Europäisches Patentamt *EP001477474A1* (19) European Patent Office Office européen des brevets (11) EP 1 477 474 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07C 221/00, C07C 223/02 17.11.2004 Bulletin 2004/47 (21) Application number: 03425306.2 (22) Date of filing: 13.05.2003 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Banfi, Aldo HU IE IT LI LU MC NL PT RO SE SI SK TR 20131 Milano (IT) Designated Extension States: • Mancini, Alfredo AL LT LV MK 26020 Spinadesco (Cremona) (IT) (71) Applicant: Clariant Life Science Molecules (Italia) (74) Representative: Pistolesi, Roberto et al SpA Dragotti & Associati SRL 21040 Origgio (Varese) (IT) Galleria San Babila 4/c 20122 Milano (IT) (54) Process for the synthesis of N-methyl-N-phenylaminoacrolein (57) A process is disclosed for manufacturing N-me- thyl-N-phenylaminoacrolein of formula (I) wherein R is a C3-C4 alkyl, said process being charac- terized in that the reaction between N-methylformanilide and said alkyl vinyl ether of formula (III) is carried out in the presence of phosgene, diphosgene or triphosgene which comprises reacting N-methylformanilide and an in a solvent selected from dioxane, acetonitrile and/or alkyl vinyl ether of formula (III) chlorobenzene. EP 1 477 474 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 477 474 A1 2 Description [0003] More in details, compound (I) can be converted into Fenal, by reaction with compound (IV) [0001] This invention relates to the synthesis of N-me- thyl-N-phenylaminoacrolein of formula (I) 5 10 15 and its use for the preparation of 3-[3-(4-Fluorophenyl)- 1-(1-Methylethyl)-1H-Indol-2-yl]-2-Propenal (II), herein- after referred to as "Fenal", 20 in acetonitrile in the presence of POCl3, as disclosed in WO 84/82131 and US-4739073. [0004] Methods for manufacturing (I) are for instance disclosed in J.O.C., 57, 3250-3252 (1992), GB-945536, and US-5118853. More in details, the J.O.C.'s article 25 discloses a method in which N-methylformanilide is re- acted in dichloromethane with ethyl vinyl ether in the presence of POCl3; GB-945536 discloses a method in which N-methylformanilide is reacted in dichloroethane with ethyl vinyl ether in the presence of phosgene; US- 30 5118853 discloses a method in which N-methylformani- lide is reacted in dichloromethane with ethyl vinyl ether in the presence of oxalylchloride. [0005] All the above methods are however character- ized by the use of low boiling chlorinated solvents which, 35 for well known safety reasons, are normally avoided in industrial processes. The purpose of the present inven- Background of the invention tion is therefore that of finding an alternative method for manufacturing Fenal which is devoided of the draw- [0002] Fenal is used as starting material for the prep- backs of the known methods and which may possibly aration of compounds having HMG-CoA reductase in- 40 afford higher yields. hibiting activity, such as Fluvastatin (CAS Registry number 93957-54-1), whose chemical formula is report- Description of the invention ed here-below: [0006] According to the process of the present inven- 45 tion, (I) is obtained in one step by adding phosgene (1.0-1.3 equivalents) or diphosgene (0.5- 0.65 equiva- lents) or triphosgene (0.34 - 0.43 equivalents) to a so- lution of N-methylformanilide (1 equivalent) and an alkyl vinyl ether of formula (III) (1÷ 2 equivalents, preferably 50 1 equivalent) 55 2 3 EP 1 477 474 A1 4 where R is a C3-C4 alkyl, preferably selected from ethyl, about 7 by adding sodium hydroxide 30% aqueous so- n-propyl, n-butyl, isobutyl, in a solvent selected from di- lution (55 g). After separation of the phases, the aque- oxane, acetonitrile and/or chlorobenzene; the reaction ous layer is extracted with tert-butyl methyl ether (70 ml) is carried out at a temperature of between 0°C and and the combined organic layers are evaporated under 50°C, preferably at 15÷25°C (even more preferably at 5 reduced pressure. To the residue tert-butyl methyl ether about 20°C). (50 ml) is added and the mixture is cooled at - 15°C for [0007] The reaction work-up can be carried out by 90 minutes. The precipitate is filtered on Buchner, adding an aqueous solution of alkaline hydroxide or al- washed twice with tert-butyl methyl ether (25 ml x 2) and kaline carbonate to the reaction mixture in order to hy- dried at room temperature under vacuum overnight. drolyse, in a biphasic system, the obtained intermediate 10 25.21 g of pure compound are obtained (70% molar and thus yield the desired acrolein (I). Alternatively, the yield) solvent can be evaporated and the thus-obtained resi- due can be taken up with an aqueous solution of alkaline Example 2 hydroxide or alkaline carbonate together with a solvent selected from tert-butyl methyl ether, chlorobenzene 15 N-methyl-N-phenylaminoacrolein and/or toluene. [0008] After separation of the phases, acrolein (I) is [0015] To a solution of N-methylformanilide (30 g), obtained as crude compound after evaporation to resi- butyl vinyl ether (22.2 g) in 25 ml of clorobenzene under due of the organic layer. stirring at 10°C, a solution of bis-trichloromethylcar- [0009] According to an embodiment of the invention 20 bonate (24.3 g) in 50 ml of clorobenzene is added drop- the thus-obtained acrolein can be re-crystallised from wise in 2 hours. The reaction mixture is kept under stir- tert-butyl methyl ether, hexane, heptane, cyclohexane, ring at room temperature overnight. Water (50 ml) is methanol, ethanol and/or isopropanol (tert-butyl methyl added, the mixture is cooled at about 5-10°C and the ether being the preferred) at a temperature of between pH is corrected to about 7 by adding sodium hydroxide -20°C and 10°C (preferably at about -15°C). 25 30% aqueous solution (50 ml). After separation of the [0010] However, the process of the present invention phases, the aqueous layer is extracted with chloroben- affords, after the hydrolysis, a crude N-methyl-N-phe- zene (50 ml) and the combined organic layers are nylaminoacrolein (I) having such a high purity that the washed with water (20 ml) and evaporated under re- recrystallisation is no longer necessary and which can duced pressure. To the residue tert-butyl methyl ether be used without any further purification for the prepara- 30 (50 ml) is added and the mixture is cooled at - 15°C for tion of Fenal. 1 hour. The precipitate is filtered on Buchner, washed [0011] Therefore, in a preferred variant of the proc- twice with tert-butyl methyl ether (25 ml x 2) and dried ess, the crude (I) coming from the evaporation of the at 30-35°C under vacuum overnight. solvent is dissolved in acetonitrile and used for the prep- 24.66 g of pure compound are obtained (69% molar aration of Fenal (II) according to literature methods. 35 yield) [0012] More preferably, in another variant of the de- scribed process, the crude mixture of the reaction of Example 3a phosgene, diphosgene or triphosgene, N-methylform- anilide and an alkyl vinyl ether of formula (III) in the N-methyl-N-phenylaminoacrolein claimed solvents is used without any purification for the 40 "in situ" preparation of (II). [0016] To a solution of N-methylformanilide (30 g), [0013] The following examples describe representa- butyl vinyl ether (22.2 g) in 25 ml of 1,4-dioxane under tive embodiments of the invention; however it should be stirring at 10-15°C, a solution of bis-trichloromethylcar- understood that they are for purposes of illustration only. bonate (28.3 g) in 50 ml of 1,4-dioxane is added drop- 45 wise in 90 min. The reaction mixture is kept under stir- Example 1 ring at room temperature overnight, then the solvent is evaporated under reduced pressure. Toluene (50 ml) N-methyl-N-phenylaminoacrolein and water (200 ml) are added, the mixture is cooled at about 5-10°C and the pH is corrected to about 7 by add- [0014] To a solution of N-methylformanilide (30 g), 50 ing sodium hydroxide 15% aqueous solution (30 ml). Af- butyl vinyl ether (22.2 g) in 25 ml of 1,4-dioxane under ter separation of the phases, the aqueous layer is ex- stirring at 10-15°C, a solution of bis-trichloromethylcar- tracted twice with toluene (50 ml x 2) and the combined bonate (28.3 g) in 50 ml of 1,4-dioxane is added drop- organic layers are washed with water (50 ml) and evap- wise in 90 min. The reaction mixture is kept under stir- orated under reduced pressure. The obtained residue ring at room temperature overnight, then the solvent is 55 (32.3 g, containing, according to HPLC assay, 28.7 g of evaporated under reduced pressure. Tert-butyl methyl pure product, 81% molar yield) is used for the next step ether (75 ml) and water (55 ml) are added, the mixture of the synthesis without any further purification. is cooled at about 5-10°C and the pH is corrected to 3 5 EP 1 477 474 A1 6 Example 3b a solution of crude acrolein (116.9 g from Example 4a) in acetonitrile (145 ml) is added dropwise in 60 minutes. 3-[3-(4-Fluorophenyl)-1-(1-Methylethyl)-1H-Indol- [0023] The reaction mixture is then warmed to 60°C 2-yl]-2-Propenal and kept under stirring at 60°C for 6 hours; water (1100 5 ml) is added and after 1 hour at 60°C the formed solid [0017] Use of the crude acrolein coming from Exam- is filtered on Buchner and washed with water (250 ml x ple 3a.