-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N1-(Benzyl)-Nalpha-[trans-4-ethoxy-1-(sulfanylmethyl)-1-cyclohexylcarbonyl]-L-phenylalanylamide

【CA登记号】213914-60-4

【分子式】C₂₆H₃₄N₂O₃S

【分子量】454.63648

【开发单位】Novartis (Originator)

【药理作用】Oncolytic Drugs, MMP-9 (Gelatinase B) Inhibitors

合成路线1 合成路线2

合成路线1

Ethyl 4-hydroxybenzoate (I) was alkylated with EtI and K2CO3 to afford ethyl ether (II). Subsequent hydrogenation of (II) over Rh/C produced ethyl 4-ethoxycyclohexane carboxylate (III) (1). Then, alkylation of (III) using benzyl chloromethyl ether and LDA gave the benzyloxymethyl compound (IV), which was hydrolyzed with ethanolic KOH to the carboxylic acid (V). Coupling of N-Boc-L-phenylalanine (VI) with benzylamine in the presence of EDC and HOBt produced amide (VII), and further acid deprotection of the Boc group of (VII) yielded phenylalanine-N-benzylamide (VIII). This was coupled with carboxylic acid (V) by means of DCC and HOAt to provide diamide (IX), which was debenzylated by catalytic hydrogenation yielding alcohol (X).

参考文献中间体

【1】 Fink, C.A.; et al.; Design and synthesis of thiol containing inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1999, 9, 2, 195.
【2】 Fink, C.A. (Novartis AG); Certain cyclic thio substd. acylaminoacid amide derivs.. EP 0966439; US 6034136; WO 9842662 .

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)	13492	ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate	120-47-8	C₉H₁₀O₃	详情	详情
(II)	25451	ethyl 4-ethoxybenzoate	23676-09-7	C₁₁H₁₄O₃	详情	详情
(III)	25452	ethyl 4-ethoxycyclohexanecarboxylate		C₁₁H₂₀O₃	详情	详情
(IV)	25453	ethyl 1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxylate		C₁₉H₂₈O₄	详情	详情
(V)	25454	1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxylic acid		C₁₇H₂₄O₄	详情	详情
(VI)	22184	(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid		C₁₄H₁₉NO₄	详情	详情
(VII)	25506	tert-butyl (1S)-1-benzyl-2-(benzylamino)-2-oxoethylcarbamate		C₂₁H₂₆N₂O₃	详情	详情
(VIII)	25507	(2S)-2-amino-N-benzyl-3-phenylpropanamide		C₁₆H₁₈N₂O	详情	详情
(IX)	25508	N-[(1S)-1-benzyl-2-(benzylamino)-2-oxoethyl]-1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxamide		C₃₃H₄₀N₂O₄	详情	详情
(X)	25509	N-[(1S)-1-benzyl-2-(benzylamino)-2-oxoethyl]-4-ethoxy-1-(hydroxymethyl)cyclohexanecarboxamide		C₂₆H₃₄N₂O₄	详情	详情

合成路线2

The mesylation of alcohol (X) yielded mesylate (XI), which was treated with potassium thioacetate to afford the thioacetate ester (XII). Finally, this thioacetate was hydrolyzed to the target thiol with NaOH.

参考文献中间体

【1】 Fink, C.A.; et al.; Design and synthesis of thiol containing inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1999, 9, 2, 195.
【2】 Fink, C.A. (Novartis AG); Certain cyclic thio substd. acylaminoacid amide derivs.. EP 0966439; US 6034136; WO 9842662 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	25509	N-[(1S)-1-benzyl-2-(benzylamino)-2-oxoethyl]-4-ethoxy-1-(hydroxymethyl)cyclohexanecarboxamide	C₂₆H₃₄N₂O₄	详情	详情
(XI)	25510	[1-([[(1S)-1-benzyl-2-(benzylamino)-2-oxoethyl]amino]carbonyl)-4-ethoxycyclohexyl]methyl methanesulfonate	C₂₇H₃₆N₂O₆S	详情	详情
(XII)	25511	S-[[1-([[(1S)-1-benzyl-2-(benzylamino)-2-oxoethyl]amino]carbonyl)-4-ethoxycyclohexyl]methyl] ethanethioate	C₂₈H₃₆N₂O₄S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)