tert-butyl (2R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】23310

【品名】tert-butyl (2R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate

【CA登记号】

【分子式】C₁₀H₁₉NO₃

【分子量】201.2658

【元素组成】C 59.68% H 9.52% N 6.96% O 23.85%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

Treatment of (R)-2-pyrrolidine methanol (I) with di-tert-butyl dicarbonate and K2CO3 gave carbamate (II), which was converted to mesylate (III) using methanesulfonyl chloride and Et3N. Subsequent reaction of (III) with NaCN in DMF provided nitrile (IV). The catalytic hydrogenation of this nitrile in the presence of 4-methylpiperidine (V) furnished the (piperidinylethyl)pyrrolidine (VI). After Boc deprotection of (VI) with trifluoroacetic acid in refluxing CH2Cl2, the resulting pyrrolidine (VII) was finally condensed with m-toluenesulfonyl chloride (VIII) to give the target sulfonamide.

参考文献中间体

合成目标

【1】 King, F.D.; Forbes, I.T.; Rahman, S.K. (SmithKline Beecham plc); Sulphonamide derivs. and their use in the treatment of CNS disorders. WO 9748681 .

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)	23309	(2R)pyrrolidinylmethanol	68832-13-3	C₅H₁₁NO	详情	详情
(II)	23310	tert-butyl (2R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate		C₁₀H₁₉NO₃	详情	详情
(III)	23311	tert-butyl (2R)-2-[[(methylsulfonyl)oxy]methyl]-1-pyrrolidinecarboxylate		C₁₁H₂₁NO₅S	详情	详情
(IV)	23312	tert-butyl (2R)-2-(cyanomethyl)-1-pyrrolidinecarboxylate		C₁₁H₁₈N₂O₂	详情	详情
(V)	10192	4-Methylpiperidine; gamma-Pipecoline	626-58-4	C₆H₁₃N	详情	详情
(VI)	23314	tert-butyl (2R)-2-[2-(4-methyl-1-piperidinyl)ethyl]-1-pyrrolidinecarboxylate		C₁₇H₃₂N₂O₂	详情	详情
(VII)	23315	4-methyl-1-[2-[(2R)pyrrolidinyl]ethyl]piperidine		C₁₂H₂₄N₂	详情	详情
(VIII)	23316	3-methylbenzenesulfonyl chloride	1899-93-0	C₇H₇ClO₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

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

合成目标

【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

Extended Information