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【结 构 式】 
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【分子编号】31563 【品名】tetrahydro-4H-pyran-4-one 【CA登记号】29943-42-8 |
【 分 子 式 】C5H8O2 【 分 子 量 】100.11732 【元素组成】C 59.98% H 8.05% O 31.96% |
合成路线1
该中间体在本合成路线中的序号：(I)3-Nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridine (III) was prepared by heating tetrahydropyranone (I) with dinitropyridone (II) in methanolic ammonia following a reported procedure. Hydrogenation of the nitro derivative (III) and protection of the resulting amine (IV) with trichloroacetyl chloride afforded the trichloroacetamide (V). Oxidation of the pyridine ring of (V) with 3-chloroperoxybenzoic acid gave the N-oxide (VI). Nitration of the pyridine ring of (VI) with fuming nitric acid, followed by amide hydrolysis with ammonium hydroxide provided the 3-amino-4-nitropyridine N-oxide (VII). Reduction of the N-oxide and 4-nitro groups of (VII) was accomplished in a single step by hydrogenation in the presence of Raney-nickel to furnish the bicyclic diaminopyridine (VIII). Subsequent monoacylation of (VIII) with isoxazole-3-carbonyl chloride (IX) followed by thermal cyclization provided the desired imidazopyranopyridine compound (1,2), which was finally isolated as the title phosphate salt
| 【1】 Takada, S.; Sasatani, T.; Chomei, N.; Adachi, M.; Fujishita, T.; Eigyo, M.; Murata, S.; Kawasaki, K.; Matsushita, A.; Synthesis and structure-activity relationships of fused imidazopyridines: A new series of benzodiazepine receptor ligands. J Med Chem 1996, 39, 14, 2844. |
| 【2】 Takada, S.; Sasatani, T.; Chomei, N.; Adachi, M.; Matsushita, A. (Shionogi & Co. Ltd.); Condensed imidazopyridine derivs. with psychotropic activity. EP 0556008; JP 1993286973; US 5378848; US 5461062 . |
| 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) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |
| (II) | 59825 | 1-methyl-3,5-dinitro-2(1H)-pyridinone | C6H5N3O5 | 详情 | 详情 | |
| (III) | 59826 | 3-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridine | C8H8N2O3 | 详情 | 详情 | |
| (IV) | 59827 | 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-amine; 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-ylamine | C8H10N2O | 详情 | 详情 | |
| (V) | 59828 | 2,2,2-trichloro-N-(7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)acetamide | C10H9Cl3N2O2 | 详情 | 详情 | |
| (VI) | 59829 | 3-[(2,2,2-trichloroacetyl)amino]-7,8-dihydro-5H-pyrano[4,3-b]pyridin-1-ium-1-olate | C10H9Cl3N2O3 | 详情 | 详情 | |
| (VII) | 59830 | 3-amino-4-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-1-ium-1-olate | C8H9N3O4 | 详情 | 详情 | |
| (VIII) | 59831 | 3-amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-4-ylamine; 7,8-dihydro-5H-pyrano[4,3-b]pyridine-3,4-diamine | C8H11N3O | 详情 | 详情 | |
| (IX) | 59832 | 3-isoxazolecarbonyl chloride | C4H2ClNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Reductive condensation of p-nitrobenzylamine (X) with tetrahydropyran-4-one (XI) in the presence of sodium triacetoxyborohydride gave the tetrahydropyranylamine (XII), and further reductive condensation with formaldehyde afforded the tertiary amine (XIII). Reduction of the nitro group of (XIII) with iron in acetic acid yielded aniline (XIV), which was coupled with acid chloride (IX) to give amide (XV). Quaternization of (XV) with methyl iodide in DMF produced the ammonium iodide (XVI). This was finally converted to the title chloride salt employing an ion exchange resin.
| 【1】 Kitayoshi, T.; Aramaki, Y.; Oda, T.; Honda, S.; Shiraishi, M. (Takeda Chemical Industries, Ltd.); Anilide deriv., production and use thereof. JP 1999263764; WO 9932468 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 31561 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carbonyl chloride | C19H17ClO | 详情 | 详情 | |
| (X) | 31562 | (4-nitrophenyl)methanamine; 4-nitrobenzylamine | C7H8N2O2 | 详情 | 详情 | |
| (XI) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |
| (XII) | 31564 | N-(4-nitrobenzyl)-N-tetrahydro-2H-pyran-4-ylamine; N-(4-nitrobenzyl)tetrahydro-2H-pyran-4-amine | C12H16N2O3 | 详情 | 详情 | |
| (XIII) | 31565 | N-methyl-N-(4-nitrobenzyl)tetrahydro-2H-pyran-4-amine; N-methyl-N-(4-nitrobenzyl)-N-tetrahydro-2H-pyran-4-ylamine | C13H18N2O3 | 详情 | 详情 | |
| (XIV) | 31566 | N-(4-aminobenzyl)-N-methyltetrahydro-2H-pyran-4-amine; N-(4-aminobenzyl)-N-methyl-N-tetrahydro-2H-pyran-4-ylamine | C13H20N2O | 详情 | 详情 | |
| (XV) | 31567 | 2-(4-methylphenyl)-N-(4-[[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C32H36N2O2 | 详情 | 详情 | |
| (XVI) | 31568 | N,N-dimethyl-N-[4-([[2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cyclohepten-8-yl]carbonyl]amino)benzyl]tetrahydro-2H-pyran-4-aminium iodide | C33H39IN2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The reaction of the benzocycloheptanone (I) with dimethylcarbonate in the presence of NaOMe gave the beta-ketoester (II). The benzocycloheptene-8-carboxylic acid (III) was prepared by NaBH4 reduction of (II) in CH2Cl2/MeOH and subsequent dehydration by mesylation and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in THF and alkaline hydrolysis. On the other hand, the aniline (VII) was obtained by reductive aminations of 4-nitrobenzylamine (IV) successively with tetrahydropyran-4-one (V) and formalin in 1,2-dichloroethane using NaBH(OAc)3, followed by Fe reduction in AcOH or hydrogenation in EtOH of the resulting nitrobenzylamine (VI). The carboxylic acid (III) was reacted with oxalyl chloride in CH2Cl2/cat. DMF to afford the acid chloride, which was condensed with the aniline (VII) in THF/Et3N to give the anilide derivative (VIII). Compound (VIII) was treated with iodomethane in DMF to provide the quaternary ammonium iodide, which was converted to TAK-779 using ion exchange resin (Cl-).
| 【1】 Shiraishi, M.; Aramaki, Y.; Seto, M.; et al.; Discovery of small molecule CCR5 antagonists. 19th Symp Med Chem and 8th Annu Meet Div Med Chem Jpn (Nov 17-19, Tokyo) 1999, Abst 2P-06. |
| 【2】 Shiraishi, M.; Seto, M.; Aramaki, Y.; et al.; TAK-779, a small molecule CCR5 antagonist: Design, synthesis, and in vitro activity of anilide derivatives. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F911. |
| 【3】 Aramaki, Y.; Seto, M.; Shiraishi, M.; et al.; Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety. J Med Chem 2000, 43, 10, 2049. |
| 【4】 Kanzaki, N.; Shiraishi, M.; Fujino, M.; Nishimura, O.; Baba, M.; Lizawa, Y.; TAK-779. Drugs Fut 2000, 25, 3, 252. |
| 【5】 Kitayoshi, T.; Aramaki, Y.; Oda, T.; Honda, S.; Shiraishi, M. (Takeda Chemical Industries, Ltd.); Anilide deriv., production and use thereof. JP 1999263764; WO 9932468 . |
| 【6】 Kuroshima, K.; Kanzaki, N.; Nishimura, O.; Shiraishi, M.; Sawada, H.; Baba, M.; Aramaki, Y. (Takeda Chemical Industries, Ltd.); Pharmaceutical composition for antagonizing CCR5 comprising anilide derivative. JP 2000128782; JP 2000128842; US 6096780; WO 9932100 . |
| 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) | 31555 | 3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H18O | 详情 | 详情 | |
| (II) | 33422 | methyl 3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C20H20O3 | 详情 | 详情 | |
| (III) | 31560 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxylic acid | C19H18O2 | 详情 | 详情 | |
| (IV) | 31562 | (4-nitrophenyl)methanamine; 4-nitrobenzylamine | C7H8N2O2 | 详情 | 详情 | |
| (V) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |
| (VI) | 31566 | N-(4-aminobenzyl)-N-methyltetrahydro-2H-pyran-4-amine; N-(4-aminobenzyl)-N-methyl-N-tetrahydro-2H-pyran-4-ylamine | C13H20N2O | 详情 | 详情 | |
| (VII) | 31566 | N-(4-aminobenzyl)-N-methyltetrahydro-2H-pyran-4-amine; N-(4-aminobenzyl)-N-methyl-N-tetrahydro-2H-pyran-4-ylamine | C13H20N2O | 详情 | 详情 | |
| (VIII) | 31567 | 2-(4-methylphenyl)-N-(4-[[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C32H36N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)A new large-scaleable synthesis of TAK-779 has been developed: The reduction of 4'-methylbiphenyl-4-carbonitrile (I) with sodium bis(2-methoxyethoxy)aluminum hydride (SBMEA) in THF gives the corresponding aldehyde (II), which is submitted to a Wittig condensation with the phosphonium bromide (III) by means of NaOMe in methanol to yield the pentenoic acid derivative (IV). Reduction of the double bond of (IV) with H2 over Pd/C in THF, followed by cyclization with hot PPA affords the benzocycloheptanone (V), which is treated with refluxing dimethyl carbonate and NaOMe to provide the beta-ketoester (VI). The reduction of (VI) with NaBH4 in THF gives the hydroxyester (VII), which is dehydrated with Ms-Cl and DBU and hydrolyzed with NaOH to yield 8-(4-methylphenyl)benzocyclohept-1-ene-2-carboxylic acid (VIII). Condensation of (VIII) with 4-aminobenzyl alcohol (IX) by means of (COCl)2 and TEA in THF affords the corresponding amide (X), which is treated with SOCl2 in THF to provide the chloromethyl derivative (XI). Finally, this compound is condensed with 4-(dimethylamino)tetrahydropyran (XII) in hot DMF to furnish the target ammonium salt. The tertiary amine (XII) has been obtained by reductive condensation of tetrahydropyran-4-one (XIII) with dimethylamine by means of H2 over Pd/C in THF.
| 【1】 Ikemoto, T.; Hashimoto, H.; Kaarasaki, T.; Tomimatsu, K.; Ito, T.; Nishiguchi, A.; Wakimasu, M.; Mitsudera, H.; Development of a new synthetic route of a non-peptide CCR5 antagonist, TAK-779, for large-scale preparation. Org Process Res Dev 2000, 4, 6, 520. |
| 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) | 45764 | 4'-methyl[1,1'-biphenyl]-4-carbonitrile | C14H11N | 详情 | 详情 | |
| (II) | 18985 | 4'-methyl[1,1'-biphenyl]-4-carbaldehyde | C14H12O | 详情 | 详情 | |
| (III) | 37404 | (3-carboxypropyl)(triphenyl)phosphonium bromide | 17857-14-6 | C22H22BrO2P | 详情 | 详情 |
| (IV) | 45765 | (Z)-5-(4'-methyl[1,1'-biphenyl]-4-yl)-4-pentenoic acid | C18H18O2 | 详情 | 详情 | |
| (V) | 31555 | 3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H18O | 详情 | 详情 | |
| (VI) | 33422 | methyl 3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C20H20O3 | 详情 | 详情 | |
| (VII) | 45766 | methyl 5-hydroxy-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C20H22O3 | 详情 | 详情 | |
| (VIII) | 31560 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxylic acid | C19H18O2 | 详情 | 详情 | |
| (IX) | 34430 | (4-aminophenyl)methanol | 623-04-1 | C7H9NO | 详情 | 详情 |
| (X) | 33424 | N-[4-(hydroxymethyl)phenyl]-2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C26H25NO2 | 详情 | 详情 | |
| (XI) | 33425 | N-[4-(chloromethyl)phenyl]-2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C26H24ClNO | 详情 | 详情 | |
| (XII) | 33426 | N,N-dimethyltetrahydro-2H-pyran-4-amine; N,N-dimethyl-N-tetrahydro-2H-pyran-4-ylamine | C7H15NO | 详情 | 详情 | |
| (XIII) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The reductocondensation of tetrahydropyran-4-one (I) with methylamine (II) by means of H2 over Pd/C in methanol gives 4-(methylamino)tetrahydropyran (III), which is then alkylated with 4-nitrobenzyl bromide (IV) and K2CO3 in DMF to yield the tertiary amine (V). Finally, the nitro group of (V) is educed with SnCl2 and conc. aq. HCl to afford N-(4-aminobenzyl)-N-methyl-N-(tetrahydropyran-4-yl)amine, the target intermediate (VI).
| 【1】 Hashimoto, H.; et al.; Process development of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline dihydrochloride: A key intermediate for TAK-779, a small-molecule nonpeptide CCR5 antagonist. Org Process Res Dev 2002, 6, 1, 70. |
| 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) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |
| (II) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (III) | 55002 | N-methyl-N-tetrahydro-2H-pyran-4-ylamine; N-methyltetrahydro-2H-pyran-4-amine | C6H13NO | 详情 | 详情 | |
| (IV) | 16866 | 1-(Bromomethyl)-4-nitrobenzene; para-Nitrobenzyl bromide | 100-11-8 | C7H6BrNO2 | 详情 | 详情 |
| (V) | 31565 | N-methyl-N-(4-nitrobenzyl)tetrahydro-2H-pyran-4-amine; N-methyl-N-(4-nitrobenzyl)-N-tetrahydro-2H-pyran-4-ylamine | C13H18N2O3 | 详情 | 详情 | |
| (VI) | 31566 | N-(4-aminobenzyl)-N-methyltetrahydro-2H-pyran-4-amine; N-(4-aminobenzyl)-N-methyl-N-tetrahydro-2H-pyran-4-ylamine | C13H20N2O | 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 ketone (I) with sulfone (II) by means of BuLi yields derivative (III), which is then treated with POCl3 and pyridine to afford compound (IV). Reaction of (IV) with aqueous hydroxylamine (NH2OH) in THF provides derivative (V), which is finally treated with (VI) in THF to furnish the desired compound.
| 【1】 Davidsen, S.K.; Michalides, M.; Stacey, J.R.; et al.; Development of a series of sulfone retrohydroxamates for the inhibition of matrix metalloproteinases. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 54. |
| 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) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |
| (II) | 46241 | methyl(dioxo)[4-[4-(trifluoromethoxy)phenoxy]phenyl]-lambda(6)-sulfane; methyl 4-[4-(trifluoromethoxy)phenoxy]phenyl sulfone | C14H11F3O4S | 详情 | 详情 | |
| (III) | 46242 | 1-[([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)methyl]cyclohexanol | C20H21F3O5S | 详情 | 详情 | |
| (IV) | 46243 | 4-[([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)methylene]tetrahydro-2H-pyran; tetrahydro-4H-pyran-4-ylidenemethyl 4-[4-(trifluoromethoxy)phenoxy]phenyl sulfone | C19H17F3O5S | 详情 | 详情 | |
| (V) | 46244 | 4-(hydroxyamino)-4-[([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)methyl]tetrahydro-2H-pyran; N-[4-[([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)methyl]tetrahydro-2H-pyran-4-yl]hydroxylamine | C19H20F3NO6S | 详情 | 详情 | |
| (VI) | 46245 | 2,2,2-trifluoroethyl formate | C3H3F3O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XII)The reaction of 2,6-dichloro-4-methoxybenzyl chloride (I) with tetraethylammonium cyanide in refluxing dichloromethane gives 2-(2,6-dichloro-4-methoxyphenyl)acetonitrile (II), which is condensed with ethyl acetate (III) by means of sodium ethoxide in refluxing ethanol to yield the 3-oxobutyronitrile (IV). The cyclization of (IV) with hydrazine (V) by means of HOAc in refluxing benzene affords the aminopyrazole (VI), which is further cyclized with ethyl acetoacetate (VII) in refluxing acetic acid to provide 3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol (VIII). The reaction of (VIII) with refluxing POCl3 furnishes the corresponding chloro derivative (IX), which is allowed to react with ethylenediamine (X) in hot acetonitrile to give 7-(2-aminoethylamino)-3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (XI). Finally, this compound is reductocondensed with tetrahydropyran-4-one (XII) by means of sodium cyanoborohydride in methanol/HOAc to yield the target CP-671906-01.
| 【1】 Giangiordano, M.; Tran, J.; Darrow, J.W.; De Lombaert, S.; Blum, C.; Griffith, D.A.; Carpino, P.A. (Neurogen Corp.; Pfizer Inc.); Certain alkylene diamine-substd. pyrazolo[1,5-a]-1,5-pyrimidines and pyrazolo[1,5-a]-1,3,5-triazines. US 6372743; WO 0123387 . |
| 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) | 52615 | 3,5-dichloro-4-(chloromethyl)phenyl methyl ether; 1,3-dichloro-2-(chloromethyl)-5-(methyloxy)benzene | C8H7Cl3O | 详情 | 详情 | |
| (II) | 52616 | 2-[2,6-dichloro-4-(methyloxy)phenyl]acetonitrile | C9H7Cl2NO | 详情 | 详情 | |
| (III) | 17491 | ethyl acetate | 141-78-6 | C4H8O2 | 详情 | 详情 |
| (IV) | 52621 | 2-[2,6-dichloro-4-(methyloxy)phenyl]-3-oxobutanenitrile | C11H9Cl2NO2 | 详情 | 详情 | |
| (V) | 27344 | hydrazine | 302-01-2 | H4N2 | 详情 | 详情 |
| (VI) | 52617 | 4-[2,6-dichloro-4-(methyloxy)phenyl]-3-methyl-1H-pyrazol-5-amine; 4-[2,6-dichloro-4-(methyloxy)phenyl]-3-methyl-1H-pyrazol-5-ylamine | C11H11Cl2N3O | 详情 | 详情 | |
| (VII) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (VIII) | 52618 | 3-[2,6-dichloro-4-(methyloxy)phenyl]-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol | C15H13Cl2N3O2 | 详情 | 详情 | |
| (IX) | 52619 | 7-chloro-3-[2,6-dichloro-4-(methyloxy)phenyl]-2,5-dimethylpyrazolo[1,5-a]pyrimidine; 3,5-dichloro-4-(7-chloro-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)phenyl methyl ether | C15H12Cl3N3O | 详情 | 详情 | |
| (X) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (XI) | 52620 | N~1~-{3-[2,6-dichloro-4-(methyloxy)phenyl]-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl}-1,2-ethanediamine | C17H19Cl2N5O | 详情 | 详情 | |
| (XII) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IX)Displacement of 3,5-difluorobromobenzene (VII) with the sodium alkoxide of benzyl alcohol yields the benzyl ether (VIII). Metalation of (VIII) with butyllithium, followed by addition to tetrahydropyran-4-one (IX) furnishes the carbinol adduct (X). This is converted to the methyl ether (XI) by alkylation with iodomethane in the presence of NaH. Then, hydrogenolysis of the O-benzyl group of (XI) over Pd(OH)2 provides phenol (XII). Finally, condensation between phenol (XII) and mesylate (VI) gives rise to the title compound
| 【1】 Barbey, S.; et al.; Synthesis and activity of a new methoxytetrahydropyran derivative as dual cyclooxygenase-2/5-lipoxygenase inhibitor. Bioorg Med Chem Lett 2002, 12, 5, 779. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 60606 | {1-[4-(methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl}methyl methanesulfonate | C18H18N2O5S2 | 详情 | 详情 | |
| (VII) | 30794 | 1-bromo-3,5-difluorobenzene | 461-96-1 | C6H3BrF2 | 详情 | 详情 |
| (VIII) | 60607 | 1-(benzyloxy)-3-bromo-5-fluorobenzene; benzyl 3-bromo-5-fluorophenyl ether | C13H10BrFO | 详情 | 详情 | |
| (IX) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |
| (X) | 60608 | 4-[3-(benzyloxy)-5-fluorophenyl]tetrahydro-2H-pyran-4-ol | C18H19FO3 | 详情 | 详情 | |
| (XI) | 60609 | 4-[3-(benzyloxy)-5-fluorophenyl]-4-methoxytetrahydro-2H-pyran; benzyl 3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl ether | C19H21FO3 | 详情 | 详情 | |
| (XII) | 60610 | 3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenol | C12H15FO3 | 详情 | 详情 |