-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】3-[7-(3-Benzylureidomethyl)-4-oxo-4H-quinolizin-2-ylcarboxamido]-2(S)-(phenylsulfonamido)propionic acid

【CA登记号】262278-00-2

【分子式】C₂₈H₂₇N₅O₇S

【分子量】577.62069

【开发单位】Shire BioChem (Originator)

【药理作用】ONCOLYTIC DRUGS, Integrin alphavbeta3 (Vitronectin) Antagonists

合成路线1 合成路线2

合成路线1

6-Methylnicotinonitrile (I) is oxidized by means of SeO2 in refluxing dioxane to furnish aldehyde (II). Subsequent condensation of (II) with dimethyl 2-(diethoxyphosphoryl)succinate (III) gives rise to the quinolizine derivative (IV). The cyano group of (IV) is then reduced to the primary amine (V) by catalytic hydrogenation over Pd/C. After protecting amine (V) as the corresponding N-Boc derivative (VI), alkaline hydrolysis of the methyl ester group provides acid (VII) (1). Coupling of acid (VII) with (S) t-butyl 3-amino-2-(benzenesulfonylamino)propionate (VIII) by means of HATU leads to amide (IX) (1,2).

参考文献中间体

【1】 Rej, R.; Lamothe, S.; Zacharie, B.; Labrecque, D.; Courchesne, M.; Falardeau, G.; Abbot, S.; Wang, W.; Chan, L.; Meerovitch, K.; Bergeron, F.; Attardo, G.; Synthesis and in vitro potency of quinolizinone-based alphavbeta3 receptor antagonists. Proc Am Assoc Cancer Res 2002, 43.
【2】 Attardo, G.; Lamothe, S.; Rej, R.; Zacharie, B.; Falardeau, G.; Labrecque, D.; Courchesne, M.; Abbott, S. (Shire BioChem Inc.); Quinolizinones as integrin inhibitors. EP 1115724; US 6630488; WO 0017197 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	63672	6-methylnicotinonitrile	C₇H₆N₂	详情	详情
(II)	63673	6-formylnicotinonitrile	C₇H₄N₂O	详情	详情
(III)	63674	dimethyl 2-(diethoxyphosphoryl)succinate	C₁₀H₁₉O₇P	详情	详情
(IV)	63675	methyl 7-cyano-4-oxo-4H-quinolizine-2-carboxylate	C₁₂H₈N₂O₃	详情	详情
(V)	63676	methyl 7-(aminomethyl)-4-oxo-4H-quinolizine-2-carboxylate	C₁₂H₁₂N₂O₃	详情	详情
(VI)	63677	methyl 7-{[(tert-butoxycarbonyl)amino]methyl}-4-oxo-4H-quinolizine-2-carboxylate	C₁₇H₂₀N₂O₅	详情	详情
(VII)	63678	7-{[(tert-butoxycarbonyl)amino]methyl}-4-oxo-4H-quinolizine-2-carboxylic acid	C₁₆H₁₈N₂O₅	详情	详情
(VIII)	31423	tert-butyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate	C₁₃H₂₀N₂O₄S	详情	详情
(IX)	63679	tert-butyl (2S)-3-{[(7-{[(tert-butoxycarbonyl)amino]methyl}-4-oxo-4H-quinolizin-2-yl)carbonyl]amino}-2-[(phenylsulfonyl)amino]propanoate	C₂₉H₃₆N₄O₈S	详情	详情

合成路线2

Selective deprotection of the N-Boc group of (IX) is accomplished by means of trifluoroacetic acid in CH2Cl2 at 0 C. The resultant primary amine (X) is then coupled to benzyl isocyanate (XI) to furnish urea (XII). Then, acidic cleavage of the tert-butyl ester group of (XII) leads to the title carboxylic acid (1,2).

参考文献中间体

【1】 Rej, R.; Lamothe, S.; Zacharie, B.; Labrecque, D.; Courchesne, M.; Falardeau, G.; Abbot, S.; Wang, W.; Chan, L.; Meerovitch, K.; Bergeron, F.; Attardo, G.; Synthesis and in vitro potency of quinolizinone-based alphavbeta3 receptor antagonists. Proc Am Assoc Cancer Res 2002, 43.
【2】 Attardo, G.; Lamothe, S.; Rej, R.; Zacharie, B.; Falardeau, G.; Labrecque, D.; Courchesne, M.; Abbott, S. (Shire BioChem Inc.); Quinolizinones as integrin inhibitors. EP 1115724; US 6630488; WO 0017197 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	63679	tert-butyl (2S)-3-{[(7-{[(tert-butoxycarbonyl)amino]methyl}-4-oxo-4H-quinolizin-2-yl)carbonyl]amino}-2-[(phenylsulfonyl)amino]propanoate		C₂₉H₃₆N₄O₈S	详情	详情
(X)	63680	tert-butyl (2S)-3-({[7-(aminomethyl)-4-oxo-4H-quinolizin-2-yl]carbonyl}amino)-2-[(phenylsulfonyl)amino]propanoate		C₂₄H₂₈N₄O₆S	详情	详情
(XI)	16730	1-(Isocyanatomethyl)benzene; Benzyl Isocyanate	3173-56-6	C₈H₇NO	详情	详情
(XII)	63681	tert-butyl (2S)-3-({[7-({[(benzylamino)carbonyl]amino}methyl)-4-oxo-4H-quinolizin-2-yl]carbonyl}amino)-2-[(phenylsulfonyl)amino]propanoate		C₃₂H₃₅N₅O₇S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)