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【结 构 式】 
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【分子编号】15724 【品名】2-(2-bromoethyl)-1,3-dioxolane 【CA登记号】18742-02-4 |
【 分 子 式 】C5H9BrO2 【 分 子 量 】181.02926 【元素组成】C 33.17% H 5.01% Br 44.14% O 17.68% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of ethyl 4-methylbenzoate (I) with 2-(2-bromoethyl)-1,3-dioxolane (II) by means of lithium diisopropylamide gives ethyl 4-[3-(1,3-dioxolan-2-yl)propyl]benzoate (III), which is hydrolyzed to ethyl 4-(3-formylpropyl)benzoate (IV). The condensation of (IV) with 1-(2-aminoethyl) cyclohexanol (V) affords the corresponding imine (VI), which is cyclized with methyl thioglycolate (VII) yielding ethyl 4-[3-[3-[2-[1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoate (VIII) . The hydrolysis of (VIII) with KOH gives L-644122 as a racemic mixture (IX), which is methylated with MeI and K2CO3 to the corresponding methyl ester (X). Esterification of (X) with (-)-camphanic acid (XI) by means of dicyclohexylcarbodumide in methylene chloride affords the diastereomeric mixture of esters (XII), which is separated into its components by fractionated crystallization in ethyl acetate hexane. Finally, the (+)-diastereomer (XIII) is hydrolyzed with KOH in refluxing toluene containing diclohexyl-18-crown-6.
| 【1】 Mohan, P.; Smith, E.C.R.; Cushman, M.; Synthesis an dbiological activity of structural analogues of the anticancer benzopheanthridine alkaloid nitidine chloride. J Med Chem 1983, 26, 3, 342-348. |
| 【2】 Blaine, E.H. (Merck & Co., Inc.; Merck Sharp & Dohme Ltd.); Anti-inflammatory composition. US 4379792 . |
| 【3】 Bock, M.G.; di Pardo, R.M. (Merck & Co., Inc.); Intermediates for the resolution of some interphenylene-9-thia-11-oxo-12-azaprostanoic. AT 235482; AT 378189B; GB 2100733; US 4390703 . |
| 【4】 Serradell, M.N.; Castaner, J.; L-644122. Drugs Fut 1986, 11, 5, 372. |
| 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) | 28807 | ethyl 4-methylbenzoate | 94-08-6 | C10H12O2 | 详情 | 详情 |
| (II) | 15724 | 2-(2-bromoethyl)-1,3-dioxolane | 18742-02-4 | C5H9BrO2 | 详情 | 详情 |
| (III) | 28808 | ethyl 4-[3-(1,3-dioxolan-2-yl)propyl]benzoate | C15H20O4 | 详情 | 详情 | |
| (IV) | 28809 | ethyl 4-(4-oxobutyl)benzoate | C13H16O3 | 详情 | 详情 | |
| (V) | 28810 | 1-(2-aminoethyl)cyclohexanol | C8H17NO | 详情 | 详情 | |
| (VI) | 28811 | ethyl 4-(4-[[2-(1-hydroxycyclohexyl)ethyl]imino]butyl)benzoate | C21H31NO3 | 详情 | 详情 | |
| (VII) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VIII) | 28812 | ethyl 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-1,3-thiazolidin-2-yl]propyl)benzoate | C23H33NO4S | 详情 | 详情 | |
| (IX) | 28813 | 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-1,3-thiazolidin-2-yl]propyl)benzoic acid | C21H29NO4S | 详情 | 详情 | |
| (X) | 28814 | methyl 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-1,3-thiazolidin-2-yl]propyl)benzoate | C22H31NO4S | 详情 | 详情 | |
| (XI) | 28815 | (1S,4R)-7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylic acid | C9H12O4 | 详情 | 详情 | |
| (XII) | 28816 | 1-[2-(2-[3-[4-(methoxycarbonyl)phenyl]propyl]-4-oxo-1,3-thiazolidin-3-yl)ethyl]cyclohexyl (1S,4R)-7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate | C31H41NO7S | 详情 | 详情 | |
| (XIII) | 28817 | 1-[2-((2R)-2-[3-[4-(methoxycarbonyl)phenyl]propyl]-4-oxo-1,3-thiazolidin-3-yl)ethyl]cyclohexyl (1S,4R)-7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate | C31H41NO7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)N-Benzyl-4-piperidone (I) was reacted with a Grignard reagent prepared from 4-fluorobromobenzene (II) to give the carbinol (III). The benzyl group was removed by catalytic hydrogenation and the resulting amine (IV) was alkylated with 3-bromopropionaldehyde ethylene acetal (V) to the alcohol (VI). Ring closure in hydrochloric acid gave the bicyclic endo-alcohol [(±)-VII] along with some of the exo-isomer removed by crystallization. [(±)-VII] was resolved by crystallization with (R,R)-tartaric acid mono-4-chloroanilide (VIII) to give [(+)-VII] of yet unknown absolute configuration. The latter was acylated with propionic anhydride followed by crystallization with hydrogen chloride in ether to furnish the end product.
| 【1】 Sólyom, S.; Abraham, G.; Szölössy, M.; Borsi, J.; Vitális, B.; Karimné Tapfer, M.; Szabóné Bady, E.; Csuzdi, E.; Goldschmidtné Horváth, K.; Máté, G.; Ling, I.; Miklósné Kovács, A. (Gyogyszerkutato Intezet Kft.); New 1-azabicycloalkane derivs., pharmaceutical compsns. containing them and process for preparing same. EP 0556342; JP 1994505706; WO 9207854 . |
| 【2】 Nogradi, M.; GYKI-46903. Drugs Fut 1993, 18, 5, 421. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| ((+/-)-VII | 15726 | (rac)-[(4R*,5S*)-6-(4-fluorophenyl)-1-azabicyclo[3.3.1]non-6-en-4-ol] | C14H16FNO | 详情 | 详情 | |
| ((R,R)-VII) | 15727 | (2R,3R)-4-(4-chloroanilino)-2,3-dihydroxy-4-oxobutyric acid | C10H10ClNO5 | 详情 | 详情 | |
| ((+)-VII) | 64680 | (4R,5S)-6-(4-fluorophenyl)-1-azabicyclo[3.3.1]non-6-en-4-ol | C14H16FNO | 详情 | 详情 | |
| (I) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (II) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (III) | 15722 | 1-benzyl-4-(4-fluorophenyl)-4-piperidinol | C18H20FNO | 详情 | 详情 | |
| (IV) | 15723 | 4-(4-fluorophenyl)-4-piperidinol; 4-(4-Fluorophenyl)-4-hydroxypiperidine | 3888-65-1 | C11H14FNO | 详情 | 详情 |
| (V) | 15724 | 2-(2-bromoethyl)-1,3-dioxolane | 18742-02-4 | C5H9BrO2 | 详情 | 详情 |
| (VI) | 15725 | 1-[2-(1,3-dioxolan-2-yl)ethyl]-4-(4-fluorophenyl)-4-piperidinol | C16H22FNO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The cyclization of 4-amino-3-methylbenzoic acid ethyl ester (I) by reaction with NaNO2 and HCl catalyzed by NH4BF4 gives indazole-5-carboxylic acid ethyl ester (II), which is condensed with 2-(2-bromoethyl)-1,3-dioxolane (III) by means of sodium hexamethyldisylazane (NaHMDS) yielding the addition product (IV). The hydrolysis of the dioxolane ring of (IV) with AcOH affords the aldehyde (V), which is reductocondensed with 1-tritylimidazole-2-amine (VI) by means of NaBH(OAc)3 providing the intermediate (VII). The hydrolysis of (VII) with NaOH in ethanol/water gives the carboxylic acid (VIII), which is condensed with the 3-aminopropionic ester (IX) by means of DCC and HOBT yielding the amide (X). Finally, the tert-butyl ester of (X) is hydrolyzed with TFA in dichloromethane.
| 【1】 Petraitis, J.J.; Batt, D.G.; Houghton, G.C.; et al.; Disubstituted indazolines as potent antagonists of the integrin alphavbeta3. J Med Chem 2000, 43, 1, 41. |
| 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) | 38737 | ethyl 4-amino-3-methylbenzoate | 40800-65-5 | C10H13NO2 | 详情 | 详情 |
| (II) | 38738 | ethyl 1H-indazole-5-carboxylate | C10H10N2O2 | 详情 | 详情 | |
| (III) | 15724 | 2-(2-bromoethyl)-1,3-dioxolane | 18742-02-4 | C5H9BrO2 | 详情 | 详情 |
| (IV) | 38739 | ethyl 1-[2-(1,3-dioxolan-2-yl)ethyl]-1H-indazole-5-carboxylate | C15H18N2O4 | 详情 | 详情 | |
| (V) | 38740 | ethyl 1-(3-oxopropyl)-1H-indazole-5-carboxylate | C13H14N2O3 | 详情 | 详情 | |
| (VI) | 38741 | 1-trityl-1H-imidazol-2-amine; 1-trityl-1H-imidazol-2-ylamine | C22H19N3 | 详情 | 详情 | |
| (VII) | 38742 | ethyl 1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazole-5-carboxylate | C35H33N5O2 | 详情 | 详情 | |
| (VIII) | 38743 | 1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazole-5-carboxylic acid | C14H15N5O2 | 详情 | 详情 | |
| (IX) | 36588 | tert-butyl (2S)-3-amino-2-[(mesitylsulfonyl)amino]propanoate | C16H26N2O4S | 详情 | 详情 | |
| (X) | 38744 | tert-butyl (2S)-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]-2-[(mesitylsulfonyl)amino]propanoate | C30H39N7O5S | 详情 | 详情 |