Route 1 The condensation of N-(2-bromoethyl)-2-nitrobenzamide (I) with 4-(4-fluorobenzoyl)piperidine (II) by means of Na2CO3 in refluxing methyl isobutyl ketone gives N-[2-[4-(4-fluorobenzoyl)-2-piperidinyl]ethyl]-2-nitrobenzamide (III), which is reduced with H2 over Pt/C in methanol yielding the corresponding amino derivative (IV). Finally, this compound is cyclized with urea (V) in refluxing xylene. | | Intermediates: | Serial No. | [1,1-biphenyl]-4-yl(phenyl)methanone | (V) | [[(E)-1-butyl-4-iodo-1-methyl-3-butenyl]oxy](trimethyl)silane; (E)-1-butyl-4-iodo-1-methyl-3-butenyl trimethylsilyl ether | (I) | | (II) | methyl 7-[(1R,4S)-2-oxo-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]heptanoate | (III) | methyl 7-[(1R,2S,3R)-2-[(E)-4-methyl-4-[(trimethylsilyl)oxy]-1-octenyl]-5-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]heptanoate | (IV) | | Reference 1: Janssen, C.G.M.; Lenoir, H.A.C.; Thijssen, J.B.A.; Knaeps, A.G.; Verluyten, W.L.M.; Heykants, J.J.P.; Synthesis of 3H- and 14C-ketanserin. J Label Compd Radiopharm 1988, 25, 7, 783-92. | Route 2 By condensation of 2,3-dihydro-5H-oxazole[2,3-b]quinazolin-5-one (I) with 4-(4-fluorobenzoyl)piperidine (II) in refuxing toluene. | | Intermediates: | Serial No. | | (II) | 2,2-dimethylmalonic acid | (I) | | Reference 1: Signorini, R.; Verga, A. (Ravizza SpA); Process for preparing ketanserine. EP 0098499; IT 1155357 . | Route 3 By reaction of 4-(p-fluorobenzoyl)piperidine (I) with 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (II) by means of Na2CO3 in refluxing 4-methyl-2-pentanone.The starting compounds are prepared as follows:1) The Grignard reaction of N-benzyl-4-cyanopiperidine (III) with p-fluorophenylmagnesium bromide (IV) ethyl ether gives N-benzyl-4-p-fluorobenzoyl)piperidine (V), which by reaction with Na2CO3 and ethyl chloroformate (A) is converted into N-ethoxycarbonyl-4-(p-fluorobenzoyl)piperidine (VI). Finally, this compound is hydrolyzed with 48% HBr to give (I).2) The reaction of ethyl anthranilate (VII) with ethyl chloroformate (A) in refluxing xylene gives ethyl 2-(ethoxycarbonylamino)benzoate (VIII), which is cyclized with 2-aminoethanol (B) at 170 C to afford 3-(2-hydroxyethyl)-2,4-(1H,3H)-quinazolinedione (IX). Finally, this compound is treated with SOCl2 in refluxing chloroform to afford (II). | | Intermediates: | Serial No. | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | (A) | 3-hydroxy-2-methoxypropyl octadecylcarbamate | (B) | 2-[(E)-(dimethylamino)methylidene]-1-(3-methoxyphenyl)-1,3-butanedione | (IV) | | (I) | 3-(4-chlorophenyl)-3-methylpentanedioic acid | (III) | 2-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetic acid | (V) | ethyl 2-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate | (VI) | ethyl 2-[(E)-2-(5-methyl-2-nitrophenyl)hydrazono]propanoate | (II) | ethyl 4-methyl-7-nitro-1H-indole-2-carboxylate | (VII) | 4-methyl-7-nitro-1H-indole-2-carboxylic acid | (VIII) | 4-methyl-7-nitro-1H-indole | (IX) | | Reference 1: Van Der, M.; Keninis, L.; Vandenberk, J.; Van Heertum, A. (Janssen Pharmaceutica NV); Piperidinylalkyl quinazoline compounds, composition and method of use. EP 0013612; JP 55105679; US 4335127 . Reference 2: Blancafort, P.; Paton, D.M.; Serradell, M.N.; Castaner, J.; Ketanserin. Drugs Fut 1981, 6, 11, 684. | | | |