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【结 构 式】

【分子编号】32589

【品名】2-(4-methyl-1-piperazinyl)-1-ethanol

【CA登记号】5464-12-0

【 分 子 式 】C7H16N2O

【 分 子 量 】144.21692

【元素组成】C 58.3% H 11.18% N 19.42% O 11.09%
与该中间体有关的原料药合成路线共 4 条
合成路线1合成路线2合成路线3合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

Mitsunobu coupling of 2-(4-methylpiperazin-1-yl)ethanol (I) with 3,5-dichloro-2,4-dihydroxybenzoic acid (II) in the presence of diisopropyl azodicarboxylate and triphenylphosphine afforded ether (III). Subsequent hydrolysis of the methyl ester group of (III) provided acid (IV), which was coupled with L-phenylalanine methyl ester-HCl (V) employing EDC and HOBt. The title compound was finally isolated as the corresponding dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Haruta, J.; Sakuma, K.; Watanabe, Y. (Japan Tobacco Inc.); Amide compounds and use of the same. EP 0849256 .
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) 32589 2-(4-methyl-1-piperazinyl)-1-ethanol 5464-12-0 C7H16N2O 详情 详情
(II) 32590 methyl 3,5-dichloro-2,4-dihydroxybenzoate C8H6Cl2O4 详情 详情
(III) 32591 methyl 3,5-dichloro-2-hydroxy-4-[2-(4-methyl-1-piperazinyl)ethoxy]benzoate C15H20Cl2N2O4 详情 详情
(IV) 32592 3,5-dichloro-2-hydroxy-4-[2-(4-methyl-1-piperazinyl)ethoxy]benzoic acid C14H18Cl2N2O4 详情 详情
(V) 32593 ethyl (2S)-2-amino-3-phenylpropanoate C11H15NO2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(V)

Condensation of 7-benzyloxy-4-chloro-5-(tetrahydropyran-4-yloxy)quinazole (I) with 5-chloro-1,3-benzodioxol-4-amine (II) by means of HCl in isopropanol gives the secondary amine (III), which is debenzylated by means of H2 over Pd/C in ethanol/THF to yield the 7-hydroxyquinazoline derivative (IV). Finally, this compound is condensed with 1-(2-hydroxyethyl)-4-methylpiperazine (V) by means of DBAD and PPh3 in dichloromethane (1). Scheme 1.

参考文献 中间体
合成目标
【1】 Ple, P., Hennequin, L.F.A. (AstraZeneca AB; AstraZeneca plc). Quinazoline derivatives for the treatment of tumours. CA 2407371, EP 1292594, JP 2003535859, US 2004214841, US 2006258642, US 7049438, WO 2001094341.
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) 65837 7-benzyloxy-4-chloro-5-(tetrahydropyran-4-yloxy)quinazole 　 C20H19ClN2O3 详情 详情
(II) 65838 5-chloro-1,3-benzodioxol-4-amine; 5-Chlorobenzo[1,3]dioxol-4-ylamine 379228-45-2 C7H6ClNO2 详情 详情
(III) 65839 　 　 C27H24ClN3O5 详情 详情
(IV) 65840 　 　 C20H18ClN3O5 详情 详情
(V) 32589 2-(4-methyl-1-piperazinyl)-1-ethanol 5464-12-0 C7H16N2O 详情 详情

合成路线3

该中间体在本合成路线中的序号：(V)

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.

参考文献 中间体
合成目标
【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4

该中间体在本合成路线中的序号：(V)

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.

参考文献 中间体
合成目标
【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
Extended Information