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2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic Acid Choline SaltThe reaction is carried out analogously to that described in Example II except that 159 g of ethyl 2-bromo-2-methylpropanoate are used.This gives 127 g of the expected salt in the form of a white crystalline powder, this being a yield of 70percent. The salt has a purity in excess of 99.8percent.
In a 5L reactor configured to operate under reflux or rectification conditions,A mixture of 1108 g (5.28 mol) of isopropyl 2-bromo-2-methylpropanoate and 650 g (2.79 mol) of (4-chlorophenyl)(4-hydroxyphenyl)methanone at 145 ° C under nitrogen atmosphere heating,Mix thoroughly at the same time.Then add 448 g (3.24 mol) of potassium carbonate,The temperature of the reaction medium was raised to 155 °C.The reaction mixture was stirred at this temperature for 4 hours.During this time, the resulting aqueous phase was collected in a distiller.The temperature of the reaction medium was lowered to 145 ° C, and the internal pressure of the reactor was gradually lowered to remove excess bromination reactant by distillation.These conditions were maintained for about 2 hours during which time all of the distillate was collected in a reservoir. The temperature of the mixture was then lowered to 120 ° C, and the reactor was placed under normal pressure, and 1.95 L of propanol was added.The temperature of the mixture was then brought to about 80 ° C to 90 ° C and filtered under nitrogen pressure.The residual solid was washed on the filter with about 0.75 L of hot propanol.The filtrates kept at the same temperature were combined in a 5 L reactor.790 g (2.93 mol) of 45percent choline hydroxide were added stepwise, followed by the addition of 0.80 L of propanol.The reaction mixture was then boiled under normal pressure and the resulting distillate was collected until about 1.60 L of a propanol/water/isopropanol mixture was obtained.The mixture was filtered on a purification filter, and the filtrate was gradually cooled to about 10 ° C with stirring to crystallize the salt.The crystal salt separation was washed with 0.65 L of cold propanol on an aspirator and then dried in an oven under reduced pressure.800 g of the salt in the form of white crystals (i.e., the target product) were obtained (yield = 68percent).
67.5 - 70%
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic Acid Choline SaltA mixture of 1108 g (5.28 mol) of isopropyl 2-bromo-2-methylpropanoate and 650 g (2.79 mol) of (4-chlorophenyl)(4-hydroxyphenyl)methanone is heated at 145° C. under a nitrogen atmosphere, with thorough stirring, in a 5 l reactor equipped for operation under reflux or distillation. 448 g (3.24 mol) of potassium carbonate are then added and the temperature of the reaction medium is raised to 155° C. The reaction mixture is stirred at this temperature for 4 hours. During this period the aqueous phase produced is collected in the distillate. The temperature of the reaction medium is reduced to 145° C. and the internal pressure of the reactor is lowered gradually so as to remove the excess brominated reactant by distillation. These conditions are maintained for about 2 hours, during which time all the distillates are collected in a receiver. The temperature of the mixture is then reduced to 120° C. and, with the reactor at atmospheric pressure, 1.95 l of propanol are added. The mixture is then at a temperature of about 80-90° C. and is filtered under nitrogen pressure. The residual solid is rinsed on the filter with about 0.75 l of hot propanol. The filtrates, maintained at the same temperature, are combined in the 5 l reactor and 790 g (2.93 mol) of a 45percent aqueous solution of choline hydroxide are added gradually, followed by 0.80 l of propanol. The reaction mixture is then brought to the boil at atmospheric pressure and the distillate produced is collected until about 1.60 l of a propanol/water/isopropanol mixture have been obtained. The mixture is filtered on a clarifying filter and the filtrate is gradually cooled down to a temperature of about 10° C., with stirring, in order to crystallize the salt. The crystalline salt is separated off and washed with 0.65 l of cold propanol on an aspirator and then dried in an oven under reduced pressure.This gives 824 g of the expected salt in the form of white crystals (yield=70percent).The purity of the salt obtained is checked by HPLC, the assay being performed by the method described for fenofibrate in the European Pharmacopeia or the US Pharmacopeia. The fenofibric acid can be assayed by chromatography against a reference sample. The choline present in the salt is assayed by potentiometry.Analysis of the compound shows a purity in excess of 99.5percent and the absence of impurities in a proportion greater than 0.1percent.M.p.=213° C.; 2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic Acid Choline SaltA mixture of 100 g (0.43 mol) of (4-chlorophenyl)(4-hydroxyphenyl)-methanone and 148 g (0.82 mol) of methyl 2-bromo-2-methylpropanoate is prepared in a 1 l reactor maintained under a nitrogen atmosphere. The mixture is heated to 145° C., with thorough stirring, and 69 g (0.5 mol) of potassium carbonate are added. The reaction medium is maintained at 145° C. for 3 hours, with thorough stirring, during which time the water formed by the reaction is collected in the distillate. The pressure in the reactor is then gradually reduced in order to remove the excess brominated reactant by distillation. The mixture is then cooled to about 100° C. and 300 ml de n-propanol are added. The resulting mixture is stirred for 10 min at 90° C. and then filtered at this temperature to remove the insoluble mineral salts. The residual solid is rinsed with 100 ml of hot n-propanol, which is combined with the previous filtrates. The solution obtained is placed in the 1 l reactor under a nitrogen atmosphere and 121.5 g (0.45 mol) of a 45percent aqueous solution of choline hydroxide are added. The reaction mixture is stirred for 3 hours under gentle reflux of the solvent and about 240 ml of solvent are then distilled, 130 ml of n-propanol being added to the reactor. The reactor contents are subsequently filtered on a clarifying filter and then cooled slowly to about 15° C. The resulting suspension is filtered on an aspirator and the isolated solid is rinsed with 100 ml of cold n-propanol and then dried in a vacuum oven.This gives 122 g of the expected salt in the form of a white crystalline solid (yield=67.5percent).The purity of the salt obtained is greater than 99.5percent.
Charge 10 gm <strong>[42017-89-0]fenofibric acid</strong> and 90 ml absolute ethanol and 4.5 ml triethylamine in to 250 ml RBF. Stir it for 10-15 minutes to get clear solution. Charge in to 250 ml RBF and charge 4.4 gm choline chloride. Heat it up to reflux temperature to get clear solution. Filter it through hyflo bed and wash it with absolute ethanol (10 ml). Cool it up to ambient temperature. Stir it for 12-15 hours at ambient temperature. Cool it at 0-5 C and stir for 2 hours at 0-5 C. Filter it and suck dry it. Charge wet cake in to 250 ml RBF and 50 ml absolute ethanol. Stir it for one hour at ambient temperature. Filter it and wash it with 10 ml absolute ethanol. Dry it at 50-60 C. Dry wt. - 8.0 gm (yield: -75%).
~ 75%
Example-1 Preparation of Choline Salt of Fenofibric Acid Charge 10 gm <strong>[42017-89-0]fenofibric acid</strong> and 90 ml absolute ethanol and 4.5 ml triethylamine in to 250 ml RBF. Stir it for 10-15 minutes to get clear solution. Charge in to 250 ml RBF and charge 4.4 gm choline chloride. Heat it up to reflux temperature to get clear solution. Filter it through hyflo bed and wash it with absolute ethanol (10 ml). Cool it up to ambient temperature. Stir it for 12-15 hours at ambient temperature. Cool it at 0-5 C. and stir for 2 hours at 0-5 C. Filter it and suck dry it. Charge wet cake in to 250 ml RBF and 50 ml absolute ethanol. Stir it for one hour at ambient temperature. Filter it and wash it with 10 ml absolute ethanol. Dry it at 50-60 C. Dry wt.-8.0 gm (yield: ~75%).
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