|
【结 构 式】 
|
【分子编号】26935 【品名】2-(3,4-dichlorophenyl)acetonitrile 【CA登记号】3218-49-3 |
【 分 子 式 】C8H5Cl2N 【 分 子 量 】186.03984 【元素组成】C 51.65% H 2.71% Cl 38.11% N 7.53% |
合成路线1
该中间体在本合成路线中的序号：(X)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：(VI)Alkylation of 3,4-dichlorophenylacetonitrile (VI) with (tetrahydropyranyloxy)ethyl bromide (V) (prepared by protection of 2-bromoethanol (IV) with dihydropyran) furnished nitrile (VII). Catalytic hydrogenation of (VII) in the presence of Raney-Ni and Et3N gave the primary amine (VIII). After acidic hydrolysis of the tetrahydropyranyl group of (VIII), the resultant amino alcohol was resolved by means of D-tartaric acid providing the (S)-enantiomer (IX). Reaction of amine (IX) with ethyl chloroformate afforded carbamate (X), which was further reduced to the N-methyl amine (XI) employing LiAlH4. Subsequent acylation of (XI) with benzoyl chloride furnished benzamide (XII). Mesylate (XIII) was then prepared by treatment of alcohol (XII) with methanesulfonyl chloride and triethylamine. Finally, condensation between piperidine (III) and mesylate (XIII) led to the title compound
| 【1】 Emonds-Alt, X.; Goulaouic, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthelabo); Arylalkylamines, process for their preparation and pharmaceutical compsns. containing them. EP 0474561; FR 2666335; FR 2678267; JP 1992261155; US 5236921; US 5350852 . |
| 【2】 Emonds-Alt, X.; Proietto, V.; Van Broeck, D.; Vilain, P.; Advenier, C.; Neliat, G.; Le Fur, G.; Breliere, J.-C.; Pharmacological profile and chemical synthesis of SR 48968, a non-peptide antagonist of the neurokinin A (NK2) receptor. Bioorg Med Chem Lett 1993, 3, 5, 925. |
| 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 | |
| (IV) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (V) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (VI) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (VII) | 26936 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C15H17Cl2NO2 | 详情 | 详情 | |
| (VIII) | 26937 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C15H21Cl2NO2 | 详情 | 详情 | |
| (IX) | 26939 | (3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (X) | 26940 | ethyl (2S)-2-(3,4-dichlorophenyl)-4-hydroxybutylcarbamate | C13H17Cl2NO3 | 详情 | 详情 | |
| (XI) | 26941 | (3S)-3-(3,4-dichlorophenyl)-4-(methylamino)-1-butanol | C11H15Cl2NO | 详情 | 详情 | |
| (XII) | 26942 | N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide | C18H19Cl2NO2 | 详情 | 详情 | |
| (XIII) | 62380 | (3S)-4-(benzoylamino)-3-(3,4-dichlorophenyl)butyl methanesulfonate | C18H19Cl2NO4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Alkylation of 3,4-dichlorophenylacetonitrile (I) with 2-(tetrahydropyranyloxy)ethyl bromide (II) in the presence of NaH in THF afforded nitrile (III). This was further alkylated with ethyl 3-bromopropionate (IV) using LDA to produce the cyano ester adduct (V). Catalytic hydrogenation of the cyano group of (V) in the presence of Raney-nickel, with concomitant intramolecular cyclization of the intermediate amino ester, gave rise to the piperidinone (VI). This was further reduced to piperidine (VII) using LiAlH4 in THF. After acidic deprotection of the tetrahydropyranyl group of (VII), the racemic amine was resolved by means of tartaric acid to furnish the desired enantiomer (VIII). Acylation of piperidine (VIII) with 3-isopropoxyphenylacetic acid (IX) employing BOP as the coupling reagent yielded amide (X). Conversion of (X) to the mesylate (XI) was carried out by treatment with methanesulfonyl chloride and Et3N. Then, N-alkylation of 4-phenylquinuclidine (XII) with mesylate (XI) produced the corresponding ammonium salt, which was finally subjected to anion exchange of the mesylate for a chloride group by treatment with HCl.
| 【1】 Emonds-Alt, X.; Gueule, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthelabo); Quaternary basic amides as tachykinines antagonists. EP 0591040; FR 2696178; JP 1998175976; US 5583134; US 5712288 . |
| 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) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 26936 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C15H17Cl2NO2 | 详情 | 详情 | |
| (IV) | 29132 | ethyl 3-bromopropanoate | 539-74-2 | C5H9BrO2 | 详情 | 详情 |
| (V) | 59767 | ethyl 4-cyano-4-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanoate | C20H25Cl2NO4 | 详情 | 详情 | |
| (VI) | 59768 | 5-(3,4-dichlorophenyl)-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-2-piperidinone | C18H23Cl2NO3 | 详情 | 详情 | |
| (VII) | 59769 | 2-[3-(3,4-dichlorophenyl)-3-piperidinyl]ethyl tetrahydro-2H-pyran-2-yl ether; 3-(3,4-dichlorophenyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]piperidine | C18H25Cl2NO2 | 详情 | 详情 | |
| (VIII) | 59770 | 2-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-ethanol | C13H17Cl2NO | 详情 | 详情 | |
| (IX) | 59771 | 2-(3-isopropoxyphenyl)acetic acid | C11H14O3 | 详情 | 详情 | |
| (X) | 59772 | 1-[(3S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidinyl]-2-(3-isopropoxyphenyl)-1-ethanone | C24H29Cl2NO3 | 详情 | 详情 | |
| (XI) | 59773 | 2-{(3S)-3-(3,4-dichlorophenyl)-1-[2-(3-isopropoxyphenyl)acetyl]piperidinyl}ethyl methanesulfonate | C25H31Cl2NO5S | 详情 | 详情 | |
| (XII) | 59774 | 4-phenyl-1-azabicyclo[2.2.2]octane | C13H17N | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Michael addition of methyl acrylate (XII) to (3,4-dichlorophenyl)acetonitrile (XI) produced the cyano diester adduct (XIII). Catalytic hydrogenation of the cyano group of (XIII) over Raney nickel with concomitant intramolecular cyclization gave rise to the piperidinone (XIV). After basic hydrolysis of the methyl ester function of (XIV), the resultant piperidone propionic acid (XV) was reduced to piperidino alcohol (XVI) by means of borane in THF. Resolution of the racemic piperidine (XVI) employing (+)-camphorsulfonic acid provided the dextro enantiomer (XVII). After N-protection of (XVII) as the Boc derivative (XVIII), its primary alcohol was activated as the corresponding mesylate (XIX) with methanesulfonyl chloride and Et3N. Condensation between mesylate (XIX) and intermediate piperidine (X) in acetonitrile at 60 C, produced (XX). The title benzamido derivative was then obtained by acid-promoted Boc group cleavage in (XX), followed by acylation with benzoyl chloride.
| 【1】 Bichon, D.; Van Broeck, D.; Proietto, V.; Gueule, P.; Emonds-Alt, X. (Sanofi-Synthélabo); Novel N-(3,4-dichlorophenyl-propyl)-piperidine derivs. as selective human NK3-receptor antagonists. EP 0673928; FR 2717477; FR 2717478; FR 2719311; JP 1996048669; US 5741910; US 5942523; US 6124316 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 59267 | N-methyl-N-(4-phenyl-4-piperidinyl)acetamide | C14H20N2O | 详情 | 详情 | |
| (XI) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (XII) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (XIII) | 59268 | dimethyl 4-cyano-4-(3,4-dichlorophenyl)heptanedioate | C16H17Cl2NO4 | 详情 | 详情 | |
| (XIV) | 59269 | methyl 3-[3-(3,4-dichlorophenyl)-6-oxo-3-piperidinyl]propanoate | C15H17Cl2NO3 | 详情 | 详情 | |
| (XV) | 59270 | 3-[3-(3,4-dichlorophenyl)-6-oxo-3-piperidinyl]propanoic acid | C14H15Cl2NO3 | 详情 | 详情 | |
| (XVI) | 29465 | 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
| (XVII) | 29466 | 3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
| (XVIII) | 59271 | tert-butyl (3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-1-piperidinecarboxylate | C19H27Cl2NO3 | 详情 | 详情 | |
| (XIX) | 59272 | tert-butyl (3S)-3-(3,4-dichlorophenyl)-3-{3-[(methylsulfonyl)oxy]propyl}-1-piperidinecarboxylate | C20H29Cl2NO5S | 详情 | 详情 | |
| (XX) | 59273 | tert-butyl (3R)-3-(3-{4-[acetyl(methyl)amino]-4-phenyl-1-piperidinyl}propyl)-3-(3,4-dichlorophenyl)-1-piperidinecarboxylate | C33H45Cl2N3O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)In a related synthesis, (3,4-dichlorophenyl)acetonitrile (XI) was alkylated with bromide (XXII) --prepared by protection of 3-bromopropanol (XXI) with dihydropyran-- to afford (XXIII). Subsequent Michael addition of methyl acrylate (XII) to (XXIII) in the presence of Triton B® gave the cyanoacid (XXIV). This was cyclized to the glutarimide (XXV) by refluxing in HOAc in the presence of H2SO4. Reduction of (XXV) using borane-dimethylsulfide complex produced the already reported racemic piperidinoalcohol (XVI). After acylation of the amine group of (XVI) with benzoyl chloride to yield (XXVI), its hydroxyl group was converted into the target mesylate precursor (XXVII) with methanesulfonyl chloride and Et3N.
| 【1】 Giardina, G.A.M.; et al.; A reliable and efficient synthesis of SR 142801. Bioorg Med Chem Lett 1996, 6, 19, 2307. |
| 【2】 Chen, H.G.; et al.; A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist. Bioorg Med Chem Lett 1997, 7, 5, 555. |
| 【3】 Grugni, M.; Rigolio, R.; Erhard, K.F. (GlaxoSmithKline Inc.; GlaxoSmithKline SpA); Process for the preparation of 3,3-disubstd. piperidines. WO 9805640 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (XII) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (XVI) | 29465 | 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
| (XXI) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (XXII) | 42252 | 3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran | C8H15BrO2 | 详情 | 详情 | |
| (XXIII) | 59274 | 2-(3,4-dichlorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)pentanenitrile | C16H19Cl2NO2 | 详情 | 详情 | |
| (XXIV) | 59275 | 4-cyano-4-(3,4-dichlorophenyl)-7-(tetrahydro-2H-pyran-2-yloxy)heptanoic acid | C19H23Cl2NO4 | 详情 | 详情 | |
| (XXV) | 59276 | 3-[3-(3,4-dichlorophenyl)-2,6-dioxo-3-piperidinyl]propyl acetate | C16H17Cl2NO4 | 详情 | 详情 | |
| (XXVI) | 59277 | [3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-1-piperidinyl](phenyl)methanone | C21H23Cl2NO2 | 详情 | 详情 | |
| (XXVII) | 59278 | 3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate | C22H25Cl2NO4S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)The reaction of 2-bromoethanol (I) with dihydropyran by means of a strong acid ion exchange resin gives the tetrahydropyranyl ether (II), which is condensed with 2-(3,4-dichlorophenyl)acetonitrile (III) by means of NaH in THF yielding thebutyronitrile (IV). The reduction of (IV) with H2 over RaNi in ethanol/NH4OH affords the butylamine (V), which is deprotected with HCl in methanol providing racemic 2-(3,4-dichlorophenyl)-4-hydroxybutylamine (VI). The optical resolution of (VI) with D-tartaric acid affords the corresponding (S) isomer (VII), which is treated with ethyl chloroformate and triethylamine in dichloromethane to give the carbamate (VIII). The reduction of (VIII) with LiAlH4 in THF yields N-[2(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylamine (IX), which is acylated with benzoyl chloride (X) and triethylamine in dichloromethane to affords the amide (XI). Oxidation of the hydroxyl group of (XI) with Dess-Martin periodinane yields the corresponding aldehyde (XII), which is reductocondensed with 4-[N-(trifluoroacetyl)-N-[3-(trifluoroacetamido)propyl]amino]piperidine (XIII) by means of NaBH3CN in methanol/acetic acid providing the bis(trifluoroacetylated) intermediate (XIV). The deprotection of (XIV) with KOH in methanol/water gives the diamine intermediate (XV), which is finally cyclized with carbonyldiimidazole (CDI) in chloroform.
| 【1】 Miller, S.C. (AstraZeneca plc); Therapeutic heterocycles which antagonize neurokinin receptors. JP 1997501439; US 5567700; US 5990130; US 6124279; WO 9505377 . |
| 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) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (IV) | 26936 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C15H17Cl2NO2 | 详情 | 详情 | |
| (V) | 26937 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C15H21Cl2NO2 | 详情 | 详情 | |
| (VI) | 26938 | 4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (VII) | 26939 | (3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (VIII) | 26940 | ethyl (2S)-2-(3,4-dichlorophenyl)-4-hydroxybutylcarbamate | C13H17Cl2NO3 | 详情 | 详情 | |
| (IX) | 26941 | (3S)-3-(3,4-dichlorophenyl)-4-(methylamino)-1-butanol | C11H15Cl2NO | 详情 | 详情 | |
| (X) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XI) | 26942 | N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide | C18H19Cl2NO2 | 详情 | 详情 | |
| (XII) | 26943 | N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide | C18H17Cl2NO2 | 详情 | 详情 | |
| (XIII) | 26944 | 2,2,2-trifluoro-N-(4-piperidinyl)-N-[3-[(2,2,2-trifluoroacetyl)amino]propyl]acetamide | C12H17F6N3O2 | 详情 | 详情 | |
| (XIV) | 26945 | N-[(2S)-2-(3,4-dichlorophenyl)-4-[4-((2,2,2-trifluoroacetyl)[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino)-1-piperidinyl]butyl]-N-methylbenzamide | C30H34Cl2F6N4O3 | 详情 | 详情 | |
| (XV) | 26946 | N-[(2S)-4-[4-[(3-aminopropyl)amino]-1-piperidinyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide | C26H36Cl2N4O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)The protection of 3-bromo-1-propanol (I) with dihydropyran (DHP) and p-toluenesulfonic acid gives the tetrahydropyranyl ether (II), which is condensed with 3,4-dichlorophenylacetonitrile (III) by means of NaH in THF yielding the pentanenitrile (IV). The condensation of (IV) with ethyl 3-bromopropionate (V) by means of potassium hexamethyldisylazide (KHMDS) in THF affords the heptanoate (VI), which is reductocyclized with H2 over RaNi in ethanol/aq. NH4OH affording the piperidone (VII). The reduction of (VII) by means of LiAlH4 in THF gives the piperidine (VIII), which is deprotected with HCl in ethyl ether yielding the racemic propanol (IX). The optical resolution of (IX) by means of (+)-camphorsulfonic acid in isopropanol affords the desired enantiomer (X), which is acylated with benzoyl chloride (XI) and DIEA in dichloromethane providing the benzoylpiperidine (XII). The reaction of (XII) with methanesulfonyl chloride and triethylamine gives the mesylate (XIII), which is treated with KI in refluxing acetone to yield the 3-iodopropyl derivative (XIV). Finally, (XIV) is condensed with 4-hydroxy-4-phenylpiperidine (XV) by means of KHCO3 in hot acetonitrile. The intermediate 4-hydroxy-4-phenylpiperidine (XV) has been obtained as follows: The reaction of 1-benzyl-4-piperidone (XVI) with phenyllithium in THF gives 1-benzyl-4-hydroxy-4-phenylpiperidine (XVII), which is then debenzy-lated by hydrogenation with H2.
| 【1】 Kuo, B.-S.; Lee, H.T.; Roth, B.D.; Chung, F.-Z.; Atherton, J.; Chen, M.H.; Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists. Acta Pharm Sin 1999, 20, 3, 283. |
| 【2】 Chen, M.H.G.; Lee, H.T.; Chung, F.-Z. (Pfizer Inc.); 3-Alkyl-3-phenyl-piperidines. WO 9811090 . |
| 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) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (II) | 29460 | 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether | C9H17BrO2 | 详情 | 详情 | |
| (III) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (IV) | 29461 | 2-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile | C17H21Cl2NO2 | 详情 | 详情 | |
| (V) | 29132 | ethyl 3-bromopropanoate | 539-74-2 | C5H9BrO2 | 详情 | 详情 |
| (VI) | 29462 | ethyl 4-cyano-4-(3,4-dichlorophenyl)-8-(tetrahydro-2H-pyran-2-yloxy)octanoate | C22H29Cl2NO4 | 详情 | 详情 | |
| (VII) | 29463 | 5-(3,4-dichlorophenyl)-5-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-2-piperidinone | C20H27Cl2NO3 | 详情 | 详情 | |
| (VIII) | 29464 | 3-(3,4-dichlorophenyl)-3-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]piperidine; 4-[3-(3,4-dichlorophenyl)-3-piperidinyl]butyl tetrahydro-2H-pyran-2-yl ether | C20H29Cl2NO2 | 详情 | 详情 | |
| (IX) | 29465 | 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
| (X) | 29466 | 3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
| (XI) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XII) | 29467 | [(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone | C21H23Cl2NO2 | 详情 | 详情 | |
| (XIII) | 29468 | 3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate | C22H25Cl2NO4S | 详情 | 详情 | |
| (XIV) | 29469 | [(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone | C21H22Cl2INO | 详情 | 详情 | |
| (XV) | 28021 | 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine | 40807-61-2 | C11H15NO | 详情 | 详情 |
| (XVI) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (XVII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (XVIII) | 29470 | 1-benzyl-4-phenyl-4-piperidinol | C18H21NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Dialkylation of 2-aryl acetonitrile (I) with bromoacetaldehyde dimethyl acetal (II) by means of NaNH2 in toluene provides diacetal (III), which is cyclized to cyanopiperidine derivative (IV) by first hydrolysis of the acetal groups with HCl, followed by reductive amination with methylamine in the presence of NaBH3CN in MeOH. Finally, the target product is obtained by hydrolysis of the nitrile group of (IV) with aqueous H2SO4, followed by esterification performed by heating with EtOH.
| 【1】 katz, J.L.; Trudell, M.L.; Lomenzo, S.A.; Kopajtic, T.; Gerdes, R.M.; Izenwasser, S.; Synthesis, dopamine and serotonin transporter binding affinities of novel analogues of meperidine. Bioorg Med Chem Lett 1999, 9, 23, 3273. |
| 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) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (II) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (III) | 47009 | 2-(3,4-dichlorophenyl)-2-(2,2-dimethoxyethyl)-4,4-dimethoxybutanenitrile | C16H21Cl2NO4 | 详情 | 详情 | |
| (IV) | 47010 | 4-(3,4-dichlorophenyl)-1-methyl-4-piperidinecarbonitrile | C13H14Cl2N2 | 详情 | 详情 |