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【结 构 式】 
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【分子编号】37750 【品名】tetrahydro-2H-pyran-4-ol; 4-Hydroxytetrahydropyran 【CA登记号】2081-44-9 |
【 分 子 式 】C5H10O2 【 分 子 量 】102.1332 【元素组成】C 58.8% H 9.87% O 31.33% |
合成路线1
该中间体在本合成路线中的序号：(IV)Diethyl diazomalonate (III) was prepared by reaction of diethyl malonate (I) with p-tosyl azide (II) in the presence of Et3N. Subsequent coupling of (II) with 4-hydroxytetrahydropyran (IV) using dirhodium tetraacetate as the catalyst afforded ether (V). Alkylation of (V) with 3-(tert-butoxycarbonylamino)propyl bromide (VI) yielded adduct (VII). Finally, hydrolysis of ester groups of (VII) employing LiOH furnished the title dicarboxylic acid lithium salt.
| 【1】 Fiorentino, S.; Allegretti, M.; Mantovanini, M.; Clavenna, G.; Caselli, G.; Gandolfi, C.A. (Dompé Farmaceutici SpA); Geminal carboxylic acids and esters thereof pharmaceutical formulations containing them useful in the treatment of bone dysmetabolism. EP 0792878; US 5908863 . |
| 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) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (II) | 37748 | 4-methylbenzenesulfonyl azide | 941-55-9 | C7H7N3O2S | 详情 | 详情 |
| (III) | 37749 | diethyl 2-diazomalonate | C7H10N2O4 | 详情 | 详情 | |
| (IV) | 37750 | tetrahydro-2H-pyran-4-ol; 4-Hydroxytetrahydropyran | 2081-44-9 | C5H10O2 | 详情 | 详情 |
| (V) | 37751 | diethyl 2-(tetrahydro-2H-pyran-4-yloxy)malonate | C12H20O6 | 详情 | 详情 | |
| (VI) | 37752 | tert-butyl 3-bromopropylcarbamate | C8H16BrNO2 | 详情 | 详情 | |
| (VII) | 37753 | diethyl 2-[3-[(tert-butoxycarbonyl)amino]propyl]-2-(tetrahydro-2H-pyran-4-yloxy)malonate | C20H35NO8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Reaction of 2,4,6-trifluorobenzonitrile (VI) with ammonia in hot isopropanol gives 2-amino-4,6-difluorobenzonitrile (VII), which is treated with hot aqueous H2SO4 to afford 2-amino-4,6-difluorobenzamide (VIII). Cyclization of benzamide (VIII) with triethyl orthoformate by means of HCl at 140 °C affords 5,7-difluoroquinazolin-4(3H)-one (IX), which is condensed with 4-hydroxytetrahydropyran (X) by means of t-BuOK in refluxing THF to provide the 5-(tetrahydropyran4-yloxy)quinazoline derivative (XI). Condensation of compound (XI) with 1-(2-hydroxyethyl)-4-methylpiperazine (V) by means of t-BuOK in refluxing THF gives the disubstituted quinazolinone (XII), which is inally condensed with 6-chloro-2,3-methylenedioxyaniline (II) by means of POCl3 in refluxing acetonitrile (2). Scheme 2.
Alternatively, difluoroquinazolinone (IX) is treated with POCl3 and DIEA in hot acetonitrile to give 4-chloro-5,7-difluoroquinazoline (XIII), which is condensed with 5-chloro-1,3-benzodioxol-4-amine (II) by means of DIEA in hot acetonitrile to yield the 4-amino-substituted quinazoline (XIV). Reaction of compound (XIV) with 4-hydroxytetrahydropyran (X) by means of t-BuOK in refluxing THF affords the 5-(tetrahydropyranyloxy)quinazoline derivative (XV), which is finally condensed with 1-(2-hydroxyethyl)-4-methylpiperazine (V) by means of KOH in di(2-methoxyethyl)ether at 120 °C (2). Scheme 2.
| 【2】 Ford, J.G., McCabe, J.F., O’Kearney-McMullan, A. et al. (AstraZeneca AB; AstraZeneca plc). Process for the preparation of 4-(6-chloro-2, 3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl) ethoxy]-5-tetrahydropyran-4-yloxyquinazoline, their intermediates and crystalline salts thereof. EP 1871769, JP 2008524183, WO 2006064217. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 65838 | 5-chloro-1,3-benzodioxol-4-amine; 5-Chlorobenzo[1,3]dioxol-4-ylamine | 379228-45-2 | C7H6ClNO2 | 详情 | 详情 |
| (V) | 32589 | 2-(4-methyl-1-piperazinyl)-1-ethanol | 5464-12-0 | C7H16N2O | 详情 | 详情 |
| (V) | 32589 | 2-(4-methyl-1-piperazinyl)-1-ethanol | 5464-12-0 | C7H16N2O | 详情 | 详情 |
| (VI) | 65841 | 2,4,6-Trifluorobenzonitrile | 96606-37-0 | C7H2F3N | 详情 | 详情 |
| (VII) | 65842 | 2-Amino-4,6-Difluorobenzonitrile | 190011-84-8 | C7H4F2N2 | 详情 | 详情 |
| (VIII) | 65843 | 2-amino-4,6-difluorobenzamide | 893428-66-5 | C7H6F2N2O | 详情 | 详情 |
| (IX) | 65844 | 5,7-Difluoro-3,4-dihydroquinazolin-4-one | 379228-58-7 | C8H4F2N2O | 详情 | 详情 |
| (X) | 37750 | tetrahydro-2H-pyran-4-ol; 4-Hydroxytetrahydropyran | 2081-44-9 | C5H10O2 | 详情 | 详情 |
| (XI) | 65845 | C13H13FN2O3 | 详情 | 详情 | ||
| (XII) | 65846 | 7-[2-(4-Methyl-1-piperazinyl)ethoxy]-5-[(tetrahydro-2H-pyran-4-yl)oxy]-4(3H)-quinazolinone | 893428-67-6 | C20H28N4O4 | 详情 | 详情 |
| (XIII) | 65847 | 4-Chloro-5,7-Difluoroquinazoline | 791602-75-0 | C8H3ClF2N2 | 详情 | 详情 |
| (XIV) | 65848 | C15H8ClF2N3O2 | 详情 | 详情 | ||
| (XV) | 65849 | C20H16ClFN3O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)Esterification of 2-amino-4,6-dimethoxybenzoic acid (XVI) with diazomethane in ethanol gives the corresponding methyl ester (XVII), which is cyclized with formamidine (XVIII) in refluxing 2-methoxyethanol to yield 5,7-dimethoxyquinazolin-4(3H)-one (IXX). Selective demethylation of compound (IXX) by means of MgBr2 in refluxing pyridine affords 5-hydroxy-7-methoxyquinazolin-4(3H)-one (XX), which is condensed with pivaloyloxymethyl chloride (POM-Cl) and NaH in DMF to provide the protected quinazolinone (XXI). Condensation of compound (XXI) with 4-hydroxytetrahydropyran (X) by means of PPh3 in dichloromethane gives 7-methoxy-5-(tetrahydropyran-4-yloxy)quinazolin-4(3H)-one (XXII), which is demethylated by means of PhSH and K2CO3 in NMP at 195 °C to yield the 7-hydroxyquinazolinone derivative (XXIII). Acylation of compound (XXIII) with acetic anhydride affords the 7-acetoxy derivative (XXIV) , which is treated with POCl3 at 80 °C to provide 7-acetoxy-4-chloro-5-(tetrahydropyran-4-yloxy)quinazoline (XXV). Condensation of (XXV) with 4-amino-5-chloro-1,3-benzodioxole (II) in hot isopropanol gives adduct (XXVI), which is treated with ammonia in methanol to afford the 7-hydroxyquinazoline derivative (IV). Finally, this compound is condensed with 1-(2-chloroethyl)-4-methylpiperazine (XXVII) by means of K2CO3 in DMF (3, 4). Scheme 3.
| 【3】 Oldham, K., Moore, N.C. (AstraZeneca AB; AstraZeneca plc). Quinazoline derivatives for the treatment of T cell mediated diseases. EP 1450808, US 2005038050, US 7160891, WO 2003045395. |
| 【4】 Hennequin, L.F., Allen, J., Breed, J. et al. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem 2006, 49(22): 6465-88. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 65838 | 5-chloro-1,3-benzodioxol-4-amine; 5-Chlorobenzo[1,3]dioxol-4-ylamine | 379228-45-2 | C7H6ClNO2 | 详情 | 详情 |
| (IV) | 65840 | C20H18ClN3O5 | 详情 | 详情 | ||
| (X) | 37750 | tetrahydro-2H-pyran-4-ol; 4-Hydroxytetrahydropyran | 2081-44-9 | C5H10O2 | 详情 | 详情 |
| (XVI) | 65850 | 2-Amino-4,6-dimethoxybenzoic acid | 21577-57-1 | C9H11NO4 | 详情 | 详情 |
| (XVII) | 65851 | Methyl 2-amino-4,6-dimethoxybenzoate | 379228-26-9 | C10H13NO4 | 详情 | 详情 |
| (XVIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (XIX) | 65852 | 5,7-dimethoxy-3,4-dihydroquinazoline-4-one | C10H10N2O3 | 详情 | 详情 | |
| (XX) | 65853 | 5-Hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one; 5-Hydroxy-7-methoxy-3H-quinazolin-4-one | C9H8N2O3 | 详情 | 详情 | |
| (XXI) | 65854 | C15H18N2O5 | 详情 | 详情 | ||
| (XXII) | 65855 | C14H16N2O4 | 详情 | 详情 | ||
| (XXIII) | 65856 | C13H14N2O4 | 详情 | 详情 | ||
| (XXIV) | 65857 | C14H16N2O5 | 详情 | 详情 | ||
| (XXV) | 65858 | C14H15ClN2O4 | 详情 | 详情 | ||
| (XXVI) | 65859 | C21H20ClN3O6 | 详情 | 详情 | ||
| (XXVII) | 65860 | 1-(2-chloroethyl)-4-methylpiperazine | 5753-26-4 | C7H15ClN2 | 详情 | 详情 |