SB-683698, TR-14035, -Drug Synthesis Database

【结构式】

【药物名称】SB-683698, TR-14035

【化学名称】2(S)-(2,6-Dichlorobenzamido)-3-(2',6'-dimethoxybiphenyl-4-yl)propionic acid
　　　　　　N-(2,6-Dichlorobenzoyl)-3-(2',6'-dimethoxybiphenyl-4-yl)-L-alanine
　　　　　　N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine

【CA登记号】232271-19-1

【分子式】C₂₄H₂₁Cl₂NO₅

【分子量】474.34467

【开发单位】Tanabe Seiyaku (Originator), GlaxoSmithKline (Licensee)

【药理作用】Antiarthritic Drugs, Asthma Therapy, GASTROINTESTINAL DRUGS, Immunologic Neuromuscular Disorders, Treatment of, Inflammatory Bowel Disease, Agents for, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, RESPIRATORY DRUGS, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Integrin alpha4beta1 (VLA-4) Antagonists, Integrin alpha4beta7 (LPAM-1) Antagonists

合成路线1 合成路线2

合成路线1

Treatment of N-Boc-4-bromo-L-phenylalanine (I) with ethanolic or methanolic HCl gave aminoester (II). Subsequent condensation of (II) with 2,6-dichlorobenzoyl chloride (III) produced amide (IV). Lithiation of 1,3-dimethoxybenzene (V) with n-butyllithium, followed by reaction with trimethyl borate and aqueous hydrolysis yielded boronic acid (VI). Suzuki coupling of bromide (IV) with boronic acid (VI) in the presence of palladium catalyst furnished biphenyl derivative (VII). Finally, hydrolysis of the ethyl ester of (VII) with LiOH provided the title carboxylic acid.

参考文献中间体

【1】 Sircar, I.; et al.; Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: Discovery of TR-14035, a dual alpha4beta7/alpha4beta1 integrin antagonist. Bioorg Med Chem 2002, 10, 6, 2051.
【2】 Gudmundsson, K.S.; Sircar, I.; Martin, R. (Tanabe Seiyaku Co., Ltd.); Inhibitors of alpha4 mediated cell adhesion. WO 9936393 .

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)	32546	(2S)-3-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propionic acid		C₁₄H₁₈BrNO₄	详情	详情
(II)	32547	ethyl (2S)-2-amino-3-(4-bromophenyl)propanoate		C₁₁H₁₄BrNO₂	详情	详情
(III)	25087	2,6-dichlorobenzoyl chloride	4659-45-4	C₇H₃Cl₃O	详情	详情
(IV)	32548	ethyl (2S)-3-(4-bromophenyl)-2-[(2,6-dichlorobenzoyl)amino]propanoate		C₁₈H₁₆BrCl₂NO₃	详情	详情
(V)	11934	m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether	151-10-0	C₈H₁₀O₂	详情	详情
(VI)	32549	2,6-dimethoxyphenylboronic acid	23112-96-1	C₈H₁₁BO₄	详情	详情
(VII)	32550	ethyl (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate		C₂₆H₂₅Cl₂NO₅	详情	详情

合成路线2

In an alternative procedure, N-Boc-L-tyrosine methyl ester (VIII) was treated with trifluoromethanesulfonic anhydride to afford triflate (IX). Suzuki coupling of (IX) with boronic acid (VI) produced biphenyl (X). After deprotection of the Boc group of (X) with trifluoroacetic acid, the resulting aminoester (XI) was acylated with acid chloride (III) to give amide (XII). The title compound was then obtained by hydrolysis of the methyl ester of (XII) with LiOH.

参考文献中间体

【1】 Sircar, I.; et al.; Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: Discovery of TR-14035, a dual alpha4beta7/alpha4beta1 integrin antagonist. Bioorg Med Chem 2002, 10, 6, 2051.
【2】 Hattfield, L.D.; Sircar, I.; McNutly, A.; Naubauer, B.; Discovery of TR-14035: An orally active dual alpha4beta7/alpha4beta1 integrin antagonist. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 59.
【3】 Sircar, I.; Liang, J.T.; Martin, R.; et al.; SAR of TR-14035: An orally active dual alpha4beta7/alpha4beta1 integrin antagonist. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 60.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	25087	2,6-dichlorobenzoyl chloride	4659-45-4	C₇H₃Cl₃O	详情	详情
(VI)	32549	2,6-dimethoxyphenylboronic acid	23112-96-1	C₈H₁₁BO₄	详情	详情
(VIII)	19875	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate	4326-36-7	C₁₅H₂₁NO₅	详情	详情
(IX)	32551	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(trifluoromethyl)sulfonyl]oxy]phenyl)propanoate		C₁₆H₂₀F₃NO₇S	详情	详情
(X)	32552	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate		C₂₃H₂₉NO₆	详情	详情
(XI)	32553	methyl (2S)-2-amino-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate		C₁₁H₁₆N₂O₄S	详情	详情
(XII)	32554	methyl (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate		C₂₅H₂₃Cl₂NO₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)