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【结 构 式】 
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【分子编号】31418 【品名】[6-(benzyloxy)-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][3-methoxy-4-(1-pyrrolidinylmethyl)phenyl]methanone 【CA登记号】 |
【 分 子 式 】C34H31NO4S 【 分 子 量 】549.69048 【元素组成】C 74.29% H 5.68% N 2.55% O 11.64% S 5.83% |
合成路线1
该中间体在本合成路线中的序号：(VI)The stereocontrolled reaction of 3-pentanone (I) with 2-methylpropionaldehyde (II) by means of (+)-bis(diisopinocampheyl)borane triflate and DIEA in THF, followed by silylation with Tes-Cl and imidazole gives the silylated heptenone (III), which is condensed with 3-benzyloxypropionaldehyde (IV) by means of chlorodicyclohexylborane yielding the diol (V). The protection of the hydroxy groups of (V) with 2,2-dimethoxypropane and camphorsulfonic acid (CSA) with simultaneous desilylation affords the isopropylidene ketal (VI), which is acylated with propionic anhydride and triethylamine giving the propionate (VII). The Claisen rearrangement of (VII) by means of LDA and TBDMS-Cl in HMPT yields the carboxylic acid (VIII), which by regio- and stereoselective hydroboration of its double bond with BH3, followed by oxidation with N-methylmorpholine N-oxide (NMO) and tetrapropylammonium perruthenate (TPAP) in dichloromethane affords the lactone (IX). The reaction of (IX) with Me2Al-NH2, followed by debenzylation with H2 over Pd/C provides the dihydroxyamide (X), which is oxidized with Dess-Martin periodinane (DMP) in dichloromethane giving the keto aldehyde (XI). The cyclization of (XI) with HF in acetonitrile yields the spiro carbaldehyde (XII), which is silylated with Tes-OTf in dichloromethane providing the silyl ether (XIII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of sanglifehrin A. Angew Chem. Int Ed Engl 1999, 38, 16, 2447. |
| 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) | 32415 | Propione; Dimethylacetone; Diethyl ketone; 3-Pentanone | 96-22-0 | C5H10O | 详情 | 详情 |
| (II) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (III) | 32416 | (4R,5R)-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-hepten-3-one | C15H30O2Si | 详情 | 详情 | |
| (IV) | 14688 | 3-(benzyloxy)propanal | C10H12O2 | 详情 | 详情 | |
| (V) | 32417 | (3S,4S,5S,6S,7R)-1-(benzyloxy)-4,6,8-trimethyl-7-[(triethylsilyl)oxy]-8-nonene-3,5-diol | C25H44O4Si | 详情 | 详情 | |
| (VI) | 31418 | [6-(benzyloxy)-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][3-methoxy-4-(1-pyrrolidinylmethyl)phenyl]methanone | C34H31NO4S | 详情 | 详情 | |
| (VII) | 31419 | 4-[6-(benzyloxy)-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]-1-benzothiophen-2-yl]phenol | C34H33NO3S | 详情 | 详情 | |
| (VIII) | 31420 | methyl (2S)-3-hydroxy-2-(tritylamino)propanoate | C23H23NO3 | 详情 | 详情 | |
| (IX) | 32421 | (3S,5S,6S)-6-((1S)-1-[(4S,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]ethyl)-3-ethyl-5-methyltetrahydro-2H-pyran-2-one | C26H40O5 | 详情 | 详情 | |
| (X) | 32422 | (2S,4S,5S,6R)-2-ethyl-5-hydroxy-6-[(4R,5R,6S)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl]-4-methylheptanamide | C19H37NO5 | 详情 | 详情 | |
| (XI) | 32423 | (2S,4S,6S)-2-ethyl-4-methyl-5-oxo-6-[(4S,5R,6S)-2,2,5-trimethyl-6-(2-oxoethyl)-1,3-dioxan-4-yl]heptanamide | C19H33NO5 | 详情 | 详情 | |
| (XII) | 32424 | 2-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde | C16H27NO4 | 详情 | 详情 | |
| (XIII) | 32425 | 2-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde | C22H41NO4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)Condensation of 4-benzyloxybenzaldehyde (VI) with N,N-dimethylthioformamide in the presence of LDA in THF at -78 C provided the alpha-hydroxythioacetamide (VII), which was cyclized with methanesulfonic acid to yield benzothiophene (VIII). Subsequent acylation of (VIII) with the intermediate acid chloride (V) in boiling chlorobenzene provided ketone (IX). 4-Bromophenol (X) was protected as the triisopropylsilyl ether using triisopropylsilyl trifluoromethanesulfonate and imidazole, and then converted to the corresponding Grignard reagent (XI) with Mg in THF. Displacement of the dimethylamino group from benzothiophene (IX) by Grignard reagent (XI) furnished the 2-arylbenzothiophene (XII), which was desilylated with tetrabutylammonium fluoride to give (XIII). The ketone function of (XIII) was then reduced by means of LiAlH4 to yield (XIV).
| 【1】 Antithrombotic diamines. EP 0863755; US 6025382; WO 9725033 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 31414 | 3-methoxy-4-(1-pyrrolidinylmethyl)benzoyl chloride | C13H16ClNO2 | 详情 | 详情 | |
| (VI) | 29179 | 4-(Benzyloxy)benzaldehyde | 4397-53-9 | C14H12O2 | 详情 | 详情 |
| (VII) | 29181 | 2-[4-(benzyloxy)phenyl]-2-hydroxy-N,N-dimethylethanethioamide | C17H19NO2S | 详情 | 详情 | |
| (VIII) | 29182 | 6-(benzyloxy)-N,N-dimethyl-1-benzothiophen-2-amine | C17H17NOS | 详情 | 详情 | |
| (IX) | 31415 | [6-(benzyloxy)-2-(dimethylamino)-1-benzothiophen-3-yl][3-methoxy-4-(1-pyrrolidinylmethyl)phenyl]methanone | C30H32N2O3S | 详情 | 详情 | |
| (X) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (XI) | 31416 | bromo[4-[(triisopropylsilyl)oxy]phenyl]magnesium | C15H25BrMgOSi | 详情 | 详情 | |
| (XII) | 31417 | (6-(benzyloxy)-2-[4-[(triisopropylsilyl)oxy]phenyl]-1-benzothiophen-3-yl)[3-methoxy-4-(1-pyrrolidinylmethyl)phenyl]methanone | C43H51NO4SSi | 详情 | 详情 | |
| (XIII) | 31418 | [6-(benzyloxy)-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][3-methoxy-4-(1-pyrrolidinylmethyl)phenyl]methanone | C34H31NO4S | 详情 | 详情 | |
| (XIV) | 31419 | 4-[6-(benzyloxy)-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]-1-benzothiophen-2-yl]phenol | C34H33NO3S | 详情 | 详情 |