5-Methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone

White Solid

(2) Under the protection of nitrogen, add 1500 mL of anhydrous tetrahydrofuran and 108 g of magnesium turnings to the flask, and add a few drops of methyl iodide to raise the temperature to 75 ° C.After stirring and dissolving, 602.1 g of 1-chloro-4-methoxybutane was added dropwise. After the completion of the dropwise addition, the reaction was kept at a constant temperature for 13 hours. After cooling to room temperature, 45.88 g of methyl p-trifluoromethylbenzoate prepared in the step 1 was added dropwise. , 5 g was added dropwise per minute, and the mixture was heated to 70 ° C for 4-6 hours. After being completely cooled, glacial hydrochloric acid was poured into the reaction solution.The solvent tetrahydrofuran is separated by extraction, and the extracted tetrahydrofuran is concentrated. The aqueous layer obtained after extraction is extracted with dichloromethane, and the oil phase is added to the concentrate of tetrahydrofuran.The extract product was obtained, and the obtained product was dried and dried over anhydrous sodium sulfate, and evaporated to give 152.36 g of the product 1- p-trifluorotolyl-5-methoxy-pentanone.The yield of the product was 90.5percent, and the reaction structural formula is shown in Fig. 1.(4-Methoxybutyl)(4-trifluoromethylphenyl)methanone (II) (2) Under the protection of nitrogen, add 1500 mL of anhydrous tetrahydrofuran and 108 g of magnesium turnings to the flask, and add a few drops of methyl iodide to raise the temperature to 75 C.After stirring and dissolving, 602.1 g of 1-chloro-4-methoxybutane was added dropwise. After the completion of the dropwise addition, the reaction was kept at a constant temperature for 13 hours. After cooling to room temperature, 45.88 g of methyl p-trifluoromethylbenzoate prepared in the step 1 was added dropwise. , 5 g was added dropwise per minute, and the mixture was heated to 70 C for 4-6 hours. After being completely cooled, glacial hydrochloric acid was poured into the reaction solution.The solvent tetrahydrofuran is separated by extraction, and the extracted tetrahydrofuran is concentrated. The aqueous layer obtained after extraction is extracted with dichloromethane, and the oil phase is added to the concentrate of tetrahydrofuran.The extract product was obtained, and the obtained product was dried and dried over anhydrous sodium sulfate, and evaporated to give 152.36 g of the product 1- p-trifluorotolyl-5-methoxy-pentanone.The yield of the product was 90.5%, and the reaction structural formula is shown in Fig. 1.(0048) Process for isolation of 5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one Formula II (0049) To a solution of conc. HCl (600 ml) and water (160 organic residue (250 gm) of (1E)+(1Z) of 1-N-hydroxy-5-methoxy-1-[4trifluoromethyl)phenyl]pentan-1-imine and traces of 5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one (obtained after hexane recovery from stage-1 filtrate) was added at temperature 25-30 C. under stirring. The reaction mixture was heated to 67-75 C. and maintained for 13-14 hours followed by cooling the reaction mixture at temperature 25-30 C. Then after hexane (500×2 ml) was added into the reaction mixture and stirred for 15 minutes at 25-30 C. The organic layers were separated and sodium bicarbonate solution (25 gm sodium bicarbonate dissolved in 250 ml water) was added into the hexane layer and stirred for 15 minutes. The layers were separated and water (250 ml) was added into hexane layer and stirred for 15 minutes at temperature 25-30 C. Further the layers were separated and hexane layer was added activated charcoal (12.5 gm) and stirred for 20-30 minutes at temperature 30-35 C. The reaction mixture was filtered and stirred for 5-10 minutes at 25-30 C. followed by cooling at 0 to -5 C. and stirred for 30-40 minutes at 0 to -5 C. The reaction mixture was filtered and dried to get 150 to 175 gm of title compound. HPLC purity: >99%.(0045) Stage-2: Preparation of Crude Fluvoxamine Maleate Formula I (0046) To a prepared solution of dimethyl sulphoxide (575 ml), potassium hydroxide flakes (114.64 gm) and water (69 ml), stage-1 (115 gm) was added at temperature 40-45 C. The reaction mixture was stirred to get clear solution followed by adding 2-chloroethylamine hydrochloride (8636 gm) drop wise into the reaction mixture at temperature 40-45 C. and maintained for 1-2 hour. Water (1150 ml) was added in to the reaction mixture at temperature 25-30 C. and stirred for 20-25 minutes. Then toluene (575 ml×2) was added and stirred for 30 minutes and preceded for separation of layers followed by washing the toluene layer with water (1150×5 ml). The solution of maleic acid (48.47 gm) dissolved in water (98 ml) was added into above obtained toluene layer and stirred at temperature 25-30 C. for 2-3 hours. The reaction mixture was cooled to 0-5 C. and maintained for 30-40 minutes at the same temperature. The obtained material was washed with toluene, filtered and such dried. The wet cake was then added hexane (600 ml) and stirred for 30 minutes at temperature 25-30 C., filtered, washed with hexane and dried to get 161 gm of title compound. HPLC purity: >98.5%(0043) Stage-1: Preparation of (1E)-N-hydroxy-5-methoxy-1-(4-trifluoromethyl phenyl)pentan-1-imine Formula III (0044) To a stirred solution of 5-methoxy-1 -(4-trifluoromethylphenyl)pentan-1 one (150 gm) in methanol (750 ml), sodium carbonate (granule) (72 gm) and hydroxylamine hydrochloride (59.64 gm) were added at temperature 25-30 C. The reaction mass was heated 45-50 C. for 10-15 minutes followed by maintaining the reaction mass at temperature 45-50 C. for 8-9 hours under stirring. The reaction mass was cooled to 25-30 C. and filtered under vacuum to remove unreacted inorganic matter, then distilled out the methanol completely from the collected filtrate under vacuum at temperature below 50 C. The obtained slurry was cooled to 25-30 C. and water (300 ml) was added into the residue followed by the addition of hexane (300×2 ml) and stirred for 30 minutes. The layers were separated. The collected organic layer was stirred for 5-10 minutes at temperature 25-30 C. followed by cooling the mass at temperature -5 C. to -10 C., stirred for 30-40 minutes and filtered at the same temperature. The product was suck dried at -5 to -10 C. and further in vacuum at 25-30 C. for 2-3 hours to give 138- 142 gm of title compound. HPLC purity: >98.5%5-Methoxy-4'-trifluoromethylvalerophenone O-(2-aminoethyl) oxime maleate (1:1). 20.4 Mmol (5.3 g) of (4-Methoxybutyl)(4-trifluoromethylphenyl)methanone (II) A dry three neck glass assembly, under dry nitrogen atmosphere, is charged with 150 g (6.17 moles) of magnesium and 2 L of anhydrous tetrahydrofuiran (THF). A small amount of iodine crystals or 1, 2-dibromoethane is added to facilitate the initiation of Grignard reaction. The contents of the flask are heated to 75° C. and 975 g (5.84 moles) of 1-bromo-4-methoxybutane is added slowly at such a rate that the reaction maintains a spontaneous gentle reflux until the end of its addition. The Grignard reagent thus formed is cooled to 10 to 20° C. and a solution of 500 g (2.92 moles) of 4-trifluoromethylbenzonitrile in 2 L of tetrahydrofuran is introduced during a period of 1 hour to 2 hours while maintaining the reaction temperature at 16+-2° C. by external cooling, if necessary. Thereafter the temperature is raised gradually to 60 to 70° C. over a period of 1 hour and further continued at that temperature until the reaction has gone to completion. The reaction mass is cooled, then quenched into ice cold hydrochloric acid and the THF layer is separated and concentrated. The aqueous layer is further extracted with dichloromethane which is added to the concentrate of the THF layer. The resulting dichloromethane solution washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure to obtain a crude product, which is further purified by high vacuum distillation. The compound In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported. purification of 5-MethQxv-1-f4-trifluoromethvl1-phenvl1)-pentan-1-one; The oil of the crude product from the previous step is diluted with 22.5 L ofmethanol. The mixture is heated at 50-55C and then until reflux which ismaintained for 20-40 minutes. The solution is then cooled between 10 to 20C, preferably at 14-16C and 7.5 L of water in 3-5 hours, are added. The suspension is stirred at this temperature for 2 hours and then filtered, washing the cake with water 8.5 g of desired product are obtained with spectroscopic data according to the structure required, purity by HPLC in Area Product, not less than 99% and moisture contents from 10 to 15% (molar yield: 63/67% on the dry product).In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.In the following table the results of purification obtained with dissolutions withdifferent aliphatic or aromatic hydrocarbons, alcohols or mixtures in comparisonwith purification by distillation and temperatures of crystallisation are reported.preparation of 5-methoxy-1-(4-trifluoromethvl-phenyl)-pentan-1-one:coupling step; To the previous reaction mixture cooled between -2-5--8C, a solution of 4-trifluoromethyl-benzonitrile 7.5 kg (43.8 moles) in 14 L of toluene are added in 4-6 hours, preferably from 4.5 to 5.5 hours. The rate of addition is adjust to keep the temperature below 0C. At the end the reaction mixture is kept under stirring additionally for 4 hours more at -1*+1C.Subsequently, the reaction mixture is quenched on aqueous solution of hydrochloric acid 10% w/w.The aqueous organic mixture is diluted additionally with further 5L of toluene, checking the pH at value comprise between 1-5-2. The mixture is heated at40-45C and the organic phase is separated from the aqueous one. The organic phase is then washed three times with water and concentrated until dryness. The yellowish -brownish oil (around 9 kg) of the title compound confirmed by spectroscopic attribution, is purified in the following step.preparation of 5-methoxv-1-(4-trifluoromethvl-phenyl)-pentan-1-one:coupling step; The reaction mixture coming from the cooled between -2-^-8C, a solution of 4-trifluoromethyl-benzonitrile 2.5 kg (14.6 moles) in 4.5 L of 2-Methyltetrahydrofuran are added in 4-6 hours, preferably from 4.5 to 5.5 hours. The rate of addition is adjust to keep the temperature below 0C. At the end the reaction mixture is kept under stirring additionally for 4 hours more at -1*+1 C. Subsequently, the reaction mixture is quenched on aqueous solution of hydrochloric acid 10% w/w.The aqueous organic mixture is diluted additionally with further 2 L of 2-Methyltetrahydrofuran, checking the pH at value comprise between 1+2. Themixture is heated at 40-45C and the organic phase is separated from theaqueous one. The organic phase is then washed three times with water andconcentrated until dryness. The yellowish -brownish oil (around 9 kg) of the titlecompound confirmed by spectroscopic attribution, is purified in the following step.

Fluvoxamine intermediate

Molecular Weight:260.25
XLogP3:3
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:6
Exact Mass:260.10241420
Monoisotopic Mass:260.10241420
Topological Polar Surface Area:26.3
Heavy Atom Count:18
Complexity:256
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes