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【结 构 式】

【分子编号】65970

【品名】2,5-Dihydro-3-hydroxy-4-[(2-hydroxyethyl)amino]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole

【CA登记号】 

【 分 子 式 】C13H20NO4S

【 分 子 量 】286.37214

【元素组成】C 54.52% H 7.04% N 4.89% O 22.35% S 11.2%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XXVIII)

The pyrrolo-oxazine fragments, the free base (II) or the Boc-protected (V) can be synthesized as follows. Butene-1,4-diol (XXIV) is subjected to either of the two following alternative procedures: 1) treatment with mesyl chloride in the presence of Et3N in CH2Cl2 and subsequent reaction with tosylamine, NaOH and tetrabutylammonium hydrogensulfate (TBAHS) in toluene/water at 40 °C (1, 2); or 2) chlorination with thionyl chloride followed by treatment with tosylamide by means of NaH in DMF (3) to afford 1-tosyl-2,5-dihydro-1H-pyrrole (XXV). Compound (XXV) is then epoxidated with meta-chloroperbenzoic acid (mCPBA) in refluxing dichloromethane to yield cis-N-tosyl-6-oxa-3-azabicyclo[3.1.0]hexane (XXVI) (1-3). Desymmetrization of intermediate (XXVI) is carried out by condensation with ethanolamine (XXVII) in refluxing dichloromethane to yield the racemic N-alkylated pyrrolidine derivative rac-(XXVIII), which by reaction with tosyl chloride in pyridine/THF at –10 °C affords the tosylate rac-(XXIX). Cyclization of the racemic (XXIX) by means of NaOH in THF/methanol at 0-3 °C gives the racemic pyrrolo-oxazine rac-(XXX), from which the desired enantiomer (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine (XXX) is separated by chiral chromatography. Finally, compound (XXX) is detosylated by means of HBr/AcOH and anisole at 60 °C and the resulting dihydrobromide salt (XXXI) is treated with potassium hydroxide in isopropanol to afford the free base intermediate (II) (1). Scheme 3.
In an improved method for intermediate (II), compound (XXVI) is desymmetrized by coupling with (R)-phenylethylamine (XXXII) in water (2, 3), resulting in a mixture of diastereomers that is resolved by crystallization (2) or chromatography (3). The desired isomer (XXXIII) is N-acylated with chloroacetyl chloride (XXXIV) by means of triethylamine (2) or DIEA in THF (3) to afford the N-chloroacetyl amine (XXXV), which then cyclizes in the presence of sodium hydroxide (2) or potassium tert-butoxide in dichloromethane (3). The resulting bicyclic lactam (XXXVI) is reduced with LiAlH4 in THF (3) or NaBH4 in the presence of BF3.THF complex (2) to give the pyrrolooxazine derivative (XXXVII) (2, 3), which is detosylated by treatment with HCl and subsequently with NaOH, yielding the free amine (XXXVIII). Finally, compound (XXXVIII) is subjected to hydrogenolysis over Pd/C in methanol to afford the target (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine (II) (2). Scheme 3.
The Boc-protected compound (V) is obtained by subjecting N-alkylated derivative (XXXVII) to hydrogenolysis over Pd/C in methanol followed by treatment with tert-butoxycarbonyl anhydride in dichloromethane. The resulting fully protected intermediate (XXXIX) is finally detosylated with sodium naphthalenide (3). Scheme 3.

1 Matzke, M., Petersen, U., Schenke, T. et al. (Bayer Healthcare AG). Use of 7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-quinolone carboxylic acid and naphthyridon carboxylic acid derivatives for the treatment of Helicobacter pylori infections and associated gastroduodenal diseases. CA 2274894, DE 19652239, EP 0946176, JP 200351781, JP 2000514825, US 6133260, US 6432948, WO 1998026779.
2 Wohlert, S.E., Jaetsch, T., Gallenkamp, B. et al. New fluoroquinolone finafloxacin HCI (FIN): Route of synthesis, physicochemical characteristics and activity under neutral and acid conditions. 48th Annu Intersci Conf Antimicrob Agents Chemother (ICAAC) Infect Dis Soc Am (IDSA) Annu Meet (Oct 25-28, Washington, D.C.) 2008, Abst F1-2036.
3 Hong, J., Zhang, Z., Lei, H. et al. A novel approach to finafloxacin hydrochloride (BAY35-3377). Tetrahedron Lett 2009, 50(21): 2525-8.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 65947 (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine   C6H12N2O 详情 详情
(V) 65950     C11H20N2O3 详情 详情
(XXIV) 36965 (Z)-2-butene-1,4-diol 6117-80-2 C4H8O2 详情 详情
(XXV) 65968 1-(Toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole; 1-(p-Tolylsulfonyl)-3-pyrroline; 1-(4-Methylphenylsulfonyl)-2,5-dihydropyrrole; 2,5-Dihydro-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole 16851-72-2 C11H13NO2S 详情 详情
(XXVI) 65969 3-Tosyl-6-oxa-3-azabicyclo[3.1.0]hexane 159555-66-5 C11H13NO3S 详情 详情
(XXVII) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol;2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(XXVIII) 65970 2,5-Dihydro-3-hydroxy-4-[(2-hydroxyethyl)amino]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole   C13H20NO4S 详情 详情
(XXIX) 65971     C20H26NO6S2 详情 详情
(XXX) 65972     C20H24N2O5S2 详情 详情
(XXXI) 65973 (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine dihydrobromide   C6H12N2O.2HBr 详情 详情
(XXXII) 10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情
(XXXIII) 65974     C19H24N2O3S 详情 详情
(XXXIV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XXXV) 65975     C21H25ClN2O4S 详情 详情
(XXXVI) 65976     C21H24N2O4S 详情 详情
(XXXVII) 65977      C21H26N2O3S 详情 详情
(XXXVIII) 65978     C14H20N2O 详情 详情
(XXXIX) 65979     C18H26N2O5S 详情 详情
Extended Information