酮色林 [CAS:74050-98-9]合成路线图解??有机化学网

药物详细合成路线

Chemical Name：	3-[2-[4-(4-Fluorobenzoyl)piperidin-1-yl]ethyl]quinazoline-2,4(1H,3H)-dione
Generic Name：	酮色林;Ketanserin
Other Names：	Ketanserin;R-41468;Perketal;Taseron;Serefrex;Sufrexal
CAS：	74050-98-9
Formula：	C22H22FN3O3
Mole Weight：	395.43734
structure：
Company：	Janssen (Originator), Barrier Therapeutics (Formulation)
Usage：	CARDIOVASCULAR DRUGS, Hypertension, Treatment of, 5-HT2 Antagonists

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.