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【结 构 式】 
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【分子编号】10205 【品名】1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride 【CA登记号】611-19-8 |
【 分 子 式 】C7H6Cl2 【 分 子 量 】161.03004 【元素组成】C 52.21% H 3.76% Cl 44.03% |
合成路线1
该中间体在本合成路线中的序号：(V)A new synthesis of 13C- or 14C-labeled SKF-86466 has been described: The Friedel Craft's condensation of labeled benzene (I) with oxalyl chloride by means of AlCl3 in CS2 yields benzoic acid (II), which is chlorinated by means of cupric chloride and thallium (III) trifluoroacetate in trifluoroacetic acid to give 2-chlorobenzoic acid (III). The reduction of (III) by means of borane/THF complex in THF affords 2-chlorobenzyl alcohol (IV), which is treated with hot concentrated HCl to afford 2-chlorobenzyl chloride (V). The Grignard condensation of (V) with N-methyloxazolidine (VI) by means of Mg in ether gives N-[2-(2-chlorophenyl)ethyl]-N-methyl-2-hydroxyethylamine (VII), which is finally cyclized by treatment with PCl5 in hot trichlorobenzene followed by addition of AlCl3 and heating at 215-25 C.
| 【1】 Etzkorn, F.; Villani, A.J.; Rotert, G.A.; Heys, J.R.; Synthesis of 13C, 14C and 2H13C labeled adrenoceptor antagonists: 6-c hloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine hydrochloride and its N-desmethyl analog. J Label Compd Radiopharm 1988, 25, 12, 1339. |
| 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) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (I) | 44622 | C6H6 | 详情 | 详情 | ||
| (II) | 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 |
| (II) | 44623 | C7H6O2 | 详情 | 详情 | ||
| (III) | 10203 | o-Chlorobenzoic acid; 2-Chlorobenzoic acid | 118-91-2 | C7H5ClO2 | 详情 | 详情 |
| (III) | 44624 | C7H5ClO2 | 详情 | 详情 | ||
| (IV) | 10204 | 2-Chlorobenzyl alcohol; (2-Chlorophenyl)methanol | 17849-38-6 | C7H7ClO | 详情 | 详情 |
| (IV) | 44625 | C7H7ClO | 详情 | 详情 | ||
| (V) | 10205 | 1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride | 611-19-8 | C7H6Cl2 | 详情 | 详情 |
| (V) | 44626 | C7H6Cl2 | 详情 | 详情 | ||
| (VI) | 10206 | 3-Methyl-1,3-oxazolane | C4H9NO | 详情 | 详情 | |
| (VII) | 10207 | 2-[(2-Chlorophenethyl)(methyl)amino]-1-ethanol | C11H16ClNO | 详情 | 详情 | |
| (VII) | 44627 | C11H16ClNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Reaction of o-chlorobenzyl chloride (I) with thiourea (A) in refluxing ethanol affords the isothiourea hydrochloride (II), which is treated with chlorine gas in aqueous solution equal or lower at 10 C to afford the corresponding sulfonyl chloride (III). Exposure of (III) to liquid ammonia smoothly converts (III) to the sulfonamide (IV), which is converted to the sodium salt monohydrate with ethanolic sodium hydroxide.
| 【1】 Dubey, A.; Hall, I.H.; Wyrick, S.D.; Structure-activity studies on antihyperlipidemic N-benzoylsulfamates, N-benzylsulfamates and benzylsulfonamides. J Pharm Sci 1984, 73, 374-377. |
| 【2】 Wyrick, S.D.; Hall, I.H.; o-Chlorobenzylsulfonamide Sodium Salt. Drugs Fut 1985, 10, 4, 277. |
| 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) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (I) | 10205 | 1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride | 611-19-8 | C7H6Cl2 | 详情 | 详情 |
| (II) | 29105 | 1-([[amino(imino)methyl]sulfanyl]methyl)-2-chlorobenzene | C8H9ClN2S | 详情 | 详情 | |
| (III) | 29106 | (2-chlorophenyl)methanesulfonyl chloride | C7H6Cl2O2S | 详情 | 详情 | |
| (IV) | 29107 | (2-chlorophenyl)methanesulfonamide | C7H8ClNO2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)By condensation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I) and 2-chlorobenzyl chloride (II) with K2CO3 in refluxing ethanol or by reaction of thieno[3,2-c]pyridine (III) with 2-chlorobenzyl chloride (II) in refluxing acetonitrile to give the thienopyridinium salt (IV), which is then reduced with NaBH4 in ethanol-water.
| 【1】 Eloy, F.; Maffrand, J.P.; Synthese d thienopyridines et de furopyridines d'interet therapeutique. Eur J Med Chem 1974, 9, 483. |
| 【2】 Castaner, J.; Arrigoni-Martelli, E.; Ticlopidine. Drugs Fut 1976, 1, 4, 190. |
| 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) | 34011 | 4,5,6,7-tetrahydrothieno[3,2-c]pyridine | 54903-50-3 | C7H9NS | 详情 | 详情 |
| (II) | 10205 | 1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride | 611-19-8 | C7H6Cl2 | 详情 | 详情 |
| (III) | 34010 | thieno[3,2-c]pyridine | C7H5NS | 详情 | 详情 | |
| (IV) | 34009 | 5-(2-chlorobenzyl)thieno[3,2-c]pyridin-5-ium chloride | C14H11Cl2NS | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)In an alternative procedure, alkylation of diethyl malonate with 2-chlorobenzyl chloride (XIV) afforded malonate (XV), which underwent hydrolysis and further decarboxylation to the arylpropionic acid (XVI) upon refluxing with HCl and HOAc. Coupling of acid (XVI) with the chiral amine (III) to give amide (XVII) was performed in refluxing toluene with azeotropic removal of water or, alternatively, by using DCC as the coupling reagent. Amide (XVII) was finally reduced to the corresponding amine by means of borane in tetrahydrofuran or with DIBAL in CH2Cl2.
| 【1】 Yamazaki, N.; et al.; Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue. Tetrahedron Lett 2001, 42, 30, 5029. |
| 【2】 D'Ambra, T.E.; Vanwagenen, B.C.; Duff, S.R.; Nelson, W.A. (NPS Pharmaceuticals, Inc.); Method of making a benzylpropanamine. WO 9602492 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 56140 | (R)-1-(3-Methoxyphenyl)ethylamine; (R)-3-Methoxy-alpha-methylbenzylamine; (R)-m-Methoxy-alpha-methylbenzylamine | 88196-70-7 | C9H13NO | 详情 | 详情 |
| (XIV) | 10205 | 1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride | 611-19-8 | C7H6Cl2 | 详情 | 详情 |
| (XV) | 56149 | diethyl 2-(2-chlorobenzyl)malonate | C14H17ClO4 | 详情 | 详情 | |
| (XVI) | 56150 | 3-(2-Chlorophenyl)propionic acid | 1643-28-3 | C9H9ClO2 | 详情 | 详情 |
| (XVII) | 56151 | 3-(2-chlorophenyl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]propanamide | C18H20ClNO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Alkylation of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (I) at the N-2 with benzyl chloride (II) in the presence of NaH in DMF yielded the 2-benzyl derivative (III), which was further alkylated with 2-chlorobenzyl chloride (IV) at the N-4 to provide the title compound.
| 【1】 Arranz, E.; Díaz, J.A.; Ingate, S.T.; Witvrouw, M.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Vega, S.; Novel 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine derivatives as non-nucleoside reverse transcriptase inhibitors that inhibit human immunodeficiency virus type 1 replication. J Med Chem 1998, 41, 21, 4109. |
| 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) | 27304 | 1lambda(6)-thieno[3,4-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione | C5H4N2O3S2 | 详情 | 详情 | |
| (II) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (III) | 27305 | 2-benzyl-2H-thieno[3,4-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione | C12H10N2O3S2 | 详情 | 详情 | |
| (IV) | 10205 | 1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride | 611-19-8 | C7H6Cl2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Benzyl pyrazole derivative (III) was prepared by alkylation of 3-aminopyrazole-4-carboxamide (I) with 2-chlorobenzyl chloride (II) under phase-transfer conditions. Diazotization of (III) with NaNO2/HCl then gave the title pyrazolotriazinone.
| 【1】 Lankau, H.-J.; Arnold, T.; Rostock, A.; Unverferth, K.; Kronbach, T.; Bartsch, R. (Arzneimittelwerk Dresden GmbH); Pyrazolo[3,4-d][1,2,3]triazines with anticonvulsive action and methods for producing the same. DE 19924872; WO 0073309 . |