CRL-42796, -Drug Synthesis Database

【结构式】

【药物名称】CRL-42796

【化学名称】N-[4-(4-Piperidinyl)-2-[2-(4-piperidinyl)ethyl]butyryl]glycyl-2(S)-(naphthalen-2-ylsulfonyl)-beta-alanine dihydrochloride

【CA登记号】255879-67-5, 255880-36-5 (diHCl)

【分子式】C₃₁H₄₇Cl₂N₅O₆S

【分子量】688.72014

【开发单位】Lafon (Originator)

【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

Condensation of 4-vinylpyridine (I) with diethyl malonate (II) affords the bis(pyridylethyl)malonate (III) which, upon acidic hydrolysis and decarboxylation leads to mono-acid (IV). Catalytic hydrogenation of the pyridine rings of (IV) in the presence of Pd/C furnishes the corresponding piperidinyl compound (V), which is further protected as the N-Boc derivative (VI) employing di-t-butyl dicarbonate. Acid (VI) is coupled to glycine methyl ester (VII) via activation with cyanuric fluoride to yield amide (VIII). Then, alkaline hydrolysis of the methyl ester group provides carboxylic acid (IX).

参考文献中间体

【1】 Lesur, B.; Henry, M.; Yue, C.; Giboulot, T. (Laboratoires L. Lafon); Bispiperidines as antithrombotic agents. EP 1098878; FR 2781223; JP 2002520393; US 6333338; WO 0003986 .

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)	45857	4-vinylpyridine		C₇H₇N	详情	详情
(II)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(III)	63020	diethyl 2,2-bis[2-(4-pyridinyl)ethyl]malonate		C₂₁H₂₆N₂O₄	详情	详情
(IV)	63022	4-(4-pyridinyl)-2-[2-(4-pyridinyl)ethyl]butanoic acid		C₁₆H₁₈N₂O₂	详情	详情
(V)	63023	4-(4-piperidinyl)-2-[2-(4-piperidinyl)ethyl]butanoic acid		C₁₆H₃₀N₂O₂	详情	详情
(VI)	63024	4-[1-(tert-butoxycarbonyl)-4-piperidinyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}butanoic acid		C₂₆H₄₆N₂O₆	详情	详情
(VII)	17568	methyl 2-aminoacetate		C₃H₇NO₂	详情	详情
(VIII)	63025	tert-butyl 4-(5-[1-(tert-butoxycarbonyl)-4-piperidinyl]-3-{[(2-methoxy-2-oxoethyl)amino]carbonyl}pentyl)-1-piperidinecarboxylate		C₂₉H₅₁N₃O₇	详情	详情
(IX)	63026	2-[(4-[1-(tert-butoxycarbonyl)-4-piperidinyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}butanoyl)amino]acetic acid		C₂₈H₄₉N₃O₇	详情	详情

合成路线2

After activation of acid (IX) as the mixed anhydride with isobutyl chloroformate, coupling with the mono-protected diaminopropionate (X) leads to amide (XI). Subsequent removal of the N-carbobenzoxy group by catalytic hydrogenolysis gives amino ester (XII). This is then acylated by 2-naphthalenesulfonyl chloride (XIII), yielding sulfonamide (XIV).

参考文献中间体

【1】 Lesur, B.; Henry, M.; Yue, C.; Giboulot, T. (Laboratoires L. Lafon); Bispiperidines as antithrombotic agents. EP 1098878; FR 2781223; JP 2002520393; US 6333338; WO 0003986 .

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)	63026	2-[(4-[1-(tert-butoxycarbonyl)-4-piperidinyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}butanoyl)amino]acetic acid		C₂₈H₄₉N₃O₇	详情	详情
(X)	26615	ethyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate		C₁₃H₁₈N₂O₄	详情	详情
(XI)	63027	tert-butyl 4-[(10S)-3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}-10-(ethoxycarbonyl)-4,7,12-trioxo-14-phenyl-13-oxa-5,8,11-triazatetradec-1-yl]-1-piperidinecarboxylate		C₄₁H₆₅N₅O₁₀	详情	详情
(XII)	63028	tert-butyl 4-{3-{[(2-{[(2S)-2-amino-3-ethoxy-3-oxopropyl]amino}-2-oxoethyl)amino]carbonyl}-5-[1-(tert-butoxycarbonyl)-4-piperidinyl]pentyl}-1-piperidinecarboxylate		C₃₃H₅₉N₅O₈	详情	详情
(XIII)	27989	2-naphthalenesulfonyl chloride	93-11-8	C₁₀H₇ClO₂S	详情	详情
(XIV)	63029	tert-butyl 4-[5-[1-(tert-butoxycarbonyl)-4-piperidinyl]-3-({[2-({(2S)-3-ethoxy-2-[(2-naphthylsulfonyl)amino]-3-oxopropyl}amino)-2-oxoethyl]amino}carbonyl)pentyl]-1-piperidinecarboxylate		C₄₃H₆₅N₅O₁₀S	详情	详情

合成路线3

Hydrolysis of ethyl ester (XIV) employing LiOH affords the carboxylic acid (XV). The N-Boc protecting groups are finally removed by treatment with HCl in EtOAc to provide the title compound.

参考文献中间体

【1】 Lesur, B.; Henry, M.; Yue, C.; Giboulot, T. (Laboratoires L. Lafon); Bispiperidines as antithrombotic agents. EP 1098878; FR 2781223; JP 2002520393; US 6333338; WO 0003986 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	63029	tert-butyl 4-[5-[1-(tert-butoxycarbonyl)-4-piperidinyl]-3-({[2-({(2S)-3-ethoxy-2-[(2-naphthylsulfonyl)amino]-3-oxopropyl}amino)-2-oxoethyl]amino}carbonyl)pentyl]-1-piperidinecarboxylate		C₄₃H₆₅N₅O₁₀S	详情	详情
(XV)	63031	(2S)-3-({2-[(4-[1-(tert-butoxycarbonyl)-4-piperidinyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}butanoyl)amino]acetyl}amino)-2-[(2-naphthylsulfonyl)amino]propanoic acid		C₄₁H₆₁N₅O₁₀S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)