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【结 构 式】

【分子编号】27890

【品名】Potassium phthalimide

【CA登记号】1074-82-4

【 分 子 式 】C8H4KNO2

【 分 子 量 】185.2236

【元素组成】C 51.88% H 2.18% K 21.11% N 7.56% O 17.28%
与该中间体有关的原料药合成路线共 19 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1

该中间体在本合成路线中的序号：(IV)

By condensation of 2-aminomethyl-1,4-benzodioxane (I) with 2,6-dimethoxyphenoxyethyl chloride (II) performed by heating at 160 C or by means of K2CO3 in refluxing CHCl3 - water. The starting products (I) and (II) are prepared as follows: 1) The reaction of 2-chloromethyl-1,4-benzodioxane (III) with potassium phthalimide (IV) in refluxing DMF gives 2-phthalimidomethyl-1,4-benzodioxane (V), which is then treated with hydrazine hydrate (A) in refluxing 2-ethoxyethanol to give (I). 2) The condensation of 2,6-dimethoxyphenol (VI) with ethylene carbonate (VII) by means of K2CO3 in refluxing toluene gives 2,6-dimethoxyphenoxyethanol (VIII), which is then refluxed with SOCl2 to afford (II).

参考文献 中间体
合成目标
【1】 US 3472874 .
【2】 Castaner, J.; Serradell, M.N.; Hillier, K.; Blancafort, P.; WB-4101. Drugs Fut 1979, 4, 5, 369.
【3】 Green, P.N.; et al.; Synthesis and pharmacological properties of a series of 2-(substituted-aminoethyl)-1,4-benzodioxanes. J Med Chem 1969, 12, 2, 326-329.
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) 27334 N-(2,5-dichloropentyl)-2-methoxy-5-[methyl(methylsulfonyl)amino]benzamide C15H22Cl2N2O4S 详情 详情
(I) 39477 2,3-dihydro-1,4-benzodioxin-2-ylmethanamine; 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine C9H11NO2 详情 详情
(II) 39479 2-(2-chloroethoxy)-1,3-dimethoxybenzene; 2-(2-chloroethoxy)-3-methoxyphenyl methyl ether C10H13ClO3 详情 详情
(III) 39475 2-(chloromethyl)-2,3-dihydro-1,4-benzodioxine 2164-33-2 C9H9ClO2 详情 详情
(IV) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(V) 39476 2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1H-isoindole-1,3(2H)-dione C17H13NO4 详情 详情
(VI) 20228 2,6-dimethoxyphenol 91-10-1 C8H10O3 详情 详情
(VII) 32802 1,3-dioxolan-2-one 96-49-1 C3H4O3 详情 详情
(VIII) 39478 2-(2,6-dimethoxyphenoxy)-1-ethanol C10H14O4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(III)

The cyclization of N1-(2-fluorobenzoyl)-N2-methyl-N2-phenyl-2-hydroxy-1,3-diaminopropane (I) with refluxing POCl3 gives 1-methyl-2-chloromethyl-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine (II), which by condensation with potassium phthalimide (III) in refluxing methanol yields the corresponding phthalimido derivative (IV). The cleavage of (IV) with hydrazine in refluxing ethanol affords 1-methyl-2-aminomethyl-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine (V), which is finally condensed with thiophene-3-carbonyl chloride (VI) by means of triethylamine in methylene chloride.

参考文献 中间体
合成目标
【1】 Zeugner, H.; Romer, D.; Liepmann, H.; Milkowski, W. (Kali-Chemie AG); 2-Acylaminomethyl-1,4-benzodiazepine derivs. and their salts and pharmaceutical compsns. thereof. US 4325957 .
【2】 Serradell, M.N.; Paton, D.M.; Blancafort, P.; Castaner, J.; Tifluadom. Drugs Fut 1983, 8, 6, 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
(I) 36065 2-fluoro-N-[2-hydroxy-3-(methylanilino)propyl]benzamide C17H19FN2O2 详情 详情
(II) 36066 2-(chloromethyl)-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepine C17H16ClFN2 详情 详情
(III) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(IV) 36067 2-[[5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methyl]-1H-isoindole-1,3(2H)-dione C25H20FN3O2 详情 详情
(V) 36068 [5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methanamine; [5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methylamine C17H18FN3 详情 详情
(VI) 36069 3-thiophenecarbonyl chloride 41507-35-1 C5H3ClOS 详情 详情

合成路线3

该中间体在本合成路线中的序号：(F)

This compound can be prepared in several ways from the lactone (I), which is obtained by treatment of benzyl cyanide (A) and epichlorhydrin (B) with sodium amide: 1) The opening of lactone (I) with SOBr2-ethanol gives a bromo ester, which is treated successively by ammonia and sodium hydroxide to yield the amino acid (II). The reaction of (II) with SOCl2 and diethylamine in ethanol gives the final product, which is converted to the hydrochloric salt by treatment with HCl ethanol. 2) Lactone (I), opened with 33% HBr-AcOH, gives the bromo acid (III), which is treated by SOCl2 and then diethylamine in ethanol. The bromoamide (IV) reacts with potassium phthalimide and is deprotected by hydrazine or methylamine to yield, after salification, title compound. 3) Lactone (I) is treated by potassium phthalimide and then SOCl2 and diethylamine in EtOH to give compound (V), treated as above. 4) Bromoamide (IV) can be treated by hexamethylenetetramine in butanol and hydrolyzed by refluxing with 15% HCl in ethanol.

参考文献 中间体
合成目标
【1】 Kasama, S.; et al.; Synthesis 1978, 4, 10, 304.
【2】 Patoiseau, J.-F.; Mouzin, G.; Bonnaud, B.; Cousse, H. (Pierre Fabre Medicament); Process for the preparation of (Z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclopropane. EP 0200638; FR 2581059 .
【3】 Cousse, H.; Hascoet, P. (Pierre Fabre Medicament); Industrial process for the production of midalcipran. FR 2581060 .
【4】 Mouzin, G.; Cousse, H.; Bonnaud, B.; Morre, M.; Stenger, A. (Pierre Fabre Médicament); 1-Aryl-2-aminomethyl cyclopropane carboxyamide (Z) deivatives and their use as useful drugs in the treatment of disturbances of the central nervous system. EP 0068999; FR 2508035; JP 58004752; US 4478836 .
【5】 Briley, M.; Midalcipran Hydrochloride. Drugs Fut 1986, 11, 1, 21.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(A) 17046 Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide 140-29-4 C8H7N 详情 详情
(F) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(G) 28148 1-([2-[(diethylamino)carbonyl]-2-phenylcyclopropyl]methyl)-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane C21H32N5O 详情 详情
(E) 28150 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-phenylcyclopropanecarboxylic acid C19H15NO4 详情 详情
(D) 28151 2-(hydroxymethyl)-1-phenylcyclopropanecarboxylic acid C11H12O3 详情 详情
(I) 28144 1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one C11H10O2 详情 详情
(II) 28145 2-(aminomethyl)-1-phenylcyclopropanecarboxylic acid C11H13NO2 详情 详情
(III) 28146 2-(bromomethyl)-1-phenylcyclopropanecarboxylic acid C11H11BrO2 详情 详情
(IV) 28147 2-(bromomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide C15H20BrNO 详情 详情
(V) 28149 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-1-phenylcyclopropanecarboxamide C23H24N2O3 详情 详情
(C) 28143 2-(hydroxymethyl)-1-phenylcyclopropanecarboxylic acid C11H12O3 详情 详情

合成路线4

该中间体在本合成路线中的序号：(V)

A new synthesis of lafutidine has been described: The condensation of 2-bromopyridine-4-carbaldehyde ethylene ketal (I) with 4-(tetrahydropyranyloxy)-2(Z)-buten-1-ol (II) by means of NaOH, K2CO3 and tetrabutylammonium bisulfate in refluxing toluene gives the corresponding substitution product (III), which by treatment with pyridinium p-toluenesulfonate (PPTS) in hot ethanol yields the 2(Z)-butenol (IV). The reaction of (IV) with SOCl2 and then with potassium phthalimide (V) affords the substituted phthalimide (VI), which by treatment with hydrazine hydrate in refluxing methanol gives the 2(Z)-butenamine (VII). The condensation of (VII) with 2-(2-furylmethylsulfinyl)acetic acid 4-nitrophenyl ester (VIII) in THF yields the expected amide (IX), which is treated with p-toluenesulfonic acid in refluxing acetone/water to eliminate the ethylene ketal protecting group yilding the aldehyde (X). Finally, this compound is reductocondensed with piperidine (XI) by means of NaBH4 in ethanol.

参考文献 中间体
合成目标
【1】 Hosoda, A.; Yamaura, T.; Sekine, Y.; Matsumoto, H.; Hirakawa, N.; Sekine, A.; A novel histamine 2(H2) receptor antagonist with gastroprotective activity. II. Synthesis and pharmacological evaluation of 2-furfuryl-thio and 2-furfurylsulfinyl acetamide derivatives with heteroaromatic rings. Chem Pharm Bull 1998, 46, 4, 616.
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) 27887 2-bromo-4-(1,3-dioxolan-2-yl)pyridine C8H8BrNO2 详情 详情
(II) 13026 (Z)-4-(Tetrahydro-2H-pyran-2-yloxy)-2-buten-1-ol C9H16O3 详情 详情
(III) 27888 4-(1,3-dioxolan-2-yl)-2-pyridinyl (Z)-4-(tetrahydro-2H-pyran-2-yloxy)-2-butenyl ether C17H23NO5 详情 详情
(IV) 27889 (Z)-4-[[4-(1,3-dioxolan-2-yl)-2-pyridinyl]oxy]-2-buten-1-ol C12H15NO4 详情 详情
(V) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(VI) 27891 2-((Z)-4-[[4-(1,3-dioxolan-2-yl)-2-pyridinyl]oxy]-2-butenyl)-1H-isoindole-1,3(2H)-dione C20H18N2O5 详情 详情
(VII) 27892 (Z)-4-[[4-(1,3-dioxolan-2-yl)-2-pyridinyl]oxy]-2-butenylamine C12H16N2O3 详情 详情
(VIII) 13031 4-nitrophenyl 2-[(2-furylmethyl)sulfinyl]acetate C13H11NO6S 详情 详情
(IX) 27893 N-((Z)-4-[[4-(1,3-dioxolan-2-yl)-2-pyridinyl]oxy]-2-butenyl)-2-[(2-furylmethyl)sulfinyl]acetamide C19H22N2O6S 详情 详情
(X) 27894 N-[(Z)-4-[(4-formyl-2-pyridinyl)oxy]-2-butenyl]-2-[(2-furylmethyl)sulfinyl]acetamide C17H18N2O5S 详情 详情
(XI) 10158 Piperidine 110-89-4 C5H11N 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XIII)

The Diels-Alder condensation of maleic anhydride (I) with furan (II) gives the epoxytetrahydrophthalic anhydride (III), which is reduced with H2 over Pd/C, yielding the epoxyperhydrophthalic anhydride (IV). Further reduction of (IV) with NaBH4 affords the epoxyperhydrophthalide (V), which is submitted to a third reduction with DIBAL-H to provide the lactol (VI) as a racemic mixture that is resolved with menthol. The appropriate isomer (VIIa) is treated with triphenylphosphonium bromide (VIII) and potassium tert-amyloxide to give the 5,8-epoxyperhydro-2-benzopyran-3-ol (IX), which is condensed with 4-carboxybutyltriphenylphosphonium bromide (X) by means of potassium tert-amyloxide and esterified with Amberlist-15/MeOH, yielding the cis-5-heptenoic acid methyl ester (XI). The sulfonation of the primary alcohol group of (XI) with TsOH affords the tosylate (XII), which is condensed with potassium phthalimide (XII) to provide the phthalimido derivative (XIV). The treatment of (XIV) with hydrazine gives the aminomethyl compound (XV), which is finally condensed with N-(heptanoyl)glycine (XVI) by means of CDI and hydrolyzed with LiOH to afford the target glycinamide compound.

参考文献 中间体
合成目标
【1】 Hedberg, A.; Hall, S.E.; Harris, D.N.; Ogletree, M.L.; 7-Oxabicycloheptane analogs: modulators of the arachidonate cascade. Drugs Fut 1988, 13, 2, 153.
【2】 Haslanger, M.F.; Han, W.-C.; Ogletree, M.L.; Hall, S.E.; Harris, D.N.; 9,11-Epoxy-9-homo-14-oxaprosta-5-enoic acid derivatives. Novel inhibitors of fatty acid cyclooxygenase. J Med Chem 1986, 29, 2335-2347.
【3】 Haslanger, M.F.; Greenberg, M.J.; Ogletree, M.L.; Nakane, M.; Garber, D.P.; Harris, D.N.; Reid, J.C.; Aza-substituted omega side chain modification of 7-oxabicyclo[2.2.1]heptane TxA2 receptor antagonists: Structure-activity relationships. Advances in Prostaglandin, Thromboxane and Leukotriene Research, vol. 15; O. Hayaishi and S. Yamamoto (Eds.). Raven Press: New York 1985, 291-293.
【4】 Gougoutas, J.Z.; Sprague, P.W.; Harris, D.N.; Malley, M.F.; Heikes, J.E.; Greenberg, R.; Synthesis and in vitro pharmacology of 7-oxabicyclo[2.2.1]heptane analogues of thromboxane A2/PGH2. J Med Chem 1985, 28, 1580-1590.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIa) 43719 (1R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol C8H12O3 详情 详情
(VIb) 43720 (1R,3R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol C8H12O3 详情 详情
(VIIa) 43721 (1R,2R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol C8H12O3 详情 详情
(VIIb) 43728 (1S,2S,3R,6S,7R)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol C8H12O3 详情 详情
(I) 11182 2,5-Furandione; Maleic anhydride 108-31-6 C4H2O3 详情 详情
(II) 22372 Furan 110-00-9 C4H4O 详情 详情
(III) 43717 (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C8H6O4 详情 详情
(IV) 36472 (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione C8H8O4 详情 详情
(V) 43718 (1R,2R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-one C8H10O3 详情 详情
(VIII) 25649 (methoxymethyl)(triphenyl)phosphonium bromide C20H20BrOP 详情 详情
(IX) 43722 (1S,2R,5R,7R,8R)-4,11-dioxatricyclo[6.2.1.0(2,7)]undecan-5-ol C9H14O3 详情 详情
(X) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XI) 43723 methyl (Z)-7-[(1R,2R,3R,4S)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate C15H24O4 详情 详情
(XII) 43724 methyl (Z)-7-[(1R,2R,3R,4S)-3-([[(4-methylphenyl)sulfonyl]oxy]methyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate C22H30O6S 详情 详情
(XIII) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(XIV) 43725 methyl (Z)-7-[(1R,2R,3R,4S)-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate C23H27NO5 详情 详情
(XV) 43726 methyl (Z)-7-[(1R,2R,3R,4S)-3-(aminomethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate C15H25NO3 详情 详情
(XVI) 43727 2-(heptanoylamino)acetic acid C9H17NO3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(XXVII)

Alkylation of potassium phthalimide (XXVII) with epichlorohydrin (XXVIII) provided N-glycidyl phthalimide (XXIX). Epoxide ring opening in (XXIX) with aqueous HBr led to bromohydrin (XXX), which was further oxidized to bromo ketone (XXXI) by means of CrO3. Coupling of bromo ketone (XXXI) with diethyl malonate (XXXII) to afford (XXXIII) was accomplished in the presence of NaOEt in EtOH/DMF as the solvent. Acid hydrolysis of the malonate ester (XXXIII), followed by thermal decarboxylation, gave rise to phthalimido levulinic acid (XI). The phthaloyl group of (XI) was finally hydrolyzed under acidic conditions to furnish delta-aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Collins, A.; Tschudy, D.P.; Malonic ester synthesis of delta-aminolevulinic acid. The reaction of N-3-bromoacetonylphthalimide with malonic ester. J Org Chem 1959, 24, 556.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 59147 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoic acid C13H11NO5 详情 详情
(XXVII) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(XXVIII) 10246 N-Phenyl-2-[(triphenylstannyl)selanyl]benzamide C31H25NOSeSn 详情 详情
(XXIX) 12335 2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide 5455-98-1 C11H9NO3 详情 详情
(XXX) 59158 2-(3-bromo-2-hydroxypropyl)-1H-isoindole-1,3(2H)-dione C11H10BrNO3 详情 详情
(XXXI) 59159 2-(3-Bromo-2-oxopropyl)isoindole-1,3-dione C11H8BrNO3 详情 详情
(XXXII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XXXIII) 59160 diethyl 2-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxopropyl]malonate C18H19NO7 详情 详情

合成路线7

该中间体在本合成路线中的序号：(XXVII)

The bromination of ethyl acetylsuccinate (XXXIV) produced initially the beta-bromo derivative (XXXV), which upon standing for further 12 hours in the presence of the HBr generated in the reaction underwent rearrangement to the delta-bromo isomer (XXXVI). Hydrolysis and decarboxylation of (XXXVI) in the presence of HCl produced the expected delta-bromolevulinic acid (XXXVII) along with the chloro analogue (XXXVIII). Esterification of this mixture of acids with ethanol and sulfuric acid led to the respective ethyl esters (XXXIX) and (XL). Condensation of halo esters (XXXIX) and (XL) with potassium phthalimide (XXVII) furnished ethyl delta-phthalimidolevulinate (XLI), which was finally converted to the title compound by acidic hydrolysis.

参考文献 中间体
合成目标
【1】 Lartillot, S.; Baron, C.; New route to delta-aminolevulinic and application to the synthesis of its alpha- and beta-methylated derivatives. Bull Soc Chim Fr 1966, 12, 3798.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVII) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(XXXIV) 59161 Acetonyl succinic acid diethylester; Diethyl acetylsuccinate 1115-30-6 C10H16O5 详情 详情
(XXXV) 59162 diethyl 2-acetyl-2-bromosuccinate C10H15BrO5 详情 详情
(XXXVI) 59163 diethyl 2-(2-bromoacetyl)succinate C10H15BrO5 详情 详情
(XXXVII) 59164 5-bromo-4-oxopentanoic acid C5H7BrO3 详情 详情
(XXXVIII) 59168 5-chloro-4-oxopentanoic acid C5H7ClO3 详情 详情
(XXXIX) 59165 ethyl 5-bromo-4-oxopentanoate C7H11BrO3 详情 详情
(XL) 59166 ethyl 5-chloro-4-oxopentanoate C7H11ClO3 详情 详情
(XLI) 59167 ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate C15H15NO5 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XXVII)

In a related strategy, the bromination of levulinic acid (XLII) in MeOH yielded the 3-bromo (XLIV) and 5-bromo (XLIII) esters, which could be separated by distillation. Condensation of methyl 5-bromolevulinate (XLIII) with potassium phthalimide (XXVII) provided methyl phthalimido levulinate (XLV), which was finally hydrolyzed under the same conditions as above for analogous the ethyl ester.

参考文献 中间体
合成目标
【1】 Benedikt, E.; Kost, H.-P.; Synthesis of 5-aminolevulinic acid. Z Naturforsch B Anorg Chem Org Chem 1986, 41B, 12, 1593.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVII) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(XLII) 36170 4-oxopentanoic acid 123-76-2 C5H8O3 详情 详情
(XLIII) 59170 methyl 5-bromo-4-oxopentanoate C6H9BrO3 详情 详情
(XLIV) 59169 methyl 3-bromo-4-oxopentanoate C6H9BrO3 详情 详情
(XLV) 59171 methyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate C14H13NO5 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XVIII)

Alternatively, the reaction of the cyclic sulfate (VIII) with potassium phthalimide (XVIII) gives the N-substituted phthalimide (XIX), whose sulfate group is cleaved with sulfuric acid to yield the alcohol (XX). The reaction of (XX) with the perhydroisoquinoline (XV) by means of K2CO3 in acetonitrile/methanol affords the oxazoline (XXI), whose ring is opened with thiophenol (XVII) and KHCO3 in THF, providing a mixture of the two sulfides (XXII) and (XXIII) that are not isolated. The cleavage of the phthalimido group with refluxing ethanolamine followed by a treatment with benzoic acid gives a mixture of ammonium salts that is separated by crystallization, yielding the desired isomer (XXIV). The reaction of (XXIV) with acid chloride (XII) affords the precursor (XXV), which is finally deacetylated with NaOH to provide the target compound.

参考文献 中间体
合成目标
【1】 Albizati, K.F.; et al.; A synthesis of the HIV-protease inhibitor nelfinavir from D-tartaric acid. Tetrahedron Lett 2001, 42, 37, 6481.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 55023 [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2,2-dioxo-1,3,2lambda~6~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate C18H20O10S3 详情 详情
(XII) 46596 3-(chlorocarbonyl)-2-methylphenyl acetate C10H9ClO3 详情 详情
(XV) 13955 (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide C14H26N2O 详情 详情
(XVII) 12951 Benzenethiol; Phenylmercaptan; Phenylhydrosulfide 108-98-5 C6H6S 详情 详情
(XVIII) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(XIX) 55029 potassium 2-[(1S,2S)-3-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-(sulfonatooxy)propyl]-1,3-dioxoisoindoline C26H24KNO12S3 详情 详情
(XX) 55030 (2S,3S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate C26H25NO9S2 详情 详情
(XXI) 55031 methyl 2-((4S)-4-{(1R)-2-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-hydroxyethyl}-4,5-dihydro-1,3-oxazol-2-yl)benzoate C27H39N3O5 详情 详情
(XXII) 55032 (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R,3R)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-hydroxy-4-(phenylsulfanyl)butyl]decahydro-3-isoquinolinecarboxamide C32H41N3O4S 详情 详情
(XXIII) 55033 (3S,4aS,8aS)-N-(tert-butyl)-2-[(2S,3S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxy-4-(phenylsulfanyl)butyl]decahydro-3-isoquinolinecarboxamide C32H41N3O4S 详情 详情
(XXIV) 55034 (2R,3R)-4-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-3-hydroxy-1-(phenylsulfanyl)-2-butanaminium benzoate C31H45N3O4S 详情 详情
(XXV) 46497 4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]butanenitrile C16H20N2O2 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XII)

After conversion of cyclopentylacetic acid (IX) to the corresponding benzyl ester (X), alkylation with 1,8-diiodooctane in the presence of LDA generated the iodo ester (XI). Iodide displacement in (XI) with potassium phthalimide (XII) in hot DMF produced the substituted phthalimide (XIII). Then, hydrogenolysis of the benzyl ester group of (XIII) furnished carboxylic acid (XIV). Acylation of the intermediate dipeptide (VIII) with acid (XIV) by using BOP and HOBt yielded amide (XV). Finally, acid hydrolysis of the diethyl acetal function of (XV) gave rise to the title aldehyde.

参考文献 中间体
合成目标
【1】 Iqbal, M.; et al.; Potent inhibitors of proteasome. J Med Chem 1995, 38, 13, 2276.
【2】 Iqbal, M.; Diebold, J.; Siman, R.; Chatterjee, S.; Kauer, J.C. (Cephalon, Inc.); Multicatalytic protease inhibitors. JP 1998507465; JP 2000290197; WO 9614857 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 49100 　 C16H34N6O5 详情 详情
(IX) 49101 Cyclopentylacetic acid 1123-00-8 C7H12O2 详情 详情
(X) 49102 benzyl 2-cyclopentylacetate C14H18O2 详情 详情
(XI) 49103 benzyl 2-cyclopentyl-10-iododecanoate C22H33IO2 详情 详情
(XII) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(XIII) 49104 benzyl 2-cyclopentyl-10-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)decanoate C30H37NO4 详情 详情
(XIV) 49105 2-cyclopentyl-10-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)decanoic acid C23H31NO4 详情 详情
(XV) 49106 　 C39H63N7O8 详情 详情

合成路线11

该中间体在本合成路线中的序号：(A)

The interaction of 2-chloroethyl chloromethyl ether (I) and the sodium salt of 2-phthalimidomalonate (II) in dimethylformamide afforded the condensation product (III). An amino group was then introduced to the latter compound by means of potassium phthalimide (A), giving (IV). The racemic amino acid (V) could be obtained on removal of the phthalyl groups by treatment with hydrazine. However, the racemic phthalimide compound (IV) could be used directly for resolution through the brucine salt, and the protecting groups were then removed by hydrolysis with 6N hydrochloric acid. The levo-amino acid (V) was finally isolated as the dihydrochloride.

参考文献 中间体
合成目标
【1】 Ru-yun, J.; L-4-Oxalysine dihydrochloride. Drugs Fut 1983, 8, 5, 425.
【2】 Tesser, G.I.; Nivard, R.J.F.; Gruber, M.; The resolutiom of dl-4-oxalysine on experimental hepatittis. Recl Trav Chim Pays-Bas 1962, 81, 713-719.
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) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
L-(IV) 36044 diethyl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]methyl]malonate C26H24N2O9 详情 详情
(I) 36040 　 C15H14NNaO6 详情 详情
(II) 36041 2-chloroethyl chloromethyl ether; 1-chloro-2-(chloromethoxy)ethane 1462-33-5 C3H6Cl2O 详情 详情
(III) 36042 diethyl 2-[(2-chloroethoxy)methyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)malonate C18H20ClNO7 详情 详情
(IV) 36043 diethyl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]methyl]malonate C26H24N2O9 详情 详情

合成路线12

该中间体在本合成路线中的序号：(VIII)

The condensation of 2-methylaniline (I) with 2-fluorobenzonitrile (II) by means of BCl3 and AlCl3 gives 2-amino-2'-fluoro-3-methylbenzophenone (III), which is acylated at the amino group with bromoacetyl bromide (IV) in pyridine yielding the bromoacetamide (V). The cyclization of (V) with hydroxylamine and NaOH affords the benzodiazepinone-N-oxide (VI), which is treated with acetic anhydride to provide 3-acetoxy-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (VII). The reaction of (VII) with potassium phthalimide (VIII) and NaI gives the phthalimido derivative (IX), which by cleavage with hydrazine yields 3-amino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (X). The protection of the amino group of (X) with Boc2O and TEA affords the carbamate (XI), which is alkylated with ethyl bromoacetate (XII) by means of NaH giving the ethoxycarbonylmethyl derivative (XIII). The hydrolysis of (XIII) with NaOH affords the corresponding carboxymethyl derivative (XIV), which is condensed with 3-azabicyclo[3,2,2]nonane (XV) by means of HOBT, WSCD and TEA to give the expected amide (XVI). The cleavage of the tert-butoxycarbonyl group of (XVI) with HCl yields the amine (XVII), which is finally condensed with the activated carbamate (XVIII) to furnish the title compound.

参考文献 中间体
合成目标
【1】 Toyoda, T.; Adachi, M.; Sugasawa, T.; et al.; Aminohaloborane in organic synthesis. I. Specific ortho substitution reaction of anilines. J Am Chem Soc 1978, 100, 4842.
【2】 Satoh, Y.; Tabuchi, S.; Mitsui, H.; Design of dual CCK-A and CCK-B receptor antagonists. Drugs Fut 1997, 22, 10, 1117.
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) 15511 o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine 95-53-4 C7H9N 详情 详情
(II) 41199 2-fluorobenzonitrile 394-47-8 C7H4FN 详情 详情
(III) 41200 (2-amino-3-methylphenyl)(2-fluorophenyl)methanone C14H12FNO 详情 详情
(IV) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(V) 41201 2-bromo-N-[2-(2-fluorobenzoyl)-6-methylphenyl]acetamide C16H13BrFNO2 详情 详情
(VI) 41202 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-4-ium-4-olate C16H13FN2O2 详情 详情
(VII) 41203 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl acetate C18H15FN2O3 详情 详情
(VIII) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(IX) 41204 2-[5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-1H-isoindole-1,3(2H)-dione C24H16FN3O3 详情 详情
(X) 41205 3-amino-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one C16H14FN3O 详情 详情
(XI) 41206 tert-butyl 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate C21H22FN3O3 详情 详情
(XII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XIII) 41207 ethyl 2-[3-[(tert-butoxycarbonyl)amino]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetate C25H28FN3O5 详情 详情
(XIV) 41208 2-[3-[(tert-butoxycarbonyl)amino]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetic acid C23H24FN3O5 详情 详情
(XV) 41209 3-azabicyclo[3.2.2]nonane C8H15N 详情 详情
(XVI) 41210 tert-butyl 1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate C31H37FN4O4 详情 详情
(XVII) 41211 3-amino-1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one C26H29FN4O2 详情 详情
(XVIII) 41212 4-nitrophenyl 3-(1H-1,2,3,4-tetraazol-5-yl)phenylcarbamate C14H10N6O4 详情 详情

合成路线13

该中间体在本合成路线中的序号：(III)

The known 5-(4-chlorobutyl)-2-(tert-butyldimethylsilyl)-1-(N,N-dimethylsulfamoyl) imidazole (I) was hydrolyzed with HCl in boiling aqueous ethanol and then protected as the triphenylmethyl derivative (II) using trityl chloride and triethylamine. The required primary amine (V) was obtained by condensation of chloride (II) with potassium phthalimide (III), followed by hydrazinolysis of the resulting N-alkylated phthalimide (IV). Sulfonylation of amine (V) with 4-chlorobenzylsulfonyl chloride (VI) gave rise to the sulfonamide (VII). The trityl protecting group of (VII) was finally removed by acid treatment.

参考文献 中间体
合成目标
【1】 Kalindjian, S.B.; Shankley, N.P.; Tozer, M.J.; McDonald, I.M.; Pether, M.J.; Harper, E.A.; Watt, G.F.; Cooke, T.; Low, C.M.R. (James Black Foundation Ltd.); Histamine H3 receptor ligands. EP 0882023; JP 2000505428; US 6080871; WO 9729092 .
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) 43124 2-[tert-butyl(dimethyl)silyl]-5-(4-chlorobutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide C15H30ClN3O2SSi 详情 详情
(II) 43125 5-(4-chlorobutyl)-1-trityl-1H-imidazole C26H25ClN2 详情 详情
(III) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(IV) 43126 2-[4-(1-trityl-1H-imidazol-5-yl)butyl]-1H-isoindole-1,3(2H)-dione C34H29N3O2 详情 详情
(V) 43127 4-(1-trityl-1H-imidazol-5-yl)-1-butanamine; 4-(1-trityl-1H-imidazol-5-yl)butylamine C26H27N3 详情 详情
(VI) 43129 (4-chlorophenyl)methanesulfonyl chloride 6966-45-6 C7H6Cl2O2S 详情 详情
(VII) 43128 (4-chlorophenyl)-N-[4-(1-trityl-1H-imidazol-5-yl)butyl]methanesulfonamide C33H32ClN3O2S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(III)

Benzylic bromination of 3-chloro-4-methylbenzonitrile (I) by means of N-bromosuccinimide and azobis(isobutyronitrile) provided bromide (II). Subsequent displacement of the bromine atom of (III) by potassium phthalimide (III) afforded the N-substituted phthalimide (IV), which was then deprotected with ethanolic hydrazine to furnish the primary amine (V).

参考文献 中间体
合成目标
【1】 Antane, M.M.; Herbst, D.R.; McFarlane, G.R.; Gundersen, E.G.; Hirth, B.H.; Quagliato, D.A.; Graceffa, R.F.; Butera, J.A.; Gilbert, A.M. (American Home Products Corp.); Substd. N-arylmethylamino derivs. of cyclobutene-3, 4-diones. US 5763474; US 5780505; WO 9802413 .
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) 32959 3-chloro-4-methylbenzonitrile C8H6ClN 详情 详情
(II) 32960 4-(bromomethyl)-3-chlorobenzonitrile C8H5BrClN 详情 详情
(III) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(IV) 32961 3-chloro-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile C16H9ClN2O2 详情 详情
(V) 32962 4-(aminomethyl)-3-chlorobenzonitrile C8H7ClN2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(V)

Reaction of 2-(3,4-dimethoxyphenyl)-3-methylbutyronitrile (I) with 1,3-dibromopropane (II) in the presence of n-butyllithium at -78 C provided bromonitrile (III). Alkylation of potassium phthalimide (V) with 9-(chloromethyl)anthracene (IV) yielded the N-alkylated phthalimide (VI), and subsequent hydrazinolysis gave the aminomethyl compound (VIII). Finally, amine (VIII) was alkylated with bromide (III) in Et3N at 60 C to produce the title compound, which was isolated as the corresponding hydrochloride salt.

参考文献 中间体
合成目标
【1】 Teodori, E.; Dei, S.; Quidu, P.; et al.; Design, synthesis, and in vitro activity of catamphiphilic reverters of multidrug resistance: Discovery of a selective, highly efficacious chemosensitizer with potency in the nanomolar range. J Med Chem 1999, 42, 10, 1687.
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) 30391 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile; alpha-Isopropylveratryl cyanide 20850-49-1 C13H17NO2 详情 详情
(II) 12581 1,3-Dibromopropane 109-64-8 C3H6Br2 详情 详情
(III) 30392 5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile C16H22BrNO2 详情 详情
(IV) 30393 9-(chloromethyl)anthracene 24463-19-2 C15H11Cl 详情 详情
(V) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(VI) 30394 2-(9-anthrylmethyl)-1H-isoindole-1,3(2H)-dione C23H15NO2 详情 详情
(VII) 30395 9-anthrylmethanamine; 9-anthrylmethylamine 2476-68-8 C15H13N 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

Condensation of 4,4-bis(4-fluorophenyl)butyl bromide (I) with potassium phthalimide (II) in hot DMF yielded the substituted phthalimide (III). Deprotection of the phthalimido group of (III) to give primary amine (IV) was effected by treatment with NaBH4, followed by methanolic HCl. Subsequent coupling of (IV) with N-Boc-N-methyl-L-leucine (V) by means of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate furnished amide (VI). Finally, the Boc group of (VI) was deprotected using trifluoroacetic acid in CH2Cl2 and treated with HCl.

参考文献 中间体
合成目标
【1】 Song, Y.; Connor, D.T.; Bowersox, S.S.; et al.; (S)-4-methyl-2-(methylamino)pentanoic acid [4,4-bis(4-fluorophenyl)butyl]amide hydrochloride, a novel calcium channel antagonist, is efficacious in several animal models of pain. J Med Chem 2000, 43, 19, 3474.
【2】 Song, Y.; Rafferty, M.F.; Ryder, T.R.; Sercel, A.D.; Connor, D.T.; Malone, T.C.; Hu, L.-Y.; Roth, B.D. (Pfizer Inc.); Substd. diarylalkyl amides as calcium channel antagonists. WO 9955688 .
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) 35603 1-[4-bromo-1-(4-fluorophenyl)butyl]-4-fluorobenzene C16H15BrF2 详情 详情
(II) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(III) 35604 2-[4,4-bis(4-fluorophenyl)butyl]-1H-isoindole-1,3(2H)-dione C24H19F2NO2 详情 详情
(IV) 35605 4,4-bis(4-fluorophenyl)-1-butanamine; 4,4-bis(4-fluorophenyl)butylamine C16H17F2N 详情 详情
(V) 26295 (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid 609-23-4 C12H23NO4 详情 详情
(VI) 35607 tert-butyl (1S)-1-([[4,4-bis(4-fluorophenyl)butyl]amino]carbonyl)-3-methylbutyl(methyl)carbamate C28H38F2N2O3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(C)

Synthesis of intermediates (XX) and (XXIII): Coupling of methyl L-lactate (XII) with morpholine in presence of NaH yields amide (XIII) which is tosylated by means of NaH and p-TsCl in THF to afford (XIV). Reduction of carboxylic acid (XV) in DCE with B(OCH3)3, boron trifluoride diethyl etherate and BH3·pyr complex provides alcohol (XVI) which is then condensed with (XIV) in presence of K2CO3 in DMF to yield (XVII). Mesylation of (XVII) with MsCl in presence of Et3N in CH2Cl2 affords (XVIII), which reacts with potassium phthalimide (C) in DMF to give (XIX). Hydrogenation of phthalimide (XIX) with H2 over Pd/C in DMF provides derivative (XX). The treatment of (XIX) with NH2NH2 and p-TsOH gives amine (XXI), which is protected with di-t-butyl-dicarbonate to yield (XXII). Finally (XXIII) is obtained by reduction of the nitro moiety of (XXII) with H2 over Pd/C in EtOAc.

参考文献 中间体
合成目标
【1】 Katayama, S.; Kishimoto, H.; Ae, N.; Nagata, R. (Sumitomo Pharmaceuticals Co., Ltd.); Tricyclic indole-2-carboxylic acid cpd. used as NMDA receptor antagonist. WO 0056711 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 17075 propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate 27871-49-4 C4H8O3 详情 详情
(XIII) 41498 (2S)-2-hydroxy-1-(4-morpholinyl)-1-propanone C7H13NO3 详情 详情
(XIV) 41499 (1S)-1-methyl-2-(4-morpholinyl)-2-oxoethyl 4-methylbenzenesulfonate C14H19NO5S 详情 详情
(XV) 41500 3-hydroxy-4-nitrobenzoic acid 619-14-7 C7H5NO5 详情 详情
(XVI) 21465 5-(hydroxymethyl)-2-nitrophenol C7H7NO4 详情 详情
(XVII) 41501 (2R)-2-[5-(hydroxymethyl)-2-nitrophenoxy]-1-(4-morpholinyl)-1-propanone C14H18N2O6 详情 详情
(XVIII) 41502 (2R)-2-[5-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2-nitrophenoxy]-1-(4-morpholinyl)-1-propanone C17H24N2O6S 详情 详情
(XIX) 41503 2-(3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]-4-nitrobenzyl)-1H-isoindole-1,3(2H)-dione C22H21N3O7 详情 详情
(XX) 41506 2-(4-amino-3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]benzyl)-1H-isoindole-1,3(2H)-dione C22H23N3O5 详情 详情
(XXI) 41504 (2R)-2-[5-(aminomethyl)-2-nitrophenoxy]-1-(4-morpholinyl)-1-propanone C14H19N3O5 详情 详情
(XXII) 41505 tert-butyl 3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]-4-nitrobenzylcarbamate C19H27N3O7 详情 详情
(XXIII) 41507 tert-butyl 4-amino-3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]benzylcarbamate C19H29N3O5 详情 详情
(C) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(IV)

Alkylation of the lithium salt of 2-(3,4-dimethoxyphenyl)isobutyronitrile (I) with 1,3-dibromopropane (II) gave the bromo nitrile (III). Conversion of bromide (III) into the desired primary amine (VI) was achieved through a Gabriel synthesis by condensation with potassium phthalimide (IV), followed by hydrazinolysis of the resultant N-substituted phthalimide (V). A two-step procedure was finally employed for the reductive alkylation of amine (VI), consisting of condensation between amine (VI) and the bromo fluorenone (VII) in the presence of titanium isopropoxide and then reduction of the intermediate (VIII) with NaBH3CN.

参考文献 中间体
合成目标
【1】 Dei, S.; et al.; Structure-activity relationships and optimisation of the selective MDR modulator 2-(3,4-dimethoxyphenyl)-5-(9-fluorenylamino)-2-(methylethyl) pentanenitrile and its N-methyl derivative. Bioorg Med Chem 2001, 9, 10, 2673.
【2】 Teodori, E.; Dei, S.; Quidu, P.; et al.; Design, synthesis, and in vitro activity of catamphiphilic reverters of multidrug resistance: Discovery of a selective, highly efficacious chemosensitizer with potency in the nanomolar range. J Med Chem 1999, 42, 10, 1687.
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) 30391 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile; alpha-Isopropylveratryl cyanide 20850-49-1 C13H17NO2 详情 详情
(II) 12581 1,3-Dibromopropane 109-64-8 C3H6Br2 详情 详情
(III) 30392 5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile C16H22BrNO2 详情 详情
(IV) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(V) 53369 2-(3,4-dimethoxyphenyl)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-isopropylpentanenitrile n/a C24H26N2O4 详情 详情
(VI) 53370 5-amino-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile n/a C16H24N2O2 详情 详情
(VII) 53371 2-Bromo-9-fluorenone 3096-56-8 C13H7BrO 详情 详情
(VIII) 53372 5-({2-bromo-9-[(triisopropylsilyl)oxy]-9H-fluoren-9-yl}amino)-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile n/a C38H51BrN2O3Si 详情 详情

合成路线19

该中间体在本合成路线中的序号：(IV)

Guaiacol (I) was alkylated by means of boiling dibromoethane (II) to produce the bromoethyl ether (III). From this, the intermediate amine (VI) was prepared by Gabriel synthesis, via condensation with potassium phthalimide (IV) in hot DMF, followed by hydrazinolysis of the resultant N-substituted phthalimide (V).

参考文献 中间体
合成目标
【1】 Lin, T.-H.; Chen, I.-J.; Guaiacoxypropanolamines with alpha/beta-adrenergic blocking activity. EP 1108710; WO 0005209 .
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) 13182 Guaiacol; 2-Methoxyphenol 90-05-1 C7H8O2 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 51402 2-(2-Bromoethoxy)methoxybenzene; 1-Bromo-2-(2-methoxyphenoxy)ethane 4463-59-6 C9H11BrO2 详情 详情
(IV) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(V) 59617 2-[2-(2-methoxyphenoxy)ethyl]-1H-isoindole-1,3(2H)-dione C17H15NO4 详情 详情
(VI) 31105 2-(2-methoxyphenoxy)ethylamine; 2-(2-methoxyphenoxy)-1-ethanamine 1836-62-0 C9H13NO2 详情 详情
Extended Information