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【结 构 式】 
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【分子编号】13163 【品名】p-Dihydrobenzene; Hydroquinone 【CA登记号】123-31-9 |
【 分 子 式 】C6H6O2 【 分 子 量 】110.11244 【元素组成】C 65.45% H 5.49% O 29.06% |
合成路线1
该中间体在本合成路线中的序号：(I)The etherification of hydroquinone (I) with 2,2,2-trifluoroethyl trifluoromethanesulfonate (II) by means of K2CO3 in refluxing acetone gives the corresponding diether (III), which is submitted to a Friedel-Crafts condensation with Ac-Cl or Ac2O and AlCl3 in dichloromethane yielding the acetophenone (IV). The chlorination of (IV) with Cl2 in acetic acid at 55 C gives the alpha, alpha-dichloroacetophenone (V), which is further chlorinated with Cl2 and NaOAc in acetic acid at 100 C affording the corresponding trichloro derivative (VI). The reaction of (VI) with 2-(aminomethyl)pyridine (VII) in cyclohexane/toluene or isopropanol furnishes the benzamide (VIII), which is finally hydrogenated with H2 over Pt/C in isopropanol/acetic acid to give the target piperidine derivative.
| 【1】 Leir, C.M. (3M Pharmaceuticals); Process for the preparation of derivs. of pyrrolidine and piperidine. US 4642384 . |
| 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) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (II) | 40675 | 2,2,2-trifluoroethyl trifluoromethanesulfonate | 6226-25-1 | C3H2F6O3S | 详情 | 详情 |
| (III) | 40737 | 1,4-bis(2,2,2-trifluoroethoxy)benzene; 4-(2,2,2-trifluoroethoxy)phenyl 2,2,2-trifluoroethyl ether | 66300-61-6 | C10H8F6O2 | 详情 | 详情 |
| (IV) | 40738 | 1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-1-ethanone | 76784-40-2 | C12H10F6O3 | 详情 | 详情 |
| (V) | 40739 | 1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-2,2-dichloro-1-ethanone | C12H8Cl2F6O3 | 详情 | 详情 | |
| (VI) | 40740 | 1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-2,2,2-trichloro-1-ethanone | 76784-42-4 | C12H7Cl3F6O3 | 详情 | 详情 |
| (VII) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
| (VIII) | 33970 | N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide | C17H14F6N2O3 | 详情 | 详情 | |
| (IX) | 18983 | 1,4-dibromobenzene | 106-37-6 | C6H4Br2 | 详情 | 详情 |
| (X) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)A synthesis of RG-12525 has been published: The reaction of 2-methylquinoline (I) with chlorine gas gives 2-(chloromethyl)quinoline (II), which is condensed with an excess of hydroquinone (III) yielding 4-(quinolin-2-ylmethoxy)phenol (IV). The reaction of (IV) with an excess of alpha,alpha'-dichloro-o-xylene (V) affords the monoaddition compound (VI), which is treated with sodium cyanide giving the phenylacetonitrile derivative (VII). Finally, this compound is submitted to cyclization with sodium azide.
| 【1】 Bridge, A.W.; et al.; The process development of RG 12525 (2-'{[4-(tetrazol-5-ylmethylphenyl)-methoxy]phenoxymethyl}quinoline). Org Process Res Dev 2001, 5, 1, 9. |
| 【2】 O'Brien, M.; Sledeski, A.W.; Truesdale, L.K.; Approaches to p-hydroxyphenoxymethylquinolines which avoid intermediate chloromethylquinolines for the synthesis of the LTD4 antagonist, RG 12525. Tetrahedron Lett 1997, 38, 4, 509. |
| 【3】 Huang, F.-C.; Galemmo Jr., R.A.; Campbell, H.F. (Aventis Pharma SA); Quinoline derivs. as antagonists of leukotriene D4, compsns. containing the same and processes for their preparation. EP 0348155; EP 0784052; US 4920131 . |
| 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) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (II) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (III) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (IV) | 13164 | 4-(2-Quinolinylmethoxy)phenol | C16H13NO2 | 详情 | 详情 | |
| (V) | 13165 | 1,2-Bis(chloromethyl)benzene | 612-12-4 | C8H8Cl2 | 详情 | 详情 |
| (VI) | 13166 | 2-(Chloromethyl)benzyl 4-(2-quinolinylmethoxy)phenyl ether; 2-[(4-[[2-(Chloromethyl)benzyl]oxy]phenoxy)methyl]quinoline | C24H20ClNO2 | 详情 | 详情 | |
| (VII) | 13167 | 2-(2-[[4-(2-Quinolinylmethoxy)phenoxy]methyl]phenyl)acetonitrile | C25H20N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Synthesis of intermediate 4-(2-quinolinylmethoxy)phenol (V): The oxidation of 2-methylquinoline with urea and H2O2 in dichloromethane gives the N-oxide (II), which is treated with TsCl and K2CO3 in acetonitrile to yield the tosylate (III). Finally this compound is condensed with an excess of hydroquinone by means of NaOH in methanol/acetonitrile to afford the target intermediate (V).
| 【1】 Sledeski, A.W.; et al.; A convergent synthesis of an LTD4 antagonist, RG12525. Tetrahedron Lett 1997, 38, 7, 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) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (II) | 43890 | 2-methyl-1-quinoliniumolate | C10H9NO | 详情 | 详情 | |
| (III) | 43891 | 2-quinolinylmethyl 4-methylbenzenesulfonate | C17H15NO3S | 详情 | 详情 | |
| (IV) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (V) | 13164 | 4-(2-Quinolinylmethoxy)phenol | C16H13NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)This compound has been obtained by two different methods: The reduction of 1,4-diamino-5,8-dihydroxyanthraquinone (I) or 1,5-diamino-4,8-dihydroxyanthraquinone (II) with Na2S2O4 and NaOH in water gives the leuco derivative (III), which is condensed with N,N-dimethylethylene-1,2-diamine (IV) in refluxing ethanol and reoxidized by air to yield 1,4-bis[2-(dimethylamino)ethylamino]-5,8-dihydroxyanthraquinone (V). Finally, this compound is treated with MCPBA in dichloromethane to afford the target bis-N-oxide. Alternatively, the reduction of tetrachlorophthalic anhydride (VI) with Zn and NaOH in water at 50-60 C gives 3,4,6-trichlorophthalic anhydride (VII), which is further reduced with Zn and NaOH in refluxing water to yield 3,6-dichlorophthalic anhydride (VIII). The reaction of (VIII) with KF and NaF at 260-27 ?C affords 3,6-difluorophthalic anhydride (IX), which is cyclized with hydroquinone (X) by means of AlCl3 and NaCl at 200 +/- 5 C to provide 1,4-difluoro-5,8-dihydroxyanthraquinone (XI). Finally, this compound is condensed with N,N-dimethylethylene-1,2-diamine (IV) in pyridine to afford the already reported 1,4-bis[2-(dimethylamino)ethylamino]-5,8-dihydroxyanthraquinone (V), which is oxidized with MCPBA as before.
| 【1】 Chang, P.; Chang, C.C.; An improved practical synthesis of leuco-1,4,5,8-tetrahydroxyanthraquinone. Synth. Commun. 1995, 25, 3, 1893. |
| 【2】 Denny, W.A.; Lee, H.H.; A large-scale synthesis of the bioreductive drug 1,4-bis[[2-(dimethylamino)ethyl]amino]-5,8-dihydroxyanthracene-9,10-dione bis-N-oxide (AQ4N). J Chem Soc - Perkins Trans I 1999, 19, 2755. |
| 【3】 Patterson, L.H. (National Research Development Corp.); Anti-cancer cpds.. US 5132327; WO 9105824 . |
| 【4】 Denny, W.A.; Lee, H.H. (BTG International Ltd.); Process for the preparation of 1,4-bis[[2-(dimethylamino)ethyl]amino]-5,8-dihydroxyanthracene-9,10-dione. WO 0005194 . |
| 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) | 55217 | 1,4-diamino-5,8-dihydroxyanthra-9,10-quinone | C14H10N2O4 | 详情 | 详情 | |
| (II) | 55218 | 1,5-diamino-4,8-dihydroxyanthra-9,10-quinone | C14H10N2O4 | 详情 | 详情 | |
| (III) | 55219 | 1,4,5,8-tetrahydroxy-2,3-dihydro-9,10-anthracenedione | C14H10O6 | 详情 | 详情 | |
| (IV) | 14881 | N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine | 108-00-9 | C4H12N2 | 详情 | 详情 |
| (V) | 55220 | 1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthra-9,10-quinone | C22H28N4O4 | 详情 | 详情 | |
| (VI) | 51351 | Tetrachlorophthalic anhydride; 4,5,6,7-Tetrachloro-1,3-isobenzofurandione | 117-08-8 | C8Cl4O3 | 详情 | 详情 |
| (VII) | 55221 | 4,5,7-trichloro-2-benzofuran-1,3-dione | C8HCl3O3 | 详情 | 详情 | |
| (VIII) | 55222 | 3,6-Dichlorophthalic anhydride | C8H2Cl2O3 | 详情 | 详情 | |
| (IX) | 55223 | 3,6-Difluorophthalic anhydride | C8H2F2O3 | 详情 | 详情 | |
| (X) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (XI) | 55224 | 1,4-difluoro-5,8-dihydroxyanthra-9,10-quinone | C14H6F2O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(A)Diels-Alder reaction between (E,E)-1,4-diphenylbutadiene (I) and propiolic acid (II) in xylene in the presence of hydroxyquinone (A) yields cyclohexadiene carboxylic acid (III), which is then converted into its methyl ester derivative (IV) by treatment with MeOH in the presence of H2SO4. Condensation of methyl ester (IV) with N-trimethylsilylmethyl-N-butoxymethyl-benzylamine (V) in CH2Cl2 in the presence of TFA provides hexahydro isoindole derivative (VI), which is first treated with trifluoromethane sulfonic acid in CH2Cl2, followed by treatment with NaOH, to furnish benzo[f]isoindole derivative (VII). Debenzylation of (VII) by reaction with ammonium formate and Pd/C gives compound (VIII), which is then converted into derivative (X) by coupling with 2-(2-methoxyphenyl)acrylic acid (IX). The target product is finally obtained by hydrolysis of methyl ester (X) with NaOH in EtOH. Intermediate (IX) can be obtained as follows: Treatment of 2-methoxyphenylacetic acid (XI) with thionyl chloride in refluxing EtOH provides ethyl ester (XII), which then reacts with paraformaldehyde and tetrabutylammonium iodide (TBAI) and K2CO3 in refluxing toluene to afford acrylate (XIII). Finally, ethyl ester (XIII) is hydrolyzed by treatment with refluxing NaOH.
| 【1】 Truchon, A.; Sounigo, F.; Peyronel, J.-F.; Zucco, M.; Mailliet, P.; Commercon, A.; Lebrun, A. (Aventis Pharma SA); 4,9-Ethano-benzo(f)isoindole derivs. as farnesyl transferase inhibitors. WO 9703050 . |
| 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) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (I) | 46199 | 1-[(1E,3E)-4-phenyl-1,3-butadienyl]benzene | C16H14 | 详情 | 详情 | |
| (II) | 41770 | propiolic acid | 471-25-0 | C3H2O2 | 详情 | 详情 |
| (III) | 46200 | 3,6-diphenyl-1,4-cyclohexadiene-1-carboxylic acid | C19H16O2 | 详情 | 详情 | |
| (IV) | 46201 | methyl 3,6-diphenyl-1,4-cyclohexadiene-1-carboxylate | C20H18O2 | 详情 | 详情 | |
| (V) | 19702 | N-benzyl-N-(butoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-(butoxymethyl)(phenyl)-N-[(trimethylsilyl)methyl]methanamine | C16H29NOSi | 详情 | 详情 | |
| (VI) | 46202 | methyl (7aS)-2-benzyl-4,7-diphenyloctahydro-3aH-isoindole-3a-carboxylate | C29H31NO2 | 详情 | 详情 | |
| (VII) | 46203 | methyl (1R,8R,9S,13S)-11-benzyl-1-phenyl-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate | C29H29NO2 | 详情 | 详情 | |
| (VIII) | 46204 | methyl (1R,8R,9S,13S)-1-phenyl-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate | C22H23NO2 | 详情 | 详情 | |
| (IX) | 37790 | 2-(2-methoxyphenyl)acrylic acid | C10H10O3 | 详情 | 详情 | |
| (X) | 46205 | methyl (1R,8R,9S,13S)-11-[2-(2-methoxyphenyl)acryloyl]-1-phenyl-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate | C32H31NO4 | 详情 | 详情 | |
| (XI) | 19706 | 2-(2-methoxyphenyl)acetic acid | 93-25-4 | C9H10O3 | 详情 | 详情 |
| (XII) | 46206 | ethyl 2-(2-methoxyphenyl)acetate | C11H14O3 | 详情 | 详情 | |
| (XIII) | 46207 | ethyl 2-(2-methoxyphenyl)acrylate | C12H14O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Alkylation of hydroquinone (I) with 1-bromo-2-chloroethane and K2CO3 in acetone gave the bis(2-chloroethyl)ether (II), which was then brominated in the presence of Fe in CCl4 to provide dibromocompound (III). Lithiation, followed by intramolecular cyclization, upon treatment with two equivalents of n-BuLi in THF at 0 C furnished the tetrahydrobenzodifuran (IV). Subsequent formylation with dichloromethyl methyl ether in the presence of SnCl4 yielded aldehyde (V). This was condensed with nitroethane in the presence of ammonium acetate, and the resulting nitropropene compound (VI) was reduced with LiAlH4 to afford the aminopropane (VII). Protection of (VII) with trifluoroacetic anhydride and Et3N gave trifluoroacetamide (VIII), and then bromination in AcOH afforded bromide (IX). The aromatic benzodifuran (X) was obtained by dihydrogenation with dichlorodicyanobenzoquinone (DDQ) in toluene, and finally, the amide was deprotected by hydrolysis with NaOH to afford the target amine, which was isolated as the hydrochloride salt.
| 【1】 Parker, M.A.; Marona-Lewicka, D.,; Lucaites, V.L.; Nelson, D.L.; Nichols, D.E.; A novel (benzodifuranyl)aminoalkane with extremely potent activity at the 5-HT2A receptor. J Med Chem 1998, 41, 26, 5148. |
| 【2】 Monte, A. P.; el al.; Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups. J Med Chem 1996, 39, 15, 2953-2961. |
| 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) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (II) | 21438 | 1,4-bis(2-chloroethoxy)benzene; 4-(2-chloroethoxy)phenyl 2-chloroethyl ether | 37142-37-3 | C10H12Cl2O2 | 详情 | 详情 |
| (III) | 21439 | 2-chloroethyl 2,5-dibromo-4-(2-chloroethoxy)phenyl ether; 1,4-dibromo-2,5-bis(2-chloroethoxy)benzene | C10H10Br2Cl2O2 | 详情 | 详情 | |
| (IV) | 21440 | 2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran | C10H10O2 | 详情 | 详情 | |
| (V) | 21441 | 2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-4-carbaldehyde | C11H10O3 | 详情 | 详情 | |
| (VI) | 21442 | 4-[(E)-2-nitro-1-propenyl]-2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran | C13H13NO4 | 详情 | 详情 | |
| (VII) | 21443 | 1-methyl-2-(2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-4-yl)ethylamine; 1-(2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-4-yl)-2-propanamine | C13H17NO2 | 详情 | 详情 | |
| (VIII) | 21444 | 2,2,2-trifluoro-N-[1-methyl-2-(2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-4-yl)ethyl]acetamide | C15H16F3NO3 | 详情 | 详情 | |
| (IX) | 21445 | N-[2-(8-bromo-2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-4-yl)-1-methylethyl]-2,2,2-trifluoroacetamide | C15H15BrF3NO3 | 详情 | 详情 | |
| (X) | 21446 | N-[2-(8-bromofuro[2,3-f][1]benzofuran-4-yl)-1-methylethyl]-2,2,2-trifluoroacetamide | C15H11BrF3NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Hydroquinone (I) is converted to 1,2,4-triacetoxybenzene (II), which is condensed with malic acid (A) to afford 6,7-dihydroxycoumarin (aesculetin) (III). This is methylated with dimethyl sulfate in acetone to give Scoparone.
| 【1】 Arya, V.P.; Scoparone. Drugs Fut 1978, 3, 7, 550. |
| 【2】 Singh, G.B.; et al.; J Sci Ind Res 1956, 15, 19, Suppl. 2, 190-193. |
| 【3】 King, F.E.; et al.; J Chem Soc 1954, 106, 19, Suppl. 2, 1392-99. |
| 【4】 Thakur, R.S.; et al.; Res and Ind 1975, 3, 19, Suppl. 2, 129-131. |
| 【5】 DuH, S.B.; Parihar, D.B.; Proc Ind Acad Sci 1947, 106, 19, Suppl. 2, 153. |
| 【6】 Stefanovic, M.; et al.; Phytochem 1973, 12, 19, Suppl. 2, 2996. |
| 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) | 22743 | Hydroxysuccinic acid; Malic acid; Hydroxybutanedioic acid | 617-48-1 | C4H6O5 | 详情 | 详情 |
| (I) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (II) | 39904 | 1,2,4-Triacetoxybenzene; 2,4-bis(acetoxy)phenyl acetate | 613-03-6 | C12H12O6 | 详情 | 详情 |
| (III) | 39905 | 6,7-dihydroxy-2H-chromen-2-one | 305-01-1 | C9H6O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Monoalkylation of hydroquinone (I) with decyl bromide (II) under basic conditions provided 4-(decyloxy)phenol (III), which was further condensed with epichlorohydrin (IV) in the presence of Cs2CO3 to yield the glycidyl ether (V). Ring opening of epoxide (V) with allyl 4-hydroxybenzoate (VI) furnished adduct (VII). Then, oxidation of the secondary alcohol (VII) using the Dess-Martin reagent afforded the keto ester (VIII), which upon deprotection with palladium tetrakis(triphenylphosphine) gave the target carboxylic acid.
| 【1】 Connolly, S.; Botterll, S.; Bennion, C.; et al.; Design and synthesis of a novel and potent series of inhibitors of cytosolic phospholipase A2 based on a 1,3-disubstituted propan-2-one skeleton. J Med Chem 2002, 45, 6, 1348. |
| 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) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (II) | 58570 | 1-Bromodecane; 1-Decyl bromide; Decyl bromide; n-decyl bromide | 112-29-8 | C10H21Br | 详情 | 详情 |
| (III) | 58571 | 4-Decyloxyphenol | C16H26O2 | 详情 | 详情 | |
| (IV) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (V) | 58572 | 2-{[4-(decyloxy)phenoxy]methyl}oxirane; decyl 4-(2-oxiranylmethoxy)phenyl ether | C19H30O3 | 详情 | 详情 | |
| (VI) | 21022 | allyl 4-hydroxybenzoate | C10H10O3 | 详情 | 详情 | |
| (VII) | 58573 | allyl 4-{3-[4-(decyloxy)phenoxy]-2-hydroxypropoxy}benzoate | C29H40O6 | 详情 | 详情 | |
| (VIII) | 58574 | allyl 4-{3-[4-(decyloxy)phenoxy]-2-oxopropoxy}benzoate | C29H38O6 | 详情 | 详情 |