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【结 构 式】 
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【分子编号】27903 【品名】2-Bromoacetyl chloride 【CA登记号】22118-09-8 |
【 分 子 式 】C2H2BrClO 【 分 子 量 】157.39398 【元素组成】C 15.26% H 1.28% Br 50.77% Cl 22.52% O 10.17% |
合成路线1
该中间体在本合成路线中的序号：(B)The alkylation of 2-amino-5-chloro-2'-fluorobenzophenone (II) with 2,2,2-trifluoroethyl trichloromethylsulfonate (A) gives 2-(2,2,2-trifluoroethylamino)-5-chloro-2'-fluorobenzophenone (III), which is bromoacetylated with bromoacetyl chloride (B) in refluxing benzene yielding the bromoacetanilide (IV).This compound is cyclized with NH3 in chloroform affording 7-chloro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (I), which by reaction with P2S5 in refluxing dioxane gives the target compound.
| 【1】 Steinman, M.; Benzodiazepines and the process for their manufacture. DE 2138773; ES 393953; FR 2102114; GB 1345938 . |
| 【2】 Steinman, M.; 1-Polyfluoroalkyl-1,4-benzodiazepin-2-thiones for effecting tranquilization, sedation and treating colvulsions. US 3920818 . |
| 【3】 Castaner, J.; Thorpe, P.; Quazepam. Drugs Fut 1978, 3, 2, 139. |
| 【4】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60. |
| 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) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (A) | 33474 | 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate | 23199-56-6 | C3H2Cl3F3O3S | 详情 | 详情 |
| (I) | 33471 | 7-Chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C17H11ClF4N2O | 详情 | 详情 | |
| (II) | 32281 | 2-Amino-5-chloro-2'-fluorobenzophenone; (2-Amino-5-chlorophenyl)(2-fluorophenyl)methanone | 784-38-3 | C13H9ClFNO | 详情 | 详情 |
| (III) | 33472 | [5-Chloro-2-[(2,2,2-trifluoroethyl)amino]phenyl](2-fluorophenyl)methanone; 2-(2,2,2-Trifluoroethylamino)-5-chloro-2'-fluorobenzophenone | C15H10ClF4NO | 详情 | 详情 | |
| (IV) | 33473 | 2-bromo-N-[4-chloro-2-(2-fluorobenzoyl)phenyl]-N-(2,2,2-trifluoroethyl)acetamide | C17H11BrClF4NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The condensation of 4-phenyl-1-butanol (I) with 1,6-dibromohexane (II) by means of NaH in THF gives the ether (III), which is condensed with benzylamine (IV) by means of NaI and TEA in DMSO to yield the secondary amine (V). The condensation of (V) with 5-(bromoacetyl)-2-hydroxybenzaldehyde (VI) in refluxing acetonitrile affords the tertiary amine (VII). The reduction of both carbonyl groups of (VII) by means of NaBH4 in methanol affords the dihydroxy amine (VIII), which is finally debenzylated by means of h2 over Pd/C in the same solvent to provide the target salmeterol. The intermediate 5-(bromoacetyl)-2-hydroxybenzaldehyde (VI) has been obtained by Friedel Crafts condensation of 2-hydroxybenzaldehyde (IX) with bromoacetyl chloride (X) by means of AlCl3 in dichloromethane.
| 【1】 Rong, Y.; Ruoho, A.E.; A new synthetic approach to salmeterol. Synth Commun 1999, 29, 12, 2155. |
| 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) | 27291 | 4-phenyl-1-butanol | 3360-41-6 | C10H14O | 详情 | 详情 |
| (II) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
| (III) | 31479 | 1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene | 94749-73-2 | C16H25BrO | 详情 | 详情 |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 35837 | N-benzyl-6-(4-phenylbutoxy)-1-hexanamine; N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine | C23H33NO | 详情 | 详情 | |
| (VI) | 50873 | 5-(2-bromoacetyl)-2-hydroxybenzaldehyde | C9H7BrO3 | 详情 | 详情 | |
| (VII) | 50874 | 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzaldehyde | C32H39NO4 | 详情 | 详情 | |
| (VIII) | 35839 | 4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 | |
| (IX) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (X) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)A synthesis of [14C]-labeled fluvastatin has been described: The acylation of fluorobenzene (I) with [14C]-bromoacetyl chloride (II) by means of AlCl3 gives the expected phenacyl bromide (III), which is condensed with N-isopropylaniline (IV) in hot ethanol yielding the tertiary amine (V). The cyclization of (V) by means of anhydrous ZnCl2 in refluxing ethanol affords the indole (VI), which is alkylated with 3-(N-methyl-N-phenylamino)acroleine (VII) by means of POCl3 in refluxing acetonitrile giving 3-[3-(4-fluorophenyl)-1-isopropylindol-2-yl]acroleine (VIII). The reductocondensation of (VIII) with tert-butyl acetoacetate (IX) by means of NaH and BuLi in THF yields 7-[3-(4-fluorophenyl)-1-isopropylindol-2-yl)-5-hydroxy-3-oxo-6-heptenoic acid tert-butyl ester (X), which is further reduced with NaBH4 and diethyl(methoxy)borane in THF to the dihydroxy compound (XI) as a mixture of the two syn-enantiomers (XI). Finally, this compound is hydrolyzed with NaOH in methanol to the expected sodium salt.
| 【1】 Jones, L.; Tang, Y.S.; Sunay, U.B.; Synthesis of carbon-14 labeled fluvastatin (Lescol(R)). J Label Compd Radiopharm 1998, 41, 1, 1. |
| 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) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (II) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (II) | 45080 | 2-bromoacetyl chloride | C2H2BrClO | 详情 | 详情 | |
| (III) | 27904 | 2-bromo-1-(4-fluorophenyl)-1-ethanone | 403-29-2 | C8H6BrFO | 详情 | 详情 |
| (III) | 45081 | 2-bromo-1-(4-fluorophenyl)-1-ethanone | C8H6BrFO | 详情 | 详情 | |
| (IV) | 27905 | N-isopropyl-N-phenylamine | 768-52-5 | C9H13N | 详情 | 详情 |
| (V) | 11787 | 1-(4-Fluorophenyl)-2-(isopropylanilino)-1-ethanone | C17H18FNO | 详情 | 详情 | |
| (V) | 45082 | 1-(4-fluorophenyl)-2-(isopropylanilino)-1-ethanone | C17H18FNO | 详情 | 详情 | |
| (VI) | 11788 | 3-(4-Fluorophenyl)-1-isopropyl-1H-indole | 93957-49-4 | C17H16FN | 详情 | 详情 |
| (VI) | 45083 | 3-(4-fluorophenyl)-1-isopropyl-1H-indole | C17H16FN | 详情 | 详情 | |
| (VII) | 27906 | (E)-3-(methylanilino)-2-propenal | C10H11NO | 详情 | 详情 | |
| (VIII) | 11790 | (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal | C20H18FNO | 详情 | 详情 | |
| (VIII) | 45084 | (E)-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal | C20H18FNO | 详情 | 详情 | |
| (IX) | 27907 | Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate | 1694-31-1 | C8H14O3 | 详情 | 详情 |
| (X) | 27908 | tert-butyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate | C28H32FNO4 | 详情 | 详情 | |
| (X) | 45085 | tert-butyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate | C28H32FNO4 | 详情 | 详情 | |
| (XI) | 27909 | tert-butyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate | C28H34FNO4 | 详情 | 详情 | |
| (XI) | 45086 | tert-butyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate | C28H34FNO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)A new synthesis of FTY-720 has been described: The Friedel Crafts condensation of octylbenzene (I) with bromoacetyl chloride (II) by means of AlCl3 in dichloromethane gives the phenacyl bromide (III), which is condensed with 2-acetamidomalonic acid diethyl ester (IV) by means of EtONa in ethanol/THF to yielding the ketone-malonic ester adduct (V). Reduction of (V) with Et3SiH by means of TiCl4 in dichloromethane affords compound (VI), which is then reduced with LiAlH4 in THF followed by acetylation with acetic anhydride and pyridine to provide the acetate (VII). Finally, compound (VII) is hydrolyzed with LiOH in refluxing methanol/water and treated with HCl in ethyl ether.
| 【1】 Renault, P.; Durand, P.; Peralba, P.; Sierra, F.; A new efficient synthesis of the immunosuppressive agent FTY-720. Synthesis 2000, 4, 505. |
| 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) | 43807 | 1-octylbenzene | 2189-60-8 | C14H22 | 详情 | 详情 |
| (II) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (III) | 43808 | 2-bromo-1-(4-octylphenyl)-1-ethanone | C16H23BrO | 详情 | 详情 | |
| (IV) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (V) | 43809 | diethyl 2-(acetamido)-2-[2-(4-octylphenyl)-2-oxoethyl]malonate | C25H37NO6 | 详情 | 详情 | |
| (VI) | 16711 | diethyl 2-(acetamido)-2-(4-octylphenethyl)malonate | C25H39NO5 | 详情 | 详情 | |
| (VII) | 16712 | 2-(acetamido)-2-[(acetoxy)methyl]-4-(4-octylphenyl)butyl acetate | C25H39NO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Swern oxidation of 1-(4-pyridinyl)-4-piperidinemethanol (I) affords aldehyde (II). Reductive amination of (II) with the (R)-diaminopropionic acid derivative (III) in the presence of NaBH(OAc)3 yields (IV). Subsequent acylation of (IV) with bromoacetyl chloride (V) provides bromoacetamide (VI). Acidic cleavage of the N-Boc group of (VI), followed by cyclization in the presence of triethylamine leads to piperazinone (VII). Sulfonylation of amine (VII) with 6-chloro-2-naphthalenesulfonyl chloride (VIII) gives (IX). Finally, the target carboxylic acid is obtained by hydrolysis of ethyl ester (IX) under acidic conditions.
| 【1】 Nishida, H.; Miyazaki, Y.; Mukaihira, T.; Saitoh, F.; Fukui, M.; Harada, K.; Itoh, M.; Muraoka, A.; Matsusue, T.; Okamoto, A.; Hosaka, Y.; Matsumoto, M.; Ohnishi, S.; Mochizuki, H.; Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as a factor Xa inhibitor II. Substituent effect on biological activities. Chem Pharm Bull 2002, 50, 9, 1187. |
| 【2】 Miyazaki, Y.; Mukaihira, T.; Nishida, H.; Hosaka, Y.; Matsusue, T. (Mochida Pharmaceutical Co., Ltd.); Aromatic cpds. having cyclic amino or salts thereof. EP 1048652; WO 9933805 . |
| 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) | 45860 | [1-(4-pyridinyl)-4-piperidinyl]methanol | C11H16N2O | 详情 | 详情 | |
| (II) | 52205 | 1-(4-pyridinyl)-4-piperidinecarbaldehyde | C11H14N2O | 详情 | 详情 | |
| (III) | 45862 | ethyl (2R)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C10H20N2O4 | 详情 | 详情 | |
| (IV) | 45863 | ethyl (2R)-3-[(tert-butoxycarbonyl)amino]-2-([[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)propanoate | C21H34N4O4 | 详情 | 详情 | |
| (V) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (VI) | 45864 | ethyl (2R)-2-((2-bromoacetyl)[[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)-3-[(tert-butoxycarbonyl)amino]propanoate | C23H35BrN4O5 | 详情 | 详情 | |
| (VII) | 61247 | ethyl (2R)-6-oxo-1-{[1-(4-pyridinyl)-4-piperidinyl]methyl}-2-piperazinecarboxylate | C18H26N4O3 | 详情 | 详情 | |
| (VIII) | 45865 | 6-chloro-2-naphthalenesulfonyl chloride | C10H6Cl2O2S | 详情 | 详情 | |
| (IX) | 45866 | ethyl (2R)-4-[(6-chloro-2-naphthyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylate | C28H31ClN4O5S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)Oxidation of 1-(4-pyridyl)piperidin-4-yl methanol (I) with oxalyl chloride and DMSO in dichloromethane provides carbaldehyde (II), which is then subjected to a reductive amination with amino acid (III) by means of HOAc and triacetoxyborohydride (Na(OAc)3BH) in dichloromethane to provide compound (IV). Condensation of (IV) with bromoacetyl chloride (V) in dichloromethane in the presence of Et3N furnishes derivative (VI), which is converted into compound (VIII) by first removal of the Boc group with HCl in MeOH followed by condensation with 6-chloronaphthalen-2-ylsulfonyl chloride (VII) in dichloromethane/DMF in the presence of Et3N. Finally, the target compound is obtained by treatment of (VIII) with methanesulfonic acid (CH3SO3H) in MeOH.
| 【1】 Miyazaki, Y.; Mukaihira, T.; Nishida, H.; Hosaka, Y.; Matsusue, T. (Mochida Pharmaceutical Co., Ltd.); Aromatic cpds. having cyclic amino or salts thereof. EP 1048652; WO 9933805 . |
| 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) | 45860 | [1-(4-pyridinyl)-4-piperidinyl]methanol | C11H16N2O | 详情 | 详情 | |
| (II) | 45861 | 1-(4-pyridinyl)-4-piperidinecarboxylic acid | C11H14N2O2 | 详情 | 详情 | |
| (III) | 45862 | ethyl (2R)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C10H20N2O4 | 详情 | 详情 | |
| (IV) | 45863 | ethyl (2R)-3-[(tert-butoxycarbonyl)amino]-2-([[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)propanoate | C21H34N4O4 | 详情 | 详情 | |
| (V) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (VI) | 45864 | ethyl (2R)-2-((2-bromoacetyl)[[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)-3-[(tert-butoxycarbonyl)amino]propanoate | C23H35BrN4O5 | 详情 | 详情 | |
| (VII) | 45865 | 6-chloro-2-naphthalenesulfonyl chloride | C10H6Cl2O2S | 详情 | 详情 | |
| (VIII) | 45866 | ethyl (2R)-4-[(6-chloro-2-naphthyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylate | C28H31ClN4O5S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)By reaction of 2-aminobenzophenones (I) with bromoacetyl halide (II) or tosyloxyacetyl halide (VI) to give, respectively, 2-(bromoacetylamino)benzophenones (III) or 2-(tosyloxyacetylamino)benzophenones (VII), which are treated with ethanolamine (IV) to give the compounds (V), which with acetic acid in ethanol give the desired compounds. These compounds can also be obtained from (III) and (VI) without isolation of (V)
| 【1】 Miyadera, T.; et al.; J Heterocycl Chem 1973, 10, 6, 85-88. |
| 【2】 Shishoo, C.J.; et al.; Process for the manufacture of pharmacologically active new heterocyclic compounds and salts thereof. IN 151496 . |
| 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) | 60640 | (2-amino-5-bromophenyl)(2-fluorophenyl)methanone | C13H9BrFNO | 详情 | 详情 | |
| (II) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (III) | 60641 | 2-bromo-N-[4-bromo-2-(2-fluorobenzoyl)phenyl]acetamide | C15H10Br2FNO2 | 详情 | 详情 | |
| (IV) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (V) | 60642 | N-[4-bromo-2-(2-fluorobenzoyl)phenyl]-2-[(2-hydroxyethyl)amino]acetamide | C17H16BrFN2O3 | 详情 | 详情 | |
| (VI) | 60643 | 2-chloro-2-oxoethyl 4-methylbenzenesulfonate | C9H9ClO4S | 详情 | 详情 | |
| (VII) | 60644 | 2-[4-bromo-2-(2-fluorobenzoyl)anilino]-2-oxoethyl 4-methylbenzenesulfonate | C22H17BrFNO5S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VI)The tosylation of 2-amino-5-chlorobenzophenone (I) with tosyl chloride (II) in pyridine gives 2-tosylamido-5-chlorobenzophenone (III), which is methylated with dimethyl sulfate and sodium methoxide in toluene yielding N-methyl-2-tosylamido-5-chlorobenzophenone (IV). Hydrolysis of (IV) with aqueous sulfuric acid affords 2-methylamino-5-chlorobenzophenone (V), which is acylated with bromoacetyl chloride (VI) in benzene to give N-methyl-2-(bromoacetylamido)-5-chlorobenzophenone (VII). Finally this compound is condensed with 2-methylallylamine (VIII) in acetone
| 【1】 Mouzin, G.; Cousse, H.; Stenger, A.; Casadio, S. (Pierre Fabre S.A.); US 4372975 . |
| 【2】 Serradell, M.N.; Castaner, J.; Souto, M.; Dinazafone. Drugs Fut 1984, 9, 7, 501. |
| 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) | 10279 | (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone | 719-59-5 | C13H10ClNO | 详情 | 详情 |
| (II) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (III) | 61085 | N-(2-benzoyl-4-chlorophenyl)(phenyl)methanesulfonamide | C20H16ClNO3S | 详情 | 详情 | |
| (IV) | 61086 | N-(2-benzoyl-4-chlorophenyl)-N-methylphenylmethanesulfonamide | C21H18ClNO3S | 详情 | 详情 | |
| (V) | 33972 | [5-chloro-2-(methylamino)phenyl](phenyl)methanone | 1022-13-5 | C14H12ClNO | 详情 | 详情 |
| (VI) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (VII) | 33973 | N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-methylacetamide | C16H13BrClNO2 | 详情 | 详情 | |
| (VIII) | 61087 | 2-methyl-2-propen-1-amine; 2-methyl-2-propenylamine | C4H9N | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VII)The condensation of 4-piperidinylmethanol (I) with 4-chloropyridine (II) gives 1-(4-pyridyl)piperidin-4-ylmethanol (III), which is oxidized with (COCl)2 and TEA in DMSO to yield the carbaldehyde (IV). The reductocondensation of (IV) with N-(tert-butoxycarbonyl)ethylene-1,2-diamine (V) by means of sodium triacetoxyborohydride and acetic acid affords the corresponding adduct as the borane complex (VI), which is acylated with bromoacetyl chloride (VII) and TEA in dichloromethane, providing the bromoacetamide (VIII). The cleavage of the boron complex and the Boc protecting group of (VIII) with TFA and anisole in ethyl ether gives the precursor (IX), which is cyclized to the piperazinone (X) by means of TEA in DMF. Finally, compound (X) is condensed with 6-chloronaphthalene-2-sulfonyl chloride by means of TEA in dichloromethane to yield the target sulfonamide.
| 【1】 Nishida, H.; et al.; Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitor. Chem Pharm Bull 2001, 49, 10, 1237. |
| 【2】 Miyazaki, Y.; Mukaihira, T.; Nishida, H.; Hosaka, Y.; Matsusue, T. (Mochida Pharmaceutical Co., Ltd.); Aromatic cpds. having cyclic amino or salts thereof. EP 1048652; WO 9933805 . |
| 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) | 32954 | 4-piperidinylmethanol | C6H13NO | 详情 | 详情 | |
| (II) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (III) | 45860 | [1-(4-pyridinyl)-4-piperidinyl]methanol | C11H16N2O | 详情 | 详情 | |
| (IV) | 52205 | 1-(4-pyridinyl)-4-piperidinecarbaldehyde | C11H14N2O | 详情 | 详情 | |
| (V) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (VI) | 52206 | C22H37BN4O7 | 详情 | 详情 | ||
| (VII) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (VIII) | 52207 | C24H38BBrN4O8 | 详情 | 详情 | ||
| (IX) | 52208 | N-(2-aminoethyl)-2-bromo-N-{[1-(4-pyridinyl)-4-piperidinyl]methyl}acetamide | C15H23BrN4O | 详情 | 详情 | |
| (X) | 52209 | 1-{[1-(4-pyridinyl)-4-piperidinyl]methyl}-2-piperazinone | C15H22N4O | 详情 | 详情 | |
| (XI) | 45865 | 6-chloro-2-naphthalenesulfonyl chloride | C10H6Cl2O2S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IX)2-Bromoaniline (VIII) is acylated by bromoacetyl chloride (IX) in pyridine to produce the corresponding bromoacetanilide (X). Subsequent displacement of the aliphatic bromide of (X) with morpholine (XI) furnishes the morpholinoacetanilide (XII). Alkylation at the amide N of (XII) with iodomethane and NaH leads to the N-methyl amide (XIII). Stille coupling of aryl bromide (XIII) with tributyl (1-ethoxyvinyl)tin (XIV) yields the enol ether (XV). Bromination of enol ether (XV) with N-bromosuccinimide in moist THF produces the bromo acetophenone (XVI), which is further reacted with NaN3 to give the azido ketone (XVII). The target amino oxazole compound is finally obtained by condensation of azido ketone (XVII) with isothiocyanate (VII) in the presence of PPh3 in hot dioxane.
| 【1】 Liu, C.; Leftheris, K.; Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H. (Bristol-Myers Squibb Co.); Cpds. derived from an amine nucleus that are inhibitors of IMPDH enzyme. EP 1126843; US 6399773; WO 0025780 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 61697 | 3-methoxy-4-(1,3-oxazol-5-yl)phenyl isothiocyanate; 5-(4-isothiocyanato-2-methoxyphenyl)-1,3-oxazole | C11H8N2O2S | 详情 | 详情 | |
| (VIII) | 27739 | 2-bromoaniline | 615-36-1 | C6H6BrN | 详情 | 详情 |
| (IX) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (X) | 61698 | 2-bromo-N-(2-bromophenyl)acetamide | C8H7Br2NO | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XII) | 61699 | N-(2-bromophenyl)-2-(4-morpholinyl)acetamide | C12H15BrN2O2 | 详情 | 详情 | |
| (XIII) | 61700 | N-(2-bromophenyl)-N-methyl-2-(4-morpholinyl)acetamide | C13H17BrN2O2 | 详情 | 详情 | |
| (XIV) | 19760 | ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane | 97674-02-7 | C16H34OSn | 详情 | 详情 |
| (XV) | 61850 | N-[2-(1-ethoxyvinyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide | C17H24N2O3 | 详情 | 详情 | |
| (XVI) | 61851 | N-[2-(2-bromoacetyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide | C15H19BrN2O3 | 详情 | 详情 | |
| (XVII) | 61852 | N-[2-(2-azidoacetyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide | C15H19N5O3 | 详情 | 详情 |