|
【结 构 式】 
|
【分子编号】30560 【品名】1,5-dibromopentane 【CA登记号】111-24-0 |
【 分 子 式 】C5H10Br2 【 分 子 量 】229.9424 【元素组成】C 26.12% H 4.38% Br 69.5% |
合成路线1
该中间体在本合成路线中的序号：(A)Compound is prepared through the following sequence: The condensation of 1-methyl-7-methoxy-2-tetralone (I) with 1,5-dibromopentane (A) by means of NaH or potassium tertbutylate affords 1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone (II); this product is cyclized with NaH to give 5-methyl-3-methoxy-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-13-one (III). The ketone (III), by reaction with hydroxylamine hydrochloride in pyridine, is converted into its oxime (IV), which is reduced with H2 over Raney-Ni to a mixture of isomeric amines that were separated by crystallization of the HCl salts giving 5alpha-methyl-3-methoxy-5,6,7,8,9,11alpha,12-octahydro-5,11-methanobenzocyclodecen-13beta-amine (V), which is finally submitted to cleavage with concentrated HBr.
| 【1】 Freed, M.E.; Potoski, J.R.; Benzobicycloalkanes compounds. DE 2159324; FR 2116509; GB 1363658; GB 1363659 . |
| 【2】 Freed, M.E.; et al.; Bridged aminotetralins as novel potent analgesic substances. J Med Chem 1973, 16, 6, 595. |
| 【3】 Hopkins, S.J.; Castaner, J.; Dezocine. Drugs Fut 1976, 1, 5, 229. |
| 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) | 30560 | 1,5-dibromopentane | 111-24-0 | C5H10Br2 | 详情 | 详情 |
| (Va) | 33980 | (1R,9S,15R)-4-methoxy-1-methyltricyclo[7.5.1.0(2,7)]pentadeca-2,4,6-trien-15-ylamine; (1R,9S,15R)-4-methoxy-1-methyltricyclo[7.5.1.0(2,7)]pentadeca-2,4,6-trien-15-amine | C17H25NO | 详情 | 详情 | |
| (Vb) | 33981 | (1R,9S,15S)-4-methoxy-1-methyltricyclo[7.5.1.0(2,7)]pentadeca-2,4,6-trien-15-ylamine; (1R,9S,15S)-4-methoxy-1-methyltricyclo[7.5.1.0(2,7)]pentadeca-2,4,6-trien-15-amine | C17H25NO | 详情 | 详情 | |
| (I) | 33976 | 7-methoxy-1-methyl-3,4-dihydro-2(1H)-naphthalenone | C12H14O2 | 详情 | 详情 | |
| (II) | 33977 | 1-(5-bromopentyl)-7-methoxy-1-methyl-3,4-dihydro-2(1H)-naphthalenone | C17H23BrO2 | 详情 | 详情 | |
| (III) | 33978 | 4-methoxy-1-methyltricyclo[7.5.1.0(2,7)]pentadeca-2,4,6-trien-15-one | C17H22O2 | 详情 | 详情 | |
| (IV) | 33979 | 4-methoxy-1-methyltricyclo[7.5.1.0(2,7)]pentadeca-2,4,6-trien-15-one oxime | C17H23NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)This compound can be obtained by several different ways: 1) By condensation of 4-ethylpropiophenone (I), formaldehyde (II) and piperidine (III) in refluxing isopropanol. 2) By reaction of 4-ethyl-alpha-methyl-beta-chloropropiophenone (IV) with (III) in refluxing ethanol. 3) By cyclization of 4-ethyl-alpha-methyl-beta-amino-propiophenone (V) with 1,5-dibromopentane (VI) in hot ethanol. 4) By a Friedel-Kraft's reaction of ethylbenzene (VII) with 3-piperidinoisobutyryl chloride (VIII) by means of AlCl3 at reflux temperature. 5) By condensation of 4-ethyl-alpha-methylenepropiophenone (IX) with (III) in ethanol.
| 【1】 Murakami, M.; Sone, T.; Sako, K.; Wakabayashi, M.; Kodaira, R.; JP 7925571 . |
| 【2】 Murakami, M.; Sone, T.; Sako, K.; Wakabayashi, M.; Kodaira, R.; Preparation of propiophenone derivative. JP 54036274 . |
| 【3】 Murakami, M.; Sone, T.; Sako, K.; Wakabayashi, M.; Kodaira, R.; Novel preparation of piperidine derivatives. JP 54032480 . |
| 【4】 Murakami, M.; Sone, T.; Sako, K.; Wakabayashi, M.; Kodaira, R; Preparation of propiophenone derivative. JP 54030178 . |
| 【5】 Morita, E.; Kanai, T.; Amino-substituted propiophenone derivatives and medicaments containing same. JP 52085175 . |
| 【6】 Morita, E.; Kanai, T. (Eisai Co., Ltd.); Propiophenone derivatives in the treatment of pathological muscular conditions. US 3995047; US 4181803 . |
| 【7】 Castaner, J.; Blancafort, P.; Serradell, M.N.; EMPP. Drugs Fut 1982, 7, 2, 105. |
| 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) | 22076 | 1-(4-ethylphenyl)-1-propanone | 27465-51-6 | C11H14O | 详情 | 详情 |
| (II) | 22075 | Formaldehyde; Paraformaldehyde | 1118-66-7 | CH2O | 详情 | 详情 |
| (III) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (IV) | 31975 | 3-chloro-1-(4-ethylphenyl)-2-methyl-1-propanone | C12H15ClO | 详情 | 详情 | |
| (V) | 31976 | 3-amino-1-(4-ethylphenyl)-2-methyl-1-propanone | C12H17NO | 详情 | 详情 | |
| (VI) | 30560 | 1,5-dibromopentane | 111-24-0 | C5H10Br2 | 详情 | 详情 |
| (VII) | 31977 | 1-ethylbenzene | 100-41-4 | C8H10 | 详情 | 详情 |
| (VIII) | 31978 | 2-methyl-3-(1-piperidinyl)propanoyl chloride | C9H16ClNO | 详情 | 详情 | |
| (IX) | 31979 | 1-(4-ethylphenyl)-2-methyl-2-propen-1-one | C12H14O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The alkylation of ethyl 1,3-dithiane-2-carboxylate (I) with 1,5-dibromopentane (II) by means of NaH in DMF gives ethyl 2-(5-bromopentyl)-1,3-dithiane-2-carboxylate (III), which is treated with NBS in acetonitrile water to open the dithiane ring yielding ethyl 7-bromo-2-oxoheptanoate (IV). Hydrolysis of the ester group of (IV) with 50% HBr affords 7-bromo-2-oxoheptanoic acid (V), which is condensed with 2,2-dimethylcyclopropanecarboxamide (VI) in refluxing toluene giving 7-bromo-2-(2,2-dimethycyclopropanecarboxamido)-2-octenoic acid (VII). Finally, this compound is condensed with L-cysteine (VIII) by means of NaOH in water.
| 【1】 Graham, D.W.; Rogers, E.F.; Kahan, F.M. (Merck & Co., Inc.); 2-(Cyclopropanecarboxamido)-alkenoic acids, their esters and salts, and antibacterial compositions comprising the same a thiennamycin-type compound. EP 0048301 . |
| 【2】 Castaner, J.; Serradell, M.N.; Cilastatin. Drugs Fut 1984, 9, 5, 320. |
| 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) | 30559 | ethyl 1,3-dithiane-2-carboxylate | 20462-00-4 | C7H12O2S2 | 详情 | 详情 |
| (II) | 30560 | 1,5-dibromopentane | 111-24-0 | C5H10Br2 | 详情 | 详情 |
| (III) | 30561 | ethyl 2-(5-bromopentyl)-1,3-dithiane-2-carboxylate | C12H21BrO2S2 | 详情 | 详情 | |
| (IV) | 30562 | ethyl 7-bromo-2-oxoheptanoate | C9H15BrO3 | 详情 | 详情 | |
| (V) | 30563 | 7-bromo-2-oxoheptanoic acid | C7H11BrO3 | 详情 | 详情 | |
| (VI) | 30564 | 2,2-dimethylcyclopropanecarboxamide | C6H11NO | 详情 | 详情 | |
| (VII) | 30565 | (Z)-7-bromo-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid | C13H20BrNO3 | 详情 | 详情 | |
| (VIII) | 14643 | L-cysteine; (R)-2-Amino-3-mercaptopropionic acid | 52-90-4 | C3H7NO2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)The condensation of 3-(trifluoromethyl)benzaldehyde (I) with phosphonate (II) by means of NaH in THF gives the unsaturated ester (III), which is reduced with DIBAL in ethyl ether / hexane, yielding 3-[3-(trifluoromethyl)phenyl]allyl alcohol (IV). The Sharpless asymmetric epoxidation of (IV) affords the epoxyalcohol (V), which is oxidized with pyridine·SO3 to the corresponding aldehyde and condensed with phosphorane (A) to provide the unsaturated epoxyaldehyde (VI). The condensation of aldehyde (VI) with the pentylphosphonium derivative (VII) by means of NaNH2 in THF gives the corresponding adduct (VIII). The addition of 4-oxo-7-sulfanyl-4H-1-benzopyran-2-carboxylic acid methyl ester (IX) to the epoxide group of (VIII) by means of Et3N in methanol yields the expected alpha-hydroxy thioether (X), which is finally hydrolyzed with NaOH in THF/water to afford the target sodium salt. The intermediate pentylphosphonium derivative (VII) has been obtained by selective alkylation of 2,4-dihydroxy-3-propylacetophenone (XI) with 1,5-dibromopentane (XII) followed by reaction of the resulting ether with triphenylphosphine in refluxing toluene.
| 【1】 Von Sprecher, A.; Beck, A.; Sallmann, A.; Breitenstein, W.; Wiestner, H.; Kimmel, S.; Anderson, G.P.; Subramanian, N.; Bray, M.A.; Peptidoleukotriene antagonists: Structural analogs of leukotriene D4 with special emphasis on CGP 45715A. Drugs Fut 1991, 16, 9, 827. |
| 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) | 20110 | 2-(triphenylphosphoranyl)acetaldehyde | C20H19OP | 详情 | 详情 | |
| (I) | 35964 | 3-(trifluoromethyl)benzaldehyde | 454-89-7 | C8H5F3O | 详情 | 详情 |
| (II) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (III) | 42936 | ethyl (E)-3-[3-(trifluoromethyl)phenyl]-2-propenoate | 113048-68-3 | C12H11F3O2 | 详情 | 详情 |
| (IV) | 42937 | (E)-3-[3-(trifluoromethyl)phenyl]-2-propen-1-ol | C10H9F3O | 详情 | 详情 | |
| (V) | 42938 | [(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]methanol | C10H9F3O2 | 详情 | 详情 | |
| (VI) | 42939 | (E)-3-[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]-2-propenal | C12H9F3O2 | 详情 | 详情 | |
| (VII) | 42940 | [5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl](triphenyl)phosphonium bromide | C34H38BrO3P | 详情 | 详情 | |
| (VIII) | 42941 | 1-[2-hydroxy-3-propyl-4-[((5Z,7E)-8-[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]-5,7-octadienyl)oxy]phenyl]-1-ethanone | C28H31F3O4 | 详情 | 详情 | |
| (IX) | 42942 | methyl 4-oxo-7-sulfanyl-4H-chromene-2-carboxylate | C11H8O4S | 详情 | 详情 | |
| (X) | 42943 | methyl 7-[((1S,2E,4Z)-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-[(R)-hydroxy[3-(trifluoromethyl)phenyl]methyl]-2,4-nonadienyl)sulfanyl]-4-oxo-4H-chromene-2-carboxylate | C39H39F3O8S | 详情 | 详情 | |
| (XI) | 13137 | 2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone | 40786-69-4 | C11H14O3 | 详情 | 详情 |
| (XII) | 30560 | 1,5-dibromopentane | 111-24-0 | C5H10Br2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)The condensation of 2-methylcyclohexanone (I) with 2-thienyl lithium (II) or 2-thienylmagnesium bromide (III) gives cyclohexanol (IV) as a diastereomeric mixture, which was treated with Na-N3 in trichloroacetic acid to yield the azide (V). The reduction of (V) with LiAlH4 or RaNi/iPr-OH affords the corresponding amine (VI), preferentially with the cis-configuration. Finally, this compound is condensed with 1,5-dibromopentane (VII) by means of K2CO3 in acetonitrile to provide the target compound as a diastereomeric mixture. The separation of the cis- and trans- racemates has been performed by HPLC. The optical resolution was performed by a cumbersome crystallization process using CSA and di-p-toluoyltartaric acid.
| 【1】 Michaud, M.; et al.; Homochiral structures derived from 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) are potent non-competitive antagonists of glutamate at NMDA receptor sites. Eur J Med Chem 1994, 29, 11, 869. |
| 【2】 Kamenka, J.-M.; Privat, A.; Chicheportiche, R.; Rondouin, G. (CNRS (Centre National de la Recherche Scientifique)); Pharmaceutical compsns. for neuroprotection containing arylcyclohexylamines. US 5179109; WO 9005524 . |
| 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) | 54406 | 2-Methylcyclohexanone; Tetrahydro-o-cresol; o-Methylcyclohexanone | 583-60-8 | C7H12O | 详情 | 详情 |
| (II) | 21682 | 2-thienyllithium | 2786-07-4 | C4H3LiS | 详情 | 详情 |
| (III) | 32082 | bromo(2-thienyl)magnesium | 5713-61-1 | C4H3BrMgS | 详情 | 详情 |
| (IV) | 54407 | (1R,2S)-2-methyl-1-(2-thienyl)cyclohexanol | C11H16OS | 详情 | 详情 | |
| (V) | 54408 | (1R,2S)-2-methyl-1-(2-thienyl)cyclohexyl azide; 2-[(1R,2S)-1-azido-2-methylcyclohexyl]thiophene | C11H15N3S | 详情 | 详情 | |
| (VI) | 54409 | (1R,2S)-2-methyl-1-(2-thienyl)cyclohexanamine; (1R,2S)-2-methyl-1-(2-thienyl)cyclohexylamine | C11H17NS | 详情 | 详情 | |
| (VII) | 30560 | 1,5-dibromopentane | 111-24-0 | C5H10Br2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The reaction of 4-nitrophenol (I) with 1,5-dibromopentane (II) and NaOH in refluxing water gives the aryl ether (III), which is finally condensed with pyrrolidine (IV) in refluxing ethanol.
| 【1】 Ganellin, C.; et al.; Synthesis of potent non-imidazole histamine H3-receptor antagonists. Arch Pharm 1998, 331, 12, 395. |
| 【2】 Stark, H.; Ligneau, X.; Garbarg, M.; Schunack, W.G.; Ganellin, C.R.; Lecomte, J.-M.; Arrang, J.-M.; Leurquin, F.; Sigurd, E.; Schwartz, J.-C. (Societe Civile Bioprojet); Non-imidazole aryloxy (or arylthio) alkylamines as histamine H3-receptor antagonists and their therapeutic applications. EP 0978512 . |