(2S)pyrrolidinylmethanol -Drug Synthesis Database

【结构式】

【分子编号】64118

【品名】(2S)pyrrolidinylmethanol

【CA登记号】

【分子式】C₅H₁₁NO

【分子量】101.14848

【元素组成】C 59.37% H 10.96% N 13.85% O 15.82%

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)

Condensation between 1,2-difluoro-4-nitrobenzene (I) and L-prolinol (II) affords the N-aryl prolinol (III). Subsequent conversion of alcohol (III) into bromide (IV) is achieved by treatment with CBr4 and PPh3. Displacement of bromide (IV) with sodium thioacetate, followed by basic hydrolysis of the resultant thioacetate ester (V) leads to thiol (VI). Intramolecular cyclization of (VI) in the presence of NaH generates the pyrrolobenzothiazine system (VII). Catalytic hydrogenation of the nitro group of (VII) gives amine (VIII), which is acylated by benzyl chloroformate to provide carbamate (IX). The lithium anion of carbamate (IX) is condensed with (R)-glycidyl butyrate (X) to furnish oxazolidinone (XI). Then, treatment of alcohol (XI) with methanesulfonyl chloride produces mesylate (XII).

参考文献中间体

合成目标

【1】 Selvakumar, N.; Reddy, B.Y.; Kumar, G.S.; Khera, M.K.; Srinivas, D.; Kumar, M.S.; Das, J.; Iqbal, J.; Trehan, S.; SAR studies on certain conformationally constrained oxazolidinones. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1324.

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)	17013	1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene	369-34-6	C₆H₃F₂NO₂	详情	详情
(II)	64118	(2S)pyrrolidinylmethanol		C₅H₁₁NO	详情	详情
(III)	64119	[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]methanol		C₁₁H₁₃FN₂O₃	详情	详情
(IV)	64120	2-(bromomethyl)-1-(2-fluoro-4-nitrophenyl)pyrrolidine		C₁₁H₁₂BrFN₂O₂	详情	详情
(V)	64121	S-{[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]methyl} ethanethioate		C₁₃H₁₅FN₂O₃S	详情	详情
(VI)	64122	[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]methylhydrosulfide; [1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]methanethiol		C₁₁H₁₃FN₂O₂S	详情	详情
(VII)	64123	7-nitro-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazine		C₁₁H₁₂N₂O₂S	详情	详情
(VIII)	64124	2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-7-ylamine; 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-7-amine		C₁₁H₁₄N₂S	详情	详情
(IX)	64125	phenylmethyl 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-7-ylcarbamate		C₁₉H₂₀N₂O₂S	详情	详情
(X)	18385	(2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate	60456-26-0	C₇H₁₂O₃	详情	详情
(XI)	64126	3-(2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-7-yl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one		C₁₅H₁₈N₂O₃S	详情	详情
(XII)	64127	[3-(2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate		C₁₆H₂₀N₂O₅S₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

4-Benzyloxy-5-methoxy-2-nitrobenzoic acid (I) is treated with oxalyl chloride to provide the corresponding acid chloride (II), which is subsequently coupled with (S)-2-pyrrolidinemethanol (III) to give amide (IV). Hydrogenation of (IV) over Pd/C removes the benzyl protecting group and reduces the nitro substituent to the amino benzamide (V). Reaction of the aniline (V) with allyl chloroformate affords the carbamate (VI). The phenolic hydroxyl of (VI) is alkylated with trichloroethyl 6-bromohexanoate (VII) to yield (VIII). Dess-Martin oxidation of the primary alcohol group of (VIII) with concomitant intramolecular cyclization leads to the desired pyrrolobenodiazepine (X) together with the overoxidized dione (IX), which can be separated by column chromatography.

参考文献中间体

合成目标

【1】 Tercel, M.; Stribbling, S.M.; Sheppard, H.; Siim, B.G.; Wu, K.; Pullen, S.M.; Botting, K.J.; Wilson, W.R.; Denny, W.A.; Unsymmetrical DNA cross-linking agents: Combination of the CBI and PBD pharmacophores. J Med Chem 2003, 46, 11, 2132.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	64815	4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid	C₁₅H₁₃NO₆	详情	详情
(II)	64816	4-(benzyloxy)-5-methoxy-2-nitrobenzoyl chloride	C₁₅H₁₂ClNO₅	详情	详情
(III)	64118	(2S)pyrrolidinylmethanol	C₅H₁₁NO	详情	详情
(IV)	64817	[4-(benzyloxy)-5-methoxy-2-nitrophenyl][(2S)-2-(hydroxymethyl)pyrrolidinyl]methanone	C₂₀H₂₂N₂O₆	详情	详情
(V)	64818		C₁₃H₁₈N₂O₄	详情	详情
(VI)	64819	allyl 5-hydroxy-2-{[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl}-4-methoxyphenylcarbamate	C₁₇H₂₂N₂O₆	详情	详情
(VII)	64820	2,2,2-trichloroethyl 6-bromohexanoate	C₈H₁₂BrCl₃O₂	详情	详情
(VIII)	64821	2,2,2-trichloroethyl 6-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl}-2-methoxyphenoxy)hexanoate	C₂₅H₃₃Cl₃N₂O₈	详情	详情
(IX)	64822	allyl (11aS)-7-methoxy-5,11-dioxo-8-{[6-oxo-6-(2,2,2-trichloroethoxy)hexyl]oxy}-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate	C₂₅H₂₉Cl₃N₂O₈	详情	详情
(X)	64823	allyl (11aS)-11-hydroxy-7-methoxy-5-oxo-8-{[6-oxo-6-(2,2,2-trichloroethoxy)hexyl]oxy}-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate	C₂₅H₃₁Cl₃N₂O₈	详情	详情

Extended Information