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【结 构 式】 
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【分子编号】17573 【品名】N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide 【CA登记号】37595-74-7 |
【 分 子 式 】C8H5F6NO4S2 【 分 子 量 】357.2544592 【元素组成】C 26.9% H 1.41% F 31.91% N 3.92% O 17.91% S 17.95% |
合成路线1
该中间体在本合成路线中的序号：The acylation of 3-hydroxypiperidine with tosyl chloride followed by oxidation of the OH group with CrO3 and H2SO4 gives 1-tosylpiperidine-3-one (II), which is converted into the enol triflate (III) by reaction with LHMDS and PhN(SO2CF3)2 in THF. The condensation of (III) with 1-(tert-butoxycarbonyl)-2-vinylpiperidine (IV) by means of Pd(OAc)2 affords the diene (V), which is selectively deprotected with NaOH in methanol to afford the piperidine (VI). The condensation of (VI) with silylated methyl propenoate (VII) by means of triethylamine in dichloromethane gives the nonisolated intermediate (VIII) that cyclizes to the tetracyclic compound (IX) (as major isomer). The reaction of (IX) with HF and pyridine in refluxing dichloromethane affords the silylated tetracyclic ketone (X) (as major isomer), which is desilylated with KF, KHCO3 and H2O2 in refluxing methanol/THF providing the tetracyclic hydroxyketone (XI) (as major isomer), separated by column chromatography. Elimination of the OH group of (XI) with C6F5OC(S)-Cl, Bu3SnH and AIBN in refluxing benzdene yields the tetracyclic ketone (XII), which is finally reduced with LiAlH4 in THF.
| 【1】 Brosius, A.D.; et al.; Total synthesis of (+)-aloperine. Use of a nitrogen-bound silicon tether in a intramolecular diels - Alder reaction. J Am Chem Soc 1999, 121, 4, 700. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17573 | N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 37595-74-7 | C8H5F6NO4S2 | 详情 | 详情 | |
| (I) | 24255 | 3-piperidinol | 6859-99-0 | C5H11NO | 详情 | 详情 |
| (II) | 26735 | 1-(methylsulfonyl)-3-piperidinone | C6H11NO3S | 详情 | 详情 | |
| (III) | 26736 | 1-(methylsulfonyl)-1,4,5,6-tetrahydro-3-pyridinyl trifluoromethanesulfonate | C7H10F3NO5S2 | 详情 | 详情 | |
| (IV) | 26737 | tert-butyl (2R)-2-vinyl-1-piperidinecarboxylate | C12H21NO2 | 详情 | 详情 | |
| (V) | 26738 | tert-butyl (2R)-2-[(E)-2-[1-(methylsulfonyl)-1,4,5,6-tetrahydro-3-pyridinyl]ethenyl]-1-piperidinecarboxylate | C18H30N2O4S | 详情 | 详情 | |
| (VI) | 26739 | 1-(methylsulfonyl)-5-[(E)-2-[(2R)piperidinyl]ethenyl]-1,2,3,4-tetrahydropyridine | C13H22N2O2S | 详情 | 详情 | |
| (VII) | 26750 | methyl (E)-3-(dimethyl[[(trifluoromethyl)sulfonyl]oxy]silyl)-2-propenoate | C7H11F3O5SSi | 详情 | 详情 | |
| (VIII) | 26741 | methyl (E)-3-[dimethyl((2R)-2-[(E)-2-[1-(methylsulfonyl)-1,4,5,6-tetrahydro-3-pyridinyl]ethenyl]piperidinyl)silyl]-2-propenoate | C19H32N2O4SSi | 详情 | 详情 | |
| (IX) | 26742 | methyl (5aR,5bR,11aR,12S,12aS)-11,11-dimethyl-1-(methylsulfonyl)-1,2,3,4,5a,5b,6,7,8,9,11,11a,12,12a-tetradecahydropyrido[2',1':5,1][1,2]azasilolo[4,3-g]quinoline-12-carboxylate | C19H32N2O4SSi | 详情 | 详情 | |
| (X) | 26743 | (1R,2S,9S,10R,17R)-17-[fluoro(dimethyl)silyl]-3-(methylsulfonyl)-3,15-diazatetracyclo[7.7.1.0(2,7).0(10,15)]heptadec-7-en-16-one | C18H29FN2O3SSi | 详情 | 详情 | |
| (XI) | 26744 | (1R,2S,9R,10R,17R)-17-hydroxy-3-(methylsulfonyl)-3,15-diazatetracyclo[7.7.1.0(2,7).0(10,15)]heptadec-7-en-16-one | C16H24N2O4S | 详情 | 详情 | |
| (XII) | 26745 | (1S,2S,9S,10R)-3-(methylsulfonyl)-3,15-diazatetracyclo[7.7.1.0(2,7).0(10,15)]heptadec-7-en-16-one | C16H24N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)A new synthesis of ML-3000 has been published: The reaction of 3-phenyl-2-propynyl chloride (I) with isobutyraldehyde (II) by means of tetrabutylammonium iodide/NaI/NaOH in toluene/water gives 2,2-dimethyl-5-phenyl-4-pentynal (III), which is condensed with glycine methyl ester by means of NaBH(OAc)3 and triethylamine in dichloromethane yielding the N-alkyl-glycine (V). The cyclization of (V) by means of pivalic acid at 150 C affords the bicyclic ketone (VI), which is condensed with diethyl oxalate (VII) by means of sodium ethoxide in ethanol giving the ethoxalyl derivative (VIII). The esterification of (VIII) with the triflic amide (IX) yields the triflate (X), which is condensed with 4-chlorophenylboronic acid (XI) by means of palladium tetrakis(triphenylphosphine) as catalyst in refluxing THF affording the compound (XII). The reduction of the oxoacetic group with tosyl hydrazide (XIII) in refluxing ethanol gives the expected acetate derivative (XIV), which is finally hydrolyzed with NaOH in hot ethanol/water.
| 【1】 Cossy, J.; Belotti, D.; Synthesis of ML-3000, an inhibitor of cyclooxygenase and 5-lipoxygenase. J Org Chem 1997, 62, 23, 7900. |
| 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) | 17565 | 1-(3-chloro-1-propynyl)benzene | C9H7Cl | 详情 | 详情 | |
| (II) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (III) | 17567 | 2,2-dimethyl-5-phenyl-4-pentynal | C13H14O | 详情 | 详情 | |
| (IV) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (V) | 17569 | methyl 2-[(2,2-dimethyl-5-phenyl-4-pentynyl)amino]acetate | C16H21NO2 | 详情 | 详情 | |
| (VI) | 17570 | 2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-6(5H)-one | C15H17NO | 详情 | 详情 | |
| (VII) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (VIII) | 17572 | ethyl 2-(6-hydroxy-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate | C19H21NO4 | 详情 | 详情 | |
| (IX) | 17573 | N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 37595-74-7 | C8H5F6NO4S2 | 详情 | 详情 |
| (X) | 17574 | ethyl 2-(2,2-dimethyl-7-phenyl-6-[[(trifluoromethyl)sulfonyl]oxy]-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate | C20H20F3NO6S | 详情 | 详情 | |
| (XI) | 17575 | 4-chlorophenylboronic acid | 1679-18-1 | C6H6BClO2 | 详情 | 详情 |
| (XII) | 17576 | ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetate | C25H24ClNO3 | 详情 | 详情 | |
| (XIII) | 17577 | p-Toluenesulfonyl Hydrazide; 4-methylbenzenesulfonohydrazide | 1576-35-8 | C7H10N2O2S | 详情 | 详情 |
| (XIV) | 16723 | ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate | C25H26ClNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The chlorination of 5-(hydroxymethyl)imidazo[1,2-a]pyridine (I) with SOCl2 in dichloromethane gives the corresponding chloromethyl derivative (II), which is condensed with 1,4-diaminobutane (III) in refluxing acetonitrile to yield 5-(4-aminobutylaminomethyl)imidazo[1,2-a]pyridine (IV). The sulfonation of (IV) with N-phenyltrifluoromethylsulfonimide (V) and TEA in acetonitrile affords the sulfonamide (VI), which is protected with Boc2O in ethanol to provide the carbamate (VII). The acylation of (VII) with trichloroacetyl chloride and DMAP in refluxing chloroform gives the 3-trichloroacetyl derivative (VIII), which is finally cyclized by means of Tms-I and NaHCO3 in chloroform.
| 【1】 Ikemoto, T.; et al.; A practical synthesis of the chronic renal disease agent, 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one derivatives, using regioselective chlorination of ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxy with N-chlorosuccinimide. Tetrahedron 2000, 56, 40, 7915. |
| 【2】 Takatani, M.; Shibouta, Y.; Tomimatsu, K.; Kawamoto, T. (Takeda Chemical Industries, Ltd.); Tricyclic cpds., their production and use. EP 0771319; JP 1996081467; WO 9602542 . |
| 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) | 42068 | imidazo[1,2-a]pyridin-5-ylmethanol | C8H8N2O | 详情 | 详情 | |
| (II) | 42069 | 5-(chloromethyl)imidazo[1,2-a]pyridine | C8H7ClN2 | 详情 | 详情 | |
| (III) | 42070 | 1,4-butanediamine; 4-aminobutylamine | 110-60-1 | C4H12N2 | 详情 | 详情 |
| (IV) | 42071 | N(1)-(imidazo[1,2-a]pyridin-5-ylmethyl)-1,4-butanediamine; N-(4-aminobutyl)-N-(imidazo[1,2-a]pyridin-5-ylmethyl)amine | C12H18N4 | 详情 | 详情 | |
| (V) | 17573 | N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 37595-74-7 | C8H5F6NO4S2 | 详情 | 详情 |
| (VI) | 42072 | trifluoro-N-[4-[(imidazo[1,2-a]pyridin-5-ylmethyl)amino]butyl]methanesulfonamide | C13H17F3N4O2S | 详情 | 详情 | |
| (VII) | 42073 | tert-butyl imidazo[1,2-a]pyridin-5-ylmethyl(4-[[(trifluoromethyl)sulfonyl]amino]butyl)carbamate | C18H25F3N4O4S | 详情 | 详情 | |
| (VIII) | 42074 | tert-butyl [3-(2,2,2-trichloroacetyl)imidazo[1,2-a]pyridin-5-yl]methyl(4-[[(trifluoromethyl)sulfonyl]amino]butyl)carbamate | C20H24Cl3F3N4O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)The reaction of ethyl chloroacetate (I) with ethyl formate (II) by means of potassium tert-butoxide in diisopropyl ether gives the 2-formylchloroacetate (III), which is cyclized with 6-methylpyridine-2-amine (IV) by means of conc. H2SO4, yielding 5-methylimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (V). The chlorination of (V) with NCS in THF affords the chloromethyl derivative (VI), which is condensed with the monoprotected diamine (VII) by means of TEA to provide the adduct (VIII). The cyclization of (VIII) by means of NaOMe, TEA and NaI in DMF gives 4-[4-(benzyloxycarbonylamino)butyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one (IX), which is deprotected with H2 over Pd/C in MeOH, yielding the butylamine derivative (X). Finally, this compound is sulfonated with N-phenyltrifluoromethylsulfonimide (XI) and TEA in DMF.
| 【1】 Ikemoto, T.; et al.; A practical synthesis of the chronic renal disease agent, 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one derivatives, using regioselective chlorination of ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxy with N-chlorosuccinimide. Tetrahedron 2000, 56, 40, 7915. |
| 【2】 Takatani, M.; Shibouta, Y.; Tomimatsu, K.; Kawamoto, T. (Takeda Chemical Industries, Ltd.); Tricyclic cpds., their production and use. EP 0771319; JP 1996081467; WO 9602542 . |
| 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) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (II) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (III) | 16600 | ethyl 2-chloro-3-oxopropanoate | C5H7ClO3 | 详情 | 详情 | |
| (IV) | 19678 | 6-methyl-2-pyridinamine; 6-methyl-2-pyridinylamine; 6-amino-2-picoline; 2-Amino-6-methylpyridine | 1824-81-3 | C6H8N2 | 详情 | 详情 |
| (V) | 42075 | ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate | C11H12N2O2 | 详情 | 详情 | |
| (VI) | 42076 | ethyl 5-(chloromethyl)imidazo[1,2-a]pyridine-3-carboxylate | C11H11ClN2O2 | 详情 | 详情 | |
| (VII) | 42077 | benzyl 4-aminobutylcarbamate | 62146-62-7 | C12H18N2O2 | 详情 | 详情 |
| (VIII) | 42078 | ethyl 5-[[(4-[[(benzyloxy)carbonyl]amino]butyl)amino]methyl]imidazo[1,2-a]pyridine-3-carboxylate | C23H28N4O4 | 详情 | 详情 | |
| (IX) | 42079 | benzyl 4-(3-oxo-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-4-yl)butylcarbamate | C21H22N4O3 | 详情 | 详情 | |
| (X) | 42080 | 4-(4-aminobutyl)-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one | C13H16N4O | 详情 | 详情 | |
| (XI) | 17573 | N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 37595-74-7 | C8H5F6NO4S2 | 详情 | 详情 |