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【结 构 式】 
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【分子编号】21583 【品名】2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine 【CA登记号】821-48-7 |
【 分 子 式 】C4H9Cl2N 【 分 子 量 】142.0276 【元素组成】C 33.83% H 6.39% Cl 49.92% N 9.86% |
合成路线1
该中间体在本合成路线中的序号：(X)Flesinoxan hydrochloride is obtained in a multiple-step synthesis, including the resolution of one of the racemic intermediates (VIII), starting with the monobenzyl ether of catechol (I). Treatment of (I) with sulfuryl chloride in methylene chloride gives (II). This chloro compound is nitrated with nitric acid resulting in the mononitro derivative (III). In a one-pot procedure compound (III) is converted to the racemic benzodioxan structure (V) by condensation with epichlorohydrin, followed by treatment of the intermediate (IV) with hydrochloric acid and with potassium hydroxide, respectively. After conversion of the hydroxymethyl derivative to the benzoic ester (VI), compound (VII) can be obtained by catalytic hydrogenation of (VI). Treatment of (VII) with bischloroethylamine results in the racemic piperazine analogue (VIII). In this phase the resolution of the piperazine is carried out with (+)-camphorsulfonic acid. After several recrystallizations, the optically pure (+)-enantiomer is obtained. Reaction of this (+)-N-[2-(hydroxymethyl)-1,4-benzodioxan-5-yl]piperazine (VIII) with N-(4-fluorobenzoyl)aziridine, saponification of the benzoate ester and treatment with hydrochloric acid gives flesinoxan monohydrochloride.
| 【1】 Hartog, J.; Wouters, W.; FLESINOXAN HYDROCHLORIDE < Rec INN >. Drugs Fut 1988, 13, 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) | 15209 | Phenol, 2-(phenylmethoxy)-; 2-(benzyloxy)phenol | 6272-38-4 | C13H12O2 | 详情 | 详情 |
| (II) | 21575 | 2-(benzyloxy)-4-chlorophenol | C13H11ClO2 | 详情 | 详情 | |
| (III) | 21576 | 2-(benzyloxy)-4-chloro-6-nitrophenol | C13H10ClNO4 | 详情 | 详情 | |
| (IV) | 21577 | 2-[[2-(benzyloxy)-4-chloro-6-nitrophenoxy]methyl]oxirane; benzyl 5-chloro-3-nitro-2-(2-oxiranylmethoxy)phenyl ether | C16H14ClNO5 | 详情 | 详情 | |
| (V) | 21578 | (7-chloro-5-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol | C9H8ClNO5 | 详情 | 详情 | |
| (VI) | 21579 | (7-chloro-5-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl benzoate | C16H12ClNO6 | 详情 | 详情 | |
| (VII) | 21580 | (5-amino-2,3-dihydro-1,4-benzodioxin-2-yl)methyl benzoate | C16H15NO4 | 详情 | 详情 | |
| (VIII) | 21581 | [5-(1-piperazinyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl benzoate | C20H22N2O4 | 详情 | 详情 | |
| (IX) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (X) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Eltoprazine can be obtained in a 3-step procedure starting from 5-nitrobenzodioxane (I): Catalytic hydrogenation of benzodioxane (I) results in the aniline hydrochloride (II) in high yieId. From the crude product obtained after treatment of (II) with bischloroethylamine dihydrochloride and subsequent crystallization from ethanol, pure eltoprazine hydrochloride is isolated.
| 【1】 Martikus, R.S.; Udrenajte, E.B.; Daukshas, V.K.; Rimkunajte, L.V. (Viln G Univ Im V Kapuskasa); Method of preparing 5-amino-1,4-benzodioxane.. SU 456521 . |
| 【2】 Hartog, J.; Olivier, B.; ELTOPRAZINE HYDROCHLORIDE < Prop INN >. Drugs Fut 1988, 13, 3, 222. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 | |
| (I) | 21999 | 5-nitro-2,3-dihydro-1,4-benzodioxine | C8H7NO4 | 详情 | 详情 | |
| (II) | 22000 | 2,3-dihydro-1,4-benzodioxin-5-amine; 2,3-dihydro-1,4-benzodioxin-5-ylamine; 5-Amino-1,4-benzodioxane | 16081-46-2 | C8H9NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The intermediate N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate (IV) was prepared by an improved procedure consisting of addition of phosphoryl chloride to 2-bromoethanol (I) in the presence of Et3N, followed by in situ treatment of the resulting intermediate (II) with bis(2-chloroethyl)amine (III).
| 【1】 Lyttle, M.H.; et al.; Glutathione-S-transferase activates novel alkylating agents. J Med Chem 1994, 37, 10, 1501. |
| 【2】 Kauvar, L.; Lyttle, M.H.; Satyam, A. (Telik, Inc.); Glutathione S-transferase-activated cpds.. WO 9509866 . |
| 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) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (II) | 13033 | Dichlorophosphoric acid 2-bromoethyl ester | C2H4BrCl2O2P | 详情 | 详情 | |
| (III) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (IV) | 46425 | C10H20BrCl4N2O2P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)Vilazodone can be prepared by two related ways: 1) The condensation of indole-5-carbonitrile (I) with 4-chlorobutyryl chloride (II) gives 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (III), which is reduced with diborane, yielding 3-(4-chlorobutyl)-1H-indole-5-carbonitrile (IV). Reaction of compound (IV) with 5-(1-piperazinyl)benzofuran-2-carboxylic acid (V) affords the expected 1,4-disubstituted piperazine (VI). Finally, the carboxy group of (VI) is converted into the target carboxamide by reaction with 2-chloro-1-methylpyridinium methanesulfonate (CMPM) and ammonia gas. 5-(1-Piperazinyl)benzofuran-2-carboxylic acid (V) is obtained by cyclization of 5-aminobenzofuran-2-carboxylic acid (VII) with bis(2-chloroethyl)amine (VIII). 2) The hydrogenation of 5-nitrobenzofuran-2-carboxylic acid ethyl ester (IX) with H2 and Raney nickel in MeOH gives the corresponding 5-aminobenzofuran compound (X), which is cyclized with bis(2-chloroethyl)amine (VIII) in dichloromethane to afford 5-(1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (XI). Reaction of compound (XI) with di-tert-butyl dicarbonate in THF provides the protected amine compound 5-[4-(tert-butoxycarbonyl)-1-piperazinyl]benzofuran-2-carboxylic acid ethyl ester (XII), which first is reacted with formamide and sodium alkoxide in N-methylpyrrolidone to provide the corresponding amide (XIII) and then is deprotected by treatment with HCl/MeOH to give 5-(1-piperazinyl)benzofuran-2-carboxamide (XIV). Finally, amide (XIV) is condensed with 3-(4-chlorobutyl)-1H-indole-5-carbonitrile (IV).
| 【1】 Rabasseda, X.; Sorbera, L.A.; Silvestre, J.S.; Castaner, J.; Vilazodone Hydrochloride. Drugs Fut 2001, 26, 3, 247. |
| 【2】 Bottcher, H.; Greiner, H.; Seyfried, C.; Bartoszyk, G. (Merck Patent GmbH); Indole derivs.. DE 4101686; EP 0496222; JP 1992334366; US 5418237 . |
| 【3】 Bottcher, H.; Seyfried, C.; Bartoszyk, G.; Greiner, H. (Merck Patent GmbH); Piperidine and piperazine derivs. which affect the CNS. CA 2133152; DE 4333254; EP 0648767; US 5532241 . |
| 【4】 Bathe, A.; Helfert, B.; Bottcher, H.; Schuster, K. (Merck Patent GmbH); 5-Amino-benzofuran-2-carboxylic acid derivs.. CA 2174494; DE 19514567; EP 0738722; JP 1996291161; US 5723614 . |
| 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) | 31341 | 5-Cyanoindole; Indole-5-carbonitrile; 1H-Indole-5-carbonitrile | 15861-24-2 | C9H6N2 | 详情 | 详情 |
| (II) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
| (III) | 45735 | 3-(4-chlorobutanoyl)-1H-indole-5-carbonitrile | C13H11ClN2O | 详情 | 详情 | |
| (IV) | 45736 | 3-(4-chlorobutyl)-1H-indole-5-carbonitrile | C13H13ClN2 | 详情 | 详情 | |
| (V) | 45737 | 5-(1-piperazinyl)-1-benzofuran-2-carboxylic acid | C13H14N2O3 | 详情 | 详情 | |
| (VI) | 45738 | 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-1-benzofuran-2-carboxylic acid | C26H26N4O3 | 详情 | 详情 | |
| (VII) | 45739 | 5-amino-1-benzofuran-2-carboxylic acid | C9H7NO3 | 详情 | 详情 | |
| (VIII) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (IX) | 42308 | ethyl 5-nitro-1-benzofuran-2-carboxylate | 69404-00-8 | C11H9NO5 | 详情 | 详情 |
| (X) | 45740 | ethyl 5-amino-1-benzofuran-2-carboxylate | C11H11NO3 | 详情 | 详情 | |
| (XI) | 45741 | ethyl 5-(1-piperazinyl)-1-benzofuran-2-carboxylate | C15H18N2O3 | 详情 | 详情 | |
| (XII) | 45742 | tert-butyl 4-[2-(ethoxycarbonyl)-1-benzofuran-5-yl]-1-piperazinecarboxylate | C20H26N2O5 | 详情 | 详情 | |
| (XIII) | 45743 | tert-butyl 4-[2-(aminocarbonyl)-1-benzofuran-5-yl]-1-piperazinecarboxylate | C18H23N3O4 | 详情 | 详情 | |
| (XIV) | 45744 | 5-(1-piperazinyl)-1-benzofuran-2-carboxamide | C13H15N3O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)Pyrimidinyl pyrazole (III) was prepared by condensation of diketone (I) with 2-hydrazinopyrimidine (II). Subsequent Mannich reaction with N-(3-chlorophenyl)piperazine (IV) and paraformaldehyde furnished piperazinyl propanone (V). This was reduced to alcohol (VI) with NaBH4. Alcohol dehydration employing p-toluenesulfonic acid yielded the title compound, that was finally isolated as the hydrochloride salt. The intermediate N-(3-chlorophenyl)piperazine (IV) has been obtained by cyclization of bis(2-chloroethyl)amine (VII) with 3-chloroaniline (VIII) by means of Na2CO3 in refluxing butanol.
| 【1】 DE 2038503; US 3723433 . |
| 【2】 Ejima, A.; Sugimori, M.; Mitsui, I. (Daiichi Pharmaceutical Co., Ltd.); Pyrimidinylpyrazole deriv.. EP 0784055; JP 1997048776; US 5852019; WO 9610024 . |
| 【3】 Ishii, M.; Ejima, A.; Hirotani, K.; Iwahana, M.; Sugimori, M.; Mitsui, I.; Naito, H.; Nakamura, Y.; Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. Chem Pharm Bull 1999, 47, 12, 1679. |
| 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) | 41449 | 3-(ethoxymethylene)-2,4-pentanedione | C8H12O3 | 详情 | 详情 | |
| (II) | 41450 | 2-hydrazinopyrimidine | C4H6N4 | 详情 | 详情 | |
| (III) | 41451 | 1-[5-methyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]-1-ethanone | C10H10N4O | 详情 | 详情 | |
| (IV) | 22114 | 1-(3-chlorophenyl)piperazine | 6640-24-0 | C10H13ClN2 | 详情 | 详情 |
| (V) | 41452 | 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]-1-propanone | C21H23ClN6O | 详情 | 详情 | |
| (VI) | 41453 | 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]-1-propanol | C21H25ClN6O | 详情 | 详情 | |
| (VII) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (VIII) | 25239 | 3-chloroaniline; 3-chlorophenylamine | 108-42-9 | C6H6ClN | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The condensation of 2-nitrophenol (I) with 2,2,2-trrifluoroethyl p-toluenesulfonate (II) by means of K2CO3 in DMF gives 2-(2,2,2-trifluoroethoxy) nitrobenzene (III), which isreduced with H2 over PtO2 in ethanol yiedling the aniline (IV). The cyclization of (IV) with bis (2-chloroethyl)amine (V) and K2CO3 affords the piperazine (VI), which is condensed with 1-benzyl-3-(3-chloro-propyl)-5-methylpyrimidine-2,4(1H,3H)-dione (VII) by means of K2CO3 in refluxing acetonitrile to give the benzylated target compound (VIII). Finally, this compound is deprotected by hydrogenation with ammonium formate and Pd/C. The intermediate pyrimidine (VII) has been obtained by benzylation of thymine (IX) with benzyl bromide and K2CO3 to give the 1-benzylthymine (X), which is alkylated with 1-bromo-3-chloropropane and K2CO3 to the target intemediate (VII).
| 【1】 Bantle, G.W.; Elworthy, T.R.; Guzman, A.; Jaime-Figueroa, S.; Lopez-Tapia, F.J.; Morgans, D.J. Jr.; Perez-Medrano, A.; Pfister, J.R.; Sjogren, E.B.; Talamas, F.X. (F. Hoffmann-La Roche AG); Pyrimidinedione, pyrimidinetrione, triazinedione, tetrahydroquinazolinedione derivs. as alpha1-adrenergic receptor antagonists. EP 0748800; JP 1997100269 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 | |
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (I) | 19106 | 2-nitrophenol | 88-75-5 | C6H5NO3 | 详情 | 详情 |
| (II) | 29561 | 2,2,2-trifluoroethyl 4-methylbenzenesulfonate | 433-06-7 | C9H9F3O3S | 详情 | 详情 |
| (III) | 29562 | 2-nitrophenyl 2,2,2-trifluoroethyl ether; 1-nitro-2-(2,2,2-trifluoroethoxy)benzene | C8H6F3NO3 | 详情 | 详情 | |
| (IV) | 29563 | 2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine | C8H8F3NO | 详情 | 详情 | |
| (V) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (VI) | 29564 | 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether | C12H15F3N2O | 详情 | 详情 | |
| (VII) | 29565 | 1-benzyl-3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione | C15H17ClN2O2 | 详情 | 详情 | |
| (VIII) | 29566 | 1-benzyl-5-methyl-3-(3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl)-2,4(1H,3H)-pyrimidinedione | C27H31F3N4O3 | 详情 | 详情 | |
| (IX) | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
| (X) | 29567 | 1-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione | C12H12N2O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The intermediate arylpiperazine (VI) was prepared as follows: Reaction of 2,4-difluoronitrobenzene (I) with trifluoroethanol (II) in the presence of potassium tert-butoxide yielded the trifluoroethyl ether (III). After catalytic hydrogenation of the nitro group of (III), the resultant aniline (IV) was cyclized with bis(2-chloroethyl) amine hydrochloride (V) in a refluxing mixture of o-dichlorobenzene and n-hexanol to afford the target piperazine (VI).
| 【1】 Bantle, G.W.; Elworthy, T.R.; Guzman, A.; Jaime-Figueroa, S.; Lopez-Tapia, F.J.; Morgans, D.J. Jr.; Perez-Medrano, A.; Pfister, J.R.; Sjogren, E.B.; Talamas, F.X. (F. Hoffmann-La Roche AG); Pyrimidinedione, pyrimidinetrione, triazinedione, tetrahydroquinazolinedione derivs. as alpha1-adrenergic receptor antagonists. EP 0748800; JP 1997100269 . |
| 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) | 32036 | 2,4-difluoro-1-nitrobenzene | 446-35-5 | C6H3F2NO2 | 详情 | 详情 |
| (II) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |
| (III) | 54365 | 4-fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene; 5-fluoro-2-nitrophenyl 2,2,2-trifluoroethyl ether | C8H5F4NO3 | 详情 | 详情 | |
| (IV) | 54366 | 4-fluoro-2-(2,2,2-trifluoroethoxy)aniline; 4-fluoro-2-(2,2,2-trifluoroethoxy)phenylamine | C8H7F4NO | 详情 | 详情 | |
| (V) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (VI) | 54367 | 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 5-fluoro-2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether | C12H14F4N2O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)The condensation of L-asparagine (I) with benzenesulfonyl chloride (II) in the presence of NaOH gave sulfonamide (III). Subsequent Hofmann rearrangement of (III) employing sodium hypobromite produced the diaminopropionic acid derivative (IV), which was protected as the tert-butyl ester (V) using isobutylene in the presence of H2SO4. Condensation of methyl 4-aminobenzoate (VI) with bis(2-chloroethyl)amine (VII) in refluxing butanol yielded the arylpiperazine (VIII), which was protected with di tert-butyl dicarbonate to give the corresponding carbamate (IX). Basic hydrolysis of the methyl ester of (IX) provided carboxylic acid (X). This was then coupled with amine (V) using benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) to afford amide (XI). Finally, deprotection of the tert-butyl ester and BOC group of (XI) with trifluoroacetic acid furnished the title compound.
| 【1】 Egbertson, M.S.; Turchi, L.M.; Hartman, G.D.; Halczenko, W.; Whitman, D.B.; Perkins, J.J.; Krause, A.E.; Ihle, N.; Claremon, D.A.; Hoffman, W.; Duggan, M.E. (Merck & Co., Inc.); Fibrinogen receptor antagonists. EP 0673247; JP 1996504194; WO 9412181 . |
| 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) | 25972 | S-(+)-Asparagine; S-(+)-2-Aminosuccinamic acid; L-Asparagine | 70-47-3 | C4H8N2O3 | 详情 | 详情 |
| (II) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |
| (III) | 25973 | (2S)-4-amino-4-oxo-2-[(phenylsulfonyl)amino]butyric acid | C10H12N2O5S | 详情 | 详情 | |
| (IV) | 31422 | (2S)-3-amino-2-[(phenylsulfonyl)amino]propionic acid | C9H12N2O4S | 详情 | 详情 | |
| (V) | 31423 | tert-butyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate | C13H20N2O4S | 详情 | 详情 | |
| (VI) | 20537 | methyl 4-aminobenzoate | 619-45-4 | C8H9NO2 | 详情 | 详情 |
| (VII) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (VIII) | 31424 | methyl 4-(1-piperazinyl)benzoate | C12H16N2O2 | 详情 | 详情 | |
| (IX) | 31425 | tert-butyl 4-[4-(methoxycarbonyl)phenyl]-1-piperazinecarboxylate | C17H24N2O4 | 详情 | 详情 | |
| (X) | 31426 | 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]benzoic acid | C16H22N2O4 | 详情 | 详情 | |
| (XI) | 31427 | tert-butyl 4-[4-[([(2S)-3-(tert-butoxy)-3-oxo-2-[(phenylsulfonyl)amino]propyl]oxy)carbonyl]phenyl]-1-piperazinecarboxylate | C29H39N3O8S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)The synthesis of SLV308 was obtained as follows: The first step is the reduction of just one nitro group, which was accomplished by treating 2,6-dinitrophenol (I) with sodium sulfide in the presence of sodium hydrogencarbonate dissolved in a water/MeOH mixture to yield 2-amino-6-nitro-phenol (II) in 62%. To construct the heterocyclic ring, (II) was reacted with carbonyldiimidazole in dry tetrahydrofuran to give the nitro benzoxazolinone (III) almost quantitatively. The reduction of the nitro group of (III) was performed in acetone/Raney-Ni, resulting in the corresponding aniline (IV) (72%). Transforming the aniline (IV) into the piperazine was done by heating (IV) and bis(2-chloroethyl)amine in chlorobenzene at reflux temperature; after 70 hours the desired piperazine (V) was obtained after chromatographic purification in 60% yield. The last step, introduction of the methyl group, was achieved by a reductive amination; formaldehyde, sodium triacetoxyborohydride and triethylamine dissolved in dichloroethane were added to (V). After work-up, chromatographic purification and subsequent treatment with ethanolic HCl, SLV308 was isolated in 81% yield.
| 【1】 van Scharrenburg, G.; Feenstra, R.; Long, S.; Koopman, T.; Stoker, M.; de Vries, M.; Ronken, E.; van Charldorp, K.; McCreary, A.; SLV308. Drugs Fut 2001, 26, 2, 128. |
| 【2】 Feenstra, R.W.; Visser, G.M.; Van der Heijden, J.A.M.; Long, S.K.; Toorop, G.P.; Van Scharrenburg, G.J.M.; Kruse, C.G.; Mos, J.; Toorop, A.G. (Duphar International Research BV); New piperazine and piperidine cpds.. WO 0029397 . |
| 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) | 44357 | 2,6-dinitrophenol | 573-56-8 | C6H4N2O5 | 详情 | 详情 |
| (II) | 44358 | 2-amino-6-nitrophenol | C6H6N2O3 | 详情 | 详情 | |
| (III) | 44359 | 7-nitro-1,3-benzoxazol-2(3H)-one | C7H4N2O4 | 详情 | 详情 | |
| (IV) | 44360 | 7-amino-1,3-benzoxazol-2(3H)-one | C7H6N2O2 | 详情 | 详情 | |
| (V) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (VI) | 44361 | 7-(1-piperazinyl)-1,3-benzoxazol-2(3H)-one | C11H13N3O2 | 详情 | 详情 |