A-308165, -Drug Synthesis Database

【结构式】

【药物名称】A-308165

【化学名称】(2R,3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-[2-[bis(2-methylphenyl)methylamino]-2-oxoethyl]-2-[4-(2-isopropoxyethoxy)phenyl]pyrrolidine-3-carboxylic acid trifluoroacetate

【CA登记号】

【分子式】C₄₂H₄₅F₃N₂O₉

【分子量】778.83015

【开发单位】Abbott (Originator)

【药理作用】PHARMACOLOGICAL TOOLS, Endothelin ETB Receptor Antagonists

合成路线1 合成路线2

合成路线1

Treatment of 2,2'-dimethylbenzophenone (I) with hydroxylamine afforded oxime (II), which was reduced to the benzhydryl amine (III) with sodium metal in liquid ammonia. Condensation of (III) with bromoacetyl bromide (IV) then produced the target amide (V).

参考文献中间体

【1】 Chiou, W.J.; Liu, G.; Kozmina, N.S.; Opgenorth, T.J.; Winn, M.; Dixon, D.B.; Nguyen, B.; von geldern, T.W.; Marsh, K.C.; Design, synthesis, and activity of a series of pyrrolidine-3-carboxylic acid-based, highly specific, orally active ETB antagonists containing a diphenylmethylamine acetamide side chain. J Med Chem 1999, 42, 18, 3679.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	32201	Hydroxylamine	7803-49-8	H₃NO	详情	详情
(I)	35192	bis(2-methylphenyl)methanone		C₁₅H₁₄O	详情	详情
(II)	35193	bis(2-methylphenyl)methanone oxime		C₁₅H₁₅NO	详情	详情
(III)	35194	bis(2-methylphenyl)methanamine; bis(2-methylphenyl)methylamine		C₁₅H₁₇N	详情	详情
(IV)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(V)	35195	N-[bis(2-methylphenyl)methyl]-2-bromoacetamide		C₁₇H₁₈BrNO	详情	详情

合成路线2

4-(2-Isopropoxyethoxy)benzoic acid (VI) was activated as the corresponding imidiazolide and then condensed with magnesium monoethylmalonate to furnish, after decarboxylation, ketoester (VII). Potassium tert-butoxide-catalyzed Michael addition to (VII) of nitrostyrene (VIII) yielded adduct (IX) as a mixture of diastereoisomers. Hydrogenation of the nitro group of (IX) and further hydrogenation of the intermediate cyclic iminium trifluoroacetate salt provided the racemic cis,cis--pyrrolidine (X) as the major isomer. This was epimerized with DBU to the desired trans,trans-isomer (XI). After conversion of (XI) to the tert-butyl carbamate, resolution was carried out by chiral HPLC separation. The required (2R,3R,4S)-isomer (XII) was deprotected with trifluoroacetic acid and condensed with bromoacetamide (V) to furnish (XIII). The ethyl ester group of (XIII) was hydrolyzed with NaOH, and the title compound was finally converted to the trifluoroacetate salt.

参考文献中间体

【1】 Chiou, W.J.; Liu, G.; Kozmina, N.S.; Opgenorth, T.J.; Winn, M.; Dixon, D.B.; Nguyen, B.; von geldern, T.W.; Marsh, K.C.; Design, synthesis, and activity of a series of pyrrolidine-3-carboxylic acid-based, highly specific, orally active ETB antagonists containing a diphenylmethylamine acetamide side chain. J Med Chem 1999, 42, 18, 3679.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IXa)	35198	ethyl (2R,3R)-3-(1,3-benzodioxol-5-yl)-2-[4-(2-isopropoxyethoxy)benzoyl]-4-nitrobutanoate		C₂₅H₂₉NO₉	详情	详情
(IXb)	35199	ethyl (2S,3R)-3-(1,3-benzodioxol-5-yl)-2-[4-(2-isopropoxyethoxy)benzoyl]-4-nitrobutanoate		C₂₅H₂₉NO₉	详情	详情
(V)	35195	N-[bis(2-methylphenyl)methyl]-2-bromoacetamide		C₁₇H₁₈BrNO	详情	详情
(VI)	35196	4-(2-isopropoxyethoxy)benzoic acid		C₁₂H₁₆O₄	详情	详情
(VII)	35197	ethyl 3-[4-(2-isopropoxyethoxy)phenyl]-3-oxopropanoate		C₁₆H₂₂O₅	详情	详情
(VIII)	20675	5-[(E)-2-nitroethenyl]-1,3-benzodioxole	1485-00-3	C₉H₇NO₄	详情	详情
(X)	35200	ethyl (2R,3S,4S)-4-(1,3-benzodioxol-5-yl)-2-[4-(2-isopropoxyethoxy)phenyl]-3-pyrrolidinecarboxylate		C₂₅H₃₁NO₆	详情	详情
(XI)	35201	ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-[4-(2-isopropoxyethoxy)phenyl]-3-pyrrolidinecarboxylate		C₂₅H₃₁NO₆	详情	详情
(XII)	35202	1-(tert-butyl) 3-ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-[4-(2-isopropoxyethoxy)phenyl]-1,3-pyrrolidinedicarboxylate		C₃₀H₃₉NO₈	详情	详情
(XIII)	35203	ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-(2-[[bis(2-methylphenyl)methyl]amino]-2-oxoethyl)-2-[4-(2-isopropoxyethoxy)phenyl]-3-pyrrolidinecarboxylate		C₄₂H₄₈N₂O₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)