Elarofiban, RWJ-53308, -Drug Synthesis Database

【结构式】

【药物名称】Elarofiban, RWJ-53308

【化学名称】3(S)-[1-[3-(4-Piperidinyl)propionyl]piperidin-3(R)-ylcarboxamido]-3-(3-pyridyl)propionic acid

【CA登记号】198958-88-2

【分子式】C₂₂H₃₂N₄O₄

【分子量】416.52474

【开发单位】R.W. Johnson (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1

Knoevenagel condensation of pyridine-3-carboxaldehyde (I) with malonic acid in the presence of ammonium acetate afforded the racemic amino acid (III), which was acylated with phenylacetyl chloride (IV) to give amide (V). Optical resolution of (V) by means of penicillin amidase produced the hydrolysis of the undesired (R)-enantiomer. After isolation of the unreacted (S)-enantiomer (VI), its hydrolysis with aqueous HCl furnished the chiral amino acid (VII), which was converted to methyl ester (VIII) with 2,2-dimethoxypropane in MeOH. Coupling of (VIII) with N-Boc-(R)-nipecotic acid (IX) using 2-benzotriazolyl-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) provided amide (X). Deprotection of the Boc group of (X) was then achieved with HCl in dioxan resulting amine (XI).

参考文献中间体

【1】 Hoekstra, W.J.; Damiano, B.P.; Maryanoff, B.E.; et al.; Potent orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure - Activity studies leading to the discovery of RWJ-53308. J Med Chem 1999, 42, 25, 5254.
【2】 Costanzo, M.J.; Hoekstra, W.J.; Maryanoff, B.E. (Ortho-McNeil Pharmaceutical, Inc.); Carboxamide derivs. of pyrrolidine, piperidine and hexahydroazepine for the treatment of thrombosis disorders. EP 0923555; JP 2000510111; US 6069254; WO 9741102 .

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)	12849	Nicotinaldehyde; 3-Pyridinecarboxaldehyde	500-22-1	C₆H₅NO	详情	详情
(II)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情
(III)	27468	3-(3-pyridinyl)-beta-alanine		C₈H₁₀N₂O₂	详情	详情
(IV)	25890	2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride	103-80-0	C₈H₇ClO	详情	详情
(V)	27469	N-(2-phenylacetyl)-3-(3-pyridinyl)-beta-alanine		C₁₆H₁₆N₂O₃	详情	详情
(VI)	27470	(3S)-3-[(2-phenylacetyl)amino]-3-(3-pyridinyl)propionic acid		C₁₆H₁₆N₂O₃	详情	详情
(VII)	27471	(3S)-3-amino-3-(3-pyridinyl)propionic acid		C₈H₁₀N₂O₂	详情	详情
(VIII)	27472	methyl (3S)-3-amino-3-(3-pyridinyl)propanoate		C₉H₁₂N₂O₂	详情	详情
(IX)	27473	(3R)-1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid		C₁₁H₁₉NO₄	详情	详情
(X)	27474	tert-butyl (3R)-3-([[(1S)-3-methoxy-3-oxo-1-(3-pyridinyl)propyl]amino]carbonyl)-1-piperidinecarboxylate		C₂₀H₂₉N₃O₅	详情	详情
(XI)	27475	methyl (3S)-3-[[(3R)piperidinylcarbonyl]amino]-3-(3-pyridinyl)propanoate		C₁₅H₂₁N₃O₃	详情	详情

合成路线2

Compound (XI) was coupled with N-Boc-3-(4-piperidinyl)propionic acid (XII) to produce diamide (XIII). Finally, hydrolysis of the methyl ester of (XIII) with LiOH, followed by acid removal of the Boc group yielded the title compound.

参考文献中间体

【1】 Hoekstra, W.J.; Damiano, B.P.; Maryanoff, B.E.; et al.; Potent orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure - Activity studies leading to the discovery of RWJ-53308. J Med Chem 1999, 42, 25, 5254.
【2】 Costanzo, M.J.; Hoekstra, W.J.; Maryanoff, B.E. (Ortho-McNeil Pharmaceutical, Inc.); Carboxamide derivs. of pyrrolidine, piperidine and hexahydroazepine for the treatment of thrombosis disorders. EP 0923555; JP 2000510111; US 6069254; WO 9741102 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	27475	methyl (3S)-3-[[(3R)piperidinylcarbonyl]amino]-3-(3-pyridinyl)propanoate	C₁₅H₂₁N₃O₃	详情	详情
(XII)	27476	1-Boc-piperidin-4-ylpropionic acid; 3-[1-(tert-butoxycarbonyl)-4-piperidinyl]propionic acid	C₁₃H₂₃NO₄	详情	详情
(XIII)	27477	tert-butyl 4-[3-[(3R)-3-([[(1S)-3-methoxy-3-oxo-1-(3-pyridinyl)propyl]amino]carbonyl)piperidinyl]-3-oxopropyl]-1-piperidinecarboxylate	C₂₈H₄₂N₄O₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)