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【结 构 式】 
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【分子编号】10851 【品名】Acrylamide 【CA登记号】79-06-1 |
【 分 子 式 】C3H5NO 【 分 子 量 】71.07884 【元素组成】C 50.69% H 7.09% N 19.71% O 22.51% |
合成路线1
该中间体在本合成路线中的序号：(VIII)1) The reaction of 4-(chloromethyl)pyridine (I) with KCN in refluxing methanol gives 2-(4-pyridyl)acetonitrile (II), which is alkylated with ethyl iodide and sodium hydride in DMF, yielding 2-(4-pyridyl)butyronitrile (III). The condensation of (III) with acrylonitrile (IV) by means of Triton B in tert-butanol affords 2-cyano-2-(4-pyridyl)hexanenitrile (V), which is finally cyclized with concentrated H2SO4 in refluxing acetic acid. 2) The alkylation of 2-(4-pyridyl)acetic acid ethyl ester (VI) with ethyl iodide and potassium tert-butoxide gives 2-(4-pyridyl)butanoic acid ethyl ester (VII), which is condensed with acrylamide (VIII) by means of potassium tert-butoxide, yielding 4-carbamoyl-2-ethyl-2-(4-pyridyl)butanoic acid ethyl ester (IX). Finally, this compound is cyclized in the presence of potassium tert-butoxide. 3) The condensation of ester (VI) with acrylonitrile (IV) in the presence of Triton B gives 4-cyano-2-(4-pyridyl)butanoic acid ethyl ester (X), which is alkylated with ethyl iodide and lithium diisopropylamide yielding 4-cyano-2-ethyl-2-(4-pyridyl)butanoic acid ethyl ester (XI). Finally, this compound is cyclized with concentrated H2SO4 in refluxing acetic acid.
| 【1】 Foster, A.B.; Jarman, M.; Taylor, G.N.; Kwan, C.-S. (Institute of Cancer Research); 2,6-Dioxopiperidine derivs., their preparation and pharmaceutical compsns. containing them. EP 0147121; GB 2151226; JP 1986500613; US 5071857; WO 8502618 . |
| 【2】 Markson, A.J.; Boss, A.M.; Clissold, D.W.; Thickitt, C.P.; Mann, J.; A concise synthesis of racemic pyridoglutethimide and its resolution using chiral stationary phase HPLC. Tetrahedron 1989, 45, 18, 6011. |
| 【3】 Jarman, M.; Griggs, L.J.; Wilman, D.E.V.; Rowlands, M.G.; Foster, A.B.; Leung, C.-S.; Analogues of 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione as selective inhibitors of aromatase: Derivatives with variable 1-alkyl and 3-alkyl substituents. J Med Chem 1987, 30, 9, 1550. |
| 【4】 Sampson, P.; Taylor, G.N.; Leung, C.-S.; Rowlands, M.G.; Plevey, R.G.; Jarman, M.; Foster, A.B.; Analogues of animoglutethimide: Selective inhibition of aromatase. J Med Chem 1989, 28, 2, 200. |
| 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) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (II) | 10845 | 2-(4-Pyridinyl)acetonitrile | C7H6N2 | 详情 | 详情 | |
| (III) | 10846 | 2-(4-Pyridinyl)butanenitrile | C9H10N2 | 详情 | 详情 | |
| (IV) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (V) | 10848 | 2-Ethyl-2-(4-pyridinyl)pentanedinitrile | C12H13N3 | 详情 | 详情 | |
| (VI) | 10849 | ethyl 2-(4-pyridinyl)acetate; Ethyl 4-pyridylacetate | 54401-85-3 | C9H11NO2 | 详情 | 详情 |
| (VII) | 10850 | ethyl 2-(4-pyridinyl)butanoate | C11H15NO2 | 详情 | 详情 | |
| (VIII) | 10851 | Acrylamide | 79-06-1 | C3H5NO | 详情 | 详情 |
| (IX) | 10852 | ethyl 5-amino-2-ethyl-5-oxo-2-(4-pyridinyl)pentanoate | C14H20N2O3 | 详情 | 详情 | |
| (X) | 10853 | ethyl 4-cyano-2-(4-pyridinyl)butanoate | C12H14N2O2 | 详情 | 详情 | |
| (XI) | 10854 | ethyl 4-cyano-2-ethyl-2-(4-pyridinyl)butanoate | C14H18N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The reaction of 4-benzoyloxycyclohexanone (I) with pyrrolidine (II) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane yielding the mixture of hexahydroquinolones (V) and (VI). Benzylation of this mixture with benzylbromide (A) and NaH in THF affords the mixture of N-benzylquinolones (VII) and (VIII), which is reduced with LiAlH4 to the mixture of N-benzylhexahydroquinolines (IX) and (X). The reduction of this mixture with sodium cyanoborohydride in THF affords trans-1-benzyl-6-hydroxydecahydro quinoline (XI), which by reaction with BN in CH2Cl2 is converted to trans-1-cyano-6-hydroxydecahydro quinoline (XII). Oxidation of (XII) with CrO3/pyridine in CH2Cl2 gives the corresponding quinolone (XIII), which by reaction with dimethylformamide dimethyl acetal (XIV) in refluxing benzene is converted to 1-cyano-6-oxo-7-(dimethylaminomethylene)decahydroquinoline (XV). The cyclization of (XV) with hydrazine in refluxing methanol affords 5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVI), which by a reductive cleavage with Zn and acetic acid gives 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVII). Finally, this compound is alkylated with propionaldehyde (B) and sodium cyanoborohydride in methanol.
| 【1】 Bach, N.; Kornfeld, E.C. (Eli Lilly and Company); Prolactin inhibiting octahydropyrazolo[3,4-g]quinolines. DD 148517; EP 0013787; ES 482087; FR 2446820; FR 2446821; FR 2446822; GB 2040915; GB 2092579; US 4198415 . |
| 【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Mannhold, R.; Quinpirole Hydrochloride. Drugs Fut 1987, 12, 6, 558. |
| 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) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (B) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (I) | 16967 | N-(tert-butyl)-5-propyl-2-thiophenecarboxamide | C12H19NOS | 详情 | 详情 | |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 28829 | 4-(1-pyrrolidinyl)-3-cyclohexen-1-yl benzoate | C17H21NO2 | 详情 | 详情 | |
| (IV) | 10851 | Acrylamide | 79-06-1 | C3H5NO | 详情 | 详情 |
| (V) | 28830 | 2-oxo-1,2,3,4,5,6,7,8-octahydro-6-quinolinyl benzoate | C16H17NO3 | 详情 | 详情 | |
| (VI) | 28831 | 2-oxo-1,2,3,4,4a,5,6,7-octahydro-6-quinolinyl benzoate | C16H17NO3 | 详情 | 详情 | |
| (VII) | 28832 | 1-benzyl-2-oxo-1,2,3,4,5,6,7,8-octahydro-6-quinolinyl benzoate | C23H23NO3 | 详情 | 详情 | |
| (VIII) | 28833 | 1-benzyl-2-oxo-1,2,3,4,4a,5,6,7-octahydro-6-quinolinyl benzoate | C23H23NO3 | 详情 | 详情 | |
| (IX) | 28834 | 1-benzyl-6-hydroxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone | C16H19NO2 | 详情 | 详情 | |
| (X) | 28835 | 1-benzyl-6-hydroxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone | C16H19NO2 | 详情 | 详情 | |
| (XI) | 28836 | (4aR,8aR)-1-benzyldecahydro-6-quinolinol | C16H23NO | 详情 | 详情 | |
| (XII) | 28837 | (4aR,8aR)-1-cyanodecahydro-6-quinolinol | C10H16N2O | 详情 | 详情 | |
| (XIII) | 28838 | (4aR,8aR)-1-cyanooctahydro-6(2H)-quinolinone | C10H14N2O | 详情 | 详情 | |
| (XIV) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XV) | 28839 | (4aR,8aR)-1-cyano-7-[(Z)-(dimethylamino)methylidene]octahydro-6-quinolinone | C13H19N3O | 详情 | 详情 | |
| (XVI) | 28840 | (4aR,8aR)-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline | C11H14N4 | 详情 | 详情 | |
| (XVII) | 28841 | (4aR,8aR)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline | C10H15N3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(F)The starting 3-fluorothiophenol (I) is obtained either from 3-fluoro-1-bromobenzene (II) by reaction with Mg and a following treatment with S, or from 3-fluoroaniline (III) by the Leuckart method via 3-fluorobenzenediazonium xanthate and 3-fluorophenyl xanthate. Two different ways were described for obtaining the acid (VI): 1) Reaction of (I) with 5-chloro-2-iodobenzoic acid (A) in a boiling aqueous KOH solution in the presence of Cu, which leads to the acid (IV). This is transformed in three steps (reduction with sodium dihydrodibis(2-methoxyethoxy)aluminate, followed by reaction with SOCl2 in pyridine, and final reaction with NaCN in boiling aqueous ethanol) to the nitrile (V), which is hydrolyzed with a boiling solution of KOH in aqueous ethanol. 2) Reaction of (I) with 2,5-dichloro acetophenone (B) in dimethylformamide at 150 C in the presence of Cu. The resulting ketone (VII) is proceased by the Kindler's modification of the Willgerodt reaction: treatment with S in boiling morpholine (C) gives the thiomorpholide (VIII), which is hydrolyzed either with a boiling ethanolic KOH solution or with a refluxing mixture of dilute H2SO4 and acetic acid. The acid (VI), obtained by both routes, is cyclized with polyphosphoric acid at 150 C to the ketone (IX), which is reduced with sodium borohydride in aqueous ethanol to the alcohol (X). Treatment with HCl in benzene in the presence of CaCl2 affords the reactive chloride (XI), which can be converted to the final product (XIV) by two methods: (b) substitution reaction of (XI) with 1-(ethoxycarbonyl)piperazine (D), followed by alkaline hydrolysis of the carbamate (XII) and addition of the secondary amine (XIII) to acrylamide in tert-butyl alcohol in the presence of benzyltriethylammonium hydroxide. (a) substitution reaction with 3-(1-piperazinyl)propionamide (E) in boiling chloroform gives directly (XIV);
| 【1】 Rand, K.H.; Houck, H.; Coll Czech Chem Commun 1975, 40, 2887. |
| 【2】 Nagaoka, M.R.; et al.; Coll Czech Chem Commun 1968, 33, 1852. |
| 【3】 Coll Czech Chem Commun 1978, 43, 1276. |
| 【4】 Parola, M.; Robino, G.; Pastacaldi, S.; Gentilini, P.; Pinzani, M.; Marra, F.; Coll Czech Chem Commun 1986, 51, 2598. |
| 【5】 Yu, D.; Mortin, L.I.; Zhang, X.; Alder, J.; Li, T.; Coll Czech Chem Commun 1967, 32, 2021. |
| 【6】 Ghiro, L.; et al.; Z Physik Chem (Leipzig) 1931, 156 A, 3, 397. |
| 【7】 Pomykácek, J.; Diabac, A.; Protiva, M.; Valchár, M.; Jilek, J.; Cervena, I. (SPOFA - United Pharmaceutical Works); N-Substd.-2-chloro-7-fluoro-10-piperazino-10, 11-dihydrobenzo[b,f]thiepins and acid addition salts thereof. EP 0189310; JP 1986204181; US 4678788 . |
| 【8】 Protiva, M.; VUFB-15496. Drugs Fut 1987, 12, 7, 636. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (F) | 10851 | Acrylamide | 79-06-1 | C3H5NO | 详情 | 详情 |
| (D) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (A) | 28004 | 5-chloro-2-iodobenzoic acid | 13421-00-6 | C7H4ClIO2 | 详情 | 详情 |
| (B) | 28005 | 1-(2,5-dichlorophenyl)-1-ethanone | 2476-37-1 | C8H6Cl2O | 详情 | 详情 |
| (E) | 28016 | 3-(1-piperazinyl)propanamide | C7H15N3O | 详情 | 详情 | |
| (I) | 28003 | 3-fluorobenzenethiol | 2557-77-9 | C6H5FS | 详情 | 详情 |
| (II) | 28002 | 1-bromo-3-fluorobenzene; 3-Bromofluorobenzene | 1073-06-9 | C6H4BrF | 详情 | 详情 |
| (III) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (IV) | 28006 | 5-chloro-2-[(3-fluorophenyl)sulfanyl]benzoic acid | C13H8ClFO2S | 详情 | 详情 | |
| (V) | 28007 | 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]acetonitrile | C14H9ClFNS | 详情 | 详情 | |
| (VI) | 28008 | 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]acetic acid | C14H10ClFO2S | 详情 | 详情 | |
| (VII) | 28009 | 1-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-ethanone | C14H10ClFOS | 详情 | 详情 | |
| (VIII) | 28010 | 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-(4-morpholinyl)-1-ethanethione | C18H17ClFNOS2 | 详情 | 详情 | |
| (IX) | 28011 | 2-chloro-7-fluorodibenzo[b,f]thiepin-10(11H)-one | C14H8ClFOS | 详情 | 详情 | |
| (X) | 28012 | 2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-ol | C14H10ClFOS | 详情 | 详情 | |
| (XI) | 28013 | 2,10-dichloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine | C14H9Cl2FS | 详情 | 详情 | |
| (XII) | 28014 | ethyl 4-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinecarboxylate | C21H22ClFN2O2S | 详情 | 详情 | |
| (XIII) | 28015 | 1-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine | C18H18ClFN2S | 详情 | 详情 | |
| (C) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |