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【结 构 式】

【分子编号】10925

【品名】Iodoethane;ethyl iod

【CA登记号】75-03-6

【 分 子 式 】C2H5I

【 分 子 量 】155.96617

【元素组成】C 15.4% H 3.23% I 81.37%
与该中间体有关的原料药合成路线共 17 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1

该中间体在本合成路线中的序号：(A)

The condensation of 1-ethyl-5-aminopyrazole (I) with diethyl ethoxymethylenemalonate (II) by heating at 120 C gives diethyl [((1-ethyl-5-pyrazolyl)amino)methylene]malonate (III), which by heating at 235-5 C in diphenyl ether is converted into ethyl 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (IV). The reaction of (IV) with ethyl iodide (A) and K2CO3 in DMF affords ethyl 1-ethyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (V), which is condensed with hydrazine in refluxing ethanol with ZnCl2 yielding ethyl 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (VI). Finally, (VI) is condensed with refluxing acetone (B).

参考文献 中间体
合成目标
【1】 Hoehn, H.; Chasin, M. (Bristol-Myers Squibb Co.); Hydrazines and hydrazones of pyrazolopyridine carboxylic acids and esters. DE 2028869; GB 1317797; NL 165461C; NL 7008768 .
【2】 Chatterjee, S.S.; Etazolate. Drugs Fut 1977, 2, 4, 243.
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) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(B) 23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情
(I) 40098 1-ethyl-1H-pyrazol-5-amine; 1-ethyl-1H-pyrazol-5-ylamine 3528-58-3 C5H9N3 详情 详情
(II) 14088 Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate 87-13-8 C10H16O5 详情 详情
(III) 40099 diethyl 2-[[(1-ethyl-1H-pyrazol-5-yl)amino]methylene]malonate C13H19N3O4 详情 详情
(IV) 40100 ethyl 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate C11H13N3O3 详情 详情
(V) 40101 ethyl 4-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate C13H17N3O3 详情 详情
(VI) 40102 ethyl 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylate C11H15N5O2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

Several methods for obtaining this compoud have been described: 1) By treating the 4-isobutyl phenyl acetonitrile (I) with sodium amide and ethyl iodide, followed by the hydrolysis of the reaction product (II). 2) The reaction of the nitrile (I) with sodium ethoxide and diethyl carbonate leads to the cyanoacetic ester (III), which is treated with ethyl iodide; thus (IV) being obtained, the hydrolysis and decarboxylation of (IV) leads to the final acid. 3) The alkaline hydrolysis of the 4-isobutyl phenyl acetonitrile (I) leads to 4-isobutyl phenyl acetic acid (V). This product after treatment with Na in naphthalene and ethyl iodide (A) yields the required compound.

参考文献 中间体
合成目标
【1】 Aparicio, L.; et al.; Procedimiento para la obtencion del acido 2-(4'-isobutifenil)butirico. ES 427197; ES 435173; ES 435174 .
【2】 Aparicio, L.; Butibufen. Drugs Fut 1977, 2, 3, 156.
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) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(I) 33614 2-(4-isobutylphenyl)acetonitrile C12H15N 详情 详情
(II) 33615 2-(4-isobutylphenyl)butanenitrile C14H19N 详情 详情
(III) 33616 ethyl 2-cyano-2-(4-isobutylphenyl)acetate C15H19NO2 详情 详情
(IV) 33617 ethyl 2-cyano-2-(4-isobutylphenyl)butanoate C17H23NO2 详情 详情
(V) 33618 2-(4-isobutylphenyl)acetic acid C12H16O2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(X)

2) Hexadeuteroethyl alcohol (IX) is treated with red phosphorus and I2 at reflux temperature to give pentadeuteroethyl iodide (X), which is condensed with potassium phthalimide (XI) in DMF, yielding N-(pentadeuteroethyl)phthalimide (XII). The hydrolysis of (XII) with hydrazine and HCl affords pentadeuteroethylamine (XIII), which is condensed with 1-methylpiperidin-4-one (III) and formaldehyde (XIV) in a Mannich reaction to give 3-methyl-7-(pentadeuteroethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one (XV). The reduction of (XV) with NaBH4 as before yields the diastereomeric mixture (XVI + XVII). Finally, the alpha-isomer (XVI) is condensed with 4-chlorobenzoyl chloride (VIII) as before to give the pentadeuterium-labeled bisaramil.

参考文献 中间体
合成目标
【1】 Mlinko, S.; Simon Trompler, E.; Szammer, J.; Synthesis of bisaramil labelled with carbon-14 and deuterium. J Label Compd Radiopharm 1994, 34, 4, 313.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 10919 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one 1445-73-4 C6H11NO 详情 详情
(VIII) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(IX) 10924 Ethyl alcohol; Ethanol 1516-08-1 C2H6O 详情 详情
(IX) 44687 Ethanol-d6 C2H6O 详情 详情
(X) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(X) 44688 1-iodoethane-d5 C2H5I 详情 详情
(XI) 10926 (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium C8H4KNO2 详情 详情
(XII) 10927 2-Ethyl-1H-isoindole-1,3(2H)-dione 5022-29-7 C10H9NO2 详情 详情
(XII) 44689 2-ethyl-1H-isoindole-1,3(2H)-dione C10H9NO2 详情 详情
(XIII) 10928 Ethanamine 75-04-7 C2H7N 详情 详情
(XIII) 44690 ethylamine; 1-ethanamine C2H7N 详情 详情
(XV) 10929 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one C10H18N2O 详情 详情
(XV) 44691 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one C10H18N2O 详情 详情
(XVI) 10921 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情
(XVI) 44692 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情
(XVII) 10922 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情
(XVII) 44693 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情

合成路线4

该中间体在本合成路线中的序号：(A)

2) The condensation of quinoline (IX) with piperazine (XI) by heating at 140 C as before gives 1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-3-carboxylic acid (XII), which is finally treated with ethyl iodide and triethylamine in hot DMF.

参考文献 中间体
合成目标
【1】 Grohe, K.; Petersen, U.; Kuck, K.-H. (Bayer AG); Antimicrobial agent of quinolone-carboxylic acid b. DE 3248507; US 4563459 .
【2】 Grohe, K.; Klimetzek, V.; Metzger, K.G.; Stunkel, K.G.; Zeiler, H.-J. (Bayer AG); Immunostimulant agent. AU 8542762; DE 3420116; EP 0165474; ES 8607020; JP 1985258163; US 4659603 .
【3】 Castaner, J.; Prous, J.; Enrofloxacin. Drugs Fut 1988, 13, 4, 305.
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) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(IX) 22101 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 86393-33-1 C13H9ClFNO3 详情 详情
(XI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(XII) 22103 1-cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylic acid 85721-33-1 C17H18FN3O3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

3-Phenyl-5-aminopyrazole (I) is reacted with sodium formylacetate (III) to give (II). Alkylation ot (II) with ethyl iodide (IV) in DMF solution in the presence ot K2CO3 gives the target compound.

参考文献 中间体
合成目标
【1】 Pirisino, R.; Pecori-Vettori, L.; Ceppateli, P.; Corrias, M.; Mangano, G.; Ignesti, G.; Carla, V.; Further investigation on the antiinflammatory acti. Pharm Sci 1981, 36, 682.
【2】 Pecori-Vettori, L.; Pirisino, R.; Ignesti, G.; Bruni, F.; Auzzi, G.; Raimondi, L.; Banchelli, G.; Costanzo, A.; Corrias, M.; Cecci, L.; 2-Phenylpirazolo[1-5-a]pyrimidin-7-ones. A new cla. J Med Chem 1983, 26, 1706.
【3】 Pirisino, R.; Messori, A.; Auzzi, G.; Bruni, F.; Pecori-Vettori, L.; Costanzo, A.; Cecchi, L.; FPP-028. Drugs Fut 1987, 12, 4, 345.
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) 22906 3-phenyl-1H-pyrazol-5-amine; 3-phenyl-1H-pyrazol-5-ylamine 827-41-8 C9H9N3 详情 详情
(II) 22907 2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one C12H9N3O 详情 详情
(III) 28397 sodium 3-oxopropanoate C3H3NaO3 详情 详情
(IV) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

The alkylation of L-proline (I) with ethyl iodide (II) and K2CO3 gives N-ethylproline ethyl ester (III), which is treated with ammonia in methanol to afford N-ethyl-L-prolinamide (IV). The reduction of (IV) with LiAlH4 yields (S)-1-ethylpyrrolidin-2-ylmethylamine (V), which is condensed with 3-bromo-2,5,6-trimethoxybenzoyl chloride (VI) to provide the corresponding amide (VII). Finally, this compound is partially demethylated with BBr3 to provide the target compound.

参考文献 中间体
合成目标
【1】 Hogberg, M.; Novel substituted salicylamides and benzamides as selective dopamine D2-receptor antagonists. Drugs Fut 1991, 16, 4, 333.
【2】 Ramsby, S.; Hogberg, T.; Strom, P.; Efficient stereoconservative syntheses of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines. Acta Chem Scand 1989, 43, 660-664.
【3】 Hogberg, T.; Ramsby, S.; Strom, P.; Ebner, M.; Cyanide as an efficient and mild catalyst in the aminolysis of esters. J Org Chem 1987, 52, 2033-2036.
【4】 Hogberg, T.; et al.; Potential antipsychotic agents. 5. Synthesis and antidopaminergic properties of substituted 5, 6-dimethoxysalicylamides and related compounds. J Med Chem 1990, 33, 1155-63.
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) 16731 L-proline 147-85-3 C5H9NO2 详情 详情
(II) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(III) 42895 ethyl (2S)-1-ethyl-2-pyrrolidinecarboxylate C9H17NO2 详情 详情
(IV) 42896 (2S)-1-ethyl-2-pyrrolidinecarboxamide 55446-83-8 C7H14N2O 详情 详情
(V) 21345 (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine C7H16N2 详情 详情
(VI) 42897 3-bromo-2,5,6-trimethoxybenzoyl chloride C10H10BrClO4 详情 详情
(VII) 42898 3-bromo-N-[[(2S)-1-ethylpyrrolidinyl]methyl]-2,5,6-trimethoxybenzamide C17H25BrN2O4 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

The alkylation of L-proline (I) with ethyl iodide (II) and K2CO3 gives N-ethylproline ethyl ester (III), which is treated with ammonia in methanol to afford N-ethyl-L-prolinamide (IV). The reduction of (IV) with LiAlH4 yields (S)-1-ethylpyrrolidin-2-ylmethylamine (V), which is condensed with 3-iodo-2,5,6-trimethoxybenzoyl chloride (VI) to provide the corresponding amide (VII). Finally, this compound is partially demethylated with BBr3 to provide the target compound.

参考文献 中间体
合成目标
【1】 Hogberg, T.; Ramsby, S.; Strom, P.; Ebner, M.; Cyanide as an efficient and mild catalyst in the aminolysis of esters. J Org Chem 1987, 52, 2033-2036.
【2】 Ramsby, S.; Hogberg, T.; Strom, P.; Efficient stereoconservative syntheses of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines. Acta Chem Scand 1989, 43, 660-664.
【3】 Hogberg, M.; Novel substituted salicylamides and benzamides as selective dopamine D2-receptor antagonists. Drugs Fut 1991, 16, 4, 333.
【4】 Hogberg, T.; et al.; Potential antipsychotic agents. 5. Synthesis and antidopaminergic properties of substituted 5, 6-dimethoxysalicylamides and related compounds. J Med Chem 1990, 33, 1155-63.
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) 16731 L-proline 147-85-3 C5H9NO2 详情 详情
(II) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(III) 42895 ethyl (2S)-1-ethyl-2-pyrrolidinecarboxylate C9H17NO2 详情 详情
(IV) 42896 (2S)-1-ethyl-2-pyrrolidinecarboxamide 55446-83-8 C7H14N2O 详情 详情
(V) 21345 (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine C7H16N2 详情 详情
(VI) 42906 3-iodo-2,5,6-trimethoxybenzoyl chloride C10H10ClIO4 详情 详情
(VII) 42907 N-[[(2S)-1-ethylpyrrolidinyl]methyl]-3-iodo-2,5,6-trimethoxybenzamide C17H25IN2O4 详情 详情

合成路线8

该中间体在本合成路线中的序号：(VI)

The condensation of 4-hydroxy-6-methyl-2H-pyran-2-one (I) with 1-phenyl-1-propanol (II) by means of TsOH in toluene gives 4-hydroxy-6-methyl-3-(1-phenyl-propyl)-2H-pyran-2-one (III), which is alkylated with benzyl bromide and LDA in THF yielding 4-hydroxy-6-(2-phenylethyl)-3-(1-phenylpropyl)-2H-pyran-2-one (V). Finally this compound is submitted to a new alkylation process with ethyl iodide and LDA in THF to afford the target compound.

参考文献 中间体
合成目标
【1】 Romines, K.R.; Thaisrivongs, S.; Analogs of 4-hydroxypyrone: potent, non-peptidic HIV protease inhibitors. Drugs Fut 1995, 20, 4, 377.
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) 41231 4-hydroxy-6-methyl-2H-pyran-2-one 675-10-5 C6H6O3 详情 详情
(II) 41232 1-phenyl-1-propanol C9H12O 详情 详情
(III) 41233 4-hydroxy-6-methyl-3-(1-phenylpropyl)-2H-pyran-2-one C15H16O3 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 41234 4-hydroxy-6-phenethyl-3-(1-phenylpropyl)-2H-pyran-2-one C22H22O3 详情 详情
(VI) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情

合成路线9

该中间体在本合成路线中的序号：

Quaternization of 4-pyridylcarbinol (I) by means of iodoethane provided pyridinium salt (II), which was reduced with NaBH4 to the tetrahydropyridine (III). Subsequent Mitsunobu coupling of (III) with 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (IV) afforded ether (V). Intramolecular cyclization of (V) to the spiro compound (VI) was effected by treatment with tributyltin hydride and azobis(isobutyronitrile). The acetamide function of (VI) was then hydrolyzed by refluxing with HCl in H2O-EtOH to furnish intermediate diamine (VII).

参考文献 中间体
合成目标
【1】 Gaster, L.M.; King, F.D.; Wyman, P.A. (GlaxoSmithKline plc); Tetracyclic spiro cpds., process for their preparation and their use as 5HT1D receptor antagonists. EP 0799226; JP 1998510821; US 5972951; WO 9619477 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(I) 32835 4-pyridinylmethanol 586-95-8 C6H7NO 详情 详情
(II) 32836 1-ethyl-4-(hydroxymethyl)pyridinium iodide C8H12INO 详情 详情
(III) 32837 (1-ethyl-1,2,3,6-tetrahydro-4-pyridinyl)methanol C8H15NO 详情 详情
(IV) 19324 1-(6-bromo-5-hydroxy-2,3-dihydro-1H-indol-1-yl)-1-ethanone C10H10BrNO2 详情 详情
(V) 32838 1-[6-bromo-5-[(1-ethyl-1,2,3,6-tetrahydro-4-pyridinyl)methoxy]-2,3-dihydro-1H-indol-1-yl]-1-ethanone C18H23BrN2O2 详情 详情
(VI) 32839 1'-Ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine]; 5-Acetyl-1'-ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine] C18H24N2O2 详情 详情
(VII) 32844 1'-Ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine] C16H22N2O 详情 详情

合成路线10

该中间体在本合成路线中的序号：

The reaction of 2,6-di(tert-butyl)phenol (I) with CS2 and ethyl chloroacetate gives the dithiobenzoate (II), which is treated with hydrazine in ethanol yielding the thiobenzoyl hydrazide (III). The cyclization of (III) with CS2 in refluxing ethanol affords the thiadiazolethione (IV), which is finally condensed with ethyl iodide and NaOH in THF.

参考文献 中间体
合成目标
【1】 Sercel, A.D.; Connor, D.T.; Song, Y.; et al.; Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 2. 1,3,4- and 1,2,4-thiadiazole series. J Med Chem 1999, 42, 7, 1161.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
16601 ethyl chloroacetate; ethyl 2-chloroacetate 105-39-5 C4H7ClO2 详情 详情
(I) 25925 2,6-di(tert-butyl)phenol 128-39-2 C14H22O 详情 详情
(II) 25926 ethyl 2-[[3,5-di(tert-butyl)-4-hydroxybenzothioyl]sulfanyl]acetate C19H28O3S2 详情 详情
(III) 25927 3,5-di(tert-butyl)-4-hydroxybenzenecarbothiohydrazide C15H24N2OS 详情 详情
(IV) 25928 5-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione C16H22N2OS2 详情 详情

合成路线11

该中间体在本合成路线中的序号：

The Grignard reaction of 1-(tert-butoxycarbonyl)piperidin-4-one (I) with 3-fluorophenylmagnesium bromide (II) in THF gives the tertiary alcohol (III), which is dehydrated with TFA or HCl in dioxane yielding the tetrahydropyridine (IV). The condensation of (IV) with 2,4-dichloro-6-methylpyrimidine (V) by means of DIEA in ethanol affords 2-chloro-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine (VI), which is further condensed with 4-isopropyl-2-(methylsulfanyl)aniline (VII) by means of DIEA in refluxing ethylene glycol to give the secondary amine (VIII). Finally, this compound is alkylated with ethyl iodide and NaH in DMF.

参考文献 中间体
合成目标
【1】 Chaki, S.; Nakazato, A.; Okubo, T.; Kumagai, T.; Tomisawa, K.; Okuyama, S.; CRF1 receptor antagonists: Aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives. Symp Med Chem 1998, Abst 1-P-26.
【2】 Okubo, T.; Tanaka, H.; Chaki, S.; Okuyama, S.; Tomisawa, K.; Kumagai, T.; Nakazato, A.; Design, synthesis and structure-affinity relationships of 4-methylidenepiperidine and 4-aryl-1,2,3,6-tetrahydropyridine derivatives as corticotropin-releasing factor1 receptor antagonists. Bioorg Med Chem 2000, 8, 5, 1183.
【3】 Okubo, T.; Okuyama, S.; Nakazato, A.; Tomisawa, K.; Aibe, I.; Chaki, S.; Kumagai, T.; Tanaka, H. (Taisho Pharmaceutical Co., Ltd.); 4-Tetrahydropyridylpyrimidine derivs.. EP 0976745; JP 1999228568; WO 9842699 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(I) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 35384 bromo(3-fluorophenyl)magnesium C6H4BrFMg 详情 详情
(III) 35385 tert-butyl 4-(3-fluorophenyl)-4-hydroxy-1-piperidinecarboxylate C16H22FNO3 详情 详情
(IV) 35386 4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine C11H12FN 详情 详情
(V) 35387 2,4-dichloro-6-methylpyrimidine 5424-21-5 C5H4Cl2N2 详情 详情
(VI) 35388 2-chloro-4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-6-methylpyrimidine C16H15ClFN3 详情 详情
(VII) 35389 4-isopropyl-2-(methylsulfanyl)phenylamine; 4-isopropyl-2-(methylsulfanyl)aniline C10H15NS 详情 详情
(VIII) 35390 N-[4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-6-methyl-2-pyrimidinyl]-N-[4-isopropyl-2-(methylsulfanyl)phenyl]amine; 4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-N-[4-isopropyl-2-(methylsulfanyl)phenyl]-6-methyl-2-pyrimidinamine C26H29FN4S 详情 详情

合成路线12

该中间体在本合成路线中的序号：

The Grignard reaction of 1-(tert-butoxycarbonyl)piperidin-3-one (I) with 2-methylphenylmagnesium bromide (II) in THF gives the tertiary alcohol (III), which is dehydrated with TFA or HCl in dioxane yielding the tetrahydropyridine (IV). The condensation of (IV) with 2,4-dichloro-6-methylpyrimidine (V) by means of DIEA in ethanol affords 2-chloro-6-methyl-4-[3-(2-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl]pyrimidine (VI), which is further condensed with 4-isopropyl-2-(methylsulfanyl)aniline (VII) by means of DIEA in refluxing ethylene glycol to give the secondary amine (VIII). Finally, this compound is alkylated with ethyl iodide and NaH in DMF.

参考文献 中间体
合成目标
【1】 Chaki, S.; Nakazato, A.; Okubo, T.; Kumagai, T.; Tomisawa, K.; Okuyama, S.; CRF1 receptor antagonists: Aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives. Symp Med Chem 1998, Abst 1-P-26.
【2】 Okubo, T.; Okuyama, S.; Nakazato, A.; Tomisawa, K.; Aibe, I.; Chaki, S.; Kumagai, T.; Tanaka, H. (Taisho Pharmaceutical Co., Ltd.); 4-Tetrahydropyridylpyrimidine derivs.. EP 0976745; JP 1999228568; WO 9842699 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(I) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 35391 bromo(2-methylphenyl)magnesium C7H7BrMg 详情 详情
(III) 35392 tert-butyl 3-hydroxy-3-(2-methylphenyl)-1-piperidinecarboxylate C17H25NO3 详情 详情
(IV) 35393 5-(2-methylphenyl)-1,2,3,6-tetrahydropyridine C12H15N 详情 详情
(V) 35387 2,4-dichloro-6-methylpyrimidine 5424-21-5 C5H4Cl2N2 详情 详情
(VI) 35394 2-chloro-4-methyl-6-[5-(2-methylphenyl)-3,6-dihydro-1(2H)-pyridinyl]pyrimidine C17H18ClN3 详情 详情
(VII) 35389 4-isopropyl-2-(methylsulfanyl)phenylamine; 4-isopropyl-2-(methylsulfanyl)aniline C10H15NS 详情 详情
(VIII) 35395 N-[4-isopropyl-2-(methylsulfanyl)phenyl]-4-methyl-6-[5-(2-methylphenyl)-3,6-dihydro-1(2H)-pyridinyl]-2-pyrimidinamine; N-[4-isopropyl-2-(methylsulfanyl)phenyl]-N-[4-methyl-6-[5-(2-methylphenyl)-3,6-dihydro-1(2H)-pyridinyl]-2-pyrimidinyl]amine C27H32N4S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(A)

The reduction of 2-nitro-4,5-methylenedioxyacetophenone (I) with H2 over PtO2 in ethanol gives 2-amino-4,5-methylenedioxyacetophenone (II), which is cyclized by treatment with NaNO2 and HCl in water yielding 6,7-methylenedioxycinnolin-4-ol (III). The bromination of (III) with Br2 and potassium acetate in refluxing acetic acid affords 3-bromo-6,7-methylenedioxycinnolin-4-ol (IV), which is treated with Cu2(CN)2 in refluxing DMF giving 4-hydroxy-6,7-methylenedioxycinnolin-3-carbonitrile (V). Alkylation of (V) with ethyl iodide (A) by means of NaH in DMF affords 1-ethyl-6,7-methylenedioxy-4(1H)-oxocinnolin-3-carbonitrile (VI), which is finally hydrolyzed with HCl in refluxing acetic acid.

参考文献 中间体
合成目标
【1】 Roberts, P.J.; Castañer, J.; Cinoxacin. Drugs Fut 1978, 3, 1, 22.
【2】 Un metodo para la preparacion de acidos 6,7-metilendioxi-4(1H)-oxocinnolin-3-carboxilicos. ES 376173; ES 402312 .
【3】 Maas, I.M. Pfeiffer, W.G.; Voithenleitner, F.; 1-niederalkyl- oder -alkylensubstituierte 6,7-Methylendioxyd-4(1H)-oxocinnolin-3-carbosauren und Zwiswhenprodukte dafur. DE 2005104; FR 2034519; GB 1296753; GB 1296754 .
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) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(I) 39691 1-(6-nitro-1,3-benzodioxol-5-yl)-1-ethanone 56136-84-6 C9H7NO5 详情 详情
(II) 18886 1-(6-amino-1,3-benzodioxol-5-yl)-1-ethanone 28657-75-2 C9H9NO3 详情 详情
(III) 39692 [1,3]dioxolo[4,5-g]cinnolin-4-ol C9H6N2O3 详情 详情
(IV) 39693 3-bromo[1,3]dioxolo[4,5-g]cinnolin-4-ol C9H5BrN2O3 详情 详情
(V) 39694 4-hydroxy[1,3]dioxolo[4,5-g]cinnoline-3-carbonitrile C10H5N3O3 详情 详情
(VI) 39695 1-ethyl-4-oxo-1,4-dihydro[1,3]dioxolo[4,5-g]cinnoline-3-carbonitrile C12H9N3O3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(IV)

Condensation between dichloropurine (I) and substituted aniline (II) in pentanol affords derivative (III), which is then alkylated with ethyl iodide (IV) by means of Cs2CO3 in DMF to provide purine (V). Finally, the desired compound is obtained by attack of amine (VI) and displacement of the chlorine atom of derivative (V) in diglyme.

参考文献 中间体
合成目标
【1】 Bruggen, J.; Caravatti, G.; Capraro, H.-G.; et al.; Chemistry and biological characterization of CGP79807, a highly selective CDK1/2 inhibitor. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 150.
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) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(II) 28662 3-aminobenzonitrile 2237-30-1 C7H6N2 详情 详情
(III) 48922 3-[(2-chloro-9H-purin-6-yl)amino]benzonitrile C12H7ClN6 详情 详情
(IV) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(V) 48923 3-[(2-chloro-9-ethyl-9H-purin-6-yl)amino]benzonitrile C14H11ClN6 详情 详情
(VI) 19581 trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; 27489-62-9 C6H13NO 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

Treatment of methyl pyrrole-2-carboxylate (I) with KOtBu and 18-crown-6 in Et2O, followed by reaction with ethyl iodide (II) in Et2O, yields methyl 1-ethylpyrrole-2-carboxylate (III), which is then subjected to saponification with NaOH to afford carboxylic acid (IV). Condensation of (IV) with beta-alanine benzyl ester p-toluene sulfonate (V) in the presence of diethyl phosphorocyanidate (DEPC) and Et3N in DMF provides benzyl ester (VI), which is then hydrogenated over Pd/C in THF, furnishing carboxylic acid (VII). Cyclization of (VII) with polyphosphoric acid (PPA) affords derivative (VIII), which is then treated with NaH in DMF and alkylated with chloro derivative (IX) in DMF to produce compound (X). Finally, treatment of (X) with hydroxylamine hydrochloride and NaOAc affords the target compound.

参考文献 中间体
合成目标
【1】 Mizuno, A.; Miya, M.; Inomata, N.; Tatsuoka, T.; Ishihara, T. (Suntory Ltd.); Pyrroloazepine cpd.. EP 0557526; JP 1993503481; US 5399557; WO 9303032 .
【2】 Yamaki, A.; Tatsuoka, T.; Miya, M.; Nakanishi, K.; Mizuno, A.; Takiguchi, C.; Hidaka, T.; Kamei, T.; Shibata, M.; Inomata, N.; Studies on antihypertensive agents with antithrombotic activity. 2. Syntheses and pharmacological evaluation of pyrrolo[2,3-c]azepine derivatives. Chem Pharm Bull 2000, 48, 8, 1129.
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) 45616 methyl 1H-pyrrole-2-carboxylate C6H7NO2 详情 详情
(II) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(III) 45617 methyl 1-ethyl-1H-pyrrole-2-carboxylate C8H11NO2 详情 详情
(IV) 45618 1-ethyl-1H-pyrrole-2-carboxylic acid C7H9NO2 详情 详情
(V) 30194 benzyl 3-aminopropanoate 27019-47-2 C10H13NO2 详情 详情
(VI) 45619 benzyl 3-[[(1-ethyl-1H-pyrrol-2-yl)carbonyl]amino]propanoate C17H20N2O3 详情 详情
(VII) 45620 N-[(1-ethyl-1H-pyrrol-2-yl)carbonyl]-beta-alanine C10H14N2O3 详情 详情
(VIII) 45621 1-ethyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione C10H12N2O2 详情 详情
(IX) 45622 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine C13H18ClFN2 详情 详情
(X) 45623 1-ethyl-7-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione C23H29FN4O2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

2-Mercapto-4-quinazolone (I) is treated with ethyl iodide (II) in the presence of sodium ethoxide to yield 2-ethylthio-4-quinazolone (III). Reaction of (III) with N-benzylpiperazine (IV) to give (V) and followed by catalytic debenzylation with H2 over Pd/C in glacial acetic acid affords Centpiperalone.

参考文献 中间体
合成目标
【1】 Gupta, C.M.; Muscimol analogs. II. Synthesis of some bicyclic 3-isoxazolol zwitterions. Med Chem 1968, 11, 3, 392.
【2】 Arya, V.P.; Centpiperalone. Drugs Fut 1979, 4, 8, 557.
【3】 Gupta, C.M.; et al.; Resveratrol regulates IGF-II in MCF-7 human breast cancer cells. Ind J Chem 1971, 9, 3, 201.
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) 61384 2-Mercapto-4(3H)-quinazolinone 2-Thio-4(3H)-quinazolinone; 2-Mercapto-4(3H)-quinazolinone 2-Thio-4(3H)-quinazolinone 13906-09-7 C8H6N2OS 详情 详情
(II) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(III) 61385 2-(ethylsulfanyl)-4(3H)-quinazolinone C10H10N2OS 详情 详情
(IV) 28542 N-Benzylpiperazine; 1-Benzylpiperazine 2759-28-6 C11H16N2 详情 详情
(V) 61386 2-(4-benzyl-1-piperazinyl)-4(3H)-quinazolinone C19H20N4O 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XII)

Friedel–Crafts acylation of 2-tert-butylphenol (I) with acetyl chloride (II) in the presence of AlCl3 in cold toluene gives 1-(3-tert-butyl-4-hydroxyphenyl)ethanone (III) (1, 2), which by nitration with HNO3 in cold H2O/CH2Cl2 provides 1-(3-tert-butyl-4-hydroxy-5-nitrophenyl)ethanone (IV). O-Alkylation of phenol (IV) with methyl iodide by means of K2CO3 in DMF produces the methyl ether (V), which is reduced at the nitro group with Fe and NH4Cl in EtOH/H2O to afford the corresponding amine (VI). Cyclocondensation of the aniline derivative (VI) with bis(2-bromoethyl) ether (VII) by means of NaI and K2CO3 in DMF provides the 3-morpholino-acetophenone derivative (VIII). α-Halogenation of acetophenone (VIII) with NBS by means of Et3N and TBDMSOTf in THF yields the corresponding bromoacetophenone (IX) , which is finally condensed with isoindole derivative (X) in THF or DMF .
The isoindole intermediate (X) is prepared by dialkylation of 3-fluorocatechol (XI) with ethyl iodide (XII) in the presence of K2CO3 in DMF to give 1,2-diethoxy-3-fluorobenzene (XIII), which is brominated with Br2 by means of NaOAc in AcOH at 70 °C to yield 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (XIV). Bromide substitution in intermediate (XIV) with CuCN in DMF at 150 °C affords 4,5-diethoxy-3-fluorophthalonitrile (XV), which is finally submitted to reductive cyclization with H2 over PtO2 in EtOAc/EtOH/MeOH .

参考文献 中间体
合成目标
【1】 Suzuki, S., Naoe, Y., Miyamoto, M. et al. (Eisai R&D Management Co., Ltd.). 2-Iminopyrrolidine derivatives. EP 1391451, EP 2385039, US 2005004204, US 7244730, WO 2002085855.
【2】 Shimomura, N., Sasho, M., Kayano, A., Yoshizawa, K., Tsujii, M., Kuroda,H., Furukawa, K. (Eisai R&D Management Co., Ltd.). Processes for producing cyclic benzamidine derivative. CA 2515715, EP 1602646, US 2006058370, US 7375236, WO 2004078721.
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) 67678 2-tert-butylphenol；o-t-Butylphenol；o-tert-Butylphenol；2-tert-Butyl-1-hydroxybenzene；2-(1,1-Dimethylethyl)phenol 88-18-6 C10H14O 详情 详情
(II) 19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
(III) 68400 1-(3-tert-butyl-4-hydroxyphenyl)ethanone 　 C12H16O2 详情 详情
(IV) 68401 1-(3-(tert-butyl)-4-hydroxy-5-nitrophenyl)ethanone 　 C12H15NO4 详情 详情
(V) 68402 1-(3-(tert-butyl)-4-methoxy-5-nitrophenyl)ethanone 　 C13H17NO4 详情 详情
(VI) 68403 1-(3-amino-5-(tert-butyl)-4-methoxyphenyl)ethanone 　 C13H19NO2 详情 详情
(VII) 63502 1-bromo-2-[(2-bromoethyl)oxy]ethane; bis(2-bromoethyl) ether 5414-19-7 C4H8Br2O 详情 详情
(VIII) 68404 1-(3-(tert-butyl)-4-methoxy-5-morpholinophenyl)ethanone 　 C17H25NO3 详情 详情
(IX) 68405 2-bromo-1-(3-(tert-butyl)-4-methoxy-5-morpholinophenyl)ethanone 　 C17H24BrNO3 详情 详情
(X) 68406 5,6-diethoxy-4-fluoro-1H-isoindol-3-amine 　 C12H15FN2O2 详情 详情
(XI) 68407 3-fluorocatechol;3-FLUORO-1,2-DIHYDROXYBENZENE;3-FLUOROBENZENE-1,2-DIOL;1-FLUORO-2,3-DIHYDROXYBENZENE;1,2-Dihydroxy-3-fluoroBenzene 363-52-0 C6H5FO2 详情 详情
(XII) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(XIII) 68408 1,2-diethoxy-3-fluorobenzene 　 C10H13FO2 详情 详情
(XIV) 68409 1,2-dibromo-4,5-diethoxy-3-fluorobenzene 　 C10H11Br2FO2 详情 详情
(XV) 68410 4,5-diethoxy-3-fluorophthalonitrile;6-(aminomethyl)-3,4-diethoxy-2-fluorobenzonitrile 474554-45-5 C12H11FN2O2 详情 详情
Extended Information