(S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinenemethanol -Drug Synthesis Database

【结构式】

【分子编号】49819

【品名】(S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinenemethanol

【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：(IX)

The reaction of L-prolinol (VIII) with Boc2O gives N-Boc-L-prolinol (IX), which is oxidized with SO3/pyridine in DMSO to afford N-Boc-L-prolinal (X). The condensation of (X) with the propionate ester (XI), by means of LDA in THF, affords the 3-hydroxy-3-(2-pyrrolidinyl)propionate ester (XII), which is methylated with diazomethane and BF3 in dichloromethane to provide the corresponding methoxy derivative (XIII). The epimerization of the (S)-methyl group of group of (XIII) by means of t-Bu-OK in THF gives the corresponding (R)-methyl derivative (XIV), which is finally hydrogenolyzed with H2 over Pd/C in ethyl acetate/methanol to yield the desired pyrrolidinylpropionic acid intermediate (XV).

参考文献中间体

合成目标

【1】 Pettit, G.R.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Hogan, F.; Burkett, D.D.; Clewlow, P.J.; The absolute configuration and synthesis of natural (-)-Dolastatin 10. J Am Chem Soc 1989, 111, Suppl. 3, 5463.
【2】 Pettit, G.R.; Srirangam, J.K.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Barkóczy, J.; Kantoci, D.; Hogan, F.; Dolastatins 24. Synthesis of (-)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleucine tert-butyl ester. J Chem Soc Perkins Trans I 1996, 8, Suppl. 3, 859-63.
【3】 Pettit, G.R.; Singh, S.B. (Arizona State University); Synthesis of dolastatin 10. US 4978744 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	21347	(2S)pyrrolidinylmethanol	23356-96-9	C₅H₁₁NO	详情	详情
(IX)	49819	(S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinenemethanol		C₁₀H₁₉NO₃	详情	详情
(X)	16724	tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal	69610-41-9	C₁₀H₁₇NO₃	详情	详情
(XI)	54631	(1S)-2-hydroxy-1,2,2-triphenylethyl propionate		C₂₃H₂₂O₃	详情	详情
(XII)	54632	tert-butyl (2S)-2-((1R,2S)-1-hydroxy-3-{[(1S)-2-hydroxy-1,2,2-triphenylethyl]oxy}-2-methyl-3-oxopropyl)-1-pyrrolidinecarboxylate		C₃₃H₃₉NO₆	详情	详情
(XIII)	54633	tert-butyl (2S)-2-((1R,2S)-3-{[(1S)-2-hydroxy-1,2,2-triphenylethyl]oxy}-1-methoxy-2-methyl-3-oxopropyl)-1-pyrrolidinecarboxylate		C₃₄H₄₁NO₆	详情	详情
(XIV)	54634	tert-butyl (2S)-2-((1R,2R)-3-{[(1S)-2-hydroxy-1,2,2-triphenylethyl]oxy}-1-methoxy-2-methyl-3-oxopropyl)-1-pyrrolidinecarboxylate		C₃₄H₄₁NO₆	详情	详情
(XV)	23520	(2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid		C₁₄H₂₅NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Treatment of N-Boc-prolinol (I) with p-toluenesulfonyl chloride and pyridine afforded tosylate (II), which was condensed with the sodium salt of phenol (III) to produce ether (IV). Acid cleavage of the Boc protecting group of (IV) then gave pyrrolidine (V). Sulfonyl chloride (VII) was prepared by chlorination of the sodium salt of 5-isatinsulfonic acid (VI) with POCl3 in tetramethylenesulfone. Acylation of pyrrolidine (V) with acid chloride (VII) gave sulfonamide (VIII). Finally, the isatin nitrogen atom was methylated employing iodomethane in the presence of K2CO3.

参考文献中间体

合成目标

【1】 Lee, D.; et al.; Potent and selective nonpeptide inhibitors of caspases 3 and 7. J Med Chem 2001, 44, 12, 2015.
【2】 Long, S.A.; Lee, D. (SmithKline Beecham Corp.); Caspases and apoptosis. EP 1001933; JP 2001512100; WO 9906367 .
【3】 Lee, D.; Long, S.A.; Elliott, J.D.; Gleason, J.G. (SmithKline Beecham Corp.); Caspases and apoptosis. WO 0122966 .

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)	49819	(S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinenemethanol		C₁₀H₁₉NO₃	详情	详情
(II)	49813	tert-butyl (2S)-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-pyrrolidinecarboxylate		C₁₇H₂₅NO₅S	详情	详情
(III)	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(IV)	49814	tert-butyl (2S)-2-(phenoxymethyl)-1-pyrrolidinecarboxylate		C₁₆H₂₃NO₃	详情	详情
(V)	49815	phenyl (2S)pyrrolidinylmethyl ether; (2S)-2-(phenoxymethyl)pyrrolidine		C₁₁H₁₅NO	详情	详情
(VI)	49816	sodium 2,3-dioxo-5-indolinesulfonate		C₈H₄NNaO₅S	详情	详情
(VII)	49817	2,3-dioxo-5-indolinesulfonyl chloride		C₈H₄ClNO₄S	详情	详情
(VIII)	49818	5-[[(2S)-2-(phenoxymethyl)pyrrolidinyl]sulfonyl]-1H-indole-2,3-dione		C₁₉H₁₈N₂O₅S	详情	详情

Extended Information