-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-(3,5-Dichlorophenylsulfonyl)-2-methyl-L-prolyl-L-phenylalanine

【CA登记号】217452-76-1

【分子式】C₂₁H₂₂Cl₂N₂O₅S

【分子量】485.38989

【开发单位】Merck & Co. (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Antiarthritic Drugs, Asthma Therapy, RESPIRATORY DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Integrin alpha4beta1 (VLA-4) Antagonists

合成路线1 合成路线2

合成路线1

N-Boc-L-Phenylalanine (I) is converted into the tert-butyl ester (II) upon treatment with tert-butyl trichloroacetimidate and boron trifluoride. Then, selective removal of the N-Boc group of (II) with HCl in EtOAc provides L-phenylalanine ester (III). Coupling of (III) with N-Cbz-2-methylproline (IV) furnishes dipeptide (V). After hydrogenolysis of the N-Cbz group of (V), the resultant amine (VI) is acylated by means of 3,5-dichlorobenzenesulfonyl chloride (VII), yielding sulfonamide (VIII). The tert-butyl ester group of (VIII) is finally cleaved by treatment with trifluoroacetic acid in CH2Cl2

参考文献中间体

【1】 Hagmann, W.K.; Durette, P.L.; Mumford, R.A.; Mills, S.G.; Kevin, N.J.; Schmidt, J.A.; MacCoss, M.; Van Riper, G.M. (Merck & Co., Inc.); Heterocyclic amide cpds. as cell adhesion inhibitors. EP 1001764; WO 9853814 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	61667	tert-butyl 2,2,2-trichloroethanimidoate	C₆H₁₀Cl₃NO	详情	详情
(I)	22184	(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid	C₁₄H₁₉NO₄	详情	详情
(II)	60836	tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate	C₁₈H₂₇NO₄	详情	详情
(III)	60837	tert-butyl (2S)-2-amino-3-phenylpropanoate	C₁₃H₁₉NO₂	详情	详情
(IV)	60838	(2S)-1-[(benzyloxy)carbonyl]-2-methyl-2-pyrrolidinecarboxylic acid	C₁₄H₁₇NO₄	详情	详情
(V)	60839	benzyl (2S)-2-({[(1S)-1-benzyl-2-(tert-butoxy)-2-oxoethyl]amino}carbonyl)-2-methyl-1-pyrrolidinecarboxylate	C₂₇H₃₄N₂O₅	详情	详情
(VI)	60840	tert-butyl (2S)-2-({[(2S)-2-methylpyrrolidinyl]carbonyl}amino)-3-phenylpropanoate	C₁₉H₂₈N₂O₃	详情	详情
(VII)	59023	3,5-dichlorobenzenesulfonyl chloride	C₆H₃Cl₃O₂S	详情	详情
(VIII)	60841	tert-butyl (2S)-2-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-methylpyrrolidinyl}carbonyl)amino]-3-phenylpropanoate	C₂₅H₃₀Cl₂N₂O₅S	详情	详情

合成路线2

In an alternative method, L-phenylalanine (I) is esterified employing SOCl2 in MeOH. The resultant phenylalanine methyl ester (II) is then acylated with the sulfonyl proline derivative (III) by means of PyBOP to furnish the sulfonyl dipeptide (IV). Finally, saponification of the methyl ester group of (IV) with LiOH leads to the title compound

参考文献中间体

【1】 Kopka, I.E.; Young, D.N.; Lin, L.S.; et al.; Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists. Bioorg Med Chem Lett 2002, 12, 4, 637.

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)	13952	(S)-(-)-Phenylalanine; L-Phenylalanine	63-91-2	C₉H₁₁NO₂	详情	详情
(II)	12324	methyl (2R)-2-amino-3-phenylpropanoate	21685-51-8	C₁₀H₁₃NO₂	详情	详情
(III)	60842	(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-methyl-2-pyrrolidinecarboxylic acid		C₁₂H₁₃Cl₂NO₄S	详情	详情
(IV)	60843	methyl (2S)-2-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-methylpyrrolidinyl}carbonyl)amino]-3-phenylpropanoate		C₂₂H₂₄Cl₂N₂O₅S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)