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【结 构 式】 
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【分子编号】30414 【品名】2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid 【CA登记号】5807-30-7 |
【 分 子 式 】C8H6Cl2O2 【 分 子 量 】205.03984 【元素组成】C 46.86% H 2.95% Cl 34.58% O 15.61% |
合成路线1
该中间体在本合成路线中的序号：(I)Esterification of 3,4-dichlorophenylacetic acid (I) with HCl/EtOH at reflux followed by radical bromination of the resulting ethyl ester (II) with NBS in the presence of HBr or (PhCOO)2 in refluxing CCl4 provides ethyl α-bromo-(3,4-dichlorophenyl)acetate (III). Tandem Michael addition and cyclization of ethyl bromoacetate (III) with ethyl acrylate (IV) by means of NaH and a catalytic amount of EtOH in ethyl ether gives diethyl cis-1-(3,4-dichlorophenyl)-1,2-cyclopropanedicarboxylate (V). After saponification with KOH in EtOH/H2O, the resulting diacid (VI) is cyclized with urea in refluxing xylene to yield the bicyclic imide (VII). Subsequent reduction of imide (VII) with BH3/THF or sodium bis(2-methoxyethoxy)aluminum hydride (Vitride, Red-Al) affords racemic 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (VIII) , which is finally treated with HCl in Et2O and submitted to enantiomeric separation by chiral chromatography .
Cyclocondensation of (3,4-dichlorophenyl)acetonitrile (X) with racemic epichlorohydrin (XIa) in the presence of NaNH2 in THF gives 1-(3,4-dichlorophenyl)-2-(hydroxymethyl)cyclopropanecarbonitrile as a diastereomeric mixture enriched in the cis-isomers (XIIa). Oxidation of alcohol (XIIa) with H5IO6 and CrO3 gives the carboxylic acid (XIII), which by esterification with MeOH in the presence of SOCl2 affords the methyl ester (XIV). Finally, reductive cyclization of the cyano ester (XIV) using BH3·Me2S in refluxing THF affords 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (VIII) .
In a stereospecific route, cyclization of nitrile (X) with (S)-epichlorohydrin (XIb) by means of NaHMDS in THF provides the cis-cyclopropanecarbonitrile (XIIb) as the major diastereoisomer, which is then reduced to aminoalcohol (XV) by means of BH3·Me2S. Chlorination of alcohol (XV) with SOCl2 in isopropyl acetate leads to the chlorinated amine (XVI), which is finally cyclized in the presence of NaOH, and then crystallized with HCl .
| 【1】 Epstein, J.W., Brabander, H.J., Osterberg, A.C. (Wyeth, LLC). Method of treating depression using azabicyclohexanes. US 4435419. |
| 【2】 Epstein, J.W., Brabander, H.J., Fanshawe, W.J. et al. 1-Aryl-3-azabicyclo[3.1.0]hexanes, a new series of nonnarcotic analgesic agents. J Med Chem 1981, 24(5): 481-90. |
| 【3】 Epstein, J.W., Lippa, A.S. (Euthymics Bioscience, Inc.). (+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as an anti-depressant agent. CA 2434616, EP 1349835, JP 2005500983, JP 2009280605, US 6372919, WO 2002066427. |
| 【4】 Phil, S., Chen, Z. (Euthymics Bioscience, Inc.). Methods and compositions for production, formulation and use of 1-aryl-3-azabicyclo[3.1.0]hexanes. US 2008058535, WO 2008013856. |
| 【5】 Corley, E.G., Feng, X., Murry, J.A., Simmons, B. (Euthymics Bioscience, Inc.). Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. EP 2012777, EP 061318, JP 2010500972, US 2008045725, WO 2007127396, WO 2008024143. |
| 【6】 Murry, J.A., Corely, E.G., Xu, F., Simmons, B. Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. US 2010298574. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIa) | 68227 | racemic epichlorohydrin | C3H5ClO | 详情 | 详情 | |
| (XIb) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (XIIa) | 68228 | racemic 1-(3,4-dichlorophenyl)-2-(hydroxymethyl)cyclopropanecarbonitrile | C11H9Cl2NO | 详情 | 详情 | |
| (XIIb) | 68229 | cis-cyclopropanecarbonitrile;(1S,2R)-1-(3,4-dichlorophenyl)-2-(hydroxymethyl);cyclopropanecarbonitrile | C11H9Cl2NO | 详情 | 详情 | |
| (XV) | 68231 | ((1S,2R)-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclopropyl)methanol | C11H12Cl3N | 详情 | 详情 | |
| (I) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (II) | 68220 | ethyl 2-(3,4-dichlorophenyl)acetate | 6725-45-7 | C10H10Cl2O2 | 详情 | 详情 |
| (III) | 68221 | ethyl 2-bromo-2-(3,4-dichlorophenyl)acetate；ethyl α-bromo-(3,4-dichlorophenyl)acetate | 41204-08-4 | C10H9BrCl2O2 | 详情 | 详情 |
| (IV) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (V) | 68222 | (1R,2S)-diethyl 1-(3,4-dichlorophenyl)cyclopropane-1,2-dicarboxylate;diethyl cis-1-(3,4-dichlorophenyl)-1,2- cyclopropanedicarboxylate | C15H16Cl2O4 | 详情 | 详情 | |
| (VI) | 68223 | (1R,2S)-1-(3,4-dichlorophenyl)cyclopropane-1,2-dicarboxylic acid | C11H8Cl2O4 | 详情 | 详情 | |
| (VII) | 68226 | (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione | C11H7Cl2NO2 | 详情 | 详情 | |
| (VIII) | 68225 | 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane;(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane | C11H11Cl2N | 详情 | 详情 | |
| (IX) | 68224 | (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride | C11H11Cl2N.HCl | 详情 | 详情 | |
| (X) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (XIII) | 68233 | racemic (1S,2R)-2-cyano-2-(3,4-dichlorophenyl)cyclopropanecarboxylic acid | C11H7Cl2NO2 | 详情 | 详情 | |
| (XIV) | 68232 | racemic (1S,2R)-methyl 2-cyano-2-(3,4-dichlorophenyl)cyclopropanecarboxylate | C12H9Cl2NO2 | 详情 | 详情 | |
| (XVI) | 68230 | ((1S,2R)-2-(chloromethyl)-1-(3,4-dichlorophenyl)cyclopropyl)methanamine hydrochloride | C11H12Cl3N.HCl | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The condensation of cyclohexene-epoxide (I) with pyrrolidine (II) gives trans-2-(1-pyrrolidinyl)cyclohexanol (III), which by reaction with NaH and methanesulfonyl chloride, and then with benzylamine is converted into trans-2-(1-pyrrolidinyl)-N-benzylcyclohexylamine (IV). The debenzylation of (IV) by hydrogenolysis with H2 over Pd/C affords trans-2-(1-pyrrolidinyl)cyclohexylamine (V), which is formylated with ethyl formate to the corresponding N-formyl-trans-2-(1-pyrrolidinyl)cyclohexylamine (VI). The reduction of (VI) with LiAlH4 in refluxing ether gives trans-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (VII), which is finally condensed with 3,4-dichlorophenylacetic acid (VIII) by means of carbonyl diimidazole (IX) in THF.
| 【1】 Blancafort, P.; Castaner, J.; Serradell, M.N.; U-50488. Drugs Fut 1982, 7, 6, 416. |
| 【2】 Szmuszkovicz, J.; 2-Aminocycloaliphatic amide compounds. DE 2749950; ES 463876; FR 2370723; GB 1569225; JP 53063351; JP 61233654; US 4145435 . |
| 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) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (B) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (I) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 14637 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexanol | C10H19NO | 详情 | 详情 | |
| (IV) | 37038 | N-phenyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]aniline | C16H24N2 | 详情 | 详情 | |
| (V) | 37040 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexylamine; (1R,2R)-2-(1-pyrrolidinyl)cyclohexanamine | C10H20N2 | 详情 | 详情 | |
| (VI) | 37011 | 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-one | C15H20N2O | 详情 | 详情 | |
| (VII) | 31357 | N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; (1R,2R)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine | C11H22N2 | 详情 | 详情 | |
| (VIII) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (IX) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (X) | 37039 | 7-azabicyclo[4.1.0]heptane | C6H11N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)In a different procedure, 3,4-dichlorophenylacetic acid (XIV) was condensed with the lithiated chiral oxazolidinone (XV), via activation as the mixed anhydride with pivaloyl chloride, to afford the N-acyl oxazolidinone (XVI). Diastereoselective alkylation of the sodium enolate of (XVI) with allyl iodide (XVII) afforded the (S)-pentenyl oxazolidinone (XVIII), which was further hydrolyzed to the chiral acid (XIX) by means of lithium peroxide. Alternatively, acid (XIX) was obtained by alkylation of the lithium dianion of 3,4-dichlorophenylacetic acid (XIV) with allyl bromide (XX), followed by resolution of the resultant racemic acid (XXI) with (S)-1-phenylethylamine. Acid (XIX) was converted to the amide (XXII) via the corresponding acid chloride. Reduction of amide (XXII) with DIBAL gave the secondary amine (XXIII), which was subsequently acylated with benzoyl chloride, yielding benzamide (XXIV). Dihydroxylation of the olefin double bond with N-methylmorpholine-N-oxide in the presence of OsO4, followed by oxidative cleavage of the resultant diol (XXV) with sodium periodate furnished aldehyde (XXVI). Finally, reductive amination of aldehyde (XXVI) with piperidine (III) in the presence of NaBH3CN provided the title compound
| 【1】 Hale, J.J.; Finke, P.E.; MacCross, M.; A facile synthesis of the novel neurokinin A antagonist SR 48968. Bioorg Med Chem Lett 1993, 3, 2, 319. |
| 【2】 Finke, P.E.; Mills, S.G.; Hale, J.J.; MacCoss, M. (Merck & Co., Inc.); Process of making chiral 2-aryl-1,4-butanediamine derivs.. WO 9407839 . |
| 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) | 59283 | N-(4-phenyl-4-piperidinyl)acetamide | C13H18N2O | 详情 | 详情 | |
| (XIV) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (XV) | 58942 | C10H10LiNO2 | 详情 | 详情 | ||
| (XVI) | 62381 | (4S)-4-benzyl-3-[2-(3,4-dichlorophenyl)acetyl]-1,3-oxazolidin-2-one | C18H15Cl2NO3 | 详情 | 详情 | |
| (XVII) | 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 |
| (XVIII) | 62382 | (4S)-4-benzyl-3-[(2S)-2-(3,4-dichlorophenyl)-4-pentenoyl]-1,3-oxazolidin-2-one | C21H19Cl2NO3 | 详情 | 详情 | |
| (XIX) | 62383 | (2S)-2-(3,4-dichlorophenyl)-4-pentenoic acid | C11H10Cl2O2 | 详情 | 详情 | |
| (XX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXI) | 50421 | 2-(3,4-dichlorophenyl)-4-pentenoic acid | C11H10Cl2O2 | 详情 | 详情 | |
| (XXII) | 62384 | (2S)-2-(3,4-dichlorophenyl)-N-methyl-4-pentenamide | C12H13Cl2NO | 详情 | 详情 | |
| (XXIII) | 62385 | (2S)-2-(3,4-dichlorophenyl)-N-methyl-4-penten-1-amine; N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylamine | C12H15Cl2N | 详情 | 详情 | |
| (XXIV) | 62386 | N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylbenzamide | C19H19Cl2NO | 详情 | 详情 | |
| (XXV) | 62387 | N-[(2S)-2-(3,4-dichlorophenyl)-4,5-dihydroxypentyl]-N-methylbenzamide | C19H21Cl2NO3 | 详情 | 详情 | |
| (XXVI) | 26943 | N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide | C18H17Cl2NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Condensation of 2-(dimethylamino)ethyl chloride hydrochloride (I) with methylamine gave trimethyl ethylenediamine (II), which was coupled with 3,4-dichlorophenylacetic acid (III) in the presence of DCC to afford amide (IV). Subsequent reduction of (IV) with aluminum hydride in THF provided the title diamine.
| 【1】 de Costa, B.R.; et al.; Synthesis, characterization, and biological evaluation of a novel class of N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: Structural requirements and binding affinity at the sigma receptor. J Med Chem 1992, 35, 1, 38. |
| 【2】 De Costa, B.R.; Radesca, L.; Bowen, W.; Long, J.; Walker, J.M.; Rice, K.C.; Gray, N.M.; Contreras, P.C. (Pharmacia Corp.); N-(Arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamine derivs. for CNS disorders. EP 0518216; WO 9222279 . |
| 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) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
| (II) | 15778 | N-[2-(dimethylamino)ethyl]-N-methylamine; N,N,N'-trimethyl-1,2-ethanediamine; N(1),N(1),N(2)-trimethyl-1,2-ethanediamine | 142-25-6 | C5H14N2 | 详情 | 详情 |
| (III) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (IV) | 30415 | 2-(3,4-dichlorophenyl)-N-[2-(dimethylamino)ethyl]-N-methylacetamide | C13H18Cl2N2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The nitration of 2-(3,4-dichlorophenyl)acetic acid (I) with HNO3 and H2SO4 gives 2-(4,5-dichloro-2-nitrophenyl)acetic acid (II), which is treated with refluxing SOCl2 to yield the corresponding acyl chloride (III). The condensation of (III) with bis(trimethylsilyl)acetylene (IV) by means of AlCl3 in dichloromethane affords 1-(2-nitro-4,5-dichlorophenyl)-4-(trimethylsilyl)-3-butyn-2-one (V), which is submitted to a reductive cyclization by means of Fe/AcOH to provide 5,6-dichloro-2-ethynyl-1H-indole (VI) after desilylation with NaOH in methanol. The reaction of (VI) with (Bu3Sn)BuCuCNLi2 gives 5,6-dichloro-2-[2(E)-(tributylstannyl)vinyl]-1H-indole (VII), which is condensed with methyl 3-bromo-2-methoxy-2-propenoate (VIII) by means of Pd(PPh3)4 in hot THF to yield the pentadienoic ester (IX). The hydrolysis of (IX) with LiOH in MeOH affords the corresponding carboxylic acid (X), which is finally condensed with the amine (XI) by means of EDC and HOBT in dichloromethane to provide the target amide.
| 【1】 Conde, J.J.; McGuire, M.; Wallace, M.; Towards the synthesis of osteoclast inhibitor SB-242784. Tetrahedron Lett 2003, 44, 15, 3081. |
| 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) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (II) | 63912 | 2-(4,5-dichloro-2-nitrophenyl)acetic acid | C8H5Cl2NO4 | 详情 | 详情 | |
| (III) | 63913 | 2-(4,5-dichloro-2-nitrophenyl)acetyl chloride | C8H4Cl3NO3 | 详情 | 详情 | |
| (IV) | 27189 | trimethyl[2-(trimethylsilyl)ethynyl]silane | 14630-40-1 | C8H18Si2 | 详情 | 详情 |
| (V) | 63914 | 1-(4,5-dichloro-2-nitrophenyl)-4-(trimethylsilyl)-3-butyn-2-one | C13H13Cl2NO3Si | 详情 | 详情 | |
| (VI) | 63915 | 5,6-dichloro-2-ethynyl-1H-indole | C10H5Cl2N | 详情 | 详情 | |
| (VII) | 63916 | 5,6-dichloro-2-[(E)-2-(tributylstannyl)ethenyl]-1H-indole | C22H33Cl2NSn | 详情 | 详情 | |
| (VIII) | 23638 | C5H7BrO3 | 详情 | 详情 | ||
| (IX) | 19103 | methyl (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate | C15H13Cl2NO3 | 详情 | 详情 | |
| (X) | 19104 | (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid | C14H11Cl2NO3 | 详情 | 详情 | |
| (XI) | 20119 | 1,2,2,6,6-pentamethyl-4-piperidinamine; 1,2,2,6,6-pentamethyl-4-piperidinylamine | C10H22N2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The nitration of 2-(3,4-dichlorophenyl)acetic acid (I) with HNO3 and H2SO4 gives 2-(4,5-dichloro-2-nitrophenyl)acetic acid (II), which is treated with refluxing SOCl2 to yield the corresponding acyl chloride (III). The condensation of (III) with bis(trimethylsilyl)acetylene (IV) by means of AlCl3 in dichloromethane affords 1-(2-nitro-4,5-dichlorophenyl)-4-(trimethylsilyl)-3-butyn-2-one (V), which is submitted to a reductive cyclization by means of Fe/AcOH to provide 5,6-dichloro-2-ethynyl-1H-indole (VI) after desilylation with NaOH in methanol. The condensation of (VI) with methyl 3-bromo-2-methoxy-2-propenoate (VII) by means of Pd(PPh3)4 and CuI in hot DMF yields the penta-2-en-4-ynoic ester (VIII), which is reduced by means of H2 over Lindlar catalyst to obtain, as expected, dienoic ester (IX) as a ZZ/EZ mixture, which is treated directly with a catalytic amount of I2 in refluxing toluene to afford dienoic ester (X) as a single isomer. Alternatively, the reduction of (VIII) to (X) can also be performed with CrSO4 in DMF, however, the yields are low. The hydrolysis of (X) with LiOH in MeOH affords the corresponding carboxylic acid (XI), which is finally condensed with the amine (XII) by means of EDC and HOBT in dichloromethane to provide the target amide.
| 【1】 Conde, J.J.; McGuire, M.; Wallace, M.; Towards the synthesis of osteoclast inhibitor SB-242784. Tetrahedron Lett 2003, 44, 15, 3081. |
| 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) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (II) | 63912 | 2-(4,5-dichloro-2-nitrophenyl)acetic acid | C8H5Cl2NO4 | 详情 | 详情 | |
| (III) | 63913 | 2-(4,5-dichloro-2-nitrophenyl)acetyl chloride | C8H4Cl3NO3 | 详情 | 详情 | |
| (IV) | 27189 | trimethyl[2-(trimethylsilyl)ethynyl]silane | 14630-40-1 | C8H18Si2 | 详情 | 详情 |
| (V) | 63914 | 1-(4,5-dichloro-2-nitrophenyl)-4-(trimethylsilyl)-3-butyn-2-one | C13H13Cl2NO3Si | 详情 | 详情 | |
| (VI) | 63915 | 5,6-dichloro-2-ethynyl-1H-indole | C10H5Cl2N | 详情 | 详情 | |
| (VII) | 23638 | C5H7BrO3 | 详情 | 详情 | ||
| (VIII) | 63918 | methyl (Z)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2-penten-4-ynoate | C15H11Cl2NO3 | 详情 | 详情 | |
| (IX) | 63919 | methyl (2Z,4Z)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate | C15H13Cl2NO3 | 详情 | 详情 | |
| (X) | 19103 | methyl (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate | C15H13Cl2NO3 | 详情 | 详情 | |
| (XI) | 19104 | (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid | C14H11Cl2NO3 | 详情 | 详情 | |
| (XIII) | 20119 | 1,2,2,6,6-pentamethyl-4-piperidinamine; 1,2,2,6,6-pentamethyl-4-piperidinylamine | C10H22N2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)Hexahydroazepine (I) was coupled with N-Boc-glycine (II) by means of EDC and HOBt, and the resulting amide (III) was reduced with LiAlH4 to give diamine (IV). Subsequent coupling of (IV) with 3,4-dichlorophenylacetic acid (V) in the presence of DCC afforded amide (VI). Finally, reduction of (VI) with aluminum hydride in THF provided the title compound.
| 【1】 de Costa, B.R.; et al.; Synthesis, characterization, and biological evaluation of a novel class of N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: Structural requirements and binding affinity at the sigma receptor. J Med Chem 1992, 35, 1, 38. |
| 【2】 De Costa, B.R.; Radesca, L.; Bowen, W.; Long, J.; Walker, J.M.; Rice, K.C.; Gray, N.M.; Contreras, P.C. (Pharmacia Corp.); N-(Arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamine derivs. for CNS disorders. EP 0518216; WO 9222279 . |
| 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) | 18672 | azepane | 111-49-9 | C6H13N | 详情 | 详情 |
| (II) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (III) | 30416 | tert-butyl 2-(1-azepanyl)-2-oxoethylcarbamate | C13H24N2O3 | 详情 | 详情 | |
| (IV) | 30417 | N-[2-(1-azepanyl)ethyl]-N-methylamine; 2-(1-azepanyl)-N-methyl-1-ethanamine | C9H20N2 | 详情 | 详情 | |
| (V) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (VI) | 30418 | N-[2-(1-azepanyl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide | C17H24Cl2N2O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)The intermediate chiral aldehyde (XIV) has been obtained as follows: Acylation of sarcosine methyl ester (II) with 3,5-dichlorobenzoyl chloride (I) provides the N-benzoyl aminoester (III). The dilithium derivative of 3,4-dichlorophenylacetic acid (IV) is condensed with ester (III) to furnish, after acidic work-up, the N-benzoyl amino ketone (V). Subsequent alkylation of (V) with 1-bromo-3-methyl-2-butene (VI) affords (VII). Treatment of ketone (VII) with hydroxylamine yields a mixture of E- and Z- oximes, from which the Z-isomer (VIII) is isolated by column chromatography. Resolution of racemic (VIII) is then accomplished by two procedures. Coupling of (VIII) with N-Boc-D-phenylglycine (IX) produces a diastereomeric mixture of O-acyl oximes, from which isomer (X) can be separated by recrystallization. Hydrazinolysis of the N-acyl oxime (X) furnishes the target (R)-enantiomer (XI). Alternatively, oxime (VIII) is acylated by pivaloyl chloride, and subsequently separated into enantiomers by means of chiral chromatography. The desired isomer (XII) is then subjected to hydrazinolysis, yielding (XI)
| 【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 . |
| 【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 . |
| 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) | 27769 | 3,5-dichlorobenzoyl chloride | 2905-62-6 | C7H3Cl3O | 详情 | 详情 |
| (II) | 10430 | methyl 2-(methylamino)acetate; methyl N-methylglycinate | 5473-12-1 | C4H9NO2 | 详情 | 详情 |
| (III) | 44268 | methyl 2-[(3,5-dichlorobenzoyl)(methyl)amino]acetate | C11H11Cl2NO3 | 详情 | 详情 | |
| (IV) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (V) | 44269 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-oxopropyl]-N-methylbenzamide | C17H13Cl4NO2 | 详情 | 详情 | |
| (VI) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (VII) | 44270 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-6-methyl-2-oxo-5-heptenyl]-N-methylbenzamide | C22H21Cl4NO2 | 详情 | 详情 | |
| (VIII) | 44271 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide | C22H22Cl4N2O2 | 详情 | 详情 | |
| (IX) | 61344 | BOC-D-alpha-phenylglycine | 33125-05-2 | C13H17NO4 | 详情 | 详情 |
| (X) | 61345 | 3,5-dichloro-N-{(Z,6R)-2-[(1R)-1-(3,4-dichlorophenyl)-4-methyl-3-pentenyl]-8-hydroxy-10,10-dimethyl-5-oxo-6-phenyl-4,9-dioxa-3,7-diaza-2-undecen-1-yl}-N-methylbenzamide | C35H39Cl4N3O5 | 详情 | 详情 | |
| (XI) | 44273 | 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide | C22H22Cl4N2O2 | 详情 | 详情 | |
| (XII) | 61346 | 3,5-dichloro-N-((3R)-3-(3,4-dichlorophenyl)-2-{[(2,2-dimethylpropanoyl)oxy]imino}-6-methyl-5-heptenyl)-N-methylbenzamide | C27H30Cl4N2O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)Acylation of sarcosine methyl ester (I) with 3,5-dichlorobenzoyl chloride (II) produced the corresponding amide (III). Claisen condensation of (III) with the dianion of 3,4-dichlorophenylacetic acid (IV), generated in the presence of lithium hexamethyldisilazide, gave, after acid decarboxylation, ketone (V). The lithium enolate of ketone (V) was then alkylated with 1-bromo-3-methyl-2-butene (VI) to afford (VII). Treatment of ketone (VII) with hydroxylamine produced a geometric mixture of oximes from which the desired (E)-isomer (VIII) was isolated by column chromatography. Resolution of the racemic (VIII) was achieved by coupling with N-Boc-D-phenylglycine (IX) followed by fractional crystallization of the desired diastereoisomer (X). Hydrazinolysis of the oxime ester then furnished the chiral intermediate (XI).
| 【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 . |
| 【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 . |
| 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) | 10430 | methyl 2-(methylamino)acetate; methyl N-methylglycinate | 5473-12-1 | C4H9NO2 | 详情 | 详情 |
| (II) | 27769 | 3,5-dichlorobenzoyl chloride | 2905-62-6 | C7H3Cl3O | 详情 | 详情 |
| (III) | 44268 | methyl 2-[(3,5-dichlorobenzoyl)(methyl)amino]acetate | C11H11Cl2NO3 | 详情 | 详情 | |
| (IV) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (V) | 44269 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-oxopropyl]-N-methylbenzamide | C17H13Cl4NO2 | 详情 | 详情 | |
| (VI) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (VII) | 44270 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-6-methyl-2-oxo-5-heptenyl]-N-methylbenzamide | C22H21Cl4NO2 | 详情 | 详情 | |
| (VIII) | 44271 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide | C22H22Cl4N2O2 | 详情 | 详情 | |
| (IX) | 22613 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid | 2900-27-8 | C13H17NO4 | 详情 | 详情 |
| (X) | 44272 | tert-butyl (1R)-2-([[(Z,2R)-1-[[(3,5-dichlorobenzoyl)(methyl)amino]methyl]-2-(3,4-dichlorophenyl)-5-methyl-4-hexenylidene]amino]oxy)-2-oxo-1-phenylethylcarbamate | C35H37Cl4N3O5 | 详情 | 详情 | |
| (XI) | 44273 | 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide | C22H22Cl4N2O2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(III)Diamine (II) was prepared by reaction of N-(2-chloroethyl)pyrrolidine hydrochloride (I) with ethylamine. Coupling of (II) with 3,4-dichlorophenylacetic acid (III) in the presence of DCC afforded amide (IV). The amide function of (IV) was finally reduced by means of aluminum hydride in THF to furnish the title diamine.
| 【1】 de Costa, B.R.; et al.; Synthesis, characterization, and biological evaluation of a novel class of N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: Structural requirements and binding affinity at the sigma receptor. J Med Chem 1992, 35, 1, 38. |
| 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) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 | |
| (II) | 47992 | N-ethyl-2-(1-pyrrolidinyl)-1-ethanamine; N-ethyl-N-[2-(1-pyrrolidinyl)ethyl]amine | C8H18N2 | 详情 | 详情 | |
| (III) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (IV) | 47993 | 2-(3,4-dichlorophenyl)-N-ethyl-N-[2-(1-pyrrolidinyl)ethyl]acetamide | C16H22Cl2N2O | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)The esterification of 3,4-dichlorophenylacetic acid (I) with methanol and ClH gives the methyl ester (II), which is alkylated with allyl bromide and LDA in THF to yield 2-(3,4-dichlorophenyl)-4-pentenoic acid methyl ester (IV). The hydrolysis of (IV) with LiOH in MeOH/water affords the corresponding free acid (V), which is epoxidated with MCPBA in refluxing chloroform to provide epoxide (VI), which, without isolation, is treated in acid medium, giving the tetrahydrofuranone (VII). The silylation of the OH group of (VII) with Tbdms-Cl and imidazole in DMF yields the protected silyl ether (VIII), which is treated with LDA in THF to afford the lithium enolate (IX). The reaction of (IX) with phenylselenyl chloride in THF provides the phenylselenyl derivative (X), which is oxidized with MCPBA to the corresponding selenoxide. This nonisolated compound undergoes spontaneous syn elimination to give, after hydrolysis of the silyl ether with AcOH, 3-(3,4-dichlorophenyl)-5-(hydroxymethyl)furan-2(5H)-one (XI). Finally, this compound is esterified with pivaloyl chloride and pyridine in dichloromethane to afford the target ester.
| 【1】 Pour, M.; et al.; 3-Phenyl-5-acyloxymethyl-2H,5H-furan-2-ones: Synthesis and biological activity of a novel group of potential antifungal drugs. J Med Chem 2001, 44, 17, 2701. |
| 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) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (II) | 47947 | methyl 2-(3,4-dichlorophenyl)acetate | C9H8Cl2O2 | 详情 | 详情 | |
| (III) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (IV) | 50420 | methyl 2-(3,4-dichlorophenyl)-4-pentenoate | C12H12Cl2O2 | 详情 | 详情 | |
| (V) | 50421 | 2-(3,4-dichlorophenyl)-4-pentenoic acid | C11H10Cl2O2 | 详情 | 详情 | |
| (VI) | 50422 | 2-(3,4-dichlorophenyl)-3-(2-oxiranyl)propionic acid | C11H10Cl2O3 | 详情 | 详情 | |
| (VII) | 50423 | 3-(3,4-dichlorophenyl)-5-(hydroxymethyl)dihydro-2(3H)-furanone | C11H10Cl2O3 | 详情 | 详情 | |
| (VIII) | 50424 | 5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-(3,4-dichlorophenyl)dihydro-2(3H)-furanone | C17H24Cl2O3Si | 详情 | 详情 | |
| (IX) | 50425 | C17H23Cl2LiO3Si | 详情 | 详情 | ||
| (X) | 50426 | 5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-(3,4-dichlorophenyl)-3-(phenylselanyl)dihydro-2(3H)-furanone | C23H28Cl2O3SeSi | 详情 | 详情 | |
| (XI) | 50427 | 3-(3,4-dichlorophenyl)-5-(hydroxymethyl)-2(5H)-furanone | C11H8Cl2O3 | 详情 | 详情 | |
| (XII) | 44281 | pivalic acid | 75-98-9 | C5H10O2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VI)Claisen condensation between 3,4-dichlorophenylacetic acid (VI) and N-Boc-sarcosine methyl ester (VII), followed by acidic decarboxylation of the intermediate keto acid, furnishes amino ketone (VIII). Alkylation of (VIII) with the silylated bromoethanol (IX) in the presence of NaH and NaI yields adduct (X). Subsequent condensation of ketone (X) with O-allyl hydroxylamine (XI) generates the corresponding oxime (XII). After desilylation of (XII) with tetrabutylammonium fluoride, the resultant primary alcohol (XIII) is oxidized under Swern conditions to furnish aldehyde (XIV)
| 【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 . |
| 【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (VII) | 60815 | methyl 2-[(tert-butoxycarbonyl)(methyl)amino]acetate | C9H17NO4 | 详情 | 详情 | |
| (VIII) | 60816 | tert-butyl 3-(3,4-dichlorophenyl)-2-oxopropyl(methyl)carbamate | C15H19Cl2NO3 | 详情 | 详情 | |
| (IX) | 55573 | 2-Bromoethoxy-t-butyldimethylsilane | 86864-60-0 | C8H19BrOSi | 详情 | 详情 |
| (X) | 60817 | tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-3-(3,4-dichlorophenyl)-2-oxopentyl(methyl)carbamate | C23H37Cl2NO4Si | 详情 | 详情 | |
| (XI) | 49195 | 3-(aminooxy)-1-propene; O-allylhydroxylamine | C3H7NO | 详情 | 详情 | |
| (XII) | 60818 | tert-butyl 2-[(allyloxy)imino]-5-{[tert-butyl(dimethyl)silyl]oxy}-3-(3,4-dichlorophenyl)pentyl(methyl)carbamate | C26H42Cl2N2O4Si | 详情 | 详情 | |
| (XIII) | 60819 | tert-butyl 2-[(allyloxy)imino]-3-(3,4-dichlorophenyl)-5-hydroxypentyl(methyl)carbamate | C20H28Cl2N2O4 | 详情 | 详情 | |
| (XIV) | 60820 | tert-butyl 2-[(allyloxy)imino]-3-(3,4-dichlorophenyl)-5-oxopentyl(methyl)carbamate | C20H26Cl2N2O4 | 详情 | 详情 |