(+)-SNAP-6552, SNAP-6552-(+), -Drug Synthesis Database

【结构式】

【药物名称】(+)-SNAP-6552, SNAP-6552-(+)

【化学名称】(+)-N3-[3-(4-Cyano-4-phenylpiperidin-1-yl)propyl]-4-(2,4-difluorophenyl)-6-ethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-3,5-dicarboxamide

【CA登记号】

【分子式】C₂₉H₃₂F₂N₆O₃

【分子量】550.61359

【开发单位】Synaptic (Originator)

【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, alpha1-Adrenoceptor Antagonists

合成路线1 合成路线2

合成路线1

The intermediate amine (IV) was prepared by alkylation of 4-cyano-4-phenylpiperidine (I) with N-(3-bromopropyl)phthalimide (II), followed by hydrazinolysis of the substituted phthalimide (III).

参考文献中间体

【1】 Wong, W.C.; Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 1021185; JP 2000506904; WO 9742956 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	43077	4-phenyl-4-piperidinecarbonitrile	40481-13-8	C₁₂H₁₄N₂	详情	详情
(II)	15216	N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione	5460-29-7	C₁₁H₁₀BrNO₂	详情	详情
(III)	43078	1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-4-phenyl-4-piperidinecarbonitrile		C₂₃H₂₃N₃O₂	详情	详情
(IV)	43079	1-(3-aminopropyl)-4-phenyl-4-piperidinecarbonitrile		C₁₅H₂₁N₃	详情	详情

合成路线2

The Knoevenagel condensation between benzyl propionylacetate (V) and 2,4-difluorobenzaldehyde (VI) afforded the benzylidene derivative (VII), which was cyclized with O-methylisourea hemisulfate (VIII), yielding the dihydropyrimidine (IX). This compound, upon reaction with 4-nitrophenyl chloroformate, regioselectively produced the carbamate ester (X). Resolution of the enantiomers of (X) was achieved by condensation with the chiral auxiliary (S)-(-)-alpha-methylbenzylamine (XI) to obtain a mixture of diastereomeric amides, which were separated by flash chromatography. The alpha-methylbenzylaminocarbonyl moiety was then removed from the desired diastereomer (+)-(XII) by treatment with DBU, and the resulting chiral dihydropyridine was again condensed with 4-nitrophenyl chloroformate to give (+)-(X). Coupling of the chiral carbamate (+)-(X) with amine (IV) provided adduct (XIII), which on treatment with aqueous HCl gave the dihydropyrimidinone (XIV). After catalytic hydrogenolysis of the benzyl ester of (XIV), the resulting acid was converted to the title amide by reaction with ammonia in the presence of EDC and DMAP.

参考文献中间体

【1】 Marzabadi, M.R.; Murali Dhar, T.G.; Nagarathnam, D.; et al.; Design and synthesis of novel alpha1a adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety. J Med Chem 1999, 42, 23, 4778.
【2】 Lagu, B.; Nagarathnam, D.; Miao, S.W.; et al.; Design and synthesis of novel alpha1a adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones. J Med Chem 1999, 42, 23, 4764.
【3】 Wong, W.C.; Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 1021185; JP 2000506904; WO 9742956 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	43079	1-(3-aminopropyl)-4-phenyl-4-piperidinecarbonitrile		C₁₅H₂₁N₃	详情	详情
(V)	43080	benzyl 3-oxopentanoate	4949-45-5	C₁₂H₁₄O₃	详情	详情
(VI)	26654	3,4-difluorobenzaldehyde	34036-07-2	C₇H₄F₂O	详情	详情
(VII)	43081	benzyl (Z)-3-(2,4-difluorophenyl)-2-propionyl-2-propenoate		C₁₉H₁₆F₂O₃	详情	详情
(VIII)	26657	O-methyl isourea; [Amino(imino)methoxy]methane	52328-05-9	C₂H₆N₂O	详情	详情
(IX)	43082	benzyl 6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate		C₂₁H₂₀F₂N₂O₃	详情	详情
(X)	43084	5-benzyl 1-(4-nitrophenyl) 6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1,5(6H)-pyrimidinedicarboxylate		C₂₈H₂₃F₂N₃O₇	详情	详情
(XI)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(XII)	43083	benzyl 6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1-([[(1R)-1-phenylethyl]amino]carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate		C₃₀H₂₉F₂N₃O₄	详情	详情
(XIII)	43085	benzyl 1-([[3-(4-cyano-4-phenyl-1-piperidinyl)propyl]amino]carbonyl)-6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate		C₃₇H₃₉F₂N₅O₄	详情	详情
(XIV)	43086	benzyl 3-([[3-(4-cyano-4-phenyl-1-piperidinyl)propyl]amino]carbonyl)-4-(2,4-difluorophenyl)-6-ethyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate		C₃₆H₃₇F₂N₅O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)