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【结 构 式】 
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【分子编号】11882 【品名】1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine 【CA登记号】35386-24-4 |
【 分 子 式 】C11H16N2O 【 分 子 量 】192.26092 【元素组成】C 68.72% H 8.39% N 14.57% O 8.32% |
合成路线1
该中间体在本合成路线中的序号：(I)By reaction of 1-(3-chloro-2-hydroxypropyl)-4-(2-methoxyphenyl)piperazine (III), obtained from 2-methoxyphenylpiperazine (I) and epichlorohydrine (II), with the sodium salt of 3,4,5-trimethoxyphenol (IV) in refluxing dioxane.
| 【1】 Kleemann, A.; DE 2814168 . |
| 【2】 Engel, J.; Jakovlev, V.; Kleemann, A.; Enciprazine. Drugs Fut 1981, 6, 5, 278. |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 37161 | 1-chloro-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-propanol | C14H21ClN2O2 | 详情 | 详情 | |
| (IV) | 37162 | sodium 3,4,5-trimethoxybenzenolate | C9H11NaO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)By reaction of 3,4,5-trimethoxyphenoxyglycidylether (VI) [obtained by reaction of 3,4,5-trimethoxyphenol (V) with epichlorohydrine (II)] with 1-(2-methoxyphenyl)piperazine (I) in refluxing isopropanol.
| 【1】 Kleemann, A.; DE 2814168 . |
| 【2】 Engel, J.; Jakovlev, V.; Kleemann, A.; Enciprazine. Drugs Fut 1981, 6, 5, 278. |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (V) | 37163 | 3,4,5-trimethoxyphenol | C9H12O4 | 详情 | 详情 | |
| (VI) | 37164 | 2,3-dimethoxy-5-(2-oxiranylmethoxy)phenyl methyl ether; 2-[(3,4,5-trimethoxyphenoxy)methyl]oxirane | C12H16O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The condensation of ethyl 2-(aminomethyl)-2-(3,4-dimethoxyphenyl)acetate (I) with 3,4-dimethoxyphenylacetyl chloride (II) by means of NaOH in hot toluene gives ethyl 2-(3,4-dimethoxyphenyl)-3-(3,4-dimethoxyphenylacetamido)propionate (III), which is cyclized by means of Cl3PO in refluxing acetonitrile yielding ethyl 1-(3,4 dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-4-carboxylate (IV). Aromatization of (IV) with sulfur at 150 C affords the corresponding isoquinoline derivative (V), which is reduced with sodium bis(2 methoxyethoxy)aluminum hydride in THF to give1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline-4-methanol (VI). The reaction of (VI) with SOCl2 in dichloromethane affords 4-(chloromethyl)-6,7-dimethoxy-1-(3,4-dimethoxybenzyl)isoquinoline (VII), which is finally condensed with 1-(2-methoxyphenyl)piperazine (VIII) by means of triethyl amine in hot DMSO.
| 【1】 Bruderer, H.; Kierstead, R.W.; Mullin, J.G. Jr.; Nakamura, K.; O'Brien, J.P.; Sidney, T.; Tateishi, M. (F. Hoffmann-La Roche AG); Substd. isoquinolines. EP 0126480; ES 8601141; JP 1984222478; US 4544657 . |
| 【2】 Castaner, J.; Prous, J.; Elziverine. Drugs Fut 1988, 13, 2, 120. |
| 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) | 21862 | ethyl 3-amino-2-(3,4-dimethoxyphenyl)propanoate | C13H19NO4 | 详情 | 详情 | |
| (II) | 20594 | 2-(3,4-dimethoxyphenyl)acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
| (III) | 21864 | ethyl 2-(3,4-dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)acetyl]amino]propanoate | C23H29NO7 | 详情 | 详情 | |
| (IV) | 21865 | ethyl 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydro-4-isoquinolinecarboxylate | C23H27NO6 | 详情 | 详情 | |
| (V) | 21866 | ethyl 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-4-isoquinolinecarboxylate | C23H25NO6 | 详情 | 详情 | |
| (VI) | 21867 | [1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-4-isoquinolinyl]methanol | C21H23NO5 | 详情 | 详情 | |
| (VII) | 21868 | 4-(chloromethyl)-1-(3,4-dimethoxybenzyl)-6-methoxy-7-isoquinolinyl methyl ether; 4-(chloromethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline | C21H22ClNO4 | 详情 | 详情 | |
| (VIII) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The reaction of 1-naphthol (I) with epichlorohydrin (II) in the presence of aqueous sodium hydroxide yields 1-(1-naphthyloxy)-2,3-epoxypropane (III). (III) is then reacted either in alcohol or without any solvent with 1-(2-methoxyphenyl)piperazine (IV).
| 【1】 Thiel, M.; Sponer, G.; Stach, K.; Witte, E.-C.; Roesch, E. (Roche Diagnostics GmbH); 1-[3-(Napht-1-yloxy)-2-hydroxypropyl]-piperazine c. GB 1445548; US 3997666 . |
| 【2】 Prous, J.; Castaner, J.; Naftopidil. Drugs Fut 1987, 12, 1, 31. |
| 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) | 22935 | alpha-naphthol; 1-naphthol | 90-15-3 | C10H8O | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 22937 | 2-[(1-naphthyloxy)methyl]oxirane; 1-naphthyl 2-oxiranylmethyl ether | C13H12O2 | 详情 | 详情 | |
| (IV) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The demethylation of 1-(4-methoxyphenyl)acetone (I) by means of AlCl3 gives the corresponding 4-hydroxy compound (III), which is condensed with epichlorohydrin (III), yielding the expected oxiranylmethyl ether (IV). The addition of 1-(2-methoxyphenyl)piperazine (V) to the epoxide ring of (IV) affords the isopropyl alcohol derivative (VI), which is condensed with dimethylformamide dimethylacetal (VII) to afford the dimethylaminobutenone (VIII). Finally, this compound is cyclized with 2-cyanoacetamide (IX) by means of sodium ethoxide, providing the target pyridone.
| 【1】 (Beiersdorf-Lilly GmbH); Phenylpiperazinylpropanol derivs.. DE 3424685; EP 0167121; ES 8608511; JP 1986030573; US 4631279; US 4631281 . |
| 【2】 Armah, B.I.; Stenzel, W.; SATERINONE (BDF 8634): A DIFFERENT CONCEPT FOR PHARMACOTHERAPY OF CONGESTIVE HEART FAILURE. Drugs Fut 1989, 14, 5, 445. |
| 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) | 10038 | 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone | 122-84-9 | C10H12O2 | 详情 | 详情 |
| (II) | 43654 | 1-(4-hydroxyphenyl)acetone | C9H10O2 | 详情 | 详情 | |
| (III) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (IV) | 43655 | 1-[4-(2-oxiranylmethoxy)phenyl]acetone | C12H14O3 | 详情 | 详情 | |
| (V) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (VI) | 43656 | 1-(4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propoxy]phenyl)acetone | C23H30N2O4 | 详情 | 详情 | |
| (VII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (VIII) | 43657 | (Z)-4-(dimethylamino)-3-(4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propoxy]phenyl)-3-buten-2-one | C26H35N3O4 | 详情 | 详情 | |
| (IX) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)For the synthesis of umespirone the following synthesis pathway was chosen: Acetone is condensed with ethyl cyanoethanoate (I) to yield ethylisopropylidenecyanoacetate (II). This product is reacted with N-butylcyanoacetamide (III) in sodium methoxide solution to give N-butyl-2,4-dicyano-3,3-dimethylglutarimide (IV). The glutarimide (IV) is cyclized with phosphoric acid to yield 3-butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetraone (V). The quaternary salt (VIII) (R = CH3), prepared from 1-(2-methoxyphenyl)piperazine (VI) and 1,4-dibromobutane (VII), undergoes reaction with (V) in the presence of potassium carbonate to afford the free base KC-9172 (IX) (R = CH3).
| 【1】 Schon, U.; Kehrbach, W.; Benson, W.; Fuchs, A.; Ruhland, M. (Kali-Chemie AG); Novel tetraoxo cpds. AU 8661619; DE 3529872; EP 0212551; ES 8801271; ES 8801272; US 4771044 . |
| 【2】 Krahling, H.; Krijzer, F.; Umespirone. Drugs Fut 1991, 16, 5, 437. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 | |
| (I) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 11878 | ethyl 2-cyano-3-methyl-2-butenoate; 2-Butenoic acid, 2-cyano-3-methyl-, ethyl ester | 759-58-0 | C8H11NO2 | 详情 | 详情 |
| (III) | 11879 | N-Butyl-2-cyanoacetamide | C7H12N2O | 详情 | 详情 | |
| (IV) | 11880 | 1-Butyl-4,4-dimethyl-2,6-dioxo-3,5-piperidinedicarbonitrile | C13H17N3O2 | 详情 | 详情 | |
| (V) | 11881 | 3-Butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetrone | C13H18N2O4 | 详情 | 详情 | |
| (VI) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (VII) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
| (VIII) | 11884 | 8-(2-Methoxyphenyl)-8-aza-5-azoniaspiro[4.5]decane bromide | C15H23BrN2O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Compound can be prepared in two different ways: 1) By condensation of o-methoxyphenylpiperazine carbonate (I) with 1,3-dimethyl-4-(3-chloropropylamino)uracil (II) in refluxing water. 2) By condensation of N-(o-methoxyphenyl)-N'-(3-aminopropyl)piperazine (III) with 1,3-dimethyl-4-chlorouracil (IV) in refluxing triethylamine.
| 【1】 Pruesse, W.; et al.; Aryl-substituted piperazinyl-alkylamino-uracils, -uracil ethers and -uracil thioethers and method for their production. FR 2073300; GB 1309324; US 3957786; US 4067982 . |
| 【2】 Castaner, J.; Garcia-Rafanell, J.; Urapidil. Drugs Fut 1978, 3, 5, 397. |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 33441 | 6-[(3-chloropropyl)amino]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione | C9H14ClN3O2 | 详情 | 详情 | |
| (III) | 33442 | 3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamine; 3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-propanamine | C14H23N3O | 详情 | 详情 | |
| (IV) | 13978 | 6-Chloro-1,3-dimethyluracil; 6-Chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione | 6972-27-6 | C6H7ClN2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)By the usual method of synthesis of fluoroquinolones: By condensation of 8-(difluoromethoxy)-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (I) with 1-(2-methoxyphenyl)piperazine (II) in pyridine.
| 【1】 Hagihara, M.; Kashiwase, H.; Ohmine, T.; Katsube, T.; Nishigaki, T.; Kimura, S.; Momota, K.; Komai, T.; Kimura, T.; Shimada, K.; Synthesis and anti-HIV activity of arylpiperazinyl fluoroquinolones: A new class of anti-HIV agents. Bioorg Med Chem Lett 1999, 9, 21, 3063. |
合成路线9
该中间体在本合成路线中的序号：(I)By condensation of 1-(2-methoxyphenyl)piperazine (I) with 6-[4-(4-chlorobutoxy)phenyl]imidazo[1,2-b]thiazole (II) by means of Na2CO3/NaI in refluxing methyl isobutyl ketone.
| 【1】 Laszlovszky, I.; Domány, G.; Ferenczy, G.; Szántay, C. Jr.; Thuroczyné Kálmán, E.; Lapis, E.; Trischler, F.; Hegedús, B.; Auth, F.; Csejtei, M.; Kárpáti, E.; Kiss, B.; Laszy, J.; Pellioniszné Paróczai, M.; Sarkadi, A.; Szabó, S. (Gedeon Richter Ltd.); 2-Methoxyphenylpiperazine derivs.. EP 0935599; US 6103724; WO 9818797 . |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 20779 | 6-[4-(4-chlorobutoxy)phenyl]imidazo[2,1-b][1,3]thiazole; 4-chlorobutyl 4-imidazo[2,1-b][1,3]thiazol-6-ylphenyl ether | C15H15ClN2OS | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(X)Reduction of ketoester (I) with NaBH4 in THF-MeOH afforded diol (II), which was treated with HCl in toluene to give chlorohydrin (III). Benzanilide (VII) was prepared by condensation of acid chloride (IV) with aniline (V), followed by catalytic hydrogenolysis of the resulting benzyl ether (VI). Then, alkylation of phenol (VII) with chloride (III) in the presence of K2CO3 provided ether (VIII). The hydroxyl group of (VIII) was converted to bromide (IX) using CBr4 and this compound was condensed with N-(2-methoxyphenyl)piperazine (X) to produce disubstituted piperazine (XI). The ethyl ester group of (XI) was finally hydrolyzed using KOH in aqueous EtOH.
| 【1】 Yoshida, K.; Horikoshi, Y.; Eta, M.; Chikazawa, J.; Ogishima, M.; Fukuda, Y.; Sato, H.; Synthesis of benzanilide derivatives as dual actin. Bioorg Med Chem Lett 1998, 8, 21, 2967. |
| 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) | 23231 | methyl 3-(4-methylphenyl)-3-oxopropanoate | C11H12O3 | 详情 | 详情 | |
| (II) | 23232 | 1-(4-methylphenyl)-1,3-propanediol | C10H14O2 | 详情 | 详情 | |
| (III) | 23233 | 3-chloro-3-(4-methylphenyl)-1-propanol | C10H13ClO | 详情 | 详情 | |
| (IV) | 23234 | 4-(benzyloxy)benzoyl chloride | C14H11ClO2 | 详情 | 详情 | |
| (V) | 21940 | ethyl 4-(2-aminophenoxy)butanoate | C12H17NO3 | 详情 | 详情 | |
| (VI) | 23236 | ethyl 4-(2-[[4-(benzyloxy)benzoyl]amino]phenoxy)butanoate | C26H27NO5 | 详情 | 详情 | |
| (VII) | 23237 | ethyl 4-[2-[(4-hydroxybenzoyl)amino]phenoxy]butanoate | C19H21NO5 | 详情 | 详情 | |
| (VIII) | 23238 | ethyl 4-[2-([4-[3-hydroxy-1-(4-methylphenyl)propoxy]benzoyl]amino)phenoxy]butanoate | C29H33NO6 | 详情 | 详情 | |
| (IX) | 23239 | ethyl 4-[2-([4-[3-bromo-1-(4-methylphenyl)propoxy]benzoyl]amino)phenoxy]butanoate | C29H32BrNO5 | 详情 | 详情 | |
| (X) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (XI) | 23241 | ethyl 4-[2-([4-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-(4-methylphenyl)propoxy]benzoyl]amino)phenoxy]butanoate | C40H47N3O6 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VI)The condensation between cyclohexanone (I) and dimethyl itaconate (II) in the presence of NaOMe in cold Et2O afforded the spirobutenolide (III) together with some hydrolyzed product (IV). A further hydrolytic treatment with aqueous NaOH provided acid (IV), which was then converted to acid chloride (V) by treatment with PCl5 in refluxing cyclohexane. Reaction of this acid chloride with N-(2-methoxyphenyl)piperazine in CH2Cl2 at 0 C produced the title amide.
| 【1】 Bador, P.; et al.; Synthesis of acetylenic spirobutenolide derivatives and evaluation of their growth inhibitory effect on cells in culture. Arzneim-Forsch Drug Res 1990, 40(II), 10, 1135-1139. |
| 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) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (II) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (II) | 21417 | methyl 3-methyl-2-oxo-1-oxaspiro[4.5]dec-3-ene-4-carboxylate | C12H16O4 | 详情 | 详情 | |
| (IV) | 21418 | 3-methyl-2-oxo-1-oxaspiro[4.5]dec-3-ene-4-carboxylic acid | C11H14O4 | 详情 | 详情 | |
| (V) | 21419 | 3-methyl-2-oxo-1-oxaspiro[4.5]dec-3-ene-4-carbonyl chloride | C11H13ClO3 | 详情 | 详情 | |
| (VI) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(I)Nitration of 1-(2-methoxyphenyl)piperazine (I) using KNO3 in H2SO4 gave (II). After protection of (II) as the N-Boc derivative (III), reduction of the nitro group by catalytic hydrogenation over Pd/C yielded aniline (IV). This was condensed with 5-chloro-3-methylbenzothiophene-2-sulfonyl chloride (V) to afford the corresponding sulfonamide (VI). Finally, the Boc protecting group of (VI) was removed with HCl in boiling THF.
| 【1】 Bromidge, S.M.; Brown, A.M.; Clarke, S.E.; Dodgson, K.; Gager, T.; Grassam, H.L.; Jeffrey, P.M.; Joiner, G.F.; King, F.D.; Middlemiss, D.N.; Moss, S.F.; Newman, H.; Riley, G.; Routledge, C.; Wyman, P.; 5-Chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046): A potent, selective, and orally bioavailable 5-HT6 receptor antagonist. J Med Chem 1999, 42, 2, 202. |
| 【2】 King, F.D.; Bromidge, S.M.; Wyman, P.A. (SmithKline Beecham plc); Sulphonamide derivs., process for their preparation, and their use as medicaments. WO 9827081 . |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 25384 | 1-(2-methoxy-5-nitrophenyl)piperazine | C11H15N3O3 | 详情 | 详情 | |
| (III) | 25385 | tert-butyl 4-(2-methoxy-5-nitrophenyl)-1-piperazinecarboxylate | C16H23N3O5 | 详情 | 详情 | |
| (IV) | 25386 | tert-butyl 4-(5-amino-2-methoxyphenyl)-1-piperazinecarboxylate | C16H25N3O3 | 详情 | 详情 | |
| (V) | 25387 | 5-chloro-3-methyl-1-benzothiophene-2-sulfonyl chloride | C9H6Cl2O2S2 | 详情 | 详情 | |
| (VI) | 25388 | tert-butyl 4-(5-[[(5-chloro-3-methyl-1-benzothiophen-2-yl)sulfonyl]amino]-2-methoxyphenyl)-1-piperazinecarboxylate | C25H30ClN3O5S2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(I)N-(2-Methoxyphenyl)piperazine (I) was alkylated with 4-bromobutyronitrile (II) to provide the 3-cyanopropylpiperazine (III). Subsequent reduction of the cyano group of (III) using LiAlH4 produced the primary amine (IV). The title amide was then obtained by condensation of (IV) with 2-naphthoic acid (V) after activation as the corresponding acid chloride with (COCl)2 or as the mixed anhydride with isobutyl chloroformate.
| 【1】 Mann, A.; Sokoloff, P.; Schwartz, J.-C.; Wermuth, C.-G.; Garrido, F.; Lecomte, J.-M. (INSERM (Institut National de la Sante et de la Recherche Medicale); Societe Civile Bioprojet); 2-Naphthamide derivs. and their therapeutic applications. EP 0779284; FR 2742149; US 5872119; US 5985895 . |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 34789 | 4-bromobutanenitrile | 5332-06-9 | C4H6BrN | 详情 | 详情 |
| (III) | 34790 | 4-[4-(2-methoxyphenyl)-1-piperazinyl]butanenitrile | C15H21N3O | 详情 | 详情 | |
| (IV) | 34791 | 4-[4-(2-methoxyphenyl)-1-piperazinyl]butylamine; 4-[4-(2-methoxyphenyl)-1-piperazinyl]-1-butanamine | C15H25N3O | 详情 | 详情 | |
| (V) | 34792 | 2-naphthoic acid | 93-09-4 | C11H8O2 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(VIII)This compound has been obtained by three related ways: 1.- The Grignard condensation of ethyl cyclohexanecarboxylate (I) with benzylmagnesium bromide (II) in THF gives 1-cyclohexyl-2-phenylethanone (III), which is condensed with bromoacetaldehyde diethyl acetal (IV) by means of potassium tert-butoxide in DMSO to yield 4-cyclohexyl-4-oxo-3-phenylbutyraldehyde diethylacetal (V). The methylation of (V) by means of methyl iodide and potassium tert-butoxide in the same solvent affords 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde diethylacetal (VI), which is treated with HCl in acetone to give the corresponding aldehyde (VII). The reductocondensation of (VII) with 1-(2-methoxyphenyl)piperazine (VIII) by means of sodium triacetoxyborohydride in dichloromethane/acetic acid yields 1-cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-methyl-2-phenyl-1-butanone (X) as a racemic mixture, which is resolved by chiral chromatography over a Chiralpak AD column. 2.- The Grignard condensation of 2-phenylpropionaldehyde (XI) with cyclohexylmagnesium chloride (XII) in ethyl ether/THF gives 1-cyclohexyl-2-phenyl-1-propanol (XIII), which is oxidized with DMSO and P2O5 in dichloromethane yielding the corresponding ketone (XIV). The condensation of (XIV) with allyl bromide by means of potassium tert-butoxide in THF affords 1-cyclohexyl-2-methyl-2-phenyl-4-penten-1-one (XV), which is ozonolyzed with O3 in methanol catalyzed by a small amount of Sudan III affording the previously reported aldehyde (VII). 3.- The condensation of aldehyde (VII) with 1-(2-methoxyphenyl)piperazine (VIII) can also be performed in isopropyl acetate giving 1-cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-methyl-2-phenyl-3-buten-1-one (IX), which is hydrogenated with H2 over Pd/C in isopropanol to afford the previously reported racemic mixture (X).
| 【1】 Xu, Y.C.; et al.; Synthesis and pharmacology of LY426965: A potent, selective orally active, and long-lasting 5-HT1A receptor antagonist. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 107. |
| 【2】 Kohlman, D.T.; O'Toole, J.C.; Godfrey, A.G.; Xu, Y.-C.; Zhang, T.Y. (Eli Lilly and Company); Arylpiperazines having activity at the serotonin 1A receptor. EP 0924205; WO 9931077 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| (I) | 31858 | ethyl cyclohexanecarboxylate | 3289-28-9 | C9H16O2 | 详情 | 详情 |
| (II) | 28308 | benzyl(bromo)magnesium; benzylmagnesium bromide | 1589-82-8 | C7H7BrMg | 详情 | 详情 |
| (III) | 31859 | 1-cyclohexyl-2-phenyl-1-ethanone | C14H18O | 详情 | 详情 | |
| (IV) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (V) | 31860 | 1-cyclohexyl-4,4-diethoxy-2-phenyl-1-butanone | C20H30O3 | 详情 | 详情 | |
| (VI) | 31861 | 1-cyclohexyl-4,4-diethoxy-2-methyl-2-phenyl-1-butanone | C21H32O3 | 详情 | 详情 | |
| (VII) | 31862 | 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutanal | C17H22O2 | 详情 | 详情 | |
| (VIII) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (IX) | 31863 | (E)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-3-buten-1-one | C28H36N2O2 | 详情 | 详情 | |
| (X) | 31864 | 1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-1-butanone | C28H38N2O2 | 详情 | 详情 | |
| (XI) | 31865 | hydratropaldehyde | 93-53-8 | C9H10O | 详情 | 详情 |
| (XII) | 31866 | chloro(cyclohexyl)magnesium | C6H11ClMg | 详情 | 详情 | |
| (XIII) | 31867 | 1-cyclohexyl-2-phenyl-1-propanol | C15H22O | 详情 | 详情 | |
| (XIV) | 31868 | 1-cyclohexyl-2-phenyl-1-propanone | C15H20O | 详情 | 详情 | |
| (XV) | 31869 | 1-cyclohexyl-2-methyl-2-phenyl-4-penten-1-one | C18H24O | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(XII)The alkylation of phenylacetylene (I) with AlMe3 and ZnCl2CP2 gives the alpha-methylstyrene (II), which is treated with paraformaldehyde and BuLi to yield 3-phenyl-2-buten-1-ol (III). The reaction of (III) with NCS and DMS affords the butenyl chloride (IV), which is treated with trichlorosilane, TEA and CuCl to provide the allylic trichlorosilane (V). The condensation of (V) with benzaldehyde (VI) by means of the chiral catalyst (VII) and tetrabutylammonium iodide in dichloromethane gives the chiral diphenylcarbinol (VIII), which is submitted to hydroboration by means of 9-BBN and NaBO3 to yield the diol (IX). The selective, two step reduction of one phenyl group of (IX) with H2 over Rh/alumina and H2 over Pt/C affords the chiral cyclohexyl-butanediol derivative (X), which is oxidized by means of (COCl)2, DMSO and TEA in dichloromethane to provide the keto-aldehyde (XI). Finally, this compound is reductocondensed with 1-(2-methoxyphenyl)piperazine (XII) by means of NaBH(OAc)3 in 1,2-dichloroethane to give the target disubstituted piperazine.
| 【1】 Denmark, S.E.; Fu, J.; Asymmetric construction of quaternary centers by enantioselective allylation: Application to the synthesis of the serotonin antagonist lY426965. Org Lett 2002, 4, 11, 1951. |
| 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) | 20597 | 1-ethynylbenzene | 536-74-3 | C8H6 | 详情 | 详情 |
| (II) | 28450 | 1-isopropenylbenzene | 98-83-9 | C9H10 | 详情 | 详情 |
| (III) | 57208 | (E)-3-phenyl-2-buten-1-ol | C10H12O | 详情 | 详情 | |
| (IV) | 57209 | 1-[(E)-3-chloro-1-methyl-1-propenyl]benzene | C10H11Cl | 详情 | 详情 | |
| (V) | 57210 | trichloro[(E)-3-phenyl-2-butenyl]silane | C10H11Cl3Si | 详情 | 详情 | |
| (VI) | 57211 | (9aS,9bS)-5-[{5-[[(9aS,9bS)-5-oxooctahydro-5lambda~5~-dipyrrolo[1,2-c:2,1-e][1,3,2]diazaphosphol-5-yl](methyl)amino]pentyl}(methyl)amino]octahydro-5lambda~5~-dipyrrolo[1,2-c:2,1-e][1,3,2]diazaphosphol-5-one | C23H44N6O2P2 | 详情 | 详情 | |
| (VII) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VIII) | 57212 | (1S,2S)-2-methyl-1,2-diphenyl-3-buten-1-ol | C17H18O | 详情 | 详情 | |
| (IX) | 57213 | (1S,2S)-2-methyl-1,2-diphenyl-1,4-butanediol | C17H20O2 | 详情 | 详情 | |
| (X) | 57214 | (1S,2S)-1-cyclohexyl-2-methyl-2-phenyl-1,4-butanediol | C17H26O2 | 详情 | 详情 | |
| (XI) | 57215 | (3S)-4-cyclohexyl-3-methyl-4-oxo-3-phenylbutanal | C17H22O2 | 详情 | 详情 | |
| (XII) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(I)Coupling of piperazine (I) with chloro derivative (II) by means of K2CO3 and KI in acetone affords protected compound (III), which is then condensed with acid chloride (IV) by means of n-BuLi in THF to yield amide (V). Deprotection of (V) by hydrogenation over Pd/C in EtOH provides (VI), which is finally cyclized by treatment with POCl3 in DMF. Alternatively, the synthesis of the target product can be achieved by an analogous route: Acylation of amine (VII) with acid chloride (IV) by means of K2CO3 in CH2Cl2 provides amide (VIII), which is then cyclized by heating with POCl3 in DMF/benzene to give oxazole (IX). Finally, (IX) is condensed with piperazine (I) by means of K2CO3 and KI in acetone.
| 【1】 Schechter, L.E.; Smith, D.L.; Nelson, F.C.; Greenblatt, L.P.; Kelly, M.G.; Novel trisubstituted oxazole derivatives as 5-HT1A receptor ligands. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 117. |
| 【2】 Kelly, M.G.; Greenblatt, L.P.; Nelson, F.C. (American Home Products Corp.); Trisubstd. oxazole derivs. as serotonin ligands. US 6242448 . |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 37926 | benzyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate | 26049-94-5 | C18H18ClNO3 | 详情 | 详情 |
| (III) | 46228 | benzyl 1-benzyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxopropylcarbamate | C29H33N3O4 | 详情 | 详情 | |
| (IV) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
| (V) | 46229 | benzyl 1-benzyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxopropyl(cyclohexylcarbonyl)carbamate | C36H43N3O5 | 详情 | 详情 | |
| (VI) | 46230 | N-[1-benzyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxopropyl]cyclohexanecarboxamide | C28H37N3O3 | 详情 | 详情 | |
| (VII) | 46231 | 3-amino-1-chloro-4-phenyl-2-butanone | C10H12ClNO | 详情 | 详情 | |
| (VIII) | 46232 | N-(1-benzyl-3-chloro-2-oxopropyl)cyclohexanecarboxamide | C17H22ClNO2 | 详情 | 详情 | |
| (IX) | 46233 | 4-benzyl-5-(chloromethyl)-2-cyclohexyl-1,3-oxazole | C17H20ClNO | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(I)1-(2-Methoxyphenyl)-4-trichloroacetylpiperazine (II), prepared from 1-(2-methoxyphenyl)piperazine (I) and trichloroacetyl chloride, was treated with chlorosulfonic acid to give the sulfonyl chloride (III). Coupling of chloride (III) with 2,5-dibromo-3-fluoroaniline (IV) afforded sulfonamide (IV). Finally, removal of the trichloroacetyl protecting group under basic conditions provided the title piperazine derivative.
| 【2】 Moss, S.F.; Bromidge, S.M. (SmithKline Beecham plc); Novel cpds.. WO 9902502 . |
| 【1】 Bromidge, S.M.; Gager, T.; Clarke, S.E.; et al.; Phenyl benzenesulfonamides are novel and selective 5-HT6 antagonists: Identification of N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134). Bioorg Med Chem Lett 2001, 11, 1, 55. |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 48007 | 2,2,2-trichloro-1-[4-(2-methoxyphenyl)-1-piperazinyl]-1-ethanone | C13H15Cl3N2O2 | 详情 | 详情 | |
| (III) | 48008 | 4-methoxy-3-[4-(2,2,2-trichloroacetyl)-1-piperazinyl]benzenesulfonyl chloride | C13H14Cl4N2O4S | 详情 | 详情 | |
| (IV) | 48009 | 2,5-dibromo-3-fluoroaniline; 2,5-dibromo-3-fluorophenylamine | C6H4Br2FN | 详情 | 详情 | |
| (V) | 48010 | N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-[4-(2,2,2-trichloroacetyl)-1-piperazinyl]benzenesulfonamide | C19H17Br2Cl3FN3O4S | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(I)Mannich reaction of N-(2-methoxyphenyl)piperazine (I) with 3-acetylthiophene (II) in the presence of paraformaldehyde and HCl in refluxing EtOH leads to the piperazinyl propanone (III). Subsequent keto group reduction with NaBH4 gives alcohol (IV). This is then condensed with 1-fluoronaphthalene (V) in the presence of NaH to produce the title naphthyl ether.
| 【1】 Oficialdegui, A.-M.; Martínez-Esparza, J.; Pérez-Sailanes, S.; et al.; New 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives, with dual action at 5-HT1A serotonin receptors and serotonin transporter, as a new class of antidepressants. J Med Chem 2001, 44, 3, 418. |
| 【2】 Bosch Rovira, A.; Roca Acin, J.; Monge Vega, A.; Del Rio Zambrana, J.; Palop Cubillo, J.A.; Lasheras Aldaz, B.; Del Castillo Nieto, J.C. (Laboratorios Vita, SA); Cpds. derived from thiophene and benzothiophene, and related utilisation and compsn.. EP 1008594; ES 2128266; JP 2002511883; US 6262056; WO 9902516 . |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 34619 | 1-(3-thienyl)-1-ethanone | 1468-83-3 | C6H6OS | 详情 | 详情 |
| (III) | 57497 | 3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-(3-thienyl)-1-propanone | C18H22N2O2S | 详情 | 详情 | |
| (IV) | 57498 | 3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-(3-thienyl)-1-propanol | C18H24N2O2S | 详情 | 详情 | |
| (V) | 40503 | 1-fluoronaphthalene | 321-38-0 | C10H7F | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(IV)Friedel-Crafts acylation of 5-fluorobenzothiophene (I) with 3-chloropropionyl chloride (II) in the presence of AlCl3 furnished the chloroketone (III). This was then condensed with N-(2-methoxyphenyl)piperazine (IV) to afford the piperazinyl ketone (V). Reduction of the keto group of (V) with NaBH4 then gave the title alcohol.
| 【1】 Martínez, J.; Oficialdegui, A.M.; Perez, S.; et al.; New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants. Eur J Med Chem 2001, 36, 1, 55. |
| 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) | 49183 | 5-fluoro-1-benzothiophene | C8H5FS | 详情 | 详情 | |
| (II) | 18936 | 3-chloropropanoyl chloride | 625-36-5 | C3H4Cl2O | 详情 | 详情 |
| (III) | 49184 | 3-chloro-1-(5-fluoro-1-benzothiophen-2-yl)-1-propanone | C11H8ClFOS | 详情 | 详情 | |
| (IV) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (V) | 49185 | 1-(5-fluoro-1-benzothiophen-2-yl)-3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-propanone | C22H23FN2O2S | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(IV)Coupling between phenol derivative (I) and 1-bromo-4-chlorobutane (II) by means of either Na2CO3/NaI or K2CO3 in refluxing 5-methyl-2-hexanone affords 4-chlorobutoxy derivative (III), which is then converted into the desired product by condensation with (2-methoxyphenyl)piperazine dihydrochloride (IV), either by means of Na2CO3/NaI or with K2CO3 in refluxing 5-methyl-2-hexanone.
| 【1】 Laszlovszky, I.; et al.; Substituted phenoxyalkylpiperazines as dopamine D3 receptor ligands. Pharmazie 2001, 56, 4, 287. |
| 【2】 Laszlovszky, I.; Domány, G.; Ferenczy, G.; Szántay, C. Jr.; Thuroczyné Kálmán, E.; Lapis, E.; Trischler, F.; Hegedús, B.; Auth, F.; Csejtei, M.; Kárpáti, E.; Kiss, B.; Laszy, J.; Pellioniszné Paróczai, M.; Sarkadi, A.; Szabó, S. (Gedeon Richter Ltd.); 2-Methoxyphenylpiperazine derivs.. EP 0935599; US 6103724; WO 9818797 . |
| 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) | 50184 | 4-imidazo[1,2-a]pyridin-2-ylphenol | C13H10N2O | 详情 | 详情 | |
| (II) | 16141 | 1-bromo-4-chlorobutane | 6940-78-9 | C4H8BrCl | 详情 | 详情 |
| (III) | 50185 | 2-[4-(4-chlorobutoxy)phenyl]imidazo[1,2-a]pyridine; 4-chlorobutyl 4-imidazo[1,2-a]pyridin-2-ylphenyl ether | C17H17ClN2O | 详情 | 详情 | |
| (IV) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(I)The target disubstituted piperazine was generated by the ring opening of dimethyl (tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide (I), equivalent to the open-chain bromobutyramide, with N-(2-methoxyphenyl)piperazine (II) in hot DMF. Subsequent treatment with HCl in CHCl3-Et2O provided the corresponding hydrochloride salt.
| 【1】 Komoto, T.; et al.; New mu-opioid receptor agonists with piperazine moiety. Chem Pharm Bull 2001, 49, 10, 1314. |
合成路线22
该中间体在本合成路线中的序号：(I)N-(2-Methoxyphenyl)piperazine (I) is protected as the trichloroacetamide (II) using trichloroacetyl chloride and diisopropylethylamine. Then, chlorosulfonation of (II) in cold CH2Cl2 furnishes sulfonyl chloride (III)
| 【1】 Bromidge, S.M.; Moss, S.F. (GlaxoSmithKline plc); N-(3,5-Dichloro-2-methoxyphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide. EP 1313720; WO 0218358 . |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 48007 | 2,2,2-trichloro-1-[4-(2-methoxyphenyl)-1-piperazinyl]-1-ethanone | C13H15Cl3N2O2 | 详情 | 详情 | |
| (III) | 48008 | 4-methoxy-3-[4-(2,2,2-trichloroacetyl)-1-piperazinyl]benzenesulfonyl chloride | C13H14Cl4N2O4S | 详情 | 详情 |