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【结 构 式】 
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【分子编号】20730 【品名】1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide 【CA登记号】103-63-9 |
【 分 子 式 】C8H9Br 【 分 子 量 】185.06346 【元素组成】C 51.92% H 4.9% Br 43.18% |
合成路线1
该中间体在本合成路线中的序号：(VII)Treatment of alanine (I) with phosgene in THF provides N-carboxyanhydride derivative (II), which is then coupled to proline (III) by means of KOH and K2CO3 in THF/H2O or acetonitrile to provide dipeptide (IV). Coupling of (IV) to ethyl 2-oxo-4-phenylbutyrate (V) by means of H2 over Raney-Ni in EtOH (or EtOH/HOAc), followed by the corresponding work-up for isomer separation, yields derivative (VI). (In turn, ketoester (V) can be obtained by treatment of 2-phenylethyl bromide (VII) with Mg turnings in refluxing THF, followed by reaction of the resulting Grignard reagent with diethyl oxalate (VIII) in THF). Finally, the desired product is obtained by saponification of the ethyl ester group of (VI) with NaOH.
| 【1】 Blacklock, T.J.; et al.; Synthesis of semisynthetic dipeptides using N-carboxyanhydrides and chiral induction on Raney nickel. A method practical for large scale. J Org Chem 1988, 53, 4, 836. |
| 【2】 Reider, P.J.; Huffman, M.A.; Leblond, C.; Sun, Y. (Merck & Co., Inc.); Improved stereoselective process for enalapril. WO 0017228 . |
| 【3】 Blacklock, T.J.; Shuman, R.F. (Merck & Co., Inc.); Process for preparing polypeptides. US 4510083 . |
| 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) | 50831 | L-Alanine; L-2-Aminopropionic acid; (S)-(+)-2-Aminopropionic acid; L-2-Aminopropionic acid; (S)-2-Aminopropionic acid; (S)-(+)-Alanine | 56-41-7 | C3H7NO2 | 详情 | 详情 |
| (II) | 50829 | (4S)-4-methyl-1,3-oxazolidine-2,5-dione; S-Alanine-N-carboxylic acid anhydride | 2224-52-4 | C4H5NO3 | 详情 | 详情 |
| (III) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (IV) | 32151 | (2S)-1-[(2S)-2-aminopropanoyl]-2-pyrrolidinecarboxylic acid | 13485-59-1 | C8H14N2O3 | 详情 | 详情 |
| (V) | 50832 | ethyl 2-oxo-4-phenylbutanoate | C12H14O3 | 详情 | 详情 | |
| (VI) | 50830 | (2S)-1-((2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-2-pyrrolidinecarboxylic acid | C20H28N2O5 | 详情 | 详情 | |
| (VII) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (VIII) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Isovanillin (I) was alkylated with phenethyl bromide (II) in the presence of K2CO3 to afford phenethyl ether (III). The aldehyde function of (III) was then reduced with NaBH4, and the resulting alcohol (IV) was converted to chloride (V) by means of SOCl2 in THF-DMF. Subsequent displacement of the chlorine atom of (V) by KCN afforded nitrile (VI), which was hydrolyzed to acid (VII) with KOH in aqueous EtOH. Further conversion of (VII) to acid chloride (VIII), followed by condensation with dipropyl amine (IX) in toluene provided amide (X). Finally, reduction with LiAlH4 gave the corresponding amine, that was isolated as the hydrochloride salt.
| 【1】 Nakazato, A.; et al.; Design, synthesis, structure-activity relationship. J Med Chem 1999, 42, 6, 1076. |
| 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) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
| (II) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (III) | 23679 | 4-methoxy-3-(phenethyloxy)benzaldehyde | C16H16O3 | 详情 | 详情 | |
| (IV) | 23680 | [4-methoxy-3-(phenethyloxy)phenyl]methanol | C16H18O3 | 详情 | 详情 | |
| (V) | 23681 | 4-(chloromethyl)-1-methoxy-2-(phenethyloxy)benzene; 5-(chloromethyl)-2-methoxyphenyl phenethyl ether | C16H17ClO2 | 详情 | 详情 | |
| (VI) | 23682 | 2-[4-methoxy-3-(phenethyloxy)phenyl]acetonitrile | C17H17NO2 | 详情 | 详情 | |
| (VII) | 23683 | 2-[4-methoxy-3-(phenethyloxy)phenyl]acetic acid | C17H18O4 | 详情 | 详情 | |
| (VIII) | 23685 | 2-[4-methoxy-3-(phenethyloxy)phenyl]acetyl chloride | C17H17ClO3 | 详情 | 详情 | |
| (IX) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (X) | 23686 | 2-[4-methoxy-3-(phenethyloxy)phenyl]-N,N-dipropylacetamide | C23H31NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 3-methoxyphenylethylamine (I) with phenylethyl bromide (II) in refluxing triethylamine gives 3-methoxy-N-(phenylethyl)phenylethylamine (III), which is alkylated with 1-iodopropane by means of K2CO3 in refluxing acetone yielding 3-methoxy-N-propyl-N-(phenylethyl)phenylethylamine (IV). Finally, this compound is demethylated by treatment with refluxing aqueous 48% HBr and formation of the HCl salt with hydrochloric acid.
| 【1】 Nedelec, L.; et al.; Synthesis of study of the dopaminergic activity of di(phenylethyl)amine derivatives. Eur J Med Chem - Chim Ther 1978, 13, 6, 553-556. |
| 【2】 Serradell, M.N.; Castañer, J.; Blancafort, P.; Owen, R.T.; RU-24213. Drugs Fut 1981, 6, 4, 237. |
| 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) | 37185 | 2-(3-methoxyphenyl)-1-ethanamine; 3-methoxyphenethylamine | 2039-67-0 | C9H13NO | 详情 | 详情 |
| (II) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (III) | 37186 | N-(3-methoxyphenethyl)-N-phenethylamine; 2-(3-methoxyphenyl)-N-phenethyl-1-ethanamine | C17H21NO | 详情 | 详情 | |
| (IV) | 28758 | 1-iodopropane | 107-08-4 | C3H7I | 详情 | 详情 |
| (V) | 37187 | N-(3-methoxyphenethyl)-N-phenethyl-N-propylamine; N-(3-methoxyphenethyl)-N-phenethyl-1-propanamine | C20H27NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)2b) The alkylation of 2-(dimethoxyphosphoryl)acetic acid tert-butyl ester (XII) with 2-phenylethyl bromide (XIII) by means of potassium tert-butoxide in DMF gives 2-(dimethoxyphosphoryl)-4-phenylbutyric acid tert-butyl ester (XIV), which is allowed to react with formaldehyde/potasium tert-butoxide in THF to afford the tert-butyl acrylate (XV). The condensation of (XV) with cyclopentanecarboxylic acid (XVI) by means of butyllithium/diisopropylamine in THF affords racemic (II), which is finally submitted to optical resolution with L-(-)-alpha-methylbenzylamine to afford the chiral (R)-intermediate (II).
| 【1】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 . |
| 【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(II) | 20753 | 1-[2-(tert-butoxycarbonyl)-4-phenylbutyl]cyclopentanecarboxylic acid | C21H30O4 | 详情 | 详情 | |
| (XII) | 20748 | tert-butyl 2-(dimethoxyphosphoryl)acetate | C8H17O5P | 详情 | 详情 | |
| (XIII) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (XIV) | 20750 | tert-butyl 2-(dimethoxyphosphoryl)-4-phenylbutanoate | C16H25O5P | 详情 | 详情 | |
| (XV) | 20751 | tert-butyl 2-phenethylacrylate | C15H20O2 | 详情 | 详情 | |
| (XVI) | 20734 | cyclopentanecarboxylic acid | 3400-45-1 | C6H10O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)2b) The chiral intermediate acid (II) has been obtained as follows: The alkylation of diethyl malonate (XII) with 2-phenylethyl bromide (XIII) by means of potassium tert-butoxide in DMF gives diethyl 2-(2-phenylethyl)malonate (XIV), which is treated with KOH in ice-cooled water to afford the corresponding monoester monoacid (XV). The reacction of (XV) with formaldehyde in piperidine/water gives teh acrylate (XVI), which is condensed with cyclopentanecarboxylic acid (XVII) by meansof butyllithium/diisopropylamine in THF to afford racemic (II). Finally, this racemate is submitted to optical resolution with L-(-)-alpha-methylbenzylamine to afford the chiral (R)-intermediate (II).
| 【1】 Sorbera, L.A.; Leeson, P.A.; Castañer, J.; SLV-306. Drugs Fut 2002, 27, 1, 27. |
| 【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
| 【3】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(II) | 20735 | 1-[2-(ethoxycarbonyl)-4-phenylbutyl]cyclopentanecarboxylic acid | C19H26O4 | 详情 | 详情 | |
| (XIII) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (XIV) | 20731 | diethyl 2-phenethylmalonate | C15H20O4 | 详情 | 详情 | |
| (XV) | 20732 | 2-(ethoxycarbonyl)-4-phenylbutyric acid | C13H16O4 | 详情 | 详情 | |
| (XVI) | 20733 | ethyl 2-phenethylacrylate | C13H16O2 | 详情 | 详情 | |
| (XVII) | 20734 | cyclopentanecarboxylic acid | 3400-45-1 | C6H10O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)2-Pyridyl acetic acid (I) is converted into its methyl ester derivative (II) by means of SOCl2 in MeOH and then vigorously hydrogenated over Pt in MeOH to afford 2-(2-piperidyl)acetic acid methyl (III). Finally, piperidine ester derivative (III) is alkylated on nitrogen with 2-phenylethylbromide (IV) in DMF in the presence of K2CO3.
| 【1】 Dunn, T.; Deutsch, H.M.; Schweri, M.M.; Ye, X.; Synthesis and pharmacology of site-specific cocaine abuse treatment agents: The role of the phenyl group in highly modified methylphenidate analogs as dopamine uptake inhibitors. Med Chem Res 1999, 9, 4, 213. |
| 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) | 44792 | 2-(3-pyridazinyl)acetic acid | C6H6N2O2 | 详情 | 详情 | |
| (II) | 44793 | methyl 2-(3-pyridazinyl)acetate | C7H8N2O2 | 详情 | 详情 | |
| (III) | 44794 | methyl 2-hexahydro-3-pyridazinylacetate | C7H14N2O2 | 详情 | 详情 | |
| (IV) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The alkylation of 1H-indole-2-carboxylic acid methyl ester (I) with 2-phenylethyl bromide (II) by means of NaH in DMF gives 1-(2-phenylethyl)-1H-indole-2-carboxylic acid methyl ester (II), with is hydrolyzed with NaOH in methanol/water yielding the corresponding free acid (IV). Finally, this compound is condensed with guanidine by means of CDI and TEA in THF/DMF.
| 【1】 Kitano, M.; Miyagishi, A.; Ohashi, N.; Noguchi, T.; Nakano, K.; Kojima, A.; Synthesis and biological activity of N-(aminoiminomethyl)-1H-indole carboxamide derivatives as Na+/H+ exchanger inhibitors. Chem Pharm Bull 1999, 47, 11, 1538. |
| 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) | 27750 | Indole-2-carboxylic acid methyl ester; 1H-indole-2-carboxylic acid methyl ester | 1202-04-6 | C10H9NO2 | 详情 | 详情 |
| (II) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (III) | 40402 | methyl 1-phenethyl-1H-indole-2-carboxylate | C18H17NO2 | 详情 | 详情 | |
| (IV) | 40403 | 1-phenethyl-1H-indole-2-carboxylic acid | C17H15NO2 | 详情 | 详情 | |
| (V) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IX)The cycloaddition of the oxidopyridinium (I) with p-tolyl(vinyl)sulfoxide (II) in refluxing dioxane gives the tropenone derivative (III), which is treated with phenylmagnesium bromide and CuBr in THF yielding the diaryl tropanone derivative (IV). The reduction of (IV) with LiAlH4 in THF affords the corresponding alcohol (V), which is deoxigenated by reaction first with O-phenyl chlorothioformate and then with tributyltin hydride and AIBN in hot toluene to provide the diaryltropane (VI). The elimination of the sulfoxide group of (VI) with PCl3 and Raney-Ni in refluxing ethanol gives the diaryl tropane (VII) (1), which is submitted to N-demethylation with alpha-chloroethyl chloroformate and proton sponge in refluxing dichloroethane yielding the intermediate (VIII), which is finally N-alkylated with 2-phenylethyl bromide (IX) and K2CO3 in DMF.
| 【1】 Kozikowski, A.P.; Araldi, G.L.; Prakash, K.R.; Zhang, M.; Johnson, K.M.; Synthesis and biological properties of new 2beta-alkyl- and 2beta-aryl-3-(substituted phenyl)tropane derivatives: Stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters. J Med Chem 1998, 41, 25, 4973. |
| 【2】 Johnson, K.M.; Tamiz, A.P.; Zhang, M,; Araldi, G.L.; Kozikowski, A.P.; Prakash, K.R.C.; N-Phenylalkyl-substituted tropane analogs of boat conformation with high selectivity for the dopamine versus serotonin transporter. Bioorg Med Chem Lett 1999, 9, 23, 3325. |
| 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) | 41384 | 1-methyl-4-(4-methylphenyl)-2-pyridiniumolate | C13H13NO | 详情 | 详情 | |
| (II) | 25801 | (4-methylphenyl)(oxo)vinyl-lambda(4)-sulfane; 4-methylphenyl vinyl sulfoxide | C9H10OS | 详情 | 详情 | |
| (III) | 41385 | (1R,5R,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-8-azabicyclo[3.2.1]oct-3-en-2-one | C22H23NO2S | 详情 | 详情 | |
| (IV) | 41386 | (1R,3R,4R,5R,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]octan-2-one | C28H29NO2S | 详情 | 详情 | |
| (V) | 41387 | (1R,3R,4R,5R,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]octan-2-ol | C28H31NO2S | 详情 | 详情 | |
| (VI) | 41388 | (1R,2R,3R,5S,7R)-8-methyl-3-(4-methylphenyl)-7-[(4-methylphenyl)sulfinyl]-2-phenyl-8-azabicyclo[3.2.1]octane; (1S,3R,4R,5R,6R)-8-methyl-3-(4-methylphenyl)-4-phenyl-8-azabicyclo[3.2.1]oct-6-yl 4-methylphenyl sulfoxide | C28H31NOS | 详情 | 详情 | |
| (VII) | 41389 | (1S,2R,3R,5R)-8-methyl-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane | C21H25N | 详情 | 详情 | |
| (VIII) | 41390 | (1S,2R,3R,5R)-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane | C20H23N | 详情 | 详情 | |
| (IX) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IX)Piperidine (VIII) is alkylated with phenethyl bromide (IX) to furnish (X). The benzyloxycarbonyl protecting group of (X) is finally removed by treatment with HBr in AcOH to provide the title compound.
| 【1】 Jegham, S.; Lochead, A.; Galli, F.; Nedelec, A.; Solignac, A.; De Cruz, L. (Sanofi-Synthélabo); 5-Phenyl-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one derivs. for use as 5-HT4 or H3 receptor ligands. EP 0863897; FR 2741069; FR 2741070; JP 2000500125; US 5929089; WO 9717345 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 63659 | benzyl 6-chloro-8-[5-oxo-4-(4-piperidinyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,4-benzodioxin-5-ylcarbamate | C23H23ClN4O6 | 详情 | 详情 | |
| (IX) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (X) | 63660 | benzyl 6-chloro-8-[5-oxo-4-(1-phenethyl-4-piperidinyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,4-benzodioxin-5-ylcarbamate | C31H31ClN4O6 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(V)In a different procedure, the potassium salt of tolevamer can be synthesized as follows. Chlorosulfonation of phenethyl bromide (V) with ClSO3H gives 4-(2-bromoethyl)benzenesulfonyl chloride (VI), which undergoes simultaneous elimination of HBr and sulfonyl chloride hydrolysis in boiling ethanolic KOH to furnish potassium 4-vinylbenzenesulfonate (VII). Subsequent polymerization of (VII) in DMF solution in the presence of tert-butyl peracetate as initiator gives rise to tolevamer potassium (4). Scheme 2.
| 【4】 Wiley, R.H., Reed, S.F., Jr. Sulfostyrenes. Polymers and copolymers of potassium p-vinylbenzenesulfonate. J Am Chem Soc 1956, 78(10): 2171-3. |
合成路线11
该中间体在本合成路线中的序号：(XII)Amination of 2-phenylethyl bromide (XII) with methylamine in THF gives N-methylphenethylamine (XIII) , which upon N-acylation with chloroacetyl chloride (XIV) in the presence of NaHCO3 in CH2Cl2 or methyl t-butyl ether yields the chloroacetamide derivative (XV) . Cyclization of intermediate (XV) by Friedel-Crafts alkylation by means of AlCl3 in 1,2-dichlorobenzene at 165 °C gives 3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (XVI) . Alternatively, compound (XVI) can be obtained from 2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (XVII) by N-methylation with methyl iodide by means of NaH in DMF . Treatment of lactam (XVI) with isoamyl nitrite (i-AmONO) in the presence of NaHMDS or LiHMDS in THF yields the 1-hydroxyiminobenzazepinone (XVIII), which is finally hydrogenated with H2 over Pd/C in the presence of HCl in EtOH at 50 °C or with H2 over Raney-Ni in the presence of NH3 in EtOH at 100 °C .
Alternatively, phenylacetyl chloride (XIX) is condensed with N-(2,2-dimethoxyethyl)-N-methylamine (XX) by means of NaHCO3 in methyl t-butyl ether/H2O to furnish the phenylacetamide derivative (XXI), which upon cyclization in the presence of H2SO4 at 110 °C affords the benzazepin-2-one derivative (XXII). Treatment of intermediate (XXII) with i-AmONO in the presence of LiHMDS in THF gives the hydroxyimino derivative (XXIII), which is finally hydrogenated with H2 over Pd/C in the presence of HCl in EtOH at 50 °C .
| 【1】 Koenig, T.M., Nissen, J.S., Mitchell, D. (Eli Lilly and Company). Lactam compound. EP 1345955, JP 2005538031, WO 2002040508. |
| 【2】 Audia, J.E., John, V., Latimer, L.H., Tung, J.S., Nissen, J.S., Thorsett, E.D., McDaniel, S.L. (Eli Lilly and Company; Elan Pharmaceuticals, Inc.). Lactam compound. JP 2004517090, WO 2002047671. |
| 【3】 Koenig, T.M., Audia, J.E., Mitchell, D., Aikins, J.A., Buccilli, L.A., Engel,G.L., McDaniel, S.L. (Eli Lilly and Company). Lactam compound. CA 2425497, EP 1353910, JP 2004521084, WO 2002040451. |
| 【4】 Audia, J.E., Diseroad, B.A., Varghese, J. et al. (Eli Lilly and Company).Lactam compound. US 2007299053, US 7468365. |
| 【5】 Mitchell, D., Hay, L.A., Koenig, T.M., McDaniel, S., Nissen, J.S., Audia, J.E.Classical and dynamic resolution of 1-amino-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one. Tetrahedron Asymmetry 2005, 16(23): 3814-9. |
| 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) | 69307 | 1-amino-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one | C11H14N2O | 详情 | 详情 | |
| (XII) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (XIII) | 69316 | N-methyl-2-phenylethanamine；N-Phenethylmethylamine;N-methylphenethylamine | 589-08-2 | C9H13N | 详情 | 详情 |
| (XIV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XV) | 69317 | 2-chloro-N-methyl-N-phenethylacetamide | C11H14ClNO | 详情 | 详情 | |
| (XVI) | 69318 | 3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one；3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one | 73644-95-8 | C11H13NO | 详情 | 详情 |
| (XVII) | 69319 | 4,5-Dihydro-1H-benzo[d]azepin-2(3H)-one;1,3,4,5-Tetrahydrobenzo[d]azepin-2-one;1,3,4,5-Tetrahydro-2H-3-benzazepin-2-one;2,3,4,5-tetrahydro-1H-3-benzazepin-2-one | 15987-50-5 | C10H11NO | 详情 | 详情 |
| (XVIII) | 69320 | (E)-1-(hydroxyimino)-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one | C11H12N2O2 | 详情 | 详情 | |
| (XIX) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (XX) | 36650 | 2,2-dimethoxy-N-methyl-1-ethanamine;1,1-Dimethoxy-2-(methylamino)-ethane;Methylaminoacetaldehyde dimethyl acetal;N-(2,2-dimethoxyethyl)-N-methylamine | 122-07-6 | C5H13NO2 | 详情 | 详情 |
| (XXI) | 69321 | N-(2,2-dimethoxyethyl)-N-methyl-2-phenylacetamide | C13H19NO3 | 详情 | 详情 | |
| (XXII) | 69322 | 3-methyl-1H-benzo[d]azepin-2(3H)-one | C11H11NO | 详情 | 详情 | |
| (XXIII) | 69323 | (E)-1-(hydroxyimino)-3-methyl-1H-benzo[d]azepin-2(3H)-one | C11H10N2O2 | 详情 | 详情 |