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【结 构 式】 
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【分子编号】11845 【品名】Diphenylmethanol; Benzhydrol 【CA登记号】91-01-0 |
【 分 子 式 】C13H12O 【 分 子 量 】184.23768 【元素组成】C 84.75% H 6.57% O 8.68% |
合成路线1
该中间体在本合成路线中的序号：(VII)The reaction of ethanolimine (I) with m-methoxyphenylacetone (II) gives the corresponding Schiff base (III), which is reduced with H2 over Pd/C to the corresponding secondary amine (IV). Methylation of (IV) with HCHO-HCOOH yields 1-(m-methoxyphenyl)-2-(N-(2-hydroxyethyl)-N-methylaminoipropane (V), which is treated with SOCl2 to afford the 2-chloroethyl derivative (VI). Finally, this compound is condensed with benzhydrol (VII) by means of NaNH2 in refluxing benzene, and treated with HCl.
| 【1】 Lindner, E.; Ehrhart, G.; Ott, H. (Aventis Pharma AG); m-Methoxy-alpha-methyl-phenethyl-amino-diphenylmethyl ethers. US 3565955 . |
| 【2】 Mannhold, R.; HOE-263. Drugs Fut 1985, 10, 6, 458. |
| 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) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (II) | 29663 | 1-(3-methoxyphenyl)acetone | 3027-13-2 | C10H12O2 | 详情 | 详情 |
| (III) | 29664 | 2-[[(E)-2-(3-methoxyphenyl)-1-methylethylidene]amino]-1-ethanol | C12H17NO2 | 详情 | 详情 | |
| (IV) | 29665 | 2-[[2-(3-methoxyphenyl)-1-methylethyl]amino]-1-ethanol | C12H19NO2 | 详情 | 详情 | |
| (V) | 29666 | 2-[[2-(3-methoxyphenyl)-1-methylethyl](methyl)amino]-1-ethanol | C13H21NO2 | 详情 | 详情 | |
| (VI) | 29667 | N-(2-chloroethyl)-N-[2-(3-methoxyphenyl)-1-methylethyl]-N-methylamine; N-(2-chloroethyl)-1-(3-methoxyphenyl)-N-methyl-2-propanamine | C13H20ClNO | 详情 | 详情 | |
| (VII) | 11845 | Diphenylmethanol; Benzhydrol | 91-01-0 | C13H12O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)This compound can be prepared in several different ways: 1) The reaction of benzhydryl bromide (I) with thiourea (II) in refluxing water gives diphenyl - methanethiol (III), which is condensed with chloroacetic acid (A) by means of NaOH in hot water yielding (benzhydrylthio)acetic acid (IV). The esterification of (IV) with ethanol and H2SO4 affords the corresponding ethyl ester (V), which is treated with hydroxylamine hydrochloride and KOH in methanol to give benzhydrylthioacetohydroxamic acid (VI). Finally, this compound is oxidized with H2O2 in acetic acid. 2) Compound (III) can also be obtained by reaction of benzhydrol (VII) with thiourea and aqueous 48% HBr at 100 C. 3) Compound (IV) can be oxidized with H2O2 in water to give benzhydrylsulfinylacetic acid (VIII), which is methylated with dimethyl sulfate and NaHCO3 in water to the corresponding methyl ester (IX). Finally, this compound is treated with hydroxylamine and NaOH in water
| 【1】 Lafon, L. (Laboratoires L. Lafon); New benzhydrysulphinyl derivatives. DE 2642511; FR 2326181; GB 1520812; JP 52046058; US 4066686 . |
| 【2】 Mignonac, S.; Guy, A.; De Lamer, V. (Sanofi-Synthelabo); Preparation of polyamine(s), substd. on terminal nitrogen atoms. FR 2714052 . |
| 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) | 11847 | 2-Chloroacetic acid; Chloroacetic Acid | 79-11-8 | C2H3ClO2 | 详情 | 详情 |
| (I) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 32695 | diphenylmethanethiol; benzhydrylhydrosulfide | C13H12S | 详情 | 详情 | |
| (IV) | 11848 | 2-(Benzhydrylsulfanyl)acetic acid | C15H14O2S | 详情 | 详情 | |
| (V) | 32696 | ethyl 2-(benzhydrylsulfanyl)acetate | C17H18O2S | 详情 | 详情 | |
| (VI) | 32697 | 2-(benzhydrylsulfanyl)-N-hydroxyacetamide | 63547-44-4 | C15H15NO2S | 详情 | 详情 |
| (VII) | 11845 | Diphenylmethanol; Benzhydrol | 91-01-0 | C13H12O | 详情 | 详情 |
| (VIII) | 11851 | 2-(Benzhydrylsulfinyl)acetic acid | C15H14O3S | 详情 | 详情 | |
| (IX) | 11852 | methyl 2-(benzhydrylsulfinyl)acetate | C16H16O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)This compound can be obtained by two related ways: 1) The condensation of benzhydrol (I) with chloroacetic acid (II) by means of thiourea (III) in concentrated hydrobromic acid at 95 C gives 2-(diphenylmethylthio)acetic acid (IV), which by reaction with SOCl2 in refluxing benzene is converted into the acid chloride (V). The reaction of (V) with ammonium hydroxide in water - methylene chloride affords 2-(diphenylmethylthio)acetamide (VI), which is finally oxidized with hydrogen peroxide. 2) Acid (IV) can also be oxidized with hydrogen peroxide to give 2-(diphenylmethylsulfinyl)acetic acid (VII), which is methylated with dimethylsulfate and NaHCO3 to the corresponding methyl ester (VIII). Finally, this compound is treated with ammonia in anhydrous methanol.
| 【1】 Lafon, L. (Laboratoires L. Lafon); Acetamide derivs. DE 2809625; FR 2385693; US 4177290 . |
| 【2】 Prous, J.; Castaner, J.; MODAFINIL. Drugs Fut 1990, 15, 2, 130. |
| 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) | 11845 | Diphenylmethanol; Benzhydrol | 91-01-0 | C13H12O | 详情 | 详情 |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 11847 | 2-Chloroacetic acid; Chloroacetic Acid | 79-11-8 | C2H3ClO2 | 详情 | 详情 |
| (IV) | 11848 | 2-(Benzhydrylsulfanyl)acetic acid | C15H14O2S | 详情 | 详情 | |
| (V) | 11849 | 2-(Benzhydrylsulfanyl)acetyl chloride | C15H13ClOS | 详情 | 详情 | |
| (VI) | 11850 | 2-(Benzhydrylsulfanyl)acetamide | C15H15NOS | 详情 | 详情 | |
| (VII) | 11851 | 2-(Benzhydrylsulfinyl)acetic acid | C15H14O3S | 详情 | 详情 | |
| (VIII) | 11852 | methyl 2-(benzhydrylsulfinyl)acetate | C16H16O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Reaction of carbinol derivative (I) with 1-(2-hydroxyethyl)-2-methyl-5-nitro-1H-imidazole (II) and TsOH in benzene allows preparation of the target compound.
| 【1】 La Colla, P.; Artico, M.; Marceddu, T.; Silvestri, R.; Massa, S.; De Montis, F.; 1-[2-(Diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole: A potent lead for the design of novel NNRTIs. Bioorg Med Chem Lett 2000, 10, 3, 253. |
合成路线5
该中间体在本合成路线中的序号：(V)Alkylation of 2-pyridin-4-ylethanol (I) with 4-fluorobenzyl chloride (II), followed by reduction of the resultant pyridinium salt (III) with NaBH4 leads to the tetrahydropyridine (IV). Acid-catalyzed condensation of alcohol (IV) with benzhydrol (V) then provides the benzhydryl ether (VI) (1). Hydroboration of tetrahydropyridine (VI) and subsequent oxidative work up gives rise to the racemic trans piperidinol rac-(VII) (1,2). Resolution of (VII) is accomplished via esterification with (-)-camphanic chloride (VIII), followed by HPLC separation of the resulting diastereoisomers. The desired isomer (IX) is finally hydrolyzed employing K2CO3 in MeOH to provide the target enantiomer
| 【1】 Ghorai, S.K.; Cook, C.; Davis, M.; Venkataraman, S.K.; George, C.; Beardsley, P.M.; Reith, M.E.A.; Dutta, A.K.; High affinity hydroxypiperidine analogues of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the dopamine transporter: Stereospecific interactions in vitro and in vivo. J Med Chem 2003, 46, 7, 1220. |
| 【2】 Dutta, A.K. (Wayne State University); N- and O-substd. 4-[2-(diphenylmethoxy)-ethyl]-1-[(phenyl)methyl]piperidine analogs and methods of treating CNS disorders therewith. WO 0198266 . |
| 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) | 52533 | 2-(4-Pyridinyl)-1-ethanol; 2-Pyridin-4-ylethanol | C7H9NO | 详情 | 详情 | |
| (II) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (III) | 63533 | 1-[(4-fluorophenyl)methyl]-4-(2-hydroxyethyl)pyridinium chloride | C14H15ClFNO | 详情 | 详情 | |
| (IV) | 63534 | 2-{1-[(4-fluorophenyl)methyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-ethanol | C14H18FNO | 详情 | 详情 | |
| (V) | 11845 | Diphenylmethanol; Benzhydrol | 91-01-0 | C13H12O | 详情 | 详情 |
| (VI) | 63535 | diphenylmethyl 2-{1-[(4-fluorophenyl)methyl]-1,2,3,6-tetrahydro-4-pyridinyl}ethyl ether; 4-{2-[(diphenylmethyl)oxy]ethyl}-1-[(4-fluorophenyl)methyl]-1,2,3,6-tetrahydropyridine | C27H28FNO | 详情 | 详情 | |
| (VII) | 63536 | 4-{2-[(diphenylmethyl)oxy]ethyl}-1-[(4-fluorophenyl)methyl]-3-piperidinol | C27H30FNO2 | 详情 | 详情 | |
| (VIII) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
| (IX) | 63537 | 4-{2-[(diphenylmethyl)oxy]ethyl}-1-[(4-fluorophenyl)methyl]-3-piperidinyl 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate | C37H42FNO5 | 详情 | 详情 |