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【结 构 式】

【分子编号】11176

【品名】3-Bromopropyne; 3-Bromo-1-propyne

【CA登记号】106-96-7

【 分 子 式 】C3H3Br

【 分 子 量 】118.96082

【元素组成】C 30.29% H 2.54% Br 67.17%
与该中间体有关的原料药合成路线共 33 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26合成路线27合成路线28合成路线29合成路线30合成路线31合成路线32合成路线33

合成路线1

该中间体在本合成路线中的序号：(II)

The alkylation of diethyl N-(4-aminobenzoyl)glutamate (I) with propargyl bromide (II) in hot ethanol gives diethyl N-[4-(propargylamino)benzoyl]glutamate (III), which is condensed with 2-amino-6-bromomethyl-4-hydroxyquinazoline (IV) by means of triethylamine in hot 2-ethoxyethanol (or CaCO3 in dimethylacetamide) yielding diethyl N-[4-[N-[(2-amino-4-hydroxy-6-quinazolinyl)methyl]prop-2-ynylamino]benzoyl]-L-glutamate (V). Finally, this compound is saponified with NaOH in ethanol-water.

参考文献 中间体
合成目标
【1】 Jones, T.R.; Harrap, K.R.; Calvert, A.H.; Anti-cancer quinazoline derivatives. EP 0031237; GB 2065653; US 4447608; US 4564616 .
【2】 Hopkins, S.J.; Serradell, M.N.; Castaner, J.; CB-3717. Drugs Fut 1984, 9, 12, 893.
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) 25036 Diethyl N-(4-aminobenzoyl)glutamate; diethyl 2-[(4-aminobenzoyl)amino]pentanedioate C16H22N2O5 详情 详情
(II) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(III) 34311 ethyl (2S)-1-[(2R)-2-methyl-3-sulfanylpropanoyl]-2,3-dihydro-1H-indole-2-carboxylate C15H19NO3S 详情 详情
(IV) 34312 diethyl 2-[[4-(2-propynylamino)benzoyl]amino]pentanedioate C19H24N2O5 详情 详情
(V) 34313 2-amino-6-(bromomethyl)-4-quinazolinol C9H8BrN3O 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VI)

New syntheses of tandospirone have been described: 1) The hydrogenation of bicyclo[2.2.1]hept-5-ene-2,3-di-exo-carboxylic acid anhydride (I) with H2 over Pd/C in THF-water gives bicyclo[2.2.1]heptane-2,3-di-exo-carboxylic acid anhydride (II), which by reaction with ammonia in THF-water is converted into the imide (III). The reaction of (III) with 1,4-dibromobutane by means of K2CO3 in refluxing acetone yields N-(4-bromobutyl)bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (IV), which is finally condensed with 1-(2-pyrimidinyl)piperazine (V) by means of K2CO3 and KI in hot DMF. 2) Imide (III) is condensed with propargyl bromide (VI) by means of K2CO3 in refluxing acetone affording N-propargylbicyclo[2.2.1]heptane-2,3-di-exo-carboximide (VII), which is allowed to react with piperazine (V) and formaldehyde by means of CuSO4 in dioxane to give N-[4-[4-(2-pyrimidinyl)piperazin-1-yl]-2-butynyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (VIII). Finally, this compound is reduced with H2 over Pd/C. 3) The condensation of piperazine (V) with 4-chlorobutyronitrile (IX) by means of NaOH in acetone gives 4-[4-(2-pyrimidinyl)piperazin-1-yl]butyronitrile (X), which is reduced with LiAlH4 in ether yielding 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (XI). Finally, this compound is condensed with anhydride (II) in refluxing pyridine.

参考文献 中间体
合成目标
【1】 Kojima, A.; Ishizumi, K.; Antoku, F.; Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3-bicyclo[2.2.1]heptanedicarboximide (tandospirone) and related compounds. Chem Pharm Bull 1991, 39, 9, 2288.
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) 11171 (1R,2R,6S,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H8O3 详情 详情
(II) 11172 (1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]decane-3,5-dione 6004-79-1 C9H10O3 详情 详情
(III) 11173 (1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C9H11NO2 详情 详情
(IV) 11174 (1R,2S,6R,7S)-4-(4-Bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C13H18BrNO2 详情 详情
(V) 11175 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine 20980-22-7 C8H12N4 详情 详情
(VI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(VII) 11177 (1R,2S,6R,7S)-4-(2-Propynyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C12H13NO2 详情 详情
(VIII) 11178 (1R,2S,6R,7S)-4-[4-[4-(2-Pyrimidinyl)piperazino]-2-butynyl]-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C21H25N5O2 详情 详情
(IX) 11179 4-Chlorobutanenitrile; 4-Chlorobutyronitrile 628-20-6 C4H6ClN 详情 详情
(X) 11180 4-[4-(2-Pyrimidinyl)piperazino]butanenitrile C12H17N5 详情 详情
(XI) 11181 4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine 33386-20-8 C12H21N5 详情 详情

合成路线3

该中间体在本合成路线中的序号：

The synthesis of tritiated cabergoline by two similar routes has been described: 1) The acylation of 6-nor-dihydrolysergic acid methyl ester (I) with propargyl bromide yields the corresponding 6-propargyl derivative (II), which is hydrogenated with tritium gas over Pd/C in the presence of quinoline to give the ditritiated 6-allyl derivative (III). This compound is treated with 3-(dimethylamino)propylamine at 120 C, yielding the amide (IV), which is finally treated with ethyl isocyanate. 2) The reaction of the propargyl derivative (II) with 3-(dimethylamino)propylamine as before gives the amide (V). The reaction of (V) with ethyl isocyanate gives compound (VI), which is then hydrogenated with tritium as before.

参考文献 中间体
合成目标
【1】 Mantegani, S.; Brambilla, E.; Ermoli, A.; Fontana, E.; Angiuli, P.; Vicario, G.P.; Syntheses of tritium and carbon-14 labelled N-(3-dimethyl aminopropyl)-N-(ethylaminocarbonyl)-6-(2-propenyl)ergoline-8beta-carboxamide (cabergoline), a potent long lasting prolactin lowering agent. J Label Compd Radiopharm 1991, 29, 5, 519.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
28738 ethyl isocyanate 109-90-0 C3H5NO 详情 详情
(I) 11273 8beta-Methoxycarbonylergoline; Methyl (6aR,9R,10aR)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate C16H18N2O2 详情 详情
(II) 11274 methyl (6aR,9R,10aR)-7-(2-propynyl)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate C19H20N2O2 详情 详情
(III) 11279 methyl (6aR,9R,10aR)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate C19H22N2O2 详情 详情
(III) 63076 methyl (6aR,9R,10aR)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate C19H22N2O2 详情 详情
(IV) 11276 (6aR,9R,10aR)-7-allyl-N-[3-(Dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide C23H32N4O 详情 详情
(IV) 63077 (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide C23H32N4O 详情 详情
(V) 11277 (6aR,9R,10aR)-N-[3-(Dimethylamino)propyl]-7-(2-propynyl)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide C23H30N4O 详情 详情
(VI) 11278 N-[[(6aR,9R,10aR)-7-(2-Propynyl)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl]carbonyl]-N-[3-(dimethylamino)propyl]-N'-ethylurea C26H35N5O2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(B)

Compound can be prepared in several related ways: 1) The condensation of N-(1-phenylisopropyl)methylamine (I) with 1,2-dibromopropene (A) by heating at 100 C gives N-(1-phenylisopropyl)-N-methyl-2-bromopropenylamine (II), which is then dehydrobrominated and isomerized by treating with KOH in refluxing ethanol water. 2) By heating a mixture of (I) and propargyl bromide (B) at 100 C. 3) By reductocondensation of (I) with propargyl aldehyde (C) by means of amalgamated Al in ethanol. 4) By condensation of (I) with formaldehyde and acetylene by means of CuCl in hot dioxane. 5) By condensation of 1-phenylisopropyl chloride (III) with N-methylpropargylamine (IV) by heating at 80 C in a sealed tube.

参考文献 中间体
合成目标
【1】 Ecsery, Z.; et al.; AT 252901 .
【2】 Ecsery, Z.; et al.; AT 251560 .
【3】 Ecsery, Z.; et al.; Verfahren zur Herstellung von Phenylisopropylaminen. DE 1568277; NL 6605956 .
【4】 Ecsery, Z.; et al.; Verfahren zur Herstellung von Phenylisopropylaminen. CH 530953; DE 1227447 .
【5】 Roberts, P.J.; Castaner, J.; Selegiline. Drugs Fut 1979, 4, 2, 128.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
23634 acetylene 74-86-2 C2H2 详情 详情
(B) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(A) 33322 (E)-1,2-dibromo-1-propene 26391-16-2 C3H4Br2 详情 详情
(I) 33321 N-methyl-N-[(1R)-1-methyl-2-phenylethyl]amine; (2R)-N-methyl-1-phenyl-2-propanamine 537-46-2 C10H15N 详情 详情
(II) 33323 N-[(E)-3-bromo-2-butenyl]-N-methyl-N-[(1R)-1-methyl-2-phenylethyl]amine; (E)-3-bromo-N-methyl-N-[(1R)-1-methyl-2-phenylethyl]-2-buten-1-amine C14H20BrN 详情 详情
(III) 33324 1-[(2R)-2-chloropropyl]benzene C9H11Cl 详情 详情
(IV) 33325 N-methyl-2-propyn-1-amine; N-methyl-N-(2-propynyl)amine C4H7N 详情 详情
(C) 23544 propiolaldehyde C3H2O 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XI)

Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (S)-(+)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with D-(+)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt.

参考文献 中间体
合成目标
【1】 Pedersen, H.; et al.; Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. Bioorg Med Chem 1999, 7, 5, 795.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 25580 3-amino-2-methylpropanenitrile C4H8N2 详情 详情
(II) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(III) 25581 3-[(2-cyanoethyl)amino]-2-methylpropanenitrile C7H11N3 详情 详情
(IV) 25582 5-methyl-4-oxo-3-piperidinecarbonitrile C7H10N2O 详情 详情
(V) 25583 ethyl 3-cyano-5-methyl-4-oxo-1-piperidinecarboxylate C10H14N2O3 详情 详情
(VI) 25584 ethyl 3-(aminocarbonyl)-5-methyl-4-oxo-1-piperidinecarboxylate C10H16N2O4 详情 详情
(VII) 25585 ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate C17H23N3O3 详情 详情
(VIII) 25586 ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C10H14N2O3S 详情 详情
(IX) 25587 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol C7H10N2OS 详情 详情
(X) 25588 tert-butyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C12H18N2O3S 详情 详情
(XI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XII) 25589 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl 2-propynyl ether C10H12N2OS 详情 详情

合成路线6

该中间体在本合成路线中的序号：(XI)

Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (R)-(-)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with L-(-)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt .

参考文献 中间体
合成目标
【1】 Pedersen, H.; et al.; Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. Bioorg Med Chem 1999, 7, 5, 795.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 25580 3-amino-2-methylpropanenitrile C4H8N2 详情 详情
(II) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(III) 25581 3-[(2-cyanoethyl)amino]-2-methylpropanenitrile C7H11N3 详情 详情
(IV) 25582 5-methyl-4-oxo-3-piperidinecarbonitrile C7H10N2O 详情 详情
(V) 25583 ethyl 3-cyano-5-methyl-4-oxo-1-piperidinecarboxylate C10H14N2O3 详情 详情
(VI) 25584 ethyl 3-(aminocarbonyl)-5-methyl-4-oxo-1-piperidinecarboxylate C10H16N2O4 详情 详情
(VII) 25585 ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate C17H23N3O3 详情 详情
(VIII) 25586 ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C10H14N2O3S 详情 详情
(IX) 25587 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol C7H10N2OS 详情 详情
(X) 25588 tert-butyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C12H18N2O3S 详情 详情
(XI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XII) 25589 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl 2-propynyl ether C10H12N2OS 详情 详情

合成路线7

该中间体在本合成路线中的序号：(III)

Reduction of vitamin D derivative (I) with NaBH4 in ethanol-THF affords alcohol (II), which is alkylated with propargyl bromide (III) and potassium tert-butoxide in the presence of a crown ether. The resulting propargyl ether (IV) is condensed with hexafluoroacetone, by means of butyl litium, to provide tertiary alcohol (V). This compound is then photochemically isomerized in the presence of anthracene as a sensitizer to give (VI). Final deprotection of TBDMS groups with tetrabutylammonium fluoride in THF yields the title compound.

参考文献 中间体
合成目标
【1】 Calverley, M.J.; Grue-Sorensen, G.; Binderup, E.T. (Leo Pharmaceutical Products Ltd. A/S); Novel vitamin D analogues. EP 0522013; JP 1993505613; US 5374629; WO 9115475 .
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) 27521 (2R)-2-[(1R,3aS,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]propanal C34H60O3Si2 详情 详情
(II) 27522 (2R)-2-[(1R,3aS,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-propanol C34H62O3Si2 详情 详情
(III) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(IV) 27523 (1R,5S)-3-((E)-2-[(1R,3aS,7aR)-7a-methyl-1-[(1R)-1-methyl-2-(2-propynyloxy)ethyl]octahydro-4H-inden-4-ylidene]ethylidene)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylenecyclohexyl tert-butyl(dimethyl)silyl ether C37H64O3Si2 详情 详情
(V) 27524 5-[((2R)-2-[(1R,3aS,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]propyl)oxy]-1,1,1-trifluoro-2-(trifluoromethyl)-3-pentyn-2-ol C40H64F6O4Si2 详情 详情
(VI) 27525 5-[((2R)-2-[(1R,3aS,7aR)-4-[(Z)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]propyl)oxy]-1,1,1-trifluoro-2-(trifluoromethyl)-3-pentyn-2-ol C40H64F6O4Si2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

The condensation of 3-hydroxy-1-azabicyclo[2.2.2]octan borane complex (I) with 2-propynyl bromide (II) by means of NaH in DMF gives racemic 3-(2-propynyloxy)-1-azabicyclo[2.2.2]octane (III), which is then submitted to optical resolution with (+)- or (-)-dibenzoyltartaric acid. The optically pure tartrates are treated with aqueous K2CO3 and finally with fumaric acid to obtain the optically pure fumarates.

参考文献 中间体
合成目标
【1】 Walther, G.; Weber, K.-H.; Stransky, W.; Kuhn, F.; Müller, E.; Ensinger, H. (Boehringer Ingelheim GmbH); Novel quinuclidines, their pharmaceutical use and process for their preparation. AU 8945403; DE 3839385; EP 0370415; JP 1990243688; US 5286864; US 5451587 .
【2】 Mealy, N.; Prous, J.; Castaner, J.; WAL-2014-FU. Drugs Fut 1994, 19, 1, 35.
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) 16127 3-Hydroxyquinuclidine borane complex C7H16BNO 详情 详情
(II) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(III) 64697 1-azabicyclo[2.2.2]oct-3-yl 2-propynyl ether; 3-(2-propynyloxy)-1-azabicyclo[2.2.2]octane C10H15NO 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XI)

The reaction of indan-5-amine (I) with acetic anhydride gives the acetamide (II), which is brominated with Br2 in acetic acid yielding the 6-bromo derivative (III). The reaction of (III) with CuCN in 1-methyl-2-pyrrolidone at 125 C affords the corresponding nitrile (IV), which is cyclized by means of H2O2 and NaOH in hot ethanol/water giving the tricyclic ketone (V). The reaction of (V) with chloromethyl pivalate (A) and potassium tert-butoxide in DMSO yields the pivaloyloxymethyl derivative (VI), which is oxidized with CrO3 and tert-butyl peroxide in dichloromethane affording the diketone (VII) (after chromatographic separation of the undesired regioisomer). The condensation of (VII) with N-(4-aminobenzoyl)-Lglutamic acid diethyl ester (VIII) by means of TsOH in refluxing DME gives the imino derivative (IX), which without isolation, is reduced to the secondary amine (X) (as a diastereomeric mixture) with NaBH3CN in methanol/acetic acid. The alkylation of the secondary amine group of (X) with propargyl bromide (XI) and CaCO3 in hot DMA yields the tertiary amine (XII), which is hydrolyzed and deprotected with first with NaOH in methanol/water, and then with aqueous HCl to provide the target compound as a diastereomeric mixture. Finally, this compound is resolved by a treatment with carboxypeptidase G2 and ZnCl2 in water that hydrolyzes selectively the undesired isomer.

参考文献 中间体
合成目标
【1】 Bavetsias, V.; Matusiak, Z.; Melin, C.; Neidle, S.; Marriott, J.H.; Boyle, F.T.; Jackman, A.L.; Chemoenzymatic preparation of the novel antifolate thymidylate synthase inhibitor N-(4-{N-[(6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}-benzoyl)-L-glutamic acid and its glutamyl cleavage product. J Chem Soc - Perkins Trans I 1999, 11, 1495.
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) 16166 chloromethyl pivalate 18997-19-8 C6H11ClO2 详情 详情
(I) 21473 5-indanamine; 2,3-dihydro-1H-inden-5-ylamine 24425-40-9 C9H11N 详情 详情
(II) 21474 N-(2,3-dihydro-1H-inden-5-yl)acetamide C11H13NO 详情 详情
(III) 31073 N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide C11H12BrNO 详情 详情
(IV) 31074 N-(6-cyano-2,3-dihydro-1H-inden-5-yl)acetamide C12H12N2O 详情 详情
(V) 31075 2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one C12H12N2O 详情 详情
(VI) 31076 (2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate C18H22N2O3 详情 详情
(VII) 31077 (2-methyl-4,6-dioxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate C18H20N2O4 详情 详情
(VIII) 31078 diethyl (2S)-2-[(4-aminobenzoyl)amino]pentanedioate; Diethyl N-(4-aminobenzoyl)-L-glutamate 13726-52-8 C16H22N2O5 详情 详情
(IX) 31079 diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-ylidene)amino]benzoyl]amino)pentanedioate C34H40N4O8 详情 详情
(X) 31080 diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl]amino)pentanedioate C34H42N4O8 详情 详情
(XI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XII) 31081 diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioate C37H44N4O8 详情 详情
(XIII) 31082 (2S)-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioic acid C27H26N4O6 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 carboxylic acid (I) with refluxing cyclohexanone (II) and H2SO4 affords derivative (III), which is then condensed with propargyl bromide (IV) by means of NaH in DMF to yield propargyl ether (V). Treatment of (V) with Et3N in toluene followed by condensation with 4-cloro-iodobenzene (VI) by means of PdCl2, PPh3 and CuI provides propinyloxy derivative (VII), which is then converted into propenyloxy derivative (VIII) by hydrogenation over Pd/ BaSO4 in pyridine. Opening of the lactone ring of (VIII) by means of NaH in MeOH and THF affords methyl ester (IX), which is then condensed with benzoyl chloride (X) by means of DMAP and Et3N in CH2Cl2 to give benzoate (XI). Treatment of (XI) with Et2Zn and chloroiodomethane in dichloroethane (or alternatively in CH2Cl2 or THF) followed by recrystallization from isopropanol furnishes cyclopropane derivative (XII), which is then hydrolyzed by treatment with NaOH in dioxane to yield alcohol (XIII). Finally, (XIII) is condensed with intermediate (XIV) by means of NaH in DMF and then deprotected by treatment with HCl in dioxane to afford the target compound.

参考文献 中间体
合成目标
【1】 Hemmerle, H.; Schindler, P.; Herling, A. (Aventis SA); Derivs. of substd. cyclohexane, their process of preparation and their application for the treatment of diseases. EP 0587088; JP 1994211736; US 5463062 .
【2】 Hemmerle, H.; Schubert, G.; Burger, H.-J.; Herling, A.; Efendic, S. (Aventis SA); Cyclohexane derivs., processes for their preparation and their use as glucose-6-phosphatase inhibitors. CA 2149007; CA 4416433; EP 0682024; JP 1995330767; US 5739147 .
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) 44864 Quinic acid; 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid C7H12O6 详情 详情
(II) 11059 Cyclohexanone 108-94-1 C6H10O 详情 详情
(III) 44855 　 C13H18O5 详情 详情
(IV) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(V) 44856 　 C16H20O5 详情 详情
(VI) 19395 1-chloro-4-iodobenzene 637-87-6 C6H4ClI 详情 详情
(VII) 44857 　 C22H23ClO5 详情 详情
(VIII) 44858 　 C22H25ClO5 详情 详情
(IX) 44859 　 C23H29ClO6 详情 详情
(X) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XI) 44860 　 C30H33ClO7 详情 详情
(XII) 44861 　 C31H35ClO7 详情 详情
(XIII) 44862 　 C23H29ClO6 详情 详情
(XIV) 44863 　 C17H12N6O 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

Alkylation of methyl 4-(acetylamino)-2-hydroxybenzoate (I) with propargyl bromide (II) in the presence of K2CO3 in refluxing acetonitrile gave propargyl ether (III), and subsequent chlorination with N-chlorosuccinimide in DMF yielded (IV). Then, a Claisen-type rearrangement of (IV) in boiling diphenyl ether furnished the benzopyran (V), which was hydrogenated over Pt/C to give dihydrobenzopyran (VI). Subsequent treatment of (VI) with 4 N KOH produced the hydrolysis of both ester and amide functions, affording acid (VII). Treatment of dicyclopropyl ketone (VIII) with HCl gas provided 1,7-dichloro-4-heptanone (IX). Cyclization of (IX) with cyanoacetic acid in a two-phase system of aqueous ammonia and n-hexane gave bicyclic intermediate (X), which upon decarboxylation yielded nitrile (XI). Subsequent hydrogenation in the presence of Raney-Ni and NaOH furnished 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (XII) (3). The title compound was then obtained by coupling of acid (VII) with amine (XII) using carbonyldiimidazole (CDI), followed by conversion to the hemifumarate salt.

参考文献 中间体
合成目标
【1】 Kakigami, T.; et al.; Synthesis and structure-activity relationship of 3-substituted benzamide, benzo[b]furan-7-carboxamide, 2,3-dihydrobenzo[b]furan-7-carboxamide, and indole-5-carboxamide derivatives as selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 1998, 46, 1, 42.
【2】 Suzuki, T.; et al.; N-[2-(1-Azabicyclo[3.3.0]octan-5-yl)ethyl]-2-nitroaniline, a potent muscarinic agonist. Chem Pharm Bull 1997, 45, 7, 1218.
【3】 Kakigami, T.; et al.; A 3D-quantitative structure-activity relationship study of benzamide type serotonin 5-HT4 receptor agonists based on a comparative molecular field analysis model, and the design and synthesis of potent agonists. Chem Pharm Bull 1998, 46, 12, 1881.
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) 12330 methyl 4-(acetamido)-2-hydroxybenzoate C10H11NO4 详情 详情
(II) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(III) 19907 methyl 4-(acetamido)-2-(2-propynyloxy)benzoate C13H13NO4 详情 详情
(IV) 19908 methyl 4-(acetamido)-5-chloro-2-(2-propynyloxy)benzoate C13H12ClNO4 详情 详情
(V) 19909 methyl 5-(acetamido)-6-chloro-2H-chromene-8-carboxylate C13H12ClNO4 详情 详情
(VI) 19910 methyl 5-(acetamido)-6-chloro-8-chromanecarboxylate C13H14ClNO4 详情 详情
(VII) 19911 5-amino-6-chloro-8-chromanecarboxylic acid C10H10ClNO3 详情 详情
(VIII) 19912 Dicyclopropylmethanone; Dicyclopropyl ketone 1121-37-5 C7H10O 详情 详情
(IX) 19913 1,7-dichloro-4-heptanone 40624-07-5 C7H12Cl2O 详情 详情
(X) 19914 2-cyano-2-tetrahydro-1H-pyrrolizin-7(5H)-ylacetic acid C10H14N2O2 详情 详情
(XI) 19915 2-tetrahydro-1H-pyrrolizin-7(5H)-ylacetonitrile C9H14N2 详情 详情
(XII) 19916 2-tetrahydro-1H-pyrrolizin-7(5H)-ylethylamine; 2-tetrahydro-1H-pyrrolizin-7(5H)-yl-1-ethanamine C9H18N2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(X)

5-Aminoindan (I) was acetylated, and the resulting anilide (II) was brominated in HOAc to afford (III). Displacement of the bromine of (III) with CuCN in N-methylpyrrolidinone at 125 C furnished nitrile (IV), which was cyclized to the desired quinazolinone derivative (V) upon treatment with sodium hydroperoxide. Protection of the NH group of (V) was achieved by alkylation with chloromethyl pivaloate yielding (VI). Benzylic bromination of (VI) with N-bromosuccinimide in the presence of benzoyl peroxide gave bromide (VII). This was condensed with diethyl p-aminobenzoyl-L-glutamate (VIII) by means of CaCO3 to produce adduct (IX). Further alkylation of (IX) with propargyl bromide (X) using CaCO3 provided propargyl amine (XI). Hydrolysis of the ethyl esters and pivaloyloxymethyl protecting group of (XI) with NaOH afforded (XII). The glutamic acid moiety of (XII) was then removed by enzimatic hydrolysis with carboxypeptidase G2 to furnish intermediate (XIII).

参考文献 中间体
合成目标
【1】 Bavetsias, V.; Boyle, F.T.; Hennequin, L.F.A.; Marriott, J.H. (AstraZeneca plc; BTG plc); Anti-cancer cpds. containing cyclopentaquinazoline ring. EP 0758328; GB 2290082; JP 1997512812; US 5747499; WO 9530673 .
【2】 Jackman, A.L.; Melin, C.; Bavetsias, V.; Matusiak, Z.S.; Marriott, J.H.; Kimbel, C.; Boyle, F.T.; Design and synthesis of cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents. J Med Chem 2000, 43, 10, 1910.
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) 21473 5-indanamine; 2,3-dihydro-1H-inden-5-ylamine 24425-40-9 C9H11N 详情 详情
(II) 21474 N-(2,3-dihydro-1H-inden-5-yl)acetamide C11H13NO 详情 详情
(III) 31073 N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide C11H12BrNO 详情 详情
(IV) 31074 N-(6-cyano-2,3-dihydro-1H-inden-5-yl)acetamide C12H12N2O 详情 详情
(V) 31075 2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one C12H12N2O 详情 详情
(VI) 31076 (2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate C18H22N2O3 详情 详情
(VII) 41348 (6-bromo-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate C18H21BrN2O3 详情 详情
(VIII) 31078 diethyl (2S)-2-[(4-aminobenzoyl)amino]pentanedioate; Diethyl N-(4-aminobenzoyl)-L-glutamate 13726-52-8 C16H22N2O5 详情 详情
(IX) 31080 diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl]amino)pentanedioate C34H42N4O8 详情 详情
(X) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XI) 31081 diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioate C37H44N4O8 详情 详情
(XII) 31082 (2S)-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioic acid C27H26N4O6 详情 详情
(XIII) 41349 4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoic acid C22H19N3O3 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VI)

Conjugate addition of tolylmagnesium bromide (II) to ecgonidine methyl ester (I) provided the 3-beta-tolyl tropane derivative (III). N-Dealkylation of (III) to produce the nortropane analogue (V) was carried out via acylation with trichloroethyl chloroformate, followed by reductive cleavage of the resultant trichloroethyl carbamate (IV) with Zn and HOAc. Alkylation of the secondary amine (V) with propargyl bromide (VI) afforded the corresponding propargyl amine (VII). Subsequent hydrostannylation of the propargyl group furnished the desired (E)-stannylpropenyl compound (VIII) along with the corresponding (Z)-isomer. In an improved procedure, amine (V) was alkylated with (E)-3-chloro-1-(tributylstannyl)-1-propene (IX) to yield pure (VIII). Finally, the title vinyl iodide was obtained by iododestannylation of (VIII) employing iodine in cold CHCl3.

参考文献 中间体
合成目标
【1】 Emond, P.; et al.; Synthesis and ligand bindin of nortropane derivatives: N-substituted 2beta-carbomethoxy-3beta-(4'-iodophenyl)nortropane and N-(3-iodotrop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-disubstituted phenyl)nortropane. New high-affinity and selective compounds. J Med Chem 1997, 40, 9, 1366.
【2】 Mauclaire, L.; Edmond, P.; Guilloteau, D.; Besnard, J.-C.; Frangin, Y. (CIS Bio International); Tropane derivs. useable in particular for in vivo detection of dopamine transporters. EP 0901491; JP 2000510141; US 6180083; WO 9743285 .
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) 21118 methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate C10H15NO2 详情 详情
(II) 35657 bromo(4-methylphenyl)magnesium 4294-57-9 C7H7BrMg 详情 详情
(III) 50267 methyl (1R,2S,3S,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate C17H23NO2 详情 详情
(IV) 50993 2-methyl 8-(2,2,2-trichloroethyl) (1R,2S,3S,5S)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate C19H22Cl3NO4 详情 详情
(V) 50994 methyl (1R,2S,3S,5S)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate C16H21NO2 详情 详情
(VI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(VII) 50995 tributyl[(E)-3-chloro-1-propenyl]stannane C15H31ClSn 详情 详情
(VIII) 50996 methyl (1R,2S,3S,5S)-3-(4-methylphenyl)-8-(2-propynyl)-8-azabicyclo[3.2.1]octane-2-carboxylate C19H23NO2 详情 详情
(IX) 50997 methyl (1R,2S,3S,5S)-3-(4-methylphenyl)-8-[(E)-3-(tributylstannyl)-2-propenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate C31H51NO2Sn 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

The protected acid chloride (X) was prepared by several methods. Alkylation of 4-mercaptophenol (I) with propargyl bromide (II) gave thioether (III). The phenolic hydroxyl of (III) was subsequently protected as the sulfonate ester (IV) by treatment with benzenesulfonyl chloride. The sulfide group of (IV) was then oxidized to the sulfoxide (V) by means of in situ generated performic acid. Rearrangement of the propargyl sulfoxide (V) in refluxing DME gave rise to the 3-(hydroxymethyl)benzothiophene (VI). Oxidation of alcohol (VI) to the corresponding aldehyde (VII) by means of NaOCl in the presence of TEMPO, followed by oxidation with sodium chlorite, furnished the carboxylic acid (VIII). Alternatively, the sulfonate acid (VIII) was obtained by acylation of the known 5-hydroxybenzothiophene-3-carboxylic acid (IX) with benzenesulfonyl chloride. Conversion of acid (VIII) into acid chloride (X) was effected by chlorination with SOCl2 in the presence of a catalytic amount of DMF.

参考文献 中间体
合成目标
【1】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 .
【2】 Okada, T.; Honma, T.; Kakinuma, M.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Process for producing benzothiophenecarboxylic acid amide derivs.. EP 1069123; WO 9950261 .
【3】 Hiramatsu, Y.; Honma, T. (Shionogi & Co. Ltd.); Process for producing 5-hydroxybenzo[b]thiophene-3-carboxylic acid derivs.. EP 1069122; WO 9950260 .
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) 22546 4-sulfanylphenol 637-89-8 C6H6OS 详情 详情
(II) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(III) 60664 4-(2-propynylsulfanyl)phenol C9H8OS 详情 详情
(IV) 60655 (2S)-2-methyl-5-((2R,3S)-2-methyl-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)pentyl triethylsilyl ether; 2-methyl-4-{(E,3S)-2-methyl-4-((2S,3R)-3-methyl-3-{(4S)-4-methyl-5-[(triethylsilyl)oxy]pentyl}oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl}-1,3-thiazole C30H57NO3SSi2 详情 详情
(V) 60666 4-(2-propynylsulfinyl)phenyl benzenesulfonate C15H12O4S2 详情 详情
(VI) 60667 3-(hydroxymethyl)-1-benzothiophen-5-yl benzenesulfonate C15H12O4S2 详情 详情
(VII) 60668 3-formyl-1-benzothiophen-5-yl benzenesulfonate C15H10O4S2 详情 详情
(VIII) 52696 5-[(phenylsulfonyl)oxy]-1-benzothiophene-3-carboxylic acid C15H10O5S2 详情 详情
(IX) 52240 5-hydroxy-1-benzothiophene-3-carboxylic acid C9H6O3S 详情 详情
(X) 52252 3-(chlorocarbonyl)-1-benzothiophen-5-yl benzenesulfonate C15H9ClO4S2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

In a related procedure, the N-octanoyl sultam (I) is alkylated by propargyl bromide (II) to produce (III). Hydrolysis of (III) by means of hydrogen peroxide-tetrabutylammonium hydroxide or lithium hydroxide-hydrogen peroxide furnishes acid (IV). Then, catalytic hydrogenation of the propargyloctanoic acid (IV) in the presence of either Pd/C or Pt/C provides the title compound.

参考文献 中间体
合成目标
【1】 Hasegawa, T.; Yamamoto, H.; A practical synthesis of optically active (R)-2-propyloctanoic acid: Therapeutic agent for Alzheimer's disease. Bull Chem Soc Jpn 2000, 73, 2, 423.
【2】 Yamamoto, H. (Ono Pharmaceutical Co., Ltd.); Novel intermediates and processes for the preparation of optically active octanoic acid derivs.. EP 1078921; US 6333415; WO 9958513 .
【3】 Iguchi, Y.; Yamaguchi, K.; Toda, N. (Ono Pharmaceutical Co., Ltd.; Tokyo Kasei Kogyo Co., Ltd.); Process for the preparation of (2R)-2-propyloctanoic acid. EP 1153910; WO 0048982 .
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) 58243 (1S,5R,7R)-10,10-dimethyl-4-octanoyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C18H31NO3S 详情 详情
(II) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(III) 58247 (1S,5R,7R)-4-[(2S)-2-hexyl-4-pentynoyl]-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C21H33NO3S 详情 详情
(IV) 58248 (2S)-2-hexyl-4-pentynoic acid C11H18O2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(A)

Alkylation of protected erythromycin (I) at the 6-hydroxyl group with propargyl bromide provided ether (II). Hydrolysis of the cyclohexylidene ketal group of (II) with concomitant desilylation with AcOH gave (III). The oxime function of (III) was then hydrolyzed using either sodium bisulfite and formic acid or sodium nitrite and HCl to afford the title ketone.

参考文献 中间体
合成目标
【1】 Bui, M.H.; Plattner, J.J.; Ramney, p.M.; Nilius, A.M.; Chu, D.T.W.; Or, Y.S.; Wang, S.; Clark, R.F.; Henry, R.F.; Ma, Z.; Novel 6-O-substituted erythromycin A derivatives. Synthesis and antibacterial activity. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-125.
【2】 Or, Y.S.; Chu, D.T.; Clark, R.F.; Ma, Z. (Abbott Laboratories Inc.); 6-O-Substd. erythromycins and method for making them. EP 0918783; EP 1007530; JP 2000509712; US 6075011; WO 9742204; WO 9742206 .
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) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(I) 28388 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-14-ethyl-7,12,13-trihydroxy-4-([(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C54H104N2O12Si2 详情 详情
(II) 28394 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-14-ethyl-12,13-dihydroxy-4-([(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-7-(2-propynyloxy)-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C57H106N2O12Si2 详情 详情
(III) 28395 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-12,13-dihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-3,5,7,9,11,13-hexamethyl-7-(2-propynyloxy)-2,10-oxacyclotetradecanedione 10-oxime C40H70N2O13 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XI)

Treatment of (R)-1-aminoindan (I) with trifluoroacetic anhydride in toluene affords trifluoroacetyl derivative (II), which is condensed with chloroacetyl chloride (III) by means of AlCl3 in 1,2-dichloroethane to provide compound (IV). Oxidation of chloroacetyl derivative (IV) with 3-chloroperoxybenzoic acid (mCPBA) and TFA in CH2Cl2 allows formation of chloroacetoxy (V), which is converted into the hydroxy form (VI) by heating in hot methanol/H2O in the presence of K2CO3. N-Protection of (VI) is then performed by treatment with di-t-butyl dicarbonate and Et3N in THF to furnish Boc derivative (VII), which is then converted into derivative (IX) by O-acylation with N-Me, N-Et carbamoyl chloride (VIII) by means of NaH in acetonitrile. Removal of the Boc group of (IX) by treatment with HCl (gas) in dioxane gives hydrochloride (X), which is finally N-alkylated with propargyl bromide (XI) by means of K2CO3 in acetonitrile to yield the desired product.

参考文献 中间体
合成目标
【1】 Youdim, M.B.H.; Herzig, Y.; Sterling, J.; Goren, T.; Chorev, M. (Technion - Israel Institute of Technology; Teva Pharmaceutical Industries Ltd.; Yissum Research Development Co.); Aminoindan derivs.. EP 0966435; JP 2001506269; WO 9827055 .
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) 14863 (1R)-2,3-Dihydro-1H-inden-1-ylamine; (R)-(-)-1-Aminoindan; (1R)-2,3-Dihydro-1H-inden-1-amine 10277-74-4 C9H11N 详情 详情
(II) 46687 N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2,2,2-trifluoroacetamide C11H10F3NO 详情 详情
(III) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(IV) 46688 N-[(1R)-6-(2-chloroacetyl)-2,3-dihydro-1H-inden-1-yl]-2,2,2-trifluoroacetamide C13H11ClF3NO2 详情 详情
(V) 46689 (3R)-3-[(2,2,2-trifluoroacetyl)amino]-2,3-dihydro-1H-inden-5-yl 1lambda(3)-dichlorane-1-carboxylate C12H10Cl2F3NO3 详情 详情
(VI) 46690 (3R)-3-amino-2,3-dihydro-1H-inden-5-ol C9H11NO 详情 详情
(VII) 46691 tert-butyl (1R)-6-hydroxy-2,3-dihydro-1H-inden-1-ylcarbamate C14H19NO3 详情 详情
(VIII) 46692 1,2-dimethyl-1-hydrazinecarbonyl chloride C3H7ClN2O 详情 详情
(IX) 46693 (3R)-3-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl 1,2-dimethyl-1-hydrazinecarboxylate C17H25N3O4 详情 详情
(X) 46694 (3R)-3-amino-2,3-dihydro-1H-inden-5-yl 1,2-dimethyl-1-hydrazinecarboxylate C12H17N3O2 详情 详情
(XI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情

合成路线18

该中间体在本合成路线中的序号：(XVI)

Ketoester (II) was prepared by condensation of dimethyl carbonate with 5-methoxy-2-tetralone (I) in the presence of NaOMe. The alkylation of (II) with allyl bromide using two equivalents of LDA at -78 C proceeded selectively on the C-3 position to give (III). Further decarbomethoxylation of (III) was carried out with LiCl in moist DMSO at high temperature, and the resulting ketone (IV) was converted to ethylene ketal (V) with ethylene glycol and p-TsOH. Then, hydroboration of (V) with disiamyl borane (VI) in cold THF, followed by oxidation of borane (VII) with H2O2-NaOH furnished the primary alcohol (VIII). After Jones oxidation of alcohol (VIII), the resulting acid (IX) was esterified with MeOH and H2SO4 to give ketoester (X). Subsequent cyclization of (X) with benzylamine (XI) and AcOH in refluxing benzene afforded the intermediate tricyclic enamide (XII), which was sequentially reduced with LiAlH4 to enamine (XIII), and then with NaBH4 in the presence of AcOH to furnish a mixture of cis and trans octahydrobenzo[g]quinolines (XIV). Separation of the major trans isomer by flash chromatography was followed by hydrogenolysis of the benzyl group over Pd/C, yielding the secondary amine (XV), whitch was N-alkylated with propargyl bromide (XVI) in hot DMF to give (XVII).

参考文献 中间体
合成目标
【1】 Tagmatarchis, N.; Thermos, K.; Katerinopoulos, H.E.; N-(Iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines: Synthesis and adrenergic and dopaminergic activity studies. J Med Chem 1998, 41, 21, 4165.
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) 14647 5-methoxy-3,4-dihydro-2(1H)-naphthalenone 32940-15-1 C11H12O2 详情 详情
(II) 20448 methyl 5-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthalenecarboxylate C13H14O4 详情 详情
(III) 20449 methyl 3-allyl-5-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthalenecarboxylate C16H18O4 详情 详情
(IV) 20450 3-allyl-5-methoxy-3,4-dihydro-2(1H)-naphthalenone C14H16O2 详情 详情
(V) 20451 3'-Allyl-5'-methoxy-1',2',3',4'-tetrahydrospiro[1,3-dioxolan-2,2'-naphthalene] C16H20O3 详情 详情
(VI) 20452 bis(1,2-dimethylpropyl)borane 132509-17-2 C10H23B 详情 详情
(VII) 20453 B-[3-[5'-Methoxy-1',2',3',4'-tetrahydrospiro[1,3-dioxolan-2,2'-naphthalen]-3'-yl]propyl]-B,B-bis(1,2-dimethylpropyl)borane C26H43BO3 详情 详情
(VIII) 20454 3-[5'-Methoxy-1',2',3',4'-tetrahydrospiro[1,3-dioxolan-2,2'-naphthalen]-3'-yl]propan-1-ol C16H22O4 详情 详情
(IX) 20455 3-(8-methoxy-3-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propionic acid C14H16O4 详情 详情
(X) 20456 methyl 3-(8-methoxy-3-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propanoate C15H18O4 详情 详情
(XI) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(XII) 20458 1-benzyl-6-methoxy-3,4,4a,5-tetrahydrobenzo[g]quinolin-2(1H)-one C21H21NO2 详情 详情
(XIII) 20459 1-benzyl-6-methoxy-1,2,3,4,4a,5-hexahydrobenzo[g]quinoline; 1-benzyl-1,2,3,4,4a,5-hexahydrobenzo[g]quinolin-6-yl methyl ether C21H23NO 详情 详情
(XIV) 20460 1-benzyl-6-methoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline; 1-benzyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl methyl ether C21H25NO 详情 详情
(XV) 20461 (4aS,10aS)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl methyl ether; (4aS,10aS)-6-methoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline C14H19NO 详情 详情
(XVI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XVII) 20463 (4aS,10aS)-1-(2-propynyl)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl methyl ether; (4aS,10aS)-6-methoxy-1-(2-propynyl)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline C17H21NO 详情 详情

合成路线19

该中间体在本合成路线中的序号：(X)

Iodination of 4-aminopyridine (VI), followed by protection with Boc2O, provided the N-Boc iodopyridine (VIII). Piperazinone (XI) was prepared by alkylation of 4-(benzyloxycarbonyl)-2-piperazinone (IX) with propargyl bromide (X). Palladium-catalyzed coupling of propargyl piperazinone (XI) with iodopyridine (VIII) furnished adduct (XII), which was subsequently cyclized to the pyrrolopyridine derivative (XIII) upon treatment with DBU. The benzyloxycarbonyl group of (XIII) was then cleaved by transfer hydrogenolysis to yield the intermediate piperazinone (XIV).

参考文献 中间体
合成目标
【2】 Myers, M.R.; Becker, M.R.; Ewing, W.R.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. oxoazaheterocyclyl factor Xa inhibitors. WO 0032590; WO 0107436 .
【1】 Hanney, B.A.; He, W.; Poli, G.B.; Spada, A.P.; Myers, M.R.; Burns, C.J.; Pauls, H.W.; Jiang, J.Z.; Condon, S.M.; Ewing, W.R.; Becker, M.R.; Li, A.; Choi-Sledeski, Y.M.; Lau, W.F.; Davis, R.S. (Aventis Pharmaceuticals, Inc.); Substd. oxoazaheterocyclyl factor Xa inhibitors. EP 1051176; WO 9937304 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 25661 4-pyridinamine; 4-aminopyridine 5044-74-5 C5H6N2 详情 详情
(VII) 48102 3-iodo-4-pyridinamine; 3-iodo-4-pyridinylamine C5H5IN2 详情 详情
(VIII) 48103 tert-butyl 3-iodo-4-pyridinylcarbamate C10H13IN2O2 详情 详情
(IX) 48104 benzyl 3-oxo-1-piperazinecarboxylate C12H14N2O3 详情 详情
(X) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XI) 48105 benzyl 3-oxo-4-(2-propynyl)-1-piperazinecarboxylate C15H16N2O3 详情 详情
(XII) 48106 benzyl 4-(3-[4-[(tert-butoxycarbonyl)amino]-3-pyridinyl]-2-propynyl)-3-oxo-1-piperazinecarboxylate C25H28N4O5 详情 详情
(XIII) 48107 tert-butyl 2-([4-[(benzyloxy)carbonyl]-2-oxo-1-piperazinyl]methyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate C25H28N4O5 详情 详情
(XIV) 48108 tert-butyl 2-[(2-oxo-1-piperazinyl)methyl]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate C17H22N4O3 详情 详情

合成路线20

该中间体在本合成路线中的序号：

3-(tert-Butoxycarbonylamino)-2-pyrrolidinone (II), obtained by cyclization of (S)-Boc-2,4-diaminobutyric acid (I) in the presence of EDC, was regioselectively alkylated with propargyl bromide and NaH to give the N-propargyl pyrrolidinone (III). Subsequent acid-promoted deprotection of the Boc group of (III) provided aminopyrrolidinone (IV). Sulfonyl chloride (VII) was prepared by lithiation of thienopyridine (V), followed by addition of SO2, and further chlorination of the resulting sulfinic acid (VI) with sulfuryl chloride. This sulfonyl chloride (VII) was then coupled with aminopyrrolidinone (III), yielding sulfonamide (VIII). Lithiation of 3-(tert-butoxycarbonylamino)pyridine (IX) and subsequent treatment with iodine in cold THF provided the iodopyridine derivative (X). Palladium-mediated coupling of (X) with propargyl pyrrolidinone (VIII) furnished adduct (XI), which was cyclized to the pyrrolopyridine system (XII) upon treatment with DBU. Finally, the Boc protecting group of (XII) was removed using trifluoroacetic acid.

参考文献 中间体
合成目标
【1】 Choi-Sledeski, Y.M.; Becker, M.R.; Pauls, H.W.; et al.; Azaindole pyrrolidinone inhibitors of factor Xa: SAR, synthesis, and X-ray crystal structure of a novel surrogate for basic P1 moieties. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 33.
【2】 Choi-Sledeski, Y.M.; Pauls, H.W.; Green, D.M.; Barton, J.N.; Becker, M.R.; Ewing, W.R. (Aventis Pharmaceuticals, Inc.); Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide cpds.. EP 0944386; WO 9825611 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(I) 29493 (2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid C9H18N2O4 详情 详情
(II) 29492 tert-butyl (3S)-2-oxopyrrolidinylcarbamate C9H16N2O3 详情 详情
(III) 35566 tert-butyl (3S)-2-oxo-1-(2-propynyl)pyrrolidinylcarbamate C12H18N2O3 详情 详情
(IV) 35567 (3S)-3-amino-1-(2-propynyl)-2-pyrrolidinone C7H10N2O 详情 详情
(V) 29500 thieno[3,2-b]pyridine C7H5NS 详情 详情
(VI) 35568 thieno[3,2-b]pyridine-2-sulfonic acid C7H5NO3S2 详情 详情
(VII) 29496 thieno[3,2-b]pyridine-2-sulfonyl chloride C7H4ClNO2S2 详情 详情
(VIII) 35569 N-[(3S)-2-oxo-1-(2-propynyl)pyrrolidinyl]thieno[3,2-b]pyridine-2-sulfonamide C14H13N3O3S2 详情 详情
(IX) 35570 tert-butyl 3-pyridinylcarbamate 56700-70-0 C10H14N2O2 详情 详情
(X) 35571 tert-butyl 4-iodo-3-pyridinylcarbamate C10H13IN2O2 详情 详情
(XI) 35572 tert-butyl 4-(3-[(3S)-2-oxo-3-[(thieno[3,2-b]pyridin-2-ylsulfonyl)amino]pyrrolidinyl]-1-propynyl)-3-pyridinylcarbamate C24H25N5O5S2 详情 详情
(XII) 35573 tert-butyl 2-([(3S)-2-oxo-3-[(thieno[3,2-b]pyridin-2-ylsulfonyl)amino]pyrrolidinyl]methyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate C24H25N5O5S2 详情 详情

合成路线21

该中间体在本合成路线中的序号：

N-alkylation of (S)-3-(benzyloxycarbonylamino)-2-pyrrolidinone (XIII) with propargyl bromide produced (XIV). Palladium-mediated coupling (XIV) with iodopyridine (X) gave adduct (XV), which was cyclized to the pyrrolopyridine (XVI) by means of DBU. The benzyloxycarbonyl protecting group of (XVI) was removed by transfer catalytic hydrogenolysis with formic acid, and the deprotected amine (XVII) was then condensed with sulfonyl chloride (VII) to furnish sulfonamide (XII). Deprotection of the Boc group of (XII) as above gave rise to the title compound.

参考文献 中间体
合成目标
【1】 Choi-Sledeski, Y.M.; Becker, M.R.; Pauls, H.W.; et al.; Azaindole pyrrolidinone inhibitors of factor Xa: SAR, synthesis, and X-ray crystal structure of a novel surrogate for basic P1 moieties. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 33.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(VII) 29496 thieno[3,2-b]pyridine-2-sulfonyl chloride C7H4ClNO2S2 详情 详情
(X) 35571 tert-butyl 4-iodo-3-pyridinylcarbamate C10H13IN2O2 详情 详情
(XII) 35573 tert-butyl 2-([(3S)-2-oxo-3-[(thieno[3,2-b]pyridin-2-ylsulfonyl)amino]pyrrolidinyl]methyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate C24H25N5O5S2 详情 详情
(XIII) 35574 benzyl (3S)-2-oxopyrrolidinylcarbamate C12H14N2O3 详情 详情
(XIV) 35575 benzyl (3S)-2-oxo-1-(2-propynyl)pyrrolidinylcarbamate C15H16N2O3 详情 详情
(XV) 35576 benzyl (3S)-1-(3-[3-[(tert-butoxycarbonyl)amino]-4-pyridinyl]-2-propynyl)-2-oxopyrrolidinylcarbamate C25H28N4O5 详情 详情
(XVI) 35577 tert-butyl 2-[((3S)-3-[[(benzyloxy)carbonyl]amino]-2-oxopyrrolidinyl)methyl]-1H-pyrrolo[2,3-c]pyridine-1-carboxylate C25H28N4O5 详情 详情
(XVII) 35578 tert-butyl 2-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-1H-pyrrolo[2,3-c]pyridine-1-carboxylate C17H22N4O3 详情 详情

合成路线22

该中间体在本合成路线中的序号：(X)

5-Aminoindan (I) was acetylated, and the resulting anilide (II) was brominated in HOAc to afford (III). Displacement of the bromine of (III) with CuCN in N-methylpyrrolidinone at 125 C furnished nitrile (IV), which was cyclized to the desired quinazolinone derivative (V) upon treatment with sodium hydroperoxide. Protection of the NH group of (V) was achieved by alkylation with chloromethyl pivaloate yielding (VI). Benzylic bromination of (VI) with N-bromosuccinimide in the presence of benzoyl peroxide gave bromide (VII). This was condensed with diethyl p-aminobenzoyl-L-glutamate (VIII) by means of CaCO3 to produce adduct (IX). Further alkylation of (IX) with propargyl bromide (X) using CaCO3 provided propargyl amine (XI). Hydrolysis of the ethyl esters and pivaloyloxymethyl protecting group of (XI) with NaOH afforded (XII). The glutamic acid moiety of (XII) was then removed by enzimatic hydrolysis with carboxypeptidase G2 to furnish intermediate (XIII).

参考文献 中间体
合成目标
【1】 Boyle, F.; Crook, J.W.; Matusiak, Z.S. (AstraZeneca plc; BTG plc); Tricyclic cpds. with pharmaceutical activity. EP 0667864; GB 2272217; JP 1996505838; US 5789417; WO 9411354 .
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) 21473 5-indanamine; 2,3-dihydro-1H-inden-5-ylamine 24425-40-9 C9H11N 详情 详情
(II) 21474 N-(2,3-dihydro-1H-inden-5-yl)acetamide C11H13NO 详情 详情
(III) 31073 N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide C11H12BrNO 详情 详情
(IV) 31074 N-(6-cyano-2,3-dihydro-1H-inden-5-yl)acetamide C12H12N2O 详情 详情
(V) 31075 2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one C12H12N2O 详情 详情
(VI) 31076 (2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate C18H22N2O3 详情 详情
(VII) 41348 (6-bromo-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate C18H21BrN2O3 详情 详情
(VIII) 31078 diethyl (2S)-2-[(4-aminobenzoyl)amino]pentanedioate; Diethyl N-(4-aminobenzoyl)-L-glutamate 13726-52-8 C16H22N2O5 详情 详情
(IX) 31080 diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl]amino)pentanedioate C34H42N4O8 详情 详情
(X) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XI) 31081 diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioate C37H44N4O8 详情 详情
(XII) 31082 (2S)-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioic acid C27H26N4O6 详情 详情
(XIII) 41349 4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoic acid C22H19N3O3 详情 详情

合成路线23

该中间体在本合成路线中的序号：(VIII)

Ethyl isonipecotate (I) was protected as the N-Boc derivative (II) employing di-tert-butyl dicarbonate. Sulfenylation of the lithium enolate of ester (II) with the disulfide (IV), generated from the oxidation of 4-fluorothiophenol (III), furnished the phenylsulfanyl derivative (V). Thioether (V) was then oxidized to the corresponding sulfone (VI) by means of meta-chloroperbenzoic acid. After acidic Boc group cleavage in (VI), the resultant piperidine (VII) was alkylated with propargyl bromide (VIII) to produce the N-propargyl piperidine (IX).

参考文献 中间体
合成目标
【1】 Becker, D.P.; Hockerman, S.L.; Barta, T.E.; et al.; Design and synthesis of beta-sulfone and alpha-sulfone hydroxamates as potent and orally active MMP inhibitors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 259.
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) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 49847 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine 142851-03-4 C13H23NO4 详情 详情
(III) 22971 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol 371-42-6 C6H5FS 详情 详情
(IV) 52287 bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene C12H8F2S2 详情 详情
(V) 52288 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfanyl]-1,4-piperidinedicarboxylate C19H26FNO4S 详情 详情
(VI) 52289 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfonyl]-1,4-piperidinedicarboxylate C19H26FNO6S 详情 详情
(VII) 52290 ethyl 4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate C14H18FNO4S 详情 详情
(VIII) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(IX) 56377 ethyl 4-[(4-fluorophenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxylate C17H20FNO4S 详情 详情

合成路线24

该中间体在本合成路线中的序号：(VII)

Alkylation of cyclohexyl ethylamine (VI) with propargyl bromide (VII) gives the tertiary amine (VIII). Then, palladium-catalyzed coupling between the propargylic amine (VIII) and aryl triflate (V) furnishes the disubstituted acetylene derivative (IX). Finally, semihydrogenation of the triple bond of (IX) in the presence of cyclohexene and Lindlar catalyst gives rise to the target cis-olefin.

参考文献 中间体
合成目标
【1】 Paul, R.; Boigegrain, R.; Nisato, D.; Casellas, P.; Herbert, J.M.; Bourrie, B.; Bourrie, M.; Lair, P.; Vernieres, J.C. (Sanofi-Synthélabo); Benzene derivs., preparation method and pharmaceutical compsns. containing same. EP 1192122; FR 2794742; JP 2003502306; US 6482986; WO 0076953 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 62830 3,5-dichloro-4-tricyclo[3.3.1.1~3,7~]dec-2-ylphenyl trifluoromethanesulfonate C17H17Cl2F3O3S 详情 详情
(VI) 59245 N-Ethylcyclohexanamine; N-Ethylcyclohexylamine; Vulkacit HX 5459-93-8 C8H17N 详情 详情
(VII) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(VIII) 62831 N-ethyl-N-(2-propynyl)cyclohexanamine; N-cyclohexyl-N-ethyl-N-(2-propynyl)amine C11H19N 详情 详情
(IX) 62832 N-[3-(3,5-dichloro-4-tricyclo[3.3.1.1~3,7~]dec-2-ylphenyl)-2-propynyl]-N-ethylcyclohexanamine; N-cyclohexyl-N-[3-(3,5-dichloro-4-tricyclo[3.3.1.1~3,7~]dec-2-ylphenyl)-2-propynyl]-N-ethylamine C27H35Cl2N 详情 详情

合成路线25

该中间体在本合成路线中的序号：(I)

Alkylation of hydroxylamine with propargyl bromide (I) provided N-propargyl hydroxylamine (II), which was subsequently acylated with 3-chloropropionyl chloride (III) in the presence of pyridine to yield the N-hydroxy amide (IV). Mannich reaction of the propargyl compound (IV) with paraformaldehyde and pyrrolidine (V) with simultaneous cyclization of the N-hydroxy chloropropionamide furnished the title compound.

参考文献 中间体
合成目标
【1】 Amstutz, R.; et al.; Position 5 at the oxotremorinic skeleton as the stearing position for activity at the muscarinic receptors. Helv Chim Acta 1987, 70, 2232.
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) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(II) 50918 3-(hydroxyamino)-1-propyne; N-(2-propynyl)hydroxylamine C3H5NO 详情 详情
(III) 18935 3,4-dimethoxyphenylamine; 3,4-dimethoxyaniline 6315-89-5 C8H11NO2 详情 详情
(IV) 50919 3-chloro-N-hydroxy-N-(2-propynyl)propanamide C6H8ClNO2 详情 详情
(V) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情

合成路线26

该中间体在本合成路线中的序号：(II)

The condensation of 2-phenylethylhydrazine (I) with propargyl bromide (II) by means of K2CO3 in aqueous acetonitrile gives the target hydrazine.

参考文献 中间体
合成目标
【1】 Sloley, B.D.; Urichuk, L.J.; Pang, P.K.T.; Coutts, R.T.; Shan, J.J.; Baker, G.B.; Ling, L.; Synthesis of N-propargylphenelzine and analogues as neuroprotective agents. Bioorg Med Chem Lett 2001, 11, 20, 2715.
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) 51937 beta-Phenylethylhydrazine C8H12N2 详情 详情
(II) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情

合成路线27

该中间体在本合成路线中的序号：(II)

The condensation of fully Boc-protected 2-phenylethylhydrazine (I) with propargyl bromide (II) by means of NaH gives the protected disubstituted hydrazine (III), which is finally deprotected with 4N HCl in dioxane to afford the target hydrazine.

参考文献 中间体
合成目标
【1】 Sloley, B.D.; Urichuk, L.J.; Pang, P.K.T.; Coutts, R.T.; Shan, J.J.; Baker, G.B.; Ling, L.; Synthesis of N-propargylphenelzine and analogues as neuroprotective agents. Bioorg Med Chem Lett 2001, 11, 20, 2715.
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) 51939 di(tert-butyl) 1-phenethyl-1,2-hydrazinedicarboxylate C18H28N2O4 详情 详情
(II) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(III) 51938 di(tert-butyl) 1-phenethyl-2-(2-propynyl)-1,2-hydrazinedicarboxylate C21H30N2O4 详情 详情

合成路线28

该中间体在本合成路线中的序号：

This compound has been obtained by two related ways: The demethylation of levorphanol (I) by the deGraw and Engstrom procedure (ethyl chloroformate and K2CO3 in refluxing chloroform and hydrolysis with NaOH) gives norlevorphanol (II), which is alkylated with propargyl bromide (III) and K2CO3 in hot DMF to yield the N-propargyl derivative (IV). The hydrostannylation of (IV) with HSnBu3 and Et3B in THF affords a mixture of the trans-(V) and cis-(VI) tributyltin precursors that are separated by column chromatography. Finally, the desired trans-isomer (V) is iodinated with I2 in CHCl3 to provide the target iodoallyl morphinan derivative. Alternatively, the hydrostannylation of propargyl alcohol (VI) by conventional methods gives the (E)-3-(tributylastannyl)allyl alcohol (VII), which is treated with CCl4 and PPh3 to yield the corresponding allyl bromide (VIII). Finally, the N-alkylation of norlevorphanol (II) with the allyl bromide (VIII) affords the already reported trans-(tributylstannyl)precursor (V).

参考文献 中间体
合成目标
【1】 Neumeyer, J.L.; Negus, S.S.; Mello, N.K.; Cohen, D.J.; Gu, X.-H.; Rusovici, D.E.; DeNunzio, N.J.; van Vliet, L.A.; Bidlack, J.M.; Mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine abuse: Synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan. Bioorg Med Chem Lett 2001, 11, 20, 2735.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(I) 43741 (1R,9R,10R)-17-methyl-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-4-ol C17H23NO 详情 详情
(II) 43742 (1R,9R,10R)-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-4-ol C16H21NO 详情 详情
(III) 54430 (1R,10R)-17-(2-propynyl)-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2,4,6-trien-4-ol C19H23NO 详情 详情
(IV) 54431 (1R,10R)-17-[(E)-3-(tributylstannyl)-2-propenyl]-17-azatetracyclo[7.5.3.0~1,10~.0~2,7~]heptadeca-2,4,6-trien-4-ol C31H51NOSn 详情 详情
(V) 54432 (1R,10R)-17-[(Z)-3-(tributylstannyl)-2-propenyl]-17-azatetracyclo[7.5.3.0~1,10~.0~2,7~]heptadeca-2,4,6-trien-4-ol C31H51NOSn 详情 详情
(VI) 16664 Propargyl Alcohol; 2-propyn-1-ol 107-19-7 C3H4O 详情 详情
(VII) 52942 (E)-3-(tributylstannyl)-2-propen-1-ol n/a C15H32OSn 详情 详情
(VIII) 50995 tributyl[(E)-3-chloro-1-propenyl]stannane C15H31ClSn 详情 详情

合成路线29

该中间体在本合成路线中的序号：(XXXI)

From the intermediate morpholine (XVIII) the title compound was obtained by several routes. Alkylation of (XVIII) with propargyl bromide (XXXI) gave the N-propargyl morpholine (XXXII). Palladium-catalyzed addition of N,N-dimethylcarbamoyl chloride to the propargyl group of (XXXII) produced the butynamide derivative (XXXIII). The target triazole system (XXXIV) was obtained by dipolar cycloaddition of NaN3 to the acetylenic triple bond of (XXXIII) in hot DMSO. Finally, amide reduction in (XXXIV) with LiAlH4 led to the title dimethylaminomethyl triazole, which was isolated as the hydrochloride salt.

参考文献 中间体
合成目标
【1】 Baker, R.; Harrison, T.; Mcleod, A.M.; Owens, A.P.; Seward, E.M.; Swain, C.J.; Teall, M.R. (Merck Sharp & Dohme Ltd.); Substd. morpholine derivs. and their use as therapeutic agents. EP 0737192; EP 1099702; JP 1997507484; JP 2000219629; US 5612337; WO 9518124 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 18293 (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine 171482-05-6 C20H18F7NO2 详情 详情
(XXXI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XXXII) 53299 (2R,3S)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)-4-(2-propynyl)morpholine; (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)-4-(2-propynyl)morpholinyl ether n/a C23H20F7NO2 详情 详情
(XXXIII) 53300 4-[(2R,3S)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholinyl]-N,N-dimethyl-2-butynamide n/a C26H25F7N2O3 详情 详情
(XXXIV) 53301 4-{[(2R,3S)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholinyl]methyl}-N,N-dimethyl-1H-1,2,3-triazole-5-carboxamide n/a C26H26F7N5O3 详情 详情

合成路线30

该中间体在本合成路线中的序号：(II)

The title ketolide was synthesized starting from 2',4''-bis-O-trimethylsilylerythromycin A 9-O-(1-isopropoxycyclohexyl)oxime (I). Selective alkylation of (I) at the 6-hydroxyl group with propargyl bromide (II) furnished the propargyl ether (III). Then, acidic hydrolysis of the oxime ketal and the silyl ether groups of (III) provided (IV). Conversion of oxime (IV) into the corresponding ketone (V) was accomplished via diazotization with NaNO2 and HCl. The 2' and 4'' hydroxyl groups of (V) were then protected by esterification with acetic anhydride and DMAP to afford diacetate (VI). Treatment of (VI) with carbonyldiimidazole and NaH caused the elimination of the 11-hydroxyl group and formation of the 12-O-imidazolide (VII).

参考文献 中间体
合成目标
【1】 Or, Y.S.; Nilius, A.M.; Chu, D.T.W.; Zhang, X.; Wang, S.; Clark, R.F.; Ma, Z.; Structure-activity relationships leading to the discovery of A-217213, a novel 6-O-substituted ketolide with excellent activity against drug-resistant pathogens. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1171.
【2】 Or, Y.S.; Ma, Z.; Clark, R.F.; Chu, D.T.; Plattner, J.J. (Abbott Laboratories Inc.); 6-O-Substd. ketolides having antibacterial activity. EP 0929563; US 5866549; WO 9809978 .
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) 59651 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-({(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-14-ethyl-7,12,13-trihydroxy-4-({(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C52H100N2O14Si2 详情 详情
(II) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(III) 59652 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-({(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-14-ethyl-12,13-dihydroxy-4-({(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-3,5,7,9,11,13-hexamethyl-7-(2-propynyloxy)-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C55H102N2O14Si2 详情 详情
(IV) 28395 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-12,13-dihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-3,5,7,9,11,13-hexamethyl-7-(2-propynyloxy)-2,10-oxacyclotetradecanedione 10-oxime C40H70N2O13 详情 详情
(V) 59653 (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-12,13-dihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-7-(2-propynyloxy)-2,10-oxacyclotetradecanedione C40H69NO13 详情 详情
(VI) 59654 (2S,3S,4R,6R)-6-{[(3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-7-(2-propynyloxy)oxacyclotetradecanyl]oxy}-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate C44H73NO15 详情 详情
(VII) 59655 (2R,3S,7R,9S,10R,11R,12S,13R)-10-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-12-{[(2R,4R,5S,6S)-5-(acetyloxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,5,7,9,11,13-hexamethyl-6,14-dioxo-9-(2-propynyloxy)oxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate C48H73N3O15 详情 详情

合成路线31

该中间体在本合成路线中的序号：(III)

N-Demethylation of cocaine (I) is accomplished by treatment with 1-chloroethyl chloroformate, followed by methanolysis of the intermediate chloroethyl carbamate. The resultant nor-cocaine (II) is alkylated with propargyl bromide (III) to afford (IV). Acidic ester hydrolysis of (IV) furnishes hydroxy acid (V). Chlorination of (V) with POCl3, followed by treatment with methanol gives rise to the unsaturated ester (VI). Radical cyclization of the enyne system (VI) in the presence of Bu3SnH and AIBN affords a Z/E mixture of tricyclic vinyl stannanes (VIIa-b) that are separated by column chromatography. The major Z isomer is then subjected to Stille coupling with the aryl iodide (VIII), yielding adduct (IX). Then, reduction of the ester function of (IX) to the primary alcohol (X) is performed by means of either LiAlH4 or DIBAL.

参考文献 中间体
合成目标
【1】 Zhang, A.; Kozilowski, A.P.; Zhang, M.; Johnson, K.M.; Mukhopadhyaya, J.; Hoepping, A.; Zhou, G.; Further studies on conformationally constrained tricyclic tropane analogues and their uptake inhibition at monoamine transporter sites: Synthesis of (Z)-9-(substituted arylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes as a novel class of serotonin transpo. J Med Chem 2002, 45, 9, 1930.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIIa) 59045 methyl (1S,2S,3R,6S)-9-[(Z)-(tributylstannyl)methylidene]-7-azatricyclo[4.3.1.0~3,7~]decane-2-carboxylate C24H43NO2Sn 详情 详情
(VIIb) 59046 methyl (1S,2S,3R,6S)-9-[(E)-(tributylstannyl)methylidene]-7-azatricyclo[4.3.1.0~3,7~]decane-2-carboxylate C24H43NO2Sn 详情 详情
(I) 21116 methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate C17H21NO4 详情 详情
(II) 59041 methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-azabicyclo[3.2.1]octane-2-carboxylate C16H19NO4 详情 详情
(III) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(IV) 59042 methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-(2-propynyl)-8-azabicyclo[3.2.1]octane-2-carboxylate C19H21NO4 详情 详情
(V) 59043 (1R,2R,3S,5S)-3-hydroxy-8-(2-propynyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid C11H15NO3 详情 详情
(VI) 59044 methyl (1R,5S)-8-(2-propynyl)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate C12H15NO2 详情 详情
(VIII) 59047 1-bromo-2-chloro-4-iodobenzene C6H3BrClI 详情 详情
(IX) 59048 methyl (1S,2S,3R,6S)-9-[(Z)-(4-bromo-3-chlorophenyl)methylidene]-7-azatricyclo[4.3.1.0~3,7~]decane-2-carboxylate C18H19BrClNO2 详情 详情
(X) 59049 {(1S,2S,3R,6S)-9-[(Z)-(4-bromo-3-chlorophenyl)methylidene]-7-azatricyclo[4.3.1.0~3,7~]dec-2-yl}methanol C17H19BrClNO 详情 详情

合成路线32

该中间体在本合成路线中的序号：(II)

Alkylation of uracil (I) with propargyl bromide (II) in the presence of DBU affords the N1-alkylated product (III). Palladium-catalyzed coupling of the terminal alkyne (III) with cis-1,2-dichloroethene (IV) furnishes the chlorovinyl adduct (V). Subsequent alkylation at the N3-position of (V) with propargyl bromide (II) and DBU leads to the open-chain enediyne (VI). This is finally cyclized to the target bicyclic compound in the presence of Pd(PPh3)4, CuI and butylamine.

参考文献 中间体
合成目标
【1】 Hakimelahi, G.H.; et al.; A novel approach towards studying non-genotoxic enediynes as potential anticancer therapeutics. Bioorg Med Chem 2002, 10, 5, 1321.
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) 30921 2,4(1H,3H)-pyrimidinedione; Uracil 66-22-8 C4H4N2O2 详情 详情
(II) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(III) 60461 1-(2-propynyl)-2,4(1H,3H)-pyrimidinedione C7H6N2O2 详情 详情
(IV) 28793 (Z)-1,2-dichloroethene 156-59-2 C2H2Cl2 详情 详情
(V) 60462 1-[(Z)-5-chloro-4-penten-2-ynyl]-2,4(1H,3H)-pyrimidinedione C9H7ClN2O2 详情 详情
(VI) 60463 1-[(Z)-5-chloro-4-penten-2-ynyl]-3-(2-propynyl)-2,4(1H,3H)-pyrimidinedione C12H9ClN2O2 详情 详情

合成路线33

该中间体在本合成路线中的序号：(V)

Condensation of 4-chloro-3-(methylsulfanyl)quinoline (I) with selenourea (II) affords the quinolinyl iso-selenourea (III). Basic hydrolysis of (III), followed by alkylation of the intermediate selenide (IV) with propargyl bromide (V) provides the target propargyl selenoquinoline.

参考文献 中间体
合成目标
【1】 Boryczka, S.; et al.; Synthesis and antiproliferative activity in vitro of new propargyl thioquinolines. Pharmazie 2002, 57, 3, 151.
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) 57719 4-chloro-3-(methylsulfanyl)quinoline; 4-chloro-3-quinolinyl methyl sulfide C10H8ClNS 详情 详情
(II) 57720 Selenourea 630-10-4 CH4N2Se 详情 详情
(III) 57721 4-{[amino(imino)methyl]selanyl}-3-(methylsulfanyl)quinoline C11H11N3SSe 详情 详情
(IV) 57722 sodium 3-(methylsulfanyl)-4-quinolineselenolate C10H8NNaSSe 详情 详情
(V) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
Extended Information