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【结 构 式】

【分子编号】17100

【品名】(2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone

【CA登记号】122151-32-0

【 分 子 式 】C14H19NO2

【 分 子 量 】233.3104

【元素组成】C 72.07% H 8.21% N 6% O 13.72%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(IV)

A new synthesis of Sch-56592 has been described: The reaction of (S)-ethyl lactate (I) with pyrrolidine (II) gives 1-[(S)-lactoyl]pyrrolidine (III), which is benzylated as usual with benzyl chloride yielding the benzyl ether (IV). The reaction of (IV) with ethylmagnesium bromide in THF affords 2(S)-benzyloxy-3-pentanone (V), which is reduced with LiBH4 in dimethoxyethane giving 2(S)-benzyloxy-3(RS)-pentanol (VI). The reaction of (VI) with 4-chlorobenzenesulfonyl chloride (VII) yields the corresponding sulfonate (VIII), which is treated with hydrazine in ethanol to afford a diastereomeric mixture of hydrazines that is resolved with L-dibenzoyltartaric acid giving the (S,S)-enantiomer (IX). The formylation of (IX) with refluxing ethyl formate yields the chiral formyl hydrazide (X), which is cyclized with N-[4-[4-[4-(trimethylsilyloxy)phenyl]piperazin-1-yl]phenyl]carbamic acid phenyl ester (XI) affording the triazolone (XII). Finally, this compound is condensed with the chiral tetrahydrofuran derivative (XIII) by means of NaOH in DMSO, and debenzylated by hydrogenation with H2 over Pd/C in formic acid

1 Andrews, D.R.; Gala, D.; Gosteli, J.; Guenter, F.; Leong, W.; Mergelsberg, I.; Sudhakar, A. (Schering Corp.); Process for the preparation of triazolones. WO 9633178 .
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) 16659 ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate 687-47-8 C5H10O3 详情 详情
(II) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(III) 17099 (2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone C7H13NO2 详情 详情
(IV) 17100 (2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone 122151-32-0 C14H19NO2 详情 详情
(V) 17101 (2S)-2-(benzyloxy)-3-pentanone C12H16O2 详情 详情
(VI) 17102 (2S)-2-(benzyloxy)-3-pentanol C12H18O2 详情 详情
(VII) 15787 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride 98-60-2 C6H4Cl2O2S 详情 详情
(VIII) 17104 (2S)-2-(benzyloxy)-1-ethylpropyl 4-chlorobenzenesulfonate C18H21ClO4S 详情 详情
(IX) 17105 1-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]hydrazine; benzyl (1S,2S)-2-hydrazino-1-methylbutyl ether C12H20N2O 详情 详情
(X) 17106 N'-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide C13H20N2O2 详情 详情
(XI) 17107 phenyl 4-(4-[4-[(trimethylsilyl)methyl]phenyl]-1-piperazinyl)phenylcarbamate C27H33N3O2Si 详情 详情
(XII) 17108 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C30H35N5O3 详情 详情
(XIII) 17109 [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-chlorobenzenesulfonate C20H18ClF2N3O4S 详情 详情
(XIV) 17110 4-[4-(4-aminophenyl)piperazino]phenol; 1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine; 1-(4-Hydroxyphenyl)-4-(4-aminophenyl)piperazine 74853-08-0 C16H19N3O 详情 详情
(XV) 17111 phenyl N-[4-[4-(4-hydroxyphenyl)piperazino]phenyl]carbamate C23H23N3O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XXXV)

In an alternative synthesis of compound (XXXII), methyl (S)-lactate (XXXIII) was converted to amide (XXXIV) by treatment with pyrrolidine, and then protected as the benzyl ether (XXXV). Reduction of (XXXV) by means of sodium bis(methoxyethoxy)aluminum hydride produced aldehyde (XXXVI). Condensation of (XXXVI) with formic hydrazide produced the formyl hydrazone (XXXVII), to which was added ethylmagnesium bromide affording a mixture of diastereoisomeric hydrazides. Separation by column chromatography provided the required (S,S) isomer (XXXVIII). Cyclization of (XXXVIII) with the phenyl carbamate (XXIII) in the presence of DBU furnished the triazolone (XXXIX). This was deprotected by hydrogenation in the presence of Pd/C and formic acid to produce compound (XXXII)

1 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0773941; WO 9638443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
15486 formic hydrazide; Formylhydrazine 624-84-0 CH4N2O 详情 详情
(XXIII) 16349 phenyl 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylcarbamate C37H36F2N6O4 详情 详情
(XXXII) 34850 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C37H42F2N8O4 详情 详情
(XXXIII) 17075 propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate 27871-49-4 C4H8O3 详情 详情
(XXXIV) 17099 (2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone C7H13NO2 详情 详情
(XXXV) 17100 (2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone 122151-32-0 C14H19NO2 详情 详情
(XXXVI) 34851 (2R)-2-(benzyloxy)propanal C10H12O2 详情 详情
(XXXVII) 34852 N'-[(E,2R)-2-(benzyloxy)propylidene]formic hydrazide C11H14N2O2 详情 详情
(XXXVIII) 17106 N'-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide C13H20N2O2 详情 详情
(XXXIX) 34853 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C44H48F2N8O4 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

 

1 Saksena AK, Girijavallabhan VM, Lovey RG, et al. 1995. Tetrahydrofuran antifungals. W0 9517407
2 Saksena AK, Girijavallabhan VM, Wang HY, et aL. 2004. Stereoselective grignard additions to N-formyl hydrazone: a concise synthesis of NoxafilR side chain and a synthesis of NonfilR. Tetrahedron Lett, 45: 8249~8251
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) 17100 (2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone 122151-32-0 C14H19NO2 详情 详情
(II) 66599 (S)-2-(benzyloxy)propanal 81445-44-5 C10H12O2 详情 详情
(III) 66600 (S,E)-N'-(2-(benzyloxy)propylidene)formohydrazide   C11H14N2O2 详情 详情
(IV) 17106 N'-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide C13H20N2O2 详情 详情
(V) 17071 N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-N-(1-phenoxyvinyl)amine C38H38F2N6O3 详情 详情
(VI) 21196 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C44H48F2N8O4 详情 详情
Extended Information