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【结 构 式】 
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【分子编号】30344 【品名】1-bromoethane；ethyl bromide 【CA登记号】74-96-4 |
【 分 子 式 】C2H5Br 【 分 子 量 】108.9657 【元素组成】C 22.05% H 4.63% Br 73.33% |
合成路线1
该中间体在本合成路线中的序号：(A)The reaction of 1-(4-methoxyphenyl)-2-phenylethan-1-one (I) with ethyl bromide (A) gave (II) in nearly quantitative yield. Demethoxylation of (II) with pyridine hydrochloride gave (III) in about 70% yield. Treatment of (III) with dimethylaminoethyl chloride (B) gave (IV) in more than 60% yield. Reaction of (IV) with 3'-(2-tetrahydropyranyloxy)phenylmagnesium bromide (C) gave (V) in about 60% yield. Refluxing a solution of (V) in ethanolic hydrochloric acid gave the stereoisomeric E- and Z-mixture (VIa, VIb) of the hydrochloric salt. Fractional crystallization of the mixture in methanol/ether yielded the pure hydrochloric salt of the E-isomer in 48% yield. Conversion of the hydrochloric salt into the free base and treatment of the latter with citric acid yielded the appropriate K-21060E citrate.
| 【1】 Schickaneder, H.; Loser, R.; Grill, H. (Klinge Pharma GmbH); 1,1,2-triphenylbut-1-ene derivatives. DE 3046719; EP 0054168; US 5047431 . |
| 【2】 Loser, R.; Seibel, K.; Janiak, P.-St.; K-21060 E. Drugs Fut 1984, 9, 3, 186. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 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 |
| (A) | 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 |
| (VIa) | 30350 | 3-((E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl)phenol | C26H29NO2 | 详情 | 详情 | |
| (VIb) | 30351 | 3-((Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl)phenol | C26H29NO2 | 详情 | 详情 | |
| (I) | 30343 | 1-(4-methoxyphenyl)-2-phenyl-1-ethanone | C15H14O2 | 详情 | 详情 | |
| (II) | 30345 | 1-(4-methoxyphenyl)-2-phenyl-1-butanone | C17H18O2 | 详情 | 详情 | |
| (III) | 30346 | 1-(4-hydroxyphenyl)-2-phenyl-1-butanone | C16H16O2 | 详情 | 详情 | |
| (IV) | 30347 | 1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-butanone | 68047-07-4 | C20H25NO2 | 详情 | 详情 |
| (V) | 30349 | 1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1-butanol | C31H39NO4 | 详情 | 详情 | |
| (C) | 30348 | bromo[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]magnesium | C11H13BrMgO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(D)The reaction of p-chlorobenzaldehyde (I) sodium cyanide and ethyl acetate gives ethyl 4-(p-chlorophenyl)-4-oxobutyrate (II), which is hydrolyzed with KOH to the corresponding free acid (III). The reduction of (III) with Zn and aqueous HCl affords 4-(p-chlorophenyl)butyric acid (IV), which is condensed with heptylamine (B) by means of oxalyl chloride (A) in refluxing benzene to yield N-heptyl-4-(p-chlorophenyl)butyramide (V), which is reduced with diborane in refluxing THF to afford N-heptyl-4-(p-chlorophenyl)butylamine (VI). The acetylation of (VI) with acetyl chloride (C) by means of Na2CO3 in acetone gives N-acetyl-N-heptyl-4-(p-chlorophenyl)butylamine (VII), which is reduced with diborane as before to yield N-ethyl-N-heptyl-4-(p-chlorophenyl)butylamine (VIII). The quaternization of (VIII) with refluxing ethyl bromide (D) gives N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butylammonium bromide (IX), which by elution through a column with Dowex 1-X8, hydroxide form, resin is converted into N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butyl ammonium hydroxide (X). Finally, this compound is salified with diluted aqueous phosphoric acid.
| 【1】 Molloy, B.B.; Steinberg, M.I.; EP 0002604 . |
| 【2】 Hillier, K.; Castaner, J.; Clofilium Phosphate. Drugs Fut 1981, 6, 12, 764. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 23252 | 1-heptanamine; heptylamine | 111-68-2 | C7H17N | 详情 | 详情 |
| (A) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (D) | 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 |
| (I) | 29029 | 4-chlorobenzaldehyde | 104-88-1 | C7H5ClO | 详情 | 详情 |
| (II) | 37460 | ethyl 4-(4-chlorophenyl)-4-oxobutanoate | C12H13ClO3 | 详情 | 详情 | |
| (III) | 37461 | 4-(4-chlorophenyl)-4-oxobutyric acid | 3984-34-7 | C10H9ClO3 | 详情 | 详情 |
| (IV) | 37462 | 4-(4-chlorophenyl)butyric acid | C10H11ClO2 | 详情 | 详情 | |
| (V) | 37463 | 4-(4-chlorophenyl)-N-heptylbutanamide | C17H26ClNO | 详情 | 详情 | |
| (VI) | 37464 | N-[4-(4-chlorophenyl)butyl]-1-heptanamine; N-[4-(4-chlorophenyl)butyl]-N-heptylamine | C17H28ClN | 详情 | 详情 | |
| (VII) | 37465 | N-[4-(4-chlorophenyl)butyl]-N-heptylacetamide | C19H30ClNO | 详情 | 详情 | |
| (VIII) | 37466 | N-[4-(4-chlorophenyl)butyl]-N-ethyl-N-heptylamine; N-[4-(4-chlorophenyl)butyl]-N-ethyl-1-heptanamine | C19H32ClN | 详情 | 详情 | |
| (IX) | 37467 | N-[4-(4-chlorophenyl)butyl]-N,N-diethyl-1-heptanaminium bromide | C21H37BrClN | 详情 | 详情 | |
| (X) | 37468 | N-[4-(4-chlorophenyl)butyl]-N,N-diethyl-1-heptanaminium hydroxide | C21H38ClNO | 详情 | 详情 | |
| (C) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：Compound can be prepared in three steps starting from (-)-scopalamine (hyoscine) (I) by demethylation of (-)-scopolamine with phosgene or potassium permanganate, by alkylation of the resulting (-)-norscopolamine (II) with ethylbromide (A) by means of sodium carbonate, and by quaternization of the resulting (-)-N-ethyl-norscopolamine (III) with methylbromide yielding Ba-253-BR.
| 【1】 Dharma, A.P.; Oxitropium bromide. Drugs Fut 1979, 4, 2, 117. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 | |
| (I) | 33311 | (1R,2S,4R,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0(2,4)]non-7-yl (2S)-3-hydroxy-2-phenylpropanoate | C17H21NO4 | 详情 | 详情 | |
| (II) | 33312 | (1R,2S,4R,5S)-3-oxa-9-azatricyclo[3.3.1.0(2,4)]non-7-yl (2S)-3-hydroxy-2-phenylpropanoate | C16H19NO4 | 详情 | 详情 | |
| (III) | 33313 | (1R,2S,4R,5S)-9-ethyl-3-oxa-9-azatricyclo[3.3.1.0(2,4)]non-7-yl (2S)-3-hydroxy-2-phenylpropanoate | C18H23NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Treatment of thiosemicarbazide hydrobromide (I) with ethyl bromide (II) in refluxing EtOH affords S-ethylthiosemicarbazide (III), which is then condensed with N-acetyl-ethylenediamine (IV) in refluxing EtOH to provide N1-(2-acetamidoethyl)-N3-aminoguanidine (V). Finally, the desired product is obtained by the formation of the corresponding hydrochloride salt by treatment of (V) with HCl in methanol. Alternatively the target compound can be obtained by reaction of N-acetylethylenediamine (IV) with cyanogen chloride in 2-propanol followed by treatment with anhydrous hydrazine.
| 【1】 Wagle, D.R.; Ulrich, P.C. (Alteon Inc.); N-Acylaminoalkyl-hydrazinecarboximidamides. US 5877217 . |
| 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) | 12954 | 1-Hydrazinecarbothioamide; Thiosemicarbazide | 79-19-6 | CH5N3S | 详情 | 详情 |
| (II) | 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 |
| (III) | 48868 | ethyl 1-hydrazinecarbimidothioate | C3H9N3S | 详情 | 详情 | |
| (IV) | 41136 | N-(2-aminoethyl)acetamide | 1001-53-2 | C4H10N2O | 详情 | 详情 |
| (V) | 48869 | N-(2-[[hydrazino(imino)methyl]amino]ethyl)acetamide | C5H13N5O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XX)The intermediate N-(2-ethoxy-4-nitrophenyl)phthalimide (IV) is prepared by N-protection of 2-amino-5-nitrophenol (XVII) with phthalic anhydride (XVIII) in the presence of AcOH at 115-120 °C to give the corresponding phthalimide (XIX), which is then alkylated at the phenolic hydroxyl with ethyl bromide (XX) in the presence of K2CO3 in DMF .
| 【1】 Chew, W., Papamichelakis, M. (Wyeth). Methods of preparing 3-cyanoquinolines and intermediates made thereby. WO 2006127205. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 69192 | 2-(2-ethoxy-4-nitrophenyl)isoindoline-1,3-dione | C16H12N2O5 | 详情 | 详情 | |
| (XVII) | 33067 | 2-amino-5-nitrophenol | 121-88-0 | C6H6N2O3 | 详情 | 详情 |
| (XVIII) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (XIX) | 69202 | 2-(2-hydroxy-4-nitrophenyl)isoindoline-1,3-dione | C14H8N2O5 | 详情 | 详情 | |
| (XX) | 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XX)N-Protection of 2-amino-5-nitrophenol (XVII) with Ac2O in the presence of AcOH gives N-(2-hydroxy-4-nitrophenyl)acetamide (XXI), which upon O-alkylation with ethyl bromide (XX) in the presence of K2CO3 in DMF at 60 °C affords N-(2-ethoxy-4-nitrophenyl) acetamide (XXII). Reduction of the nitro derivative (XXII) with H2 over Pd/C in THF furnishes the corresponding aniline (XXIII), which by condensation with ethyl 2-cyano-3-ethoxy-2-propenoate (XXIV) at reflux produces enamine (XXV). Thermal cyclization of enamino ester (XXV) in Dowtherm at 250 °C then yields 4-hydroxyquinoline derivative (XXVI) , which upon chlorination with POCl3 in 1,2-diethoxyethane at 80-85 °C affords N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (VII) . Alternatively, condensation of ethyl cyanoacetate (II) with morpholine (XXVII) at 100-110 °C gives 4-(cyanoacetyl)morpholine (XXVIII), which after coupling with 4-acetamido-3-ethoxyaniline (XXIII) in the presence of triethyl orthoformate in i-PrOH at 50-60 °C produces the arylamino propenamide (XXIX). Finally, cyclization of (XXIX) in the presence of POCl3 in acetonitrile at 60-65 °C then leads to the target intermediate (VII) .
| 【1】 Wissner, A., Rabindran, S.K., Tsou, H.-R. (Wyeth). Substituted quinolines as protein tyrosine kinase enzyme inhibitors. EP 1670473, WO 2005034955. |
| 【2】 Rabindran, S.K., Tsou, H.-R., Wissner, A. (Wyeth). Protein tyrosine kinase enzyme inhibitors. US 2005059678, US 7399865, WO 2005028443. |
| 【3】 Bernier, C., Shaw, C.-C. (Wyeth). Method of preparing 4-halogenated quinoline intermediates. WO 2009139797. |
| 【4】 Wang, Y., Warren, C. Papamichelakis, M. (Wyeth). Quinoline intermediates of receptor tyrosine kinase inhibitors and the synthesis thereof. WO 2005070890. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (VII) | 69196 | 6-acetamido-4-chloro-7-ethoxyquinoline-3-carbonitrile;4-Chloro-3-cyano-7-ethoxy-6-(acetylamino)quinoline | 848133-76-6 | C14H12ClN3O2 | 详情 | 详情 |
| (XVII) | 33067 | 2-amino-5-nitrophenol | 121-88-0 | C6H6N2O3 | 详情 | 详情 |
| (XX) | 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 |
| (XXI) | 69203 | N-(2-hydroxy-4-nitrophenyl)acetamide | C8H8N2O4 | 详情 | 详情 | |
| (XXII) | 69204 | N-(2-ethoxy-4-nitrophenyl)acetamide | C10H12N2O4 | 详情 | 详情 | |
| (XXIII) | 69205 | N-(4-amino-2-ethoxyphenyl)acetamide | C10H14N2O2 | 详情 | 详情 | |
| (XXIV) | 43563 | ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (XXV) | 69206 | (E)-ethyl 3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyanoacrylate | C16H19N3O4 | 详情 | 详情 | |
| (XXVI) | 69207 | N-(3-cyano-7-ethoxy-4-hydroxyquinolin-6-yl)acetamide | C14H13N3O3 | 详情 | 详情 | |
| (XXVII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XXVIII) | 69208 | 4-(cyanoacetyl)morpholine;Cyanoacetic acid morpholide;N-(Cyanoacetyl)morpholine;3-Morpholin-4-yl-3-oxopropionitrile;3-(4-Morpholinyl)-3-oxopropanenitrile;(Morpholinocarbonyl)acetonitrile;(Morpholin-4-ylcarbonyl)acetonitrile | 15029-32-0 | C7H10N2O2 | 详情 | 详情 |
| (XXIX) | 69209 | (E)-N-(4-((2-cyano-3-morpholino-3-oxoprop-1-en-1-yl)amino)-2-ethoxyphenyl)acetamide | C18H22N4O4 | 详情 | 详情 |