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【结 构 式】

【分子编号】20042

【品名】(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine

【CA登记号】

【 分 子 式 】C8H11N

【 分 子 量 】121.18208

【元素组成】C 79.29% H 9.15% N 11.56%
与该中间体有关的原料药合成路线共 25 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25

合成路线1

该中间体在本合成路线中的序号：(XXII)

4) The reaction of phenyl thiobutyrate (XIX) with 9-borabicyclo[3.3.1]nonane (9-BBN) gives the enol ester (XX), which is condensed with the optically active imine (XXI) [prepared from 3-(trimethylsilyl)propynal (XXIII) and (S)-alpha-methylbenzylamine (XXII)] to afford the adduct (XXIV). The cyclization of (XXIV) by means of tert-butylmagnesium chloride in ether yields 3alpha-ethyl-1-(alpha-methylbenzyl)-4beta-[2-(trimethylsilyl)ethynyl]azetidin-2-one (XXV), which is deprotected with tetrabutylammonium fluoride giving the free acetylene derivative (XXVI). The partial reduction of (XXVI) with H2 over Pd-CaCO3-PbO yields the corresponding ethylene compound (XXVII), which is hydroxylated with disiamylborane (DSB) to give the 2-hydroxyethylazetidinone (XXVIII). The protection of (XXVIII) with tert-butyldimethylsilyl chloride yields the silylated compound (XXIX), which is treated with Na-NH3 to afford 3alpha-ethyl-4beta-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XXX). The protection of (XXX) with tert-butyldimethylsilyl chloride as before gives the fully silylated compound (XXXI), which is submitted to a controlled hydrolysis yielding 3alpha-ethyl-4beta-(2-hydroxyethyl)-1-(tert-butyldimethylsilyl)azetidin-2-one (XXXII). The oxidation of (XXXII) with CrO3 - pyridine gives the acetic acid derivative (XXXIII), which is deprotected to afford 2-(3alpha-ethyl-2-oxoazetidin-4beta-yl)acetic acid (XXXIV). The reaction of (XXXIV) with carbonyldiimidazole (XXXV) gives the corresponding imidazolide (XXXVI), which is condensed with magnesium 4-nitrobenzyl malonate (XXXVII) yielding 4-nitrobenzyl 4-(3alpha-ethyl-2-oxoazetidin-4beta-yl)-3-oxobutanoate (XXXVIII). The diazotation of (XXXVIII) with 4-azidobenzoic acid (XXXIX) gives the 2-diazo-3-oxobutanoate derivative (XL), which is finally cyclized to carbapen derivative (XII) in the presence of rhodium acetate. The reaction of (XII) with diphenyl chlorophosphate affords the enol phosphate (XIII), which is condensed with N-acetylcysteamine (XIV) to give 4-nitrobenzyl ester of PS-5 (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C.

参考文献 中间体
合成目标
【1】 Shibasaki, M.; Ishida, Y.; Iwasaki, G.; Iimori, T.; Asymmetric synthesis of the carbapenem antibiotic (+)-PS-5. J Org Chem 1987, 52, 15, 3488-9.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16074 Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate 2524-64-3 C12H10ClO3P 详情 详情
44204 N,N-diethyl-2-propanamine; N,N-diethyl-N-isopropylamine C7H17N 详情 详情
(XII) 20032 4-nitrobenzyl (5R,6R)-6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate C16H16N2O6 详情 详情
(XIII) 20033 4-nitrobenzyl (5R,6R)-3-[(diphenoxyphosphoryl)oxy]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C28H25N2O9P 详情 详情
(XIV) 20034 N-(2-sulfanylethyl)acetamide 1190-73-4 C4H9NOS 详情 详情
(XV) 20035 4-nitrobenzyl (5R,6R)-3-[[2-(acetamido)ethyl]sulfanyl]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C20H23N3O6S 详情 详情
(XIX) 20039 S-phenyl butanethioate C10H12OS 详情 详情
(XX) 20040 (E)-1-(9-borabicyclo[3.3.1]non-9-yloxy)-1-butenyl phenyl sulfide; 9-[[(E)-1-(phenylsulfanyl)-1-butenyl]oxy]-9-borabicyclo[3.3.1]nonane C18H25BOS 详情 详情
(XXI) 20041 (1S)-1-phenyl-N-[(Z)-3-(trimethylsilyl)-2-propynylidene]-1-ethanamine; N-[(1S)-1-phenylethyl]-N-[(Z)-3-(trimethylsilyl)-2-propynylidene]amine C14H19NSi 详情 详情
(XXII) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(XXIII) 20043 3-(trimethylsilyl)-2-propynal C6H10OSi 详情 详情
(XXIV) 20044 S-phenyl (2R,3S)-2-ethyl-3-[[(1S)-1-phenylethyl]amino]-5-(trimethylsilyl)-4-pentynethioate C24H31NOSSi 详情 详情
(XXV) 20045 (3R,4S)-3-ethyl-1-[(1S)-1-phenylethyl]-4-[2-(trimethylsilyl)ethynyl]-2-azetidinone C18H25NOSi 详情 详情
(XXVI) 20046 (3R,4S)-3-ethyl-4-ethynyl-1-[(1S)-1-phenylethyl]-2-azetidinone C15H17NO 详情 详情
(XXVII) 20047 (3R,4R)-3-ethyl-1-[(1S)-1-phenylethyl]-4-vinyl-2-azetidinone C15H19NO 详情 详情
(XXVIII) 20048 (3R,4R)-3-ethyl-4-(2-hydroxyethyl)-1-[(1S)-1-phenylethyl]-2-azetidinone C15H21NO2 详情 详情
(XXIX) 20049 (3R,4R)-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-1-[(1S)-1-phenylethyl]-2-azetidinone C21H35NO2Si 详情 详情
(XXX) 20050 (3R,4R)-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-2-azetidinone C13H27NO2Si 详情 详情
(XXXI) 20051 (3R,4R)-1-[tert-butyl(dimethyl)silyl]-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-2-azetidinone C19H41NO2Si2 详情 详情
(XXXII) 20052 (3R,4R)-1-[tert-butyl(dimethyl)silyl]-3-ethyl-4-(2-hydroxyethyl)-2-azetidinone C13H27NO2Si 详情 详情
(XXXIII) 20053 2-[(2R,3R)-1-[tert-butyl(dimethyl)silyl]-3-ethyl-4-oxoazetidinyl]acetic acid C13H25NO3Si 详情 详情
(XXXIV) 20054 2-[(2R,3R)-3-ethyl-4-oxoazetidinyl]acetic acid C7H11NO3 详情 详情
(XXXV) 11353 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) 530-62-1 C7H6N4O 详情 详情
(XXXVI) 20056 (3R,4R)-3-ethyl-4-[2-(1H-imidazol-1-yl)-2-oxoethyl]-2-azetidinone C10H13N3O2 详情 详情
(XXXVII) 20057 Malonic acid monoethyl ester magnesium salt C20H16MgN2O12 详情 详情
(XXXVIII) 20058 4-nitrobenzyl 4-[(2R,3R)-3-ethyl-4-oxoazetidinyl]-3-oxobutanoate C16H18N2O6 详情 详情
(XXXIX) 20059 4-azidobenzoic acid 6427-66-3 C7H5N3O2 详情 详情
(XL) 20060 (2R,3R)-2-Diazo-4-(3-ethyl-4-oxoazetidin-2-yl)-3-oxobutyric acid 4-nitrobenzyl ester C16H16N4O6 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The synthesis of Bay u 3405 was carried out as follows: Reductive amination of 3-oxo-1,2,3,4-tetrahydrocarbazole (I) with S-phenethylamine (II) afforded a mixture of diastereomeric amines, of which the desired isomer (III) crystallized in high diastereomeric purity as the hydrogensulfate. Cleavage of the phenethyl group by transfer hydrogenolysis with amminium formate and palladium on charcoal yielded the enantiomerically pure (3R)-3-amino-1,2,3,4-tetrahydrocarbazole (IV). Sulfonylation of (IV) with 4-fluorobenzenesulfonyl chloride (V) to the sulfonamide (VI) followed by addition of acrylonitrile and subsequent hydrolysis gave Bay u 3405.

参考文献 中间体
合成目标
【1】 Raz, A.; Needleman, P.; Minkes, M.; Thromboxanes: Selective biosynthesis and distinct biological properties. Science 1976, 193, 163-5.
【2】 Svensson, J.; Hamberg, M.; Samuelsson, B.; Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975, 72, 8, 2994-8.
【3】 Gardiner, P.J.; Boberg, M.; Fiedler, V.B.; Perzborn, E.; Boshagen, H.; Buhner, K.; Muller, U.; Rosentreter, U.; Seuter, F.; Weber, H.; Norman, P.; Ritter, W.; Bay u 3405. Drugs Fut 1991, 16, 8, 701.
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) 12288 1,2,4,9-Tetrahydro-3H-carbazol-3-one C12H11NO 详情 详情
(II) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(III) 12290 N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine C20H22N2 详情 详情
(IV) 12291 (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-ylamine; (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine C12H14N2 详情 详情
(V) 12292 4-Fluorobenzenesulfonyl chloride 349-88-2 C6H4ClFO2S 详情 详情
(VI) 12293 4-Fluoro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]benzenesulfonamide C18H17FN2O2S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The synthesis of [14C]-labeled Bay-u-3405 by two closely related ways has been described: 1) [14C]-Labeled aniline (I) is diazotized and reduced with sodium sulfite, yielding the labeled hydrazine (II), which is condensed with the monoketal of cyclohexane-1,4-dione (III) under Fisher's indole synthesis (ZnCl2) to afford the tetrahydrocarbazole (IV). The hydrolysis of (IV) with HCl in THF/water yields 1,2,3,4-tetrahydrocarbazol-3-one (V), which is submitted to a reductive condensation with (S)-1-phenylethylamine (VI) by means of tetrabutylammonium borohydride, yielding preferentially the secondary amine (VII), which, after purification, is dealkylated with ammonium formate and Pd/C to afford 1,2,3,4-tetrahydrocarbazole-3(R)-amine (VIII). The acylation of (VIII) with 4-fluorophenylsulfonyl chloride (IX) gives the corresponding sulfonamide (X), which is condensed with acrylonitrile by means of NaH, yielding 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]pro pionitrile (XI). Finally, this compound is hydrolyzed in the usual way. 2) The condensation of the sulfonamide (X) with methyl acrylate by means of NaH as before gives 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]propionic acid methyl ester (XII), which is finally hydrolyzed in the usual way.

参考文献 中间体
合成目标
【1】 Pleiss, U.; Radtke, M.; Rosentreter, U.; Boberg, M.; Synthesis of (+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-[5,6,7,8,12,13-u-C-14]carbazolepropanoic acid, [C-14]BAY u 3405. J Label Compd Radiopharm 1994, 34, 12, 1207.
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) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(I) 45117 　 C6H7N 详情 详情
(II) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(II) 45118 　 C6H8N2 详情 详情
(III) 11377 1,4-Dioxaspiro[4.5]decan-8-one 4746-97-8 C8H12O3 详情 详情
(IV) 12297 1,2,3,4-Tetrahydrospiro[9H-carbazole-3,2'-1,3-dioxolane] C14H15NO2 详情 详情
(IV) 45119 　 C14H15NO2 详情 详情
(V) 12288 1,2,4,9-Tetrahydro-3H-carbazol-3-one C12H11NO 详情 详情
(V) 45120 　 C12H11NO 详情 详情
(VI) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VII) 12290 N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine C20H22N2 详情 详情
(VII) 45121 　 C20H22N2 详情 详情
(VIII) 12291 (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-ylamine; (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine C12H14N2 详情 详情
(VIII) 45122 　 C12H14N2 详情 详情
(IX) 12292 4-Fluorobenzenesulfonyl chloride 349-88-2 C6H4ClFO2S 详情 详情
(X) 12293 4-Fluoro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]benzenesulfonamide C18H17FN2O2S 详情 详情
(X) 45123 　 C18H17FN2O2S 详情 详情
(XI) 12304 N-[(3R)-9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide C21H20FN3O2S 详情 详情
(XI) 45124 　 C21H20FN3O2S 详情 详情
(XII) 12305 methyl 3-((3R)-3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl)propanoate C22H23FN2O4S 详情 详情
(XII) 45125 　 C22H23FN2O4S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(S-X)

3) The reaction of 3-methyl-1-[2-(1-piperidinyl)phenyl]butan-1-imine (VI) with acetic acid, triphenylphosphine and CCl4 (or with acetic anhydride and NaHCO3) gives N-[3-methyl-2-(1-piperidinyl)phenyl]-1(Z)-butenyl]acetamide (VII), with some of the (E)-isomer. The stereoselective reduction of the (Z)-isomer (VII) with the chiral complex Ru(OAc)2[(S)-2,2'-bis(diphenylphosphino-1,1'-binaphthyl] (S-BINAP), triethylamine and titanium tetraisopropoxide in methanol/methylene chloride yields N-[3-methyl-1(S)-[2-(1-piperidinyl)phenyl]butyl]acetamide (VIII). The hydrolysis of the chiral amide (VIII) with refluxing concentrated HCl affords the chiral amine (S-I), which is then condensed with the phenylacetic acid (II) by means of triphenylphosphine as before (or with dicyclohexylcarbodiimide) to give the chiral amide-ester (S-III). Finally, this ester is hydrolyzed to repaglinide with NaOH in hot ethanol. 4) The reductocondensation of 3-methyl-1-[2-(1-piperidyl)-1-butanone (IX) with 1(S)-phenylethylamine (S-X) yields the (S)-chiral ketimine (XI), which is reduced with TiCl4 in toluene yielding the (S,S)-chiral secondary amine (S,S-XII). Finally, the 1(S)-phenylethyl group of (S,S-XII) is eliminated by hydrogenolysis with H2 over Pd/C in diluted aqueous HCl to afford the (S)-chiral amine (S-I), already obtained. 5) The condensation of 1(R)-phenylethylamine (R-X) with 2-(1-piperidinyl)benzaldehyde (XIII) gives the corresponding chiral (R)-aldimine (XIV), which is converted into the (S,R)-chiral secondary amine (S,R-XII) by a Grignard reaction with isobutyl bromide in THF. Finally, the 1(R)-phenylethyl group of (S,R-XII) is eliminated by hydrogenolysis as before to afford the previously obtained (S)-chiral amine (S-I).

参考文献 中间体
合成目标
【1】 Graul, A.; Castaner, J.; Repaglinide. Drugs Fut 1996, 21, 7, 694.
【2】 Grell, W.; Greischel, A.; Zahn, G.; Mark, M.; Knorr, H.; Rupprecht, E.; Muller, U. (Dr. Karl Thomae GmbH); (S)(+)-2-(Ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl] aminocarbonylmethyl]benzoic acid. EP 0589874; JP 1994508816; WO 9300337 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
22876 bromo(isobutyl)magnesium 926-62-5 C4H9BrMg 详情 详情
(R-X) 10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情
(S,S-XII) 15312 (1S)-3-methyl-N-[(1S)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine; N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1S)-1-phenylethyl]amine C24H34N2 详情 详情
(S;R-XII) 15313 N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1R)-1-phenylethyl]amine; (1S)-3-methyl-N-[(1R)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine C24H34N2 详情 详情
(S-I) 15315 (1S)-3-methyl-1-(2-piperidinophenyl)butylamine; (1S)-3-methyl-1-(2-piperidinophenyl)-1-butanamine C16H26N2 详情 详情
(S-III) 15316 ethyl 2-ethoxy-4-(2-[[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate C29H40N2O4 详情 详情
(S-X) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(II) 15302 ethyl 2-ethoxy-4-(2-[[3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate C29H40N2O4 详情 详情
(VI) 15305 3-methyl-1-(2-piperidinophenyl)-1-butanimine C16H24N2 详情 详情
(VII) 15306 N-[(Z)-3-methyl-1-(2-piperidinophenyl)-1-butenyl]acetamide C18H26N2O 详情 详情
(VIII) 15307 N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]acetamide C18H28N2O 详情 详情
(IX) 15308 3-methyl-1-(2-piperidinophenyl)-1-butanone C16H23NO 详情 详情
(XI) 15311 N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-N-[(1S)-1-phenylethyl]amine; (1S)-N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-1-phenyl-1-ethanamine C24H32N2 详情 详情
(XIII) 15314 2-piperidinobenzaldehyde C12H15NO 详情 详情
(XIV) 63965 (1R)-1-phenyl-N-{(E)-[2-(1-piperidinyl)phenyl]methylidene}-1-ethanamine; N-[(1R)-1-phenylethyl]-N-{(E)-[2-(1-piperidinyl)phenyl]methylidene}amine C20H24N2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

A new synthesis of repaglinide has been described: The reaction of 2-(1-piperidinyl)benzonitrile (I) with isobutylmagnesium bromide (II) in THF followed by hydrolysis with aqueous NH4Cl/NH3 gives 3-methyl-1-[2-(1-piperidinyl)phenyl]butanone (III), which is condensed with 1(S)-phenylethylamine (IV) by means of TiCl4/triethylamine in toluene yielding the imine (V). The hydrogenation of (V) with H2 over Raney Nickel in ethanol affords the chiral secondary amine (IV), which is further hydrogenated with H2 over Pd/C in ethanol/aqueous HCl giving 3-methyl-2(S)-[2-(1-piperidinyl)phenyl]butylamine (VII). The condensation of (VII) with 4-(carboxymethyl)-2-ethoxybenzoic acid ethyl ester (VIII) by means of SOCl2 or carbonyldiimidazole (CDI) or triphenylphosphine/CCl4/triethylamine gives the ethyl ester of repaglinide (IX), which is finally hydrolyzed with NaOH as usual.

参考文献 中间体
合成目标
【1】 Grell, W.; Hurnaus, R.; Griss, G.; Sauter, R.; Rupprecht, E.; Mark, M.; Luger, P.; Nar, H.; Wittneben, H.; Muller, P.; Repaglinide and related hypoglycemic benzoic acid derivatives. J Med Chem 1998, 41, 26, 5219.
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) 25112 2-(1-piperidinyl)benzonitrile 72752-52-4 C12H14N2 详情 详情
(II) 22876 bromo(isobutyl)magnesium 926-62-5 C4H9BrMg 详情 详情
(III) 15308 3-methyl-1-(2-piperidinophenyl)-1-butanone C16H23NO 详情 详情
(IV) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(V) 15311 N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-N-[(1S)-1-phenylethyl]amine; (1S)-N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-1-phenyl-1-ethanamine C24H32N2 详情 详情
(VI) 15312 (1S)-3-methyl-N-[(1S)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine; N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1S)-1-phenylethyl]amine C24H34N2 详情 详情
(VII) 15315 (1S)-3-methyl-1-(2-piperidinophenyl)butylamine; (1S)-3-methyl-1-(2-piperidinophenyl)-1-butanamine C16H26N2 详情 详情
(VIII) 15301 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid C13H16O5 详情 详情
(IX) 15316 ethyl 2-ethoxy-4-(2-[[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate C29H40N2O4 详情 详情

合成路线6

该中间体在本合成路线中的序号：(V)

3-Bromobenzotrifluoride (I) is converted into the corresponding Grignard reagent (II), which is then condensed with 1,2-dibromo-1-methoxyethane (III) producing the phenethyl bromide (IV). Reaction of bromide (IV) with (S)-alpha-methylbenzylamine (V) yields amine (VI) as a diastereomeric mixture. Recrystallization of (VI) from isopropanol leads to a pure diastereoisomer, which is subsequently treated with ethyl bromoacetate to furnish amino ester (VII). Reduction of (VII) using LiAlH4 provides alcohol (VIII), and further chlorination with SOCl2 leads to chloro amine (IX). Acid (X) is then alkylated with chloride (IX) producing ester (XI). The chiral auxiliary alpha-methylbenzyl group is finally removed by hydrogenolysis to afford the title compound.

参考文献 中间体
合成目标
【1】 Wierzbicki, M.; Hugon, P.; Duhault, J.; Lacour, F.; Boulanger, M. (ADIR et Cie.); Ethanolaminebenzoate deriv., process for their preparation and pharmaceutical compsns. containing them. EP 0518769; FR 2677647; JP 1993238997; US 5266718 .
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) 26348 1-bromo-3-(trifluoromethyl)benzene; 3-Bromobenzotrifluoride 401-78-5 C7H4BrF3 详情 详情
(II) 12028 Bromo[3-(trifluoromethyl)phenyl]magnesium 402-26-6 C7H4BrF3Mg 详情 详情
(III) 58091 1,2-dibromo-1-methoxyethane; 1,2-dibromoethyl methyl ether C3H6Br2O 详情 详情
(IV) 58092 1-(2-bromo-1-methoxyethyl)-3-(trifluoromethyl)benzene; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethyl methyl ether C10H10BrF3O 详情 详情
(V) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VI) 58093 2-methoxy-N-[(1S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-1-ethanamine; N-{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}-N-[(1S)-1-phenylethyl]amine C18H20F3NO 详情 详情
(VII) 58094 ethyl 2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}acetate C22H26F3NO3 详情 详情
(VIII) 58095 2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}-1-ethanol C20H24F3NO2 详情 详情
(IX) 58096 N-(2-chloroethyl)-N-{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}-N-[(1R)-1-phenylethyl]amine; N-(2-chloroethyl)-2-methoxy-N-[(1R)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-1-ethanamine C20H23ClF3NO 详情 详情
(X) 58097 4-(2-{[2-(9H-fluoren-9-yl)acetyl]amino}ethyl)benzoic acid C24H21NO3 详情 详情
(XI) 58098 2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}ethyl 4-(2-{[2-(9H-fluoren-9-yl)acetyl]amino}ethyl)benzoate C44H43F3N2O4 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VI)

1) The condensation of 4-fluoroanisole (I) with maleic anhydride (II) by means of AlCl3 in hot 1,2-dichloroethane gives (E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid (III), which is cyclized by means of NaHCO3 in boiling water to yield racemic 6-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV). The reaction of (IV) with refluxing SOCl2 affords the corresponding acyl chloride (V), which is condensed with (S)-(-)-1-phenylethylamine (VI) affording the amide (VII) as a diastereomeric mixture (R,S + S,S), which is submitted to a fractional crystallization to give the suitable isomer (S,S)-(VII). The hydrolysis of (S,S)-(VII) with concentrated HCl in refluxing dioxane yields the corresponding acid (S)-(IV) as a pure enantiomer. The cyclization of (S)-(IV) with KCN and (NH4)2CO3 in hot water affords the acidic spiro compound (VIII), again as a diastereomeric mixture (2S,4R + 2S,4S), which is separated by fractional crystallization to obtain the desired (2S,4S)-(VIII) compound. The esterification of (2S,4S)-(VIII) with propanol/sulfuric acid affords the corresponding propyl ester (IX), which is finally treated with dry ammonia in methanol.

参考文献 中间体
合成目标
【1】 Mealy, N.; Castaner, J.; SNK-860. Drugs Fut 1996, 21, 3, 261.
【2】 Yamaguchi, T.; Miura, K.; Usui, T.; Unno, R.; Matsumoto, Y.; Fukushima, M.; Mizuno, K.; Kondo, Y.; Baba, Y.; Kurono, M.; Synthesis and aldose reductase inhibitory activity of 2-substituted-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,4'--imidazolidine]-2',5'-diones. Arzneim-Forsch Drug Res 1994, 44, 3, 344-8.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
((S)-IV) 16064 (2S)-6-fluoro-4-oxo-3,4-dihydro-2H-chromene-2-carboxylic acid C10H7FO4 详情 详情
(I) 16057 4-Fluoroanisole; 4-fluorophenyl methyl ether; 1-fluoro-4-methoxybenzene; p-Fluoroanisole 459-60-9 C7H7FO 详情 详情
(II) 11182 2,5-Furandione; Maleic anhydride 108-31-6 C4H2O3 详情 详情
(III) 16059 (E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid C10H7FO4 详情 详情
(IV) 16060 6-fluoro-4-oxo-2-chromanecarboxylic acid C10H7FO4 详情 详情
(V) 16061 6-fluoro-4-oxo-2-chromanecarbonyl chloride C10H6ClFO3 详情 详情
(VI) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VII) 16063 (2S)-6-fluoro-4-oxo-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide C18H16FNO3 详情 详情
(VIII) 16065 (2S,4S)-6-fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]2-ylcarboxylic acid C12H9FN2O5 详情 详情
(IX) 16066 (2S,4S)-6-Fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]-2-ylcarboxylic acid propyl ester C15H15FN2O5 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IX)

A synthesis of the R-(+) isomer has also been reported: Reaction of phenethyl alcohol (I) and ethyl 3,3-diethoxypropionate (VI) in the presence of titanium tetrachloride affords the isochromane (VII), which is hydrolyzed to acid (VIII) with NaOH in aqueous ethanol. Resolution of the racemic acid (VIII) is effected by conversion into the diastereomeric salt with R-(+)-a-methylbenzylamine (IX) which, after recrystallization from dichloromethane and ethyl acetate, is liberated by treatment with hydrochloric acid, to yield the R-(-) acid (X). This acid is reduced to alcohol (XI) with borane-dimethyl sulfide in tetrahydrofuran. Treatment of XI with methanesulfonyl chloride, diisopropylethylamine, and a trace of dimethylaminopyridine (DMAP) in tetrahydrofuran affords mesylate (XII), which is subsequently treated with piperazine (V) in ethylene glycol to afford the R-(+) compound, isolated as the methanesulfonate salt.

参考文献 中间体
合成目标
【1】 TenBrink, R.E.; et al.; (S)-(-)-4-[4-[2-(Isochroman-1-yl)ethyl]-piperazin-1-yl]benzenesulfonamide, a selective dopamine D(4) antagonist. J Med Chem 1996, 39, 13, 2435.
【2】 Ten Brink, R.E.; Ennis, M.D.; Lin, C.-H.; Lahti, R.A.; Romero, A.G.; Sih, J.C. (Pharmacia Corp.); Heterocyclic cpds. for the treatment of CNS and cardiovascular disorders. EP 0737189; JP 1997507224; US 5877317; WO 9518118 .
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) 17897 Phenethyl alcohol; 2-phenyl-1-ethanol 60-12-8 C8H10O 详情 详情
(V) 12143 1-(4-Fluorophenyl)piperazine 2252-63-3 C10H13FN2 详情 详情
(VI) 17901 Ethyl 3,3-diethoxypropanoate 10601-80-6 C9H18O4 详情 详情
(VII) 17902 ethyl 2-(3,4-dihydro-1H-isochromen-1-yl)acetate C13H16O3 详情 详情
(VIII) 17903 2-(3,4-dihydro-1H-isochromen-1-yl)acetic acid C11H12O3 详情 详情
(IX) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(X) 17905 2-[(1R)-3,4-dihydro-1H-isochromen-1-yl]acetic acid C11H12O3 详情 详情
(XI) 17906 2-[(1R)-3,4-dihydro-1H-isochromen-1-yl]-1-ethanol C11H14O2 详情 详情
(XII) 17907 2-[(1R)-3,4-dihydro-1H-isochromen-1-yl]ethyl methanesulfonate C12H16O4S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VI)

Condensation of alpha-methyl tryptophan methyl ester (I) with benzylchloroformate (II) in the presence of Et3N in THF yields urethane (III), which is hydrolyzed with LiOH in THF/MeOH/H2O and then activated with DCCI and pentafluorophenol (IV) to furnish ester (V). Treatment of (V) with alpha-methyl-benzylamine (VI) gives derivative (VII), which is then debenzylated by hydrogenation over Pd(OH)2 in EtOH to afford (VIII). Finally, amine (VIII) reacts in DMF with DMAP and carbonate (IX), which has been previously prepared from 2-benzofuranylmethanol (X), 4-nitrophenylchloroformate (XI) and pyridine in CH2Cl2.

参考文献 中间体
合成目标
【1】 Boyle, S.; et al.; Rational design of high affinity tachykinin NK1 receptor antagonists. Bioorg Med Chem 1994, 2, 5, 357.
【2】 Horwell, D.C.; Howson, W.; Rees, D.C.; Roberts, E.; Pritchard, M.C. (Pfizer Inc.); Tachykinin antagonists. EP 0655055; EP 1000930; US 5594022; WO 9404494 .
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) 44166 methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate C13H16N2O2 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 44167 methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate C21H22N2O4 详情 详情
(IV) 22662 2,3,4,5,6-pentafluorophenol 771-61-9 C6HF5O 详情 详情
(V) 44168 2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate C26H19F5N2O4 详情 详情
(VI) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VII) 44169 benzyl (1R)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[(1S)-1-phenylethyl]amino]ethylcarbamate C28H29N3O3 详情 详情
(VIII) 44170 (2R)-2-amino-3-(1H-indol-3-yl)-2-methyl-N-[(1S)-1-phenylethyl]propanamide C20H23N3O 详情 详情
(IX) 44171 1-benzofuran-2-ylmethyl 4-nitrophenyl carbonate C16H11NO6 详情 详情
(X) 38335 1-benzofuran-2-ylmethanol C9H8O2 详情 详情
(XI) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IV)

Treatment of [U-ring-14C] acetophenone (I) with O-methylhydroxylamine hydrochloride in pyridine/EtOH and catalytic MgSO4 yields labeled acetophenone oxime methyl ether (II), which is then subjected to Didier's enantioselective reduction with BH3·THF and 1S,2R-1-amino-indan-2-ol (III) to provide labeled (S)-(IV). Finally, phenylethylamine (S)-(IV) is coupled to chiral acid (V) with 1-hydroxybenzotriazole hydrate (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-methylmorpholine (NMM).

参考文献 中间体
合成目标
【1】 Zhang, Y.S.; Synthesis of 14C-labeled S-(-)-1-phenylethylamine and its application to the synthesis of [14C] CI-1021, a potential antiemetic agent(1). J Label Compd Radiopharm 2000, 43, 11, 1087.
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) 10317 Acetophenone 98-86-2 C8H8O 详情 详情
(I) 45337 　 C8H8O 详情 详情
(II) 44172 1-phenyl-1-ethanone O-methyloxime C9H11NO 详情 详情
(II) 45338 　 C9H11NO 详情 详情
(III) 16239 (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol 126456-43-7 C9H11NO 详情 详情
(IV) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(IV) 45339 　 C8H11N 详情 详情
(V) 44173 (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid C22H20N2O5 详情 详情

合成路线11

该中间体在本合成路线中的序号：(XII)

Treatment of N(alpha)-Cbz-D-tryptophan (I) with diazomethane (CH2N2) in Et2O/CH2Cl2 provides methyl ester derivative (II), which is then cyclized to afford pyrrolo-indole derivative (III) by long treatment with TFA. N-protection of (III) by reaction with benzyl chloroformate (IV) and Na2CO3 in dioxane yields derivative (V), which is then converted into labeled methylated derivative (VI) by first deprotonation with LHDMS followed by treatment with labeled methyl iodide (MeI) in THF. Ring opening of (VI) by means of TFA furnishes protected methyltryptophan (VII), whose Cbz groups are removed by hydrogenolysis over Pd/C in EtOH to yield derivative (VIII). Coupling of (VIII) with carbonate (IX) by means of DMAP in DMF affords derivative (X), which is then subjected to saponification with LiOH in MeOH to provide carboxylic acid derivative (XI). Finally, (XI) is coupled with methylbenzylamine (XII) by means of HOBt, EDC and N-methylmorpholine (NMM).

参考文献 中间体
合成目标
【1】 Ekhato, I.V.; Huang, Y.; Tetrahydro-pyrrolo-[2,3-b]indole-1,2,8-tricarboxylic acid ester in the enantiospecific preparation of alpha-methyltryptophan: Application in the preparation of carbon-14 labeled PD 145942 and PD 154075. J Label Compd Radiopharm 1997, 39, 12, 1019.
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) 44180 (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid C19H18N2O4 详情 详情
(II) 44174 methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propanoate C20H20N2O4 详情 详情
(III) 44175 1-benzyl 2-methyl (2R,3aS,8aS)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate C20H20N2O4 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 44176 1,8-dibenzyl 2-methyl (2R,3aS,8aR)-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate C28H26N2O6 详情 详情
(VI) 44177 1,8-dibenzyl 2-methyl (2R,3aS,8aS)-2-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate C29H28N2O6 详情 详情
(VI) 45341 1,8-dibenzyl 2-methyl (2R,3aS,8aS)-2-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate C29H28N2O6 详情 详情
(VII) 44178 benzyl 3-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxy-2-methyl-3-oxopropyl)-1H-indole-1-carboxylate C29H28N2O6 详情 详情
(VII) 45340 benzyl 3-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxy-2-methyl-3-oxopropyl)-1H-indole-1-carboxylate C29H28N2O6 详情 详情
(VIII) 44166 methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate C13H16N2O2 详情 详情
(VIII) 45342 methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate C13H16N2O2 详情 详情
(IX) 44171 1-benzofuran-2-ylmethyl 4-nitrophenyl carbonate C16H11NO6 详情 详情
(X) 44179 methyl (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate C23H22N2O5 详情 详情
(X) 45343 methyl (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate C23H22N2O5 详情 详情
(XI) 44173 (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid C22H20N2O5 详情 详情
(XI) 45344 (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid C22H20N2O5 详情 详情
(XII) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情

合成路线12

该中间体在本合成路线中的序号：(VIII)

Treatment of carboxylic acid (I) with MeOH and H2SO4 yields methyl ester (II), which is then converted into cyano derivative (III) by reaction with LiCN in DMF and AcOH. Hydrolysis of (III) with aqueous KOH in EtOH provides dicarboxylic acid (IV), which is cyclized by means of Ac2O to give the dicarboxylic anhydride (V). Alternatively, (V) can be obtained by condensation of ester (VI) with diethyl oxalate (A) in Et2O in the presence of t-BuOK to afford (VII), which is cyclized with H2SO4 and submitted to catalytic hydrogenation over Pd/C. Condensation of anhydride (V) with (S)-alpha-methylbenzylamine yields a mixture of imides, from which (3aR,9bR)-(IX) is obtained by crystallization. Reduction of (3aR,9bR)-(IX) with BH3·THF followed by hydrogenation over Pd/C affords isoindole derivative (X), which is then alkylated with chloroacetonitrile (XI) in acetonitrile in the presence of DIEA and reduced with LiAlH4 to give the primary amine (XII). Treatment of (XIII) with POCl3 and Et3N yields 2-chloro-3-cyanopyrazine (XIV), which is oxidized to provide (XV) by means of K2S2O8 in H2SO4. Treatment of N-oxide (XV) with ethyl thioglycolate (XVI) and NaOEt in DMF affords pyrazinothiophene (XVII), which is then chlorinated with POCl3 to give (XVIII). Finally, reaction of amine (XII) with (XVIII) and triphosgene in toluene and Et3N affords the desired product.

参考文献 中间体
合成目标
【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.Z.; Carroll, W.A.; Drizin, I.; Kerwin, J.F. Jr.; Lebold, S.A.; Lee, E.L.; Elmore, S.W.; Sippy, K.B.; Tietje, K.R.; Wendt, M.D.; Yamamoto, D.M. (Abbott Laboratories Inc.); Tricyclic substd. hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists. EP 0808318; US 5597823; WO 9622992 .
【2】 Basha, F.Z.; Meyer, M.D.; Altenbach, R.J.; et al.; Structure-activity studies for a novel series of tricycic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of bening prostatic hyperplasia (BPH). J Med Chem 2000, 43, 8, 1586.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(I) 42524 5-methoxy-3,4-dihydro-1-naphthalenecarboxylic acid C12H12O3 详情 详情
(II) 42525 methyl 5-methoxy-3,4-dihydro-1-naphthalenecarboxylate C13H14O3 详情 详情
(III) 42526 methyl 2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylate C14H15NO3 详情 详情
(IV) 42527 5-methoxy-1,2,3,4-tetrahydro-1,2-naphthalenedicarboxylic acid C13H14O5 详情 详情
(V) 42528 (3aR,9bR)-6-methoxy-3a,4,5,9b-tetrahydronaphtho[1,2-c]furan-1,3-dione C13H12O4 详情 详情
(VI) 42529 ethyl 4-(2-methoxyphenyl)butanoate C13H18O3 详情 详情
(VII) 42530 diethyl 2-(2-methoxyphenethyl)-3-oxosuccinate C17H22O6 详情 详情
(VIII) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(IX) 42531 (3aR,9bR)-6-methoxy-2-[(1S)-1-phenylethyl]-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione C21H21NO3 详情 详情
(X) 42532 (3aR,9bR)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-6-yl methyl ether; (3aR,9bR)-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole C13H17NO 详情 详情
(XI) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(XII) 42533 (3aR,9bR)-2-(2-aminoethyl)-6-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione C15H18N2O3 详情 详情
(XIII) 42534 3-hydroxy-2-pyrazinecarboxamide 55321-99-8 C5H5N3O2 详情 详情
(XIV) 42535 3-chloro-2-pyrazinecarbonitrile 55557-52-3 C5H2ClN3 详情 详情
(XV) 42536 3-chloro-2-cyanopyrazin-1-ium-1-olate C5H2ClN3O 详情 详情
(XVI) 23995 ethyl 2-sulfanylacetate 2713-34-0 C4H8O2S 详情 详情
(XVII) 42537 7-amino-6-(ethoxycarbonyl)thieno[2,3-b]pyrazin-1-ium-1-olate C9H9N3O3S 详情 详情
(XVIII) 42538 ethyl 7-amino-2-chlorothieno[2,3-b]pyrazine-6-carboxylate C9H8ClN3O2S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(V)

The chiral intermediate (X) was synthesized from 3-cyanobenzoic acid (I) through the following sequence. Hydrogenation of the cyano group over Raney-nickel provided 3-(aminomethyl)benzoic acid (II), which was protected as the tert-buyl carbamate (III) with Boc2O. Subsequent hydrogenation of the benzene ring of (III) over PtO2 yielded the racemic amino acid (IV), predominantly as the cis isomer. The chiral resolution of (IV) with (S)-a-methylbenzyl amine (V) in EtOAc provided the optically pure 1(R),3(S) compound (VI), which was then reduced with borane in THF. The resulting aminoalcohol (VII), after conversion to mesylate (VIII) with methanesulfonyl chloride, was treated with NaN3 to give azide (IX), and this was then reduced to amine (X) with H2 over Pd/C.

参考文献 中间体
合成目标
【1】 Yang, L.; et al.; Spiro[1H-indene-1,4'-piperidine] derivatives as potent and selective non-peptide human somatostatin receptor subtype 2 (sst2) agonists. J Med Chem 1998, 41, 13, 2175.
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) 20406 3-cyanobenzoic acid 1877-72-1 C8H5NO2 详情 详情
(II) 20407 3-(aminomethyl)benzoic acid C8H9NO2 详情 详情
(III) 20408 3-[[(tert-butoxycarbonyl)amino]methyl]benzoic acid C13H17NO4 详情 详情
(IV) 20409 3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexanecarboxylic acid C13H23NO4 详情 详情
(V) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VI) 20411 (1R,3S)-3-(Tert-butoxycarbonylamino)cyclohexanecarboxylic acid (S)-1-phenylethylamine salt C21H34N2O4 详情 详情
(VII) 20412 tert-butyl [(1S,3R)-3-(hydroxymethyl)cyclohexyl]methylcarbamate C13H25NO3 详情 详情
(VIII) 20413 ((1R,3S)-3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexyl)methyl methanesulfonate C14H27NO5S 详情 详情
(IX) 20414 tert-butyl [(1S,3R)-3-(azidomethyl)cyclohexyl]methylcarbamate C13H24N4O2 详情 详情
(X) 20415 tert-butyl [(1S,3R)-3-(aminomethyl)cyclohexyl]methylcarbamate C13H26N2O2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(V)

The intermediate fluoropyrrolidine (XIV) was obtained as follows: Alkylation of ethyl acetoacetate (I) with 1,2-dibromoethane (II) led to the cyclopropane derivative (III). Bromination of (III) provided bromo ketone (IV), which was condensed with (S)-1-phenylethylamine (V), yielding amino ketone (VI). Acylation of amine (VI) with (diethylfosfonyl)fluoroacetyl chloride (VII) gave amide (VIII). Intramolecular Wadsworth-Emmons condensation of keto phosphonate (VIII) in the presence of potassium tert-butoxide produced the pyrrolinone (IX). Catalytic hydrogenation of the pyrroline double bond of (IX), followed by separation of the resultant diastereomeric mixture, furnished pyrrolidinone (X). After saponification of the ethyl ester group of (X), the resulting acid (XI) was subjected to Curtius rearrangement in the presence of DPPA and t-BuOH, giving rise to carbamate (XII). Lactam (XII) reduction by means of borane in THF afforded pyrrolidine (XIII). The N-phenylethyl group of (XIII) was then removed by hydrogenation over Pd/C to furnish the required intermediate pyrrolidine (XIV) (See scheme no. 27170201a, intermediate (IX)).

参考文献 中间体
合成目标
【1】 Takahashi, H.; et al.; DQ-113 (D61-1113), a potent fluoroquinolone against multi-drug resistance Gram-positive bacteria: Practical synthesis, and in vitro and in vivo activities. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-550.
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) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 15171 ethyl 1-acetylcyclopropanecarboxylate C8H12O3 详情 详情
(IV) 15172 ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate C8H11BrO3 详情 详情
(V) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VI) 55739 ethyl 1-(2-{[(1S)-1-phenylethyl]amino}acetyl)cyclopropanecarboxylate C16H21NO3 详情 详情
(VII) 55740 diethyl 2-chloro-1-fluoro-2-oxoethylphosphonate C6H11ClFO4P 详情 详情
(VIII) 55741 ethyl 1-(2-{[2-(diethoxyphosphoryl)-2-fluoroacetyl][(1S)-1-phenylethyl]amino}acetyl)cyclopropanecarboxylate C22H31FNO7P 详情 详情
(IX) 55742 ethyl 1-{4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]-2,5-dihydro-1H-pyrrol-3-yl}cyclopropanecarboxylate C18H20FNO3 详情 详情
(X) 44225 ethyl 1-[(3S,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl]cyclopropanecarboxylate C18H22FNO3 详情 详情
(XI) 55743 1-{(3S,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropanecarboxylic acid C16H18FNO3 详情 详情
(XII) 55744 tert-butyl 1-{(3R,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropylcarbamate C20H27FN2O3 详情 详情
(XIII) 55745 tert-butyl 1-{(3R,4S)-4-fluoro-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropylcarbamate C20H29FN2O2 详情 详情
(XIV) 44231 tert-butyl 1-[(3R,4S)-4-fluoropyrrolidinyl]cyclopropylcarbamate C12H21FN2O2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IV)

Hydrogenation of the enantiomerically pure 1-(alpha-methylbenzyl)-3-(hydroxymethyl)pyrrolidine (I) in the presence of Pearlman's catalyst and di-tert-butyl dicarbonate produced the N-Boc pyrrolidine (II). Reaction of (II) with methanesulfonyl chloride, followed by condensation of the resulting mesylate (III) with (S)-alpha-methylbenzylamine (IV) in toluene at 150 C in a sealed tube afforded the aminomethyl pyrrolidine derivative (V). Then, acidic cleavage of the Boc protecting group yielded pyrrolidine (VI).

参考文献 中间体
合成目标
【1】 Sternfeld, F.; Guiblin, A.R.; Jelley, R.A.; et al.; Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: Potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor. J Med Chem 1999, 42, 4, 677.
【2】 Ogawa, T.; Terai, T.; Haruna, K.; Watanabe, A.; Tominaga, T.; Taguchi, H. (Senju Pharmaceuticals Co., Ltd.; Toyobo Co., Ltd.); Pharmaceutical compsn. for topical administration to the eye for treating allergic conjunctivitis. CA 2165999; EP 0719553; JP 1996231393 .
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) 34461 [(3R)-1-[(1R)-1-phenylethyl]pyrrolidinyl]methanol C13H19NO 详情 详情
(II) 34462 tert-butyl (3R)-3-(hydroxymethyl)-1-pyrrolidinecarboxylate C10H19NO3 详情 详情
(III) 34463 1-Boc-3-methanesulfonyloxymethylpyrrolidine; 1-Boc-3-methanesulfonyloxymethylpyrrolidine 141699-56-1 C11H21NO5S 详情 详情
(IV) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(V) 34464 tert-butyl (3S)-3-([[(1S)-1-phenylethyl]amino]methyl)-1-pyrrolidinecarboxylate C18H28N2O2 详情 详情
(VI) 34465 N-[(1S)-1-phenylethyl]-N-[(3R)pyrrolidinylmethyl]amine; (1S)-1-phenyl-N-[(3R)pyrrolidinylmethyl]-1-ethanamine C13H20N2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(IX)

Condensation of the anion resulting from 2-fluoro-4-methylpyridine (I) and LDA with N-methoxy-N-methyl-3-trifluoromethylbenzamide (II) afforded ketone (III). Subsequent alpha-oximination of (III) with tert-butyl nitrite and HCl provided the required E-oxime (IV) as the major isomer. Cyclization of (IV) with N-(benzyloxycarbonyl)piperidine-4-carboxaldehyde (V) and ammonium acetate in refluxing AcOH afforded hydroxyimidazole (VI). Further reduction of (VI) to imidazole (VII) was carried out with titanium trichloride. Methylation of the imidazole ring of (VII) by treatment with N,N-dimethylformamide dimethylacetal in boiling toluene gave rise to a mixture of both N-methylated imidazoles, from which the desired compound (VIII) was isolated by column chromatography as the minor isomer. Nucleophilic displacement of the fluoropyridine of (VIII) by (S)-alpha-methylbenzylamine (IX) at 150 C gave the corresponding aminopyridine derivative (X). The N-benzyloxycarbonyl protecting group was finally removed by catalytic hydrogenation over Pd/C.

参考文献 中间体
合成目标
【1】 Claiborne, C.F.; Liverton, N.J.; Butcher, J.W.; et al.; Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. J Med Chem 1999, 42, 12, 2180.
【2】 Selnick, H.G.; Claremon, D.A.; Liverton, N.J. (Merck & Co., Inc.); Substd. imidazoles having anti-cancer and cytokine inhibitory activity. JP 1999514353; US 5717100; WO 9712876 .
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) 18296 2-Fluoro-4-methylpyridine 461-87-0 C6H6FN 详情 详情
(II) 35153 N-methoxy-N-methyl-3-(trifluoromethyl)benzamide C10H10F3NO2 详情 详情
(III) 35154 2-(2-fluoro-4-pyridinyl)-1-[3-(trifluoromethyl)phenyl]-1-ethanone C14H9F4NO 详情 详情
(IV) 35155 1-(2-fluoro-4-pyridinyl)-2-[3-(trifluoromethyl)phenyl]-1,2-ethanedione 1-oxime C14H8F4N2O2 详情 详情
(V) 35156 4-Formyl-N-Cbz-piperidine; benzyl 4-formyl-1-piperidinecarboxylate 138163-08-3 C14H17NO3 详情 详情
(VI) 35157 benzyl 4-[5-(2-fluoro-4-pyridinyl)-1-hydroxy-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate C28H24F4N4O3 详情 详情
(VII) 35158 benzyl 4-[5-(2-fluoro-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate C28H24F4N4O2 详情 详情
(VIII) 35159 benzyl 4-[5-(2-fluoro-4-pyridinyl)-1-methyl-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate C29H26F4N4O2 详情 详情
(IX) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(X) 35160 benzyl 4-[1-methyl-5-(2-[[(1S)-1-phenylethyl]amino]-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate C37H36F3N5O2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(IX)

In a modified procedure, displacement of fluoropyridine (VII) by (S)-alpha-methylbenzylamine (IX) afforded aminopyridine derivative (XI). This was then alkylated with iodomethane and Cs2CO3 to provide the required N-methyl imidazole (X) as the major isomer, which was finally deprotected by catalytic hydrogenation over Pd/C.

参考文献 中间体
合成目标
【1】 Claiborne, C.F.; Liverton, N.J.; Butcher, J.W.; et al.; Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. J Med Chem 1999, 42, 12, 2180.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 35158 benzyl 4-[5-(2-fluoro-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate C28H24F4N4O2 详情 详情
(IX) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(X) 35160 benzyl 4-[1-methyl-5-(2-[[(1S)-1-phenylethyl]amino]-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate C37H36F3N5O2 详情 详情
(XI) 35161 benzyl 4-[5-(2-[[(1S)-1-phenylethyl]amino]-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate C36H34F3N5O2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(I)

The desired enantiomer was prepared by two chiral routes. Monoalkylation of (S)-alpha-methylbenzylamine (I) with benzyl bromide in N,N'-dimethylpropyleneurea gave the chiral secondary amine (II). Diastereoselective Michael addition of the lithium amide of (II) to benzyl crotonate (III) provided adduct (IV). The chiral ester (IV) was then reacted with the Grignard reagent (V) to yield the diaryl carbinol (VI). This was subsequently dehydrated to (VII) using H2SO4 in glacial HOAc. Double bond reduction and N-debenzylation of (VII) over Pearlman抯 catalyst provided the target primary amine, which was finally isolated as the hydrochloride salt.

参考文献 中间体
合成目标
【1】 Moe, S.T.; DelMar, E.G.; Smith, D.L.; et al.; Chiral synthesis and pharmacological evaluation of NPS 1407: A potent, stereoselective NMDA receptor antagonist. Bioorg Med Chem Lett 2000, 10, 21, 2411.
【2】 Moe, S.T.; Mueller, A.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9856752 .
【3】 Moe, S.T.; Mueller, A.L.; Vanwagenen, B.C.; Barmore, R.M.; Delmar, E.G.; Artman, L.D.; Balandrin, M.F.; Smith, D.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9746511 .
【4】 Barmore, R.M.; DelMar, E.G.; Balandrin, M.F.; VanWagenen, B.C.; Artman, L.D.; Mueller, A.L.; Moe, S.T. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. US 6071970 .
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) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(II) 38470 (1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine 38235-77-7 C15H17N 详情 详情
(III) 46908 benzyl (E)-2-butenoate C11H12O2 详情 详情
(IV) 46909 benzyl (3S)-3-[benzyl[(1S)-1-phenylethyl]amino]butanoate C26H29NO2 详情 详情
(V) 35384 bromo(3-fluorophenyl)magnesium C6H4BrFMg 详情 详情
(VI) 46910 (3S)-3-[benzyl[(1S)-1-phenylethyl]amino]-1,1-bis(3-fluorophenyl)-1-butanol C31H31F2NO 详情 详情
(VII) 46911 (2S)-N-benzyl-4,4-bis(3-fluorophenyl)-N-[(1S)-1-phenylethyl]-3-buten-2-amine; N-benzyl-N-[(1S)-3,3-bis(3-fluorophenyl)-1-methyl-2-propenyl]-N-[(1S)-1-phenylethyl]amine C31H29F2N 详情 详情

合成路线19

该中间体在本合成路线中的序号：(V)

6-Methoxy-2-tetralone (I) was condensed with pyrrolidine (II) to produce enamine (III). Alkylation of (III) with benzyl bromide, followed by hydrolysis of the enamine function, furnished the 1-benzylnaphthalenone (IV). After formation of the chiral enamine (VI) with (S)-alpha-methylbenzylamine (V), enantioselective Michael addition of methyl vinyl ketone (VII) provided the (R)-diketone (VIII), which underwent ring closure to the phenanthrene derivative (IX) upon treatment with NaOMe. Methyl ether cleavage by using boron trichloride in the presence of tetrabutylammonium iodide afforded phenol (X). The conjugated ketone system of (X) was diastereoselectively reduced to the trans-phenanthrenone (XI) by means of lithium in liquid ammonia. Addition of the lithium acetylide of propyne (XII) to the ketone (XI) produced a diastereomeric mixture of carbinols from which the desired isomer (XIII) was isolated by flash chromatography. The phenol group of (XIII) was then converted to the aryl triflate (XIV) by reaction with trifluoromethanesulfonic anhydride and 2,6-lutidine.

参考文献 中间体
合成目标
【1】 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 .
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) 47506 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone 2472-22-2 C11H12O2 详情 详情
(II) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(III) 47507 methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine C15H19NO 详情 详情
(IV) 51596 1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone C18H18O2 详情 详情
(V) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VI) 51597 1-benzyl-6-methoxy-N-[(1S)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine; N-(1-benzyl-6-methoxy-3,4-dihydro-2-naphthalenyl)-N-[(1S)-1-phenylethyl]amine C26H27NO 详情 详情
(VII) 30324 3-buten-2-one; methyl vinyl ketone 78-94-4 C4H6O 详情 详情
(VIII) 51598 (1R)-1-benzyl-6-methoxy-1-(3-oxobutyl)-3,4-dihydro-2(1H)-naphthalenone C22H24O3 详情 详情
(IX) 51599 (4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone C22H22O2 详情 详情
(X) 51600 (4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone C21H20O2 详情 详情
(XI) 51601 (4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone C21H22O2 详情 详情
(XII) 51602 1-Propyne C3H4 详情 详情
(XIII) 51603 (2R,4aS,10aR)-4a-benzyl-2-(1-propynyl)-1,2,3,4,4a,9,10,10a-octahydro-2,7-phenanthrenediol C24H26O2 详情 详情
(XIV) 51604 (4bS,7R,8aR)-4b-benzyl-7-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl trifluoromethanesulfonate C25H25F3O4S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(IX)

Esterification of N-benzyloxycarbonyl-(R)-tryptophan (I) with allyl alcohol (II) using DCC gave ester (III). The cyclization of (III) to afford diastereoselectively the pyrroloindole derivative (IV) was achieved in trifluoroacetic acid as the solvent. A second N-benzyloxycarbonyl protecting group was then introduced at the indoline nitrogen of (IV), yielding (V). Mannich reaction of the lithium anion of (V) with Eschenmoser's salt provided the (dimethylamino)methyl compound (VI). Ring opening of (VI) to the indole (VII) was performed with sulfuric acid in aqueous methanol. The allyl ester of (VII) was then removed by means of morpholine and palladium catalyst to produce acid (VIII), which was coupled with (S)-alpha-methylbenzylamine (IX) to give amide (X). After hydrogenolysis of the two benzyloxycarbonyl protecting groups of (X), the free amine (XI) was acylated with 2-benzofuranylmethyl chloroformate to furnish the title carbamate.

参考文献 中间体
合成目标
【1】 Ashwood, V.A.; et al.; Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK1 receptor antagonist. J Med Chem 2001, 44, 14, 2276.
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) 18652 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid 7432-21-5 C19H18N2O4 详情 详情
(II) 12234 2-Propen-1-ol; Allyl alcohol 107-18-6 C3H6O 详情 详情
(III) 51359 allyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propanoate C22H22N2O4 详情 详情
(IV) 51360 2-allyl 1-benzyl (2R,3aS,8aS)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate C22H22N2O4 详情 详情
(V) 51361 2-allyl 1,8-dibenzyl (2R,3aS,8aR)-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate C30H28N2O6 详情 详情
(VI) 51362 2-allyl 1,8-dibenzyl (2S,3aS,8aS)-2-[(dimethylamino)methyl]-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate C33H35N3O6 详情 详情
(VII) 51363 benzyl 3-[(2S)-3-(allyloxy)-2-[[(benzyloxy)carbonyl]amino]-2-[(dimethylamino)methyl]-3-oxopropyl]-1H-indole-1-carboxylate C33H35N3O6 详情 详情
(VIII) 51364 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[1-[(benzyloxy)carbonyl]-1H-indol-3-yl]-2-[(dimethylamino)methyl]propionic acid C30H31N3O6 详情 详情
(IX) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(X) 51365 benzyl 3-((2S)-2-[[(benzyloxy)carbonyl]amino]-2-[(dimethylamino)methyl]-3-oxo-3-[[(1S)-1-phenylethyl]amino]propyl)-1H-indole-1-carboxylate C38H40N4O5 详情 详情
(XI) 51367 (2S)-2-amino-3-(dimethylamino)-2-(1H-indol-3-ylmethyl)-N-[(1S)-1-phenylethyl]propanamide C22H28N4O 详情 详情
(XII) 51366 2-[[(chlorocarbonyl)oxy]methyl]-1-benzofuran C10H7ClO3 详情 详情

合成路线21

该中间体在本合成路线中的序号：(I)

Condensation between (S)-alpha-methylbenzylamine (I) and ethyl glyoxylate (II) afforded imine (III), which was subjected to hetero-Diels-Alder cycloaddition with 2-(trimethylsilyloxy)-1,3-butadiene (IV) producing piperidinecarboxylate (V) as the major diastereoisomer. Ketalization of (V) with triethyl orthoformate gave the corresponding the diethyl acetal (VI). The ester group of (VI) was then reduced to alcohol (VII) employing LiAlH4. Mitsunobu condensation of alcohol (VII) with phthalimide (VIII) gave (IX) which, followed by acidic ketal hydrolysis, furnished (X). Condensation of piperidinone (X) with t-butyl cyanoacetate (XI) in the presence of sulfur and morpholine gave rise to two regioisomeric thienopyridine derivatives (XII) and (XIII), which were separated by column chromatography.

参考文献 中间体
合成目标
【1】 Lau, J.; Andersen, H.S.; Newman, M.J.; Hansen, T.K.; Olsen, O.H.; Bakir, F.; Holsworth, D.D.; Axe, F.U.; Ge, Y.; Uyeda, R.T.; Judge, L.M.; Moeller, N.P.H.; Shapira, B.Z. (Novo Nordisk A/S; Ontogen Corp.); Modulators of protein tyrosine phosphatases (PTPases). WO 0204459 .
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) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(II) 48591 Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester 924-44-7 C4H6O3 详情 详情
(III) 58785 ethyl 2-{[(1S)-1-phenylethyl]imino}acetate C12H15NO2 详情 详情
(IV) 18557 1-methylene-2-propenyl trimethylsilyl ether; trimethyl[(1-methylene-2-propenyl)oxy]silane 38053-91-7 C7H14OSi 详情 详情
(V) 58786 ethyl (2R)-4-oxo-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate C16H21NO3 详情 详情
(VI) 58787 ethyl (2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate C20H31NO4 详情 详情
(VII) 58788 {(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methanol C18H29NO3 详情 详情
(VIII) 12376 Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione 85-41-6 C8H5NO2 详情 详情
(IX) 58789 2-({(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione C26H32N2O4 详情 详情
(X) 58790 2-({(2R)-4-oxo-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione C22H22N2O3 详情 详情
(XI) 14330 tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate 1116-98-9 C7H11NO2 详情 详情
(XII) 58791 tert-butyl (7S)-2-amino-7-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate C29H31N3O4S 详情 详情
(XIII) 58792 tert-butyl (5R)-2-amino-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate C29H31N3O4S 详情 详情

合成路线22

该中间体在本合成路线中的序号：(IV)

The acylation of N-[4-(4-aminophenyl)-2-thiazolyl]carbamic acid tert-butyl ester (I) with bromoacetyl bromide (II) gives the bromoacetamide (III), which is then condensed with (S)-alpha-methylbenzylamine (IV) to yield the glycinamide derivative (V). The acylation of (V) with 4-pyridylcarbonyl chloride affords the protected precursor (VI), which is finally deprotected to provide the target BILS 179 BS.

参考文献 中间体
合成目标
【1】 Crute, J.J.; et al.; Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat Med 2002, 8, 4, 386.
【2】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 .
【3】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Crute, J.J.; Thavonekham, B.; Grygon, C. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Antiherpes virus cpds. and methods for their preparation and use. US 6288091 .
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) 54066 tert-butyl 4-(4-aminophenyl)-1,3-thiazol-2-ylcarbamate n/a C14H17N3O2S 详情 详情
(II) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(III) 54067 tert-butyl 4-{4-[(2-bromoacetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate n/a C16H18BrN3O3S 详情 详情
(IV) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(V) 54068 tert-butyl 4-{4-[(2-{[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate n/a C24H28N4O3S 详情 详情
(VI) 27850 isonicotinoyl chloride 39178-35-3 C6H4ClNO 详情 详情
(VII) 54069 tert-butyl 4-{4-[(2-{isonicotinoyl[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate n/a C30H31N5O4S 详情 详情

合成路线23

该中间体在本合成路线中的序号：(IV)

The acylation of N-[4-(4-aminophenyl)-2-thiazolyl]carbamic acid tert-butyl ester (I) with bromoacetyl bromide (II) gives the bromoacetamide (III), which is then condensed with 4-pyridylmethylamine (IV) to yield the glycinamide derivative (V). The acylation of (V) with cyclohexanecarbonyl chloride affords the protected precursor (VI), which is finally deprotected to provide the target BILS 103 BS.

参考文献 中间体
合成目标
【1】 Crute, J.J.; et al.; Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat Med 2002, 8, 4, 386.
【2】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 .
【3】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Crute, J.J.; Thavonekham, B.; Grygon, C. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Antiherpes virus cpds. and methods for their preparation and use. US 6288091 .
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) 54066 tert-butyl 4-(4-aminophenyl)-1,3-thiazol-2-ylcarbamate n/a C14H17N3O2S 详情 详情
(II) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(III) 54067 tert-butyl 4-{4-[(2-bromoacetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate n/a C16H18BrN3O3S 详情 详情
(IV) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(V) 54068 tert-butyl 4-{4-[(2-{[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate n/a C24H28N4O3S 详情 详情
(VI) 17220 cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride 2719-27-9 C7H11ClO 详情 详情
(VII) 54070 tert-butyl 4-[4-({2-[(cyclohexylcarbonyl)(4-pyridinylmethyl)amino]acetyl}amino)phenyl]-1,3-thiazol-2-ylcarbamate n/a C29H35N5O4S 详情 详情

合成路线24

该中间体在本合成路线中的序号：(IV)

6-Methoxy-2-tetralone (I) is converted into enamine (II) by treatment with pyrrolidine in toluene by azeotropic removal of water. Alkylation of (II) with benzyl bromide, followed by hydrolysis of the enamine, provides the 1-benzyl tetralone (III). This is then condensed with (S)-alpha-methylbenzylamine (IV), and the resultant imine (V) is treated with methyl vinyl ketone (VI) to furnish, after hydrolysis of the chiral auxiliary, the tricyclic ketone (VII). Rearrangement of (VII) in the presence of NaOMe results in the phenanthrenone (VIII). Cleavage of the methyl ether of (VIII) is accomplished by treatment with boron trichloride and tetrabutylammonium iodide to form phenol (IX). Reduction of enone (IX) with lithium metal in liquid ammonia leads to the saturated ketone (X). Finally, addition of the lithium acetylide of propyne (XI) to the ketone (X) affords the title carbinol adduct.

参考文献 中间体
合成目标
【1】 Morgan, B.P.; Swick, A.G.; Hargrove, D.M.; LaFlamme, J.A.; Moynihan, M.S.; Carroll, R.S.; Martin, K.A.; Lee, E.; Decosta, D.; Bordner, J.; Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J Med Chem 2002, 45, 12, 2417.
【2】 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 .
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) 47506 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone 2472-22-2 C11H12O2 详情 详情
(II) 47507 methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine C15H19NO 详情 详情
(III) 51596 1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone C18H18O2 详情 详情
(IV) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(V) 61649 (1S)-N-[1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenylidene]-1-phenyl-1-ethanamine C26H27NO 详情 详情
(VI) 30324 3-buten-2-one; methyl vinyl ketone 78-94-4 C4H6O 详情 详情
(VII) 61650 (1R)-1-benzyl-10-hydroxy-5-methoxy-10-methyltricyclo[7.3.1.0~2,7~]trideca-2,4,6-trien-13-one C22H24O3 详情 详情
(VIII) 51599 (4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone C22H22O2 详情 详情
(IX) 51600 (4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone C21H20O2 详情 详情
(X) 51601 (4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone C21H22O2 详情 详情
(XI) 51602 1-Propyne C3H4 详情 详情

合成路线25

该中间体在本合成路线中的序号：(VIII)

5-Formylsalicylic acid (I) is protected by esterification with H2SO4/MeOH to give the methyl ester (II). After alkylation of the phenolic hydroxyl group of (II) with propyl bromide, the resultant ortho-propoxy benzoate ester (III) is hydrolyzed to carboxylic acid (IV) with LiOH in aqueous THF. Condensation of the aldehyde-acid (IV) with 2,4-thiazolidinedione (V) in the presence of morpholine leads to the benzylidene thiazolidinedione (VI). Activation of the carboxyl group of (VI) with oxalyl chloride gives rise to the corresponding acid chloride (VII), which is then condensed with (S)-alpha-methylbenzylamine (VIII) to furnish the target amide.

参考文献 中间体
合成目标
【1】 Allen, S.H.; Pfohl, J.L.; Wallace, E.; Truax, J.F.; Worley, J.K.; Townsend, C.; Peat, A.J.; Garrido, D.M.; McKay, C.; Aryl 1,3-thiazolidine-2,4-diones acting as KATP channel agonists as a class of potent antidiabetic agents. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 364.
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) 32357 5-Formylsalicylic acid; 5-formyl-2-hydroxybenzoic acid 616-76-2 C8H6O4 详情 详情
(II) 58380 ethyl 5-formyl-2-hydroxybenzoate C10H10O4 详情 详情
(III) 58381 ethyl 5-formyl-2-propoxybenzoate C13H16O4 详情 详情
(IV) 58382 5-formyl-2-propoxybenzoic acid C11H12O4 详情 详情
(V) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情
(VI) 58383 5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-propoxybenzoic acid C14H13NO5S 详情 详情
(VII) 58384 5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-propoxybenzoyl chloride C14H12ClNO4S 详情 详情
(VIII) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
Extended Information