5 M sodium hydroxide solution was added to pH of 8-12 (5.6 ml). The reaction mixture was stirred for another 30 minutes at ambient temperature. The resulting precipitation was filtered off and rapidly washed twice with ethanol (2.x.150 ml). The precipitate was then dried in vacuum over P