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【结 构 式】 
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【分子编号】13492 【品名】ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate 【CA登记号】120-47-8 |
【 分 子 式 】C9H10O3 【 分 子 量 】166.1766 【元素组成】C 65.05% H 6.07% O 28.88% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 2-(1-benzylpiperidin-4-yl)ethanol (I) with 4-hydroxybenzoic acid ethyl ester (II) by means of triphenylphosphine and diazenedicarboxylic acid diethyl ester in THF gives 4-[2-(1-benzylpiperidin-4-yl)ethoxy]benzoic acid ethyl ester (III) as fumarate salt. This compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol, yielding the free product (IV), which is finally condensed with 3-chloro-6-methylpyridazine (V) by means of K2CO3 in DMF.
| 【1】 Stokbroekx, R.A.; Van der Aa, M.J.M.; Luyckx, M.G.M.; Grauwels, G.A.J. (Janssen Pharmaceutica NV); Novel pyridazinamine derivs. AU 8825751; EP 0320032; JP 1989207278; US 4992433 . |
| 【2】 Castaner, J.; Prous, J.; Pirodavir. Drugs Fut 1992, 17, 11, 997. |
| 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) | 13491 | N-Benzyl-4-(2-hydroxyethyl)piperidine; 2-(1-Benzyl-4-piperidinyl)-1-ethanol | 76876-70-5 | C14H21NO | 详情 | 详情 |
| (II) | 13492 | ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate | 120-47-8 | C9H10O3 | 详情 | 详情 |
| (III) | 13493 | ethyl 4-[2-(1-benzyl-4-piperidinyl)ethoxy]benzoate | C23H29NO3 | 详情 | 详情 | |
| (IV) | 13494 | ethyl 4-[2-(4-piperidinyl)ethoxy]benzoate | C16H23NO3 | 详情 | 详情 | |
| (V) | 13495 | 3-Chloro-6-methylpyridazine | 1121-79-5 | C5H5ClN2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Alkylation of ethyl 4-hydroxybenzoate (I) with 1-(2-chloroethyl)piperidine (II) provided adduct (III). After saponification of the ethyl ester group of (III), the resulting carboxylic acid (IV) was treated with oxalyl chloride to furnish the desired acid chloride (V).
| 【1】 Dantzig, A.H.; Grese, T.A.; Normal, B.H.; Palkowitz, A.D.; Sluka, J.P.; Starling, J.J. II; Winter, M.A. (Eli Lilly and Company); Methods for treating resistant tumors. EP 0773217; JP 2000500138; WO 9717069 . |
| 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) | 13492 | ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate | 120-47-8 | C9H10O3 | 详情 | 详情 |
| (II) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (III) | 36993 | ethyl 4-[2-(1-piperidinyl)ethoxy]benzoate | C16H23NO3 | 详情 | 详情 | |
| (IV) | 36994 | 4-[2-(1-piperidinyl)ethoxy]benzoic acid | C14H19NO3 | 详情 | 详情 | |
| (V) | 36995 | 4-[2-(1-piperidinyl)ethoxy]benzoyl chloride | C14H18ClNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Ethyl 4-hydroxybenzoate (I) was alkylated with EtI and K2CO3 to afford ethyl ether (II). Subsequent hydrogenation of (II) over Rh/C produced ethyl 4-ethoxycyclohexane carboxylate (III) (1). Then, alkylation of (III) using benzyl chloromethyl ether and LDA gave the benzyloxymethyl compound (IV), which was hydrolyzed with ethanolic KOH to the carboxylic acid (V). Coupling of N-Boc-L-phenylalanine (VI) with benzylamine in the presence of EDC and HOBt produced amide (VII), and further acid deprotection of the Boc group of (VII) yielded phenylalanine-N-benzylamide (VIII). This was coupled with carboxylic acid (V) by means of DCC and HOAt to provide diamide (IX), which was debenzylated by catalytic hydrogenation yielding alcohol (X).
| 【1】 Fink, C.A.; et al.; Design and synthesis of thiol containing inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1999, 9, 2, 195. |
| 【2】 Fink, C.A. (Novartis AG); Certain cyclic thio substd. acylaminoacid amide derivs.. EP 0966439; US 6034136; WO 9842662 . |
| 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) | 13492 | ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate | 120-47-8 | C9H10O3 | 详情 | 详情 |
| (II) | 25451 | ethyl 4-ethoxybenzoate | 23676-09-7 | C11H14O3 | 详情 | 详情 |
| (III) | 25452 | ethyl 4-ethoxycyclohexanecarboxylate | C11H20O3 | 详情 | 详情 | |
| (IV) | 25453 | ethyl 1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxylate | C19H28O4 | 详情 | 详情 | |
| (V) | 25454 | 1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxylic acid | C17H24O4 | 详情 | 详情 | |
| (VI) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (VII) | 25506 | tert-butyl (1S)-1-benzyl-2-(benzylamino)-2-oxoethylcarbamate | C21H26N2O3 | 详情 | 详情 | |
| (VIII) | 25507 | (2S)-2-amino-N-benzyl-3-phenylpropanamide | C16H18N2O | 详情 | 详情 | |
| (IX) | 25508 | N-[(1S)-1-benzyl-2-(benzylamino)-2-oxoethyl]-1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxamide | C33H40N2O4 | 详情 | 详情 | |
| (X) | 25509 | N-[(1S)-1-benzyl-2-(benzylamino)-2-oxoethyl]-4-ethoxy-1-(hydroxymethyl)cyclohexanecarboxamide | C26H34N2O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Ethyl 4-hydroxybenzoate (I) was alkylated with EtI and K2CO3 to afford ethyl ether (II). Subsequent hydrogenation of (II) over Rh/C produced ethyl 4-ethoxycyclohexane carboxylate (III) (1). Then, alkylation of (II) using benzyl chloromethyl ether and LDA gave the benzyloxymethyl compound (IV), which was hydrolyzed with ethanolic KOH to the carboxylic acid (V). Coupling of N-Boc-L-phenylalanine (VI) with 3-pyridylamine in the presence of EDC and HOBt produced amide (VII), and further acid deprotection of the Boc group of (VII) yielded phenylalanine-N-(3-pyridyl)amide (VIII). This was coupled with carboxylic acid (V) by means of DCC and HOAt to provide diamide (IX), which was debenzylated by catalytic hydrogenation yielding alcohol (X).
| 【1】 Fink, C.A.; et al.; Design and synthesis of thiol containing inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1999, 9, 2, 195. |
| 【2】 Fink, C.A. (Novartis AG); Certain cyclic thio substd. acylaminoacid amide derivs.. EP 0966439; US 6034136; WO 9842662 . |
| 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) | 13492 | ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate | 120-47-8 | C9H10O3 | 详情 | 详情 |
| (II) | 25451 | ethyl 4-ethoxybenzoate | 23676-09-7 | C11H14O3 | 详情 | 详情 |
| (III) | 25452 | ethyl 4-ethoxycyclohexanecarboxylate | C11H20O3 | 详情 | 详情 | |
| (IV) | 25453 | ethyl 1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxylate | C19H28O4 | 详情 | 详情 | |
| (V) | 25454 | 1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxylic acid | C17H24O4 | 详情 | 详情 | |
| (VI) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (VII) | 25455 | tert-butyl (1S)-1-benzyl-2-oxo-2-(3-pyridinylamino)ethylcarbamate | C19H23N3O3 | 详情 | 详情 | |
| (VIII) | 25456 | (2S)-2-amino-3-phenyl-N-(3-pyridinyl)propanamide | C14H15N3O | 详情 | 详情 | |
| (IX) | 25457 | N-[(1S)-1-benzyl-2-oxo-2-(3-pyridinylamino)ethyl]-1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxamide | C31H37N3O4 | 详情 | 详情 | |
| (X) | 25458 | N-[(1S)-1-benzyl-2-oxo-2-(3-pyridinylamino)ethyl]-4-ethoxy-1-(hydroxymethyl)cyclohexanecarboxamide | C24H31N3O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Bromination of ethyl 4-hydroxybenzoate (I) by means of N-bromosuccinimide and HBF4.Et2O produced ethyl 3-bromo-4-hydroxybenzoate (II), which was further iodinated to (III) employing I2 and K2CO3. Subsequent condensation of (III) with ethylene glycol under Mitsunobu conditions afforded (hydroxyethyl)ether (IV). Palladium-catalyzed coupling of (IV) with 3-chlorophenylboronic acid (V) gave rise to terphenyl derivative (VI). Amide (VII) was then obtained by treatment of ester (VI) with n-dodecylamine in the presence of butyllithium. Finally, alcohol (VII) oxidation using N-methylmorpholine-N-oxide and tetrapropylammonium perruthenate furnished the title carboxylic acid.
| 【1】 Butera, J.A.; Caufield, C.E.; Greenfield, A.; Gundersen, E.G.; Lennox, J.R.; Graceffa, R.F.; Mayer, S.C.; Katz, A.H.; McDevitt, R.E.; Havran, L.M. (American Home Products Corp.); 2,3,5-Substd. biphenyls useful in the treatment of insulin resistance and hyperglycemia. WO 9961410 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40735 | 1-dodecanamine; dodecylamine | 124-22-1 | C12H27N | 详情 | 详情 | |
| (I) | 13492 | ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate | 120-47-8 | C9H10O3 | 详情 | 详情 |
| (II) | 39756 | ethyl 3-bromo-4-hydroxybenzoate | C9H9BrO3 | 详情 | 详情 | |
| (III) | 39757 | ethyl 3-bromo-4-hydroxy-5-iodobenzoate | C9H8BrIO3 | 详情 | 详情 | |
| (IV) | 39758 | ethyl 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoate | C11H12BrIO4 | 详情 | 详情 | |
| (V) | 39759 | 3-chlorophenylboronic acid | 63503-60-6 | C6H6BClO2 | 详情 | 详情 |
| (VI) | 39760 | C23H20Cl2O4 | 详情 | 详情 | ||
| (VII) | 39761 | C33H41Cl2NO3 | 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 ethyl 4-hydroxybenzoate (I) with 2-iodobenzyl bromide (II) affords the 4-benzyloxybenzoate (III). Subsequent reaction of ester (III) with hydrazine hydrate produces the hydrazide (IV), which is subjected to a Michael reaction with acrylonitrile (V), yielding (VI). Finally, cyclization of the hydrazide (VI) with triphosgene gives rise to the target ozadiazole derivative.
| 【1】 Hirata, M.; et al.; Synthesis and characterization of radioiodinated MD-230254: A new ligand for potential imaging of monoamine oxidase B activity by single photon emission computed tomography. Chem Pharm Bull 2002, 50, 5, 609. |
| 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) | 13492 | ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate | 120-47-8 | C9H10O3 | 详情 | 详情 |
| (II) | 57024 | 2-Iodobenzyl bromide; alpha-Bromo-2-iodotoluene | 40400-13-3 | C7H6BrI | 详情 | 详情 |
| (III) | 57025 | ethyl 4-[(2-iodobenzyl)oxy]benzoate | C16H15IO3 | 详情 | 详情 | |
| (IV) | 57026 | 4-[(2-iodobenzyl)oxy]benzohydrazide | C14H13IN2O2 | 详情 | 详情 | |
| (V) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (VI) | 57027 | N'-(2-cyanoethyl)-4-[(2-iodobenzyl)oxy]benzohydrazide | C17H16IN3O2 | 详情 | 详情 |