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【结 构 式】 
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【分子编号】20884 【品名】1-(3-bromopropyl)benzene 【CA登记号】637-59-2 |
【 分 子 式 】C9H11Br 【 分 子 量 】199.09034 【元素组成】C 54.3% H 5.57% Br 40.13% |
合成路线1
该中间体在本合成路线中的序号：(I)A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.
| 【1】 Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.; Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A). J Label Compd Radiopharm 1987, 24, 10, 1177-84. |
| 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) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 20885 | 4-phenylbutanenitrile | 2046-18-6 | C10H11N | 详情 | 详情 |
| (III) | 20886 | Benzenebutyric acid; 4-Phenylbutyric acid | 1821-12-1 | C10H12O2 | 详情 | 详情 |
| (IV) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (V) | 20721 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone | C10H9BrO | 详情 | 详情 | |
| (VI) | 20722 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime | C10H10BrNO | 详情 | 详情 | |
| (VII) | 20723 | 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10BrNO | 详情 | 详情 | |
| (VIII) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (IX) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (X) | 20893 | ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H16N4O3 | 详情 | 详情 | |
| (XI) | 20894 | ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | 109010-60-8 | C14H18N2O3 | 详情 | 详情 |
| (XII) | 20895 | 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid | C12H14N2O3 | 详情 | 详情 | |
| (XIII) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Condensation of bis(4-fluorophenyl)methyl 2-chloroethyl ether (I) with piperazine (II) in refluxing toluene afforded the monosubstituted piperazine (III). This was then alkylated with (3-bromopropyl)benzene (IV) in boiling EtOH to furnish the title compound.
| 【1】 Gootjes, J. (Gist-Brocades NV); Piperazine derivs., process for their preparation and their use. DE 2755752; US 4202896 . |
| 【2】 Van der Zee, P.; et al.; Aryl 1,4-dialk(en)ylpiperazines as selective and very potent inhibitors of dopamine uptake. Eur J Med Chem 1980, 15, 4, 363. |
| 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) | 54931 | 1-[(2-chloroethoxy)(4-fluorophenyl)methyl]-4-fluorobenzene; bis(4-fluorophenyl)methyl 2-chloroethyl ether | C15H13ClF2O | 详情 | 详情 | |
| (II) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (III) | 54932 | 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazine; bis(4-fluorophenyl)methyl 2-(1-piperazinyl)ethyl ether | C19H22F2N2O | 详情 | 详情 | |
| (IV) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)1-(3-Phenylpropyl)piperazine (III) has been obtained by condensation of 3-phenylpropyl bromide (I) with piperazine (II) in refluxing acetonitrile. The condensation of bis(4-fluorophenyl)methanol (IV) with 2-chloroethanol (V) by means of sulfuric acid gives the 2-chloroethyl bis(4-fluorophenyl)methyl ether (VI), which si treated with NaI to yield the corresponding iodo derivative (VII). Finally this compound is condensed with the intermediate piperazine (III) by means of aq. Na2CO3 to afford the target disubstituted piperazine.
| 【1】 Zhang, J.; Ironside, M.D.; Sugathapala, P.M.; Robertson, J.; Darey, M.C.P.; Scale-up synthesis of the dopamine uptake inhibitor GBR-12909. Org Process Res Dev 2002, 6, 5, 621. |
| 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) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (III) | 38636 | 1-(3-phenylpropyl)piperazine | C13H20N2 | 详情 | 详情 | |
| (IV) | 41974 | 4,4'-Difluorobenzhydrol; bis(4-Fluorophenyl)methanol; alpha-(4-fluorophenyl)benzenemethanol; 4-fluoro-alpha-(4-fluorophenyl)benzenemethanol | 365-24-2 | C13H10F2O | 详情 | 详情 |
| (V) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
| (VI) | 54931 | 1-[(2-chloroethoxy)(4-fluorophenyl)methyl]-4-fluorobenzene; bis(4-fluorophenyl)methyl 2-chloroethyl ether | C15H13ClF2O | 详情 | 详情 | |
| (VII) | 56868 | bis(4-fluorophenyl)methyl 2-iodoethyl ether; 1-fluoro-4-[(4-fluorophenyl)(2-iodoethoxy)methyl]benzene | C15H13F2IO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The cyclization of pyridine-3-carbaldehyde (I) with L-cysteine (II) gives 2-(3-pyridyl)thiazolidine-4(R)-carboxylic acid (II), which is finally condensed with 1-(3-phenylpropyl)piperazine (IV) by means of DCC and HOBT in DMF. The intermediate 1-(3-phenylpropyl)piperazine (IV) has been obtained as follows: The condensation of piperazine-1-carboxylic acid ethyl ester (V) with 3-phenylpropyl bromide (VI) by means of K2CO3 in 2-butanone gives 4-(3-phenylpropyl)piperazine-1-carboxylic acid ethyl ester (VII), which is decarboxylated with NaOH in refluxing ethanol.
| 【1】 Mase, T.; Hara, H.; Nagaoka, H.; Takahasi, T.; Suzuki, T.; Tomioka, K.; Yamada, T. (Yamanouchi Pharmaceutical Co., Ltd.); Saturated heterocyclic carboxamide derivs.. AU 8812080; EP 0279681; JP 1988208582; US 4987132 . |
| 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) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (II) | 38633 | (2S)-2-amino-2-(methylsulfanyl)ethanoic acid | C3H7NO2S | 详情 | 详情 | |
| (III) | 38634 | (4R)-2-(3-pyridinyl)-1,3-thiazolidine-4-carboxylic acid | C9H10N2O2S | 详情 | 详情 | |
| (IV) | 38636 | 1-(3-phenylpropyl)piperazine | C13H20N2 | 详情 | 详情 | |
| (V) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (VI) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (VII) | 38635 | ethyl 4-(3-phenylpropyl)-1-piperazinecarboxylate | C16H24N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Selenium dioxide oxidation of diaryl ethanone (I) afforded diketone (II), which was cyclized to the imidazole (III) by reaction with hexamethylenetetramine and ammonium acetate in hot AcOH. Alkylation of (III) with 1-bromo-3-phenylpropane (IV) in the presence of NaH gave rise to a mixture of regioisomeric imidazoles (V) and (VI) that were separated by column chromatography. After deprotonation of the desired isomer (V) with LDA, treatment with iodine produced iodoimidazole (VII). Then, palladium-catalyzed coupling of (VII) with 3-butyn-1-ol (VIII) yielded the title compound.
| 【1】 Malloy, E.; Wachter, M.P.; Wu, W.; Beers, S.A. (Ortho-McNeil Pharmaceutical, Inc.); Substd. imidazoles useful in the treatment of inflammatory diseases. EP 1028954; US 5965583; WO 9847892 . |
| 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) | 37912 | 2-(4-fluorophenyl)-1-(4-pyridinyl)-1-ethanone | C13H10FNO | 详情 | 详情 | |
| (II) | 37913 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1,2-ethanedione | C13H8FNO2 | 详情 | 详情 | |
| (III) | 33798 | 4-[4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridine | C14H10FN3 | 详情 | 详情 | |
| (IV) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (V) | 37914 | 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-1H-imidazol-5-yl]pyridine | C23H20FN3 | 详情 | 详情 | |
| (VI) | 37915 | 4-[5-(4-fluorophenyl)-1-(3-phenylpropyl)-1H-imidazol-4-yl]pyridine | C23H20FN3 | 详情 | 详情 | |
| (VII) | 37916 | 4-[4-(4-fluorophenyl)-2-iodo-1-(3-phenylpropyl)-1H-imidazol-5-yl]pyridine | C23H19FIN3 | 详情 | 详情 | |
| (VIII) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 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 alkylation of diethyl acetamidomalonate (II) with 1-bromo-3-phenylpropane (I) by means of NaOEt provided the substituted malonate (III), which upon hydrolysis and further decarboxylation gave rise to racemic 2-(acetylamino)-5-phenylpentanoic acid (IVa-b). Kinetic resolution employing Acylase I in the presence of CoCl2 produced a mixture of the (S)-amino acid (V) and the unaltered (R)-amide (VI), which were separated by differential solubility. The desired (R)-amide (VI) was hydrolyzed with aqueous HCl and then treated with EtOH to produce aminoester (VII). Subsequent coupling of (VII) with N-Boc-alpha-aminoisobutyric acid (VIII) employing 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) yielded the protected dipeptide (IX). Basic hydrolysis of the ethyl ester of (IX) afforded the intermediate (X).
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa),(VI) | 35759 | (2R)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (IVb) | 35775 | (2S)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (I) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (III) | 35758 | diethyl 2-(acetamido)-2-(3-phenylpropyl)malonate | C18H25NO5 | 详情 | 详情 | |
| (V) | 35760 | (2S)-2-amino-5-phenylpentanoic acid | C11H15NO2 | 详情 | 详情 | |
| (VII) | 35761 | ethyl (2R)-2-amino-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (IX) | 35762 | ethyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C22H34N2O5 | 详情 | 详情 | |
| (X) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Alkylation of diethyl acetamidomalonate (I) with 1-bromo-3-phenylpropane (II) in the presence of NaOEt afforded phenylpropyl malonate (III). Hydrolysis and subsequent decarboxylation of malonate ester (III) yielded racemic 2-(acetylamino)-5-phenylpentanoic acid (IV). Kinetic resolution was achieved by enantioselective hydrolysis of the (S)-acetamide to give amino acid (VI). The desired (R)-enantiomer (V) was then hydrolyzed with HCl and further esterified with HCl-EtOH to provide amino ester (VII). Coupling with N-Boc-alpha-aminoisobutyric acid (VIII) via activation with 2-chloro-4,6-dimethoxy-1,3,5-triazine (IX) furnished dipeptide (X). The ethyl ester group of (X) was then hydrolyzed to acid (XI) using LiOH.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 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) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (II) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (III) | 35758 | diethyl 2-(acetamido)-2-(3-phenylpropyl)malonate | C18H25NO5 | 详情 | 详情 | |
| (IV) | 38799 | N-acetyl-5-phenylnorvaline | C13H17NO3 | 详情 | 详情 | |
| (V) | 35759 | (2R)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (VI) | 35760 | (2S)-2-amino-5-phenylpentanoic acid | C11H15NO2 | 详情 | 详情 | |
| (VII) | 35761 | ethyl (2R)-2-amino-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (IX) | 38798 | 2-chloro-4,6-dimethoxy-1,3,5-triazine; 4-chloro-6-methoxy-1,3,5-triazin-2-yl methyl ether | 3140-73-6 | C5H6ClN3O2 | 详情 | 详情 |
| (X) | 35762 | ethyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C22H34N2O5 | 详情 | 详情 | |
| (XI) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Alkylation of the sodium salt of dibenzyl malonate (I) with 1-bromo-3-phenylpropane (II) afforded the (phenylpropyl)malonate (III). The benzyl ester groups of (III) were removed by hydrogenolysis in the presence of Pd/C to produce the intermediate malonic acid (IV). Subsequent condensation of diacid (IV) with formaldehyde in the presence of piperidine proceeded with concomitant decarboxylation, yielding 2-methylene-5-phenylpentanoic acid (V). Addition of HBr to the unsaturated acid (V) gave bromide (VI). Condensation of (VI) with thiophenol (VIII), prepared by nucleophilic displacement of 4-(4-chlorobenzoyl)pyridine (VI) with sodium hydrogen sulfide, furnished the sulfide adduct (IX). This was oxidized to the corresponding sulfone (X) by treatment with Oxone(R). Conversion of (X) to the desired hydroxamic acid was carried out by coupling with O-tert-butyldimethylsilyl hydroxylamine, followed by deprotection of the resulting O-silyl hydroxamate (XI) with tetrabutylammonium fluoride.
| 【1】 Baxter, A.D.; et al.; Arylsulphonyl hydroxamic acids: Potent and selective matrix metalloproteinase inhibitors. Bioorg Med Chem Lett 2001, 11, 11, 1465. |
| 【2】 Owen, D.A.; Montana, J.G.; Keily, J.F.; Watson, R.J.; Baxter, A.D. (Celltech Group plc); Hydroxamic and carboxylic acid derivs. having MMP and TNF inhibitory activity. EP 0968182; JP 2000517297; WO 9805635 . |
| 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) | 16013 | dibenzyl malonate | 15014-25-2 | C17H16O4 | 详情 | 详情 |
| (II) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (III) | 52539 | bis(phenylmethyl) 2-(3-phenylpropyl)propanedioate | C26H26O4 | 详情 | 详情 | |
| (IV) | 52540 | 2-(3-phenylpropyl)propanedioic acid | C12H14O4 | 详情 | 详情 | |
| (V) | 52541 | 2-(3-phenylpropyl)-2-propenoic acid | C12H14O2 | 详情 | 详情 | |
| (VI) | 52542 | 2-(bromomethyl)-5-phenylpentanoic acid | C12H15BrO2 | 详情 | 详情 | |
| (VII) | 52543 | (4-chlorophenyl)(4-pyridinyl)methanone | C12H8ClNO | 详情 | 详情 | |
| (VIII) | 52544 | 4-pyridinyl(4-sulfanylphenyl)methanone | C12H9NOS | 详情 | 详情 | |
| (IX) | 52545 | 5-phenyl-2-({[4-(4-pyridinylcarbonyl)phenyl]sulfanyl}methyl)pentanoic acid | C24H23NO3S | 详情 | 详情 | |
| (X) | 52546 | 5-phenyl-2-({[4-(4-pyridinylcarbonyl)phenyl]sulfonyl}methyl)pentanoic acid | C24H23NO5S | 详情 | 详情 | |
| (XI) | 52547 | N-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-phenyl-2-({[4-(4-pyridinylcarbonyl)phenyl]sulfonyl}methyl)pentanamide | C30H38N2O5SSi | 详情 | 详情 |