SB-656104(free base), SB-656104-A, -Drug Synthesis Database

【结构式】

【药物名称】SB-656104(free base), SB-656104-A

【化学名称】6-[2(R)-[2-[4-(4-Chlorophenoxy)piperidin-1-yl]ethyl]pyrrolidin-1-ylsulfonyl]-1H-indole hydrochloride

【CA登记号】446020-51-5 (free base)

【分子式】C₂₅H₃₁Cl₂N₃O₃S

【分子量】524.51412

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Sleep Disorders, Treatment of, 5-HT7 Antagonists

合成路线1 合成路线2

合成路线1

Oxidation of N-Boc-D-prolinol (I) with pyridinium dichromate affords aldehyde (II). This is subjected to Wittig condensation with methylene triphenylphosphorane to furnish N-Boc-2-vinylpyrrolidine (III). Hydroboration of (III) with 9-borabicyclononane, followed by oxidative work-up, leads to the primary alcohol (IV). Subsequent acidic Boc group cleavage in (IV) provides 2-pyrrolidinyl ethanol (V). Acylation of amine (V) with 4-methyl-3-nitrobenzenesulfonyl chloride (VI) gives sulfonamide (VII). The hydroxyl group of (VII) is further protected with methoxymethyl chloride, producing the methoxymethyl ether (VIII). Conversion of the ortho-nitrotoluene system (VIII) into indole (X) is then accomplished according to the Leimgruber-Batcho procedure, by condensation of (VIII) with dimethylformamide dimethylacetal, followed by reduction of the resultant nitro enamine (IX) with hydrazine in the presence of Raney nickel. Protection of the indole N of (X) with benzenesulfonyl chloride and NaH affords sulfonamide (XI). After acidic hydrolysis of the methoxymethyl protecting group of (XI), the N-phenylsulfonyl group is removed under alkaline conditions to yield indole (XII)

参考文献中间体

【1】 Forbes, I.T.; Gribble, A.D. (GlaxoSmithKline plc); Sulfonamide cpds., their preparation and use. WO 0262788 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	23310	tert-butyl (2R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate	C₁₀H₁₉NO₃	详情	详情
(II)	60087	tert-butyl (2R)-2-formyl-1-pyrrolidinecarboxylate	C₁₀H₁₇NO₃	详情	详情
(III)	60088	tert-butyl (2R)-2-vinyl-1-pyrrolidinecarboxylate	C₁₁H₁₉NO₂	详情	详情
(IV)	60089	tert-butyl (2R)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate	C₁₁H₂₁NO₃	详情	详情
(V)	60090	2-[(2R)pyrrolidinyl]-1-ethanol	C₆H₁₃NO	详情	详情
(VI)	60091	4-methyl-3-nitrobenzenesulfonyl chloride	C₇H₆ClNO₄S	详情	详情
(VII)	60092	2-{(2R)-1-[(4-methyl-3-nitrophenyl)sulfonyl]pyrrolidinyl}-1-ethanol	C₁₃H₁₈N₂O₅S	详情	详情
(VIII)	60093	methoxymethyl 2-{(2R)-1-[(4-methyl-3-nitrophenyl)sulfonyl]pyrrolidinyl}ethyl ether; (2R)-2-[2-(methoxymethoxy)ethyl]-1-[(4-methyl-3-nitrophenyl)sulfonyl]pyrrolidine	C₁₅H₂₂N₂O₆S	详情	详情
(IX)	60094	(E)-2-[4-({(2R)-2-[2-(methoxymethoxy)ethyl]pyrrolidinyl}sulfonyl)-2-nitrophenyl]-N,N-dimethyl-1-ethenamine; N-{(E)-2-[4-({(2R)-2-[2-(methoxymethoxy)ethyl]pyrrolidinyl}sulfonyl)-2-nitrophenyl]ethenyl}-N,N-dimethylamine	C₁₈H₂₇N₃O₆S	详情	详情
(X)	60095	6-({(2R)-2-[2-(methoxymethoxy)ethyl]pyrrolidinyl}sulfonyl)-1H-indole; {2-[(2R)-1-(1H-indol-6-ylsulfonyl)pyrrolidinyl]ethoxy}methyl methyl ether	C₁₆H₂₂N₂O₄S	详情	详情
(XI)	60096	6-({(2R)-2-[2-(methoxymethoxy)ethyl]pyrrolidinyl}sulfonyl)-1-(phenylsulfonyl)-1H-indole; methoxymethyl 2-((2R)-1-{[1-(phenylsulfonyl)-1H-indol-6-yl]sulfonyl}pyrrolidinyl)ethyl ether	C₂₂H₂₆N₂O₆S₂	详情	详情
(XII)	60097	2-[(2R)-1-(1H-indol-6-ylsulfonyl)pyrrolidinyl]-1-ethanol	C₁₄H₁₈N₂O₃S	详情	详情

合成路线2

Conversion of alcohol (XII) into alkyl bromide (XIII) is carried out by treatment with carbon tetrabromide and triphenylphosphine. Then condensation of bromide (XIII) with 4-(4-chlorophenoxy)piperidine (XIV) in the presence of NaI and NaHCO3 produces the title compound

参考文献中间体

【1】 Forbes, I.T.; Douglas, S.; Gribble, A.D.; Ife, R.J.; Lightfoot, A.P.; Garner, A.E.; Riley, G.J.; Jeffery, P.; Stevens, A.J.; Stean, T.O.; Thomas, D.R.; SB-656104-A: A novel 5-HT(7) receptor antagonist with improved in vivo properties. Bioorg Med Chem Lett 2002, 12, 22, 3341.
【2】 Forbes, I.T.; Gribble, A.D. (GlaxoSmithKline plc); Sulfonamide cpds., their preparation and use. WO 0262788 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	60097	2-[(2R)-1-(1H-indol-6-ylsulfonyl)pyrrolidinyl]-1-ethanol	C₁₄H₁₈N₂O₃S	详情	详情
(XIII)	60098	6-{[(2R)-2-(2-bromoethyl)pyrrolidinyl]sulfonyl}-1H-indole	C₁₄H₁₇BrN₂O₂S	详情	详情
(XIV)	60099	4-(4-chlorophenoxy)piperidine; 4-chlorophenyl 4-piperidinyl ether	C₁₁H₁₄ClNO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)