CGS-34225, -Drug Synthesis Database

【结构式】

【药物名称】CGS-34225

【化学名称】N-[1-[2(S)-(Acetylsulfanyl)pentanamido]cyclopent-1-ylcarbonyl]-4-phenyl-L-phenylalanine methyl ester

【CA登记号】248262-98-8

【分子式】C₂₉H₃₆N₂O₅S

【分子量】524.68467

【开发单位】Novartis (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Hypertension, Treatment of, Endothelin-Converting Enzyme Inhibitors, Neprilysin Inhibitors

合成路线1 合成路线2

合成路线1

Cycloleucine (I) is esterified with HCl/MeOH, and the resultant amino ester (II) is further protected as the tert-butyl carbamate (III) employing Boc2O and Et3N in CH2Cl2. Then, hydrolysis of the methyl ester group of (III) with LiOH furnishes N-Boc-cycloleucine (IV). N-Boc-L-Biphenylalanine (V) is simultaneously deprotected and esterified with HCl/MeOH to yield amino ester (VI). Coupling between N-Boc-cycloleucine (IV) and L-biphenylalanine methyl ester (VI) in the presence of EDC/HOAt gives rise to the protected dipeptide (VII). Subsequent removal of the N-Boc group of (VII) under acidic conditions yields the dipeptide methyl ester (VIII).

参考文献中间体

【1】 Fink, C.A.; De Lombaert, S.; Hoyer, D.W.; Jeng, A.Y.; Firoozina, F. (Novartis AG; Novartis Pharma GmbH); Certain thiol inhibitors of endothelin-converting enzyme. WO 9955726 .

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)	33149	1-aminocyclopentanecarboxylic acid	52-52-8	C₆H₁₁NO₂	详情	详情
(II)	10444	methyl 1-aminocyclopentanecarboxylate		C₇H₁₃NO₂	详情	详情
(III)	62819	methyl 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate		C₁₂H₂₁NO₄	详情	详情
(IV)	30890	1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid		C₁₁H₁₉NO₄	详情	详情
(V)	62820	(2S)-3-[1,1'-biphenyl]-4-yl-2-[(tert-butoxycarbonyl)amino]propanoic acid		C₂₀H₂₃NO₄	详情	详情
(VI)	62821	methyl (2S)-2-amino-3-[1,1'-biphenyl]-4-ylpropanoate		C₁₆H₁₇NO₂	详情	详情
(VII)	62822	methyl (2S)-3-[1,1'-biphenyl]-4-yl-2-[({1-[(tert-butoxycarbonyl)amino]cyclopentyl}carbonyl)amino]propanoate		C₂₇H₃₄N₂O₅	详情	详情
(VIII)	62823	methyl (2S)-2-{[(1-aminocyclopentyl)carbonyl]amino}-3-[1,1'-biphenyl]-4-ylpropanoate		C₂₂H₂₆N₂O₃	详情	详情

合成路线2

Diazotization of (R)-2-aminopentanoic acid (IX) in the presence of HBr/KBr gives rise to the configuration-retained alpha-bromoacid (X). This is further coupled to the dipeptide ester (VIII) in the presence of EDC/HOAt to furnish the corresponding alpha-bromo amide (XI). Finally, displacement of the bromide group of (XI) with potassium thioacetate in DMF leads to the target thioacetate ester.

参考文献中间体

【1】 Fink, C.A.; De Lombaert, S.; Hoyer, D.W.; Jeng, A.Y.; Firoozina, F. (Novartis AG; Novartis Pharma GmbH); Certain thiol inhibitors of endothelin-converting enzyme. WO 9955726 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	62823	methyl (2S)-2-{[(1-aminocyclopentyl)carbonyl]amino}-3-[1,1'-biphenyl]-4-ylpropanoate	C₂₂H₂₆N₂O₃	详情	详情
(IX)	62824	D-norvaline	C₅H₁₁NO₂	详情	详情
(X)	62825	(2R)-2-bromopentanoic acid	C₅H₉BrO₂	详情	详情
(XI)	62826	methyl (2S)-3-[1,1'-biphenyl]-4-yl-2-{[(1-{[(2R)-2-bromopentanoyl]amino}cyclopentyl)carbonyl]amino}propanoate	C₂₇H₃₃BrN₂O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)