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【结 构 式】 
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【分子编号】61447 【品名】Trimethylsilyl cyanide; Cyanotrimethylsilane; TMSCN; Trimethylsilyl carbonitrile; Trimethylsilylnitrile; Cyantrimethylsilan; Trimethylsilylnitrile; Cyanotrimethylsilane; TRIMETHYLSILYLCYANIDE; Cyanotrimethylsilane; (CYANOTRIMETHYLSILANE) 【CA登记号】7677-24-9 |
【 分 子 式 】C4H9NSi 【 分 子 量 】99.2077 【元素组成】C 48.43% H 9.14% N 14.12% Si 28.31% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 5-(benzyloxy)-3(E)-penten-2-one (I) with trimethylsilyl cyanide (II) by means of a chiral Ti catalyst gives the chiral pentenenitrile (III), which is treated with HCl in ethanol and reduced with DIBAL and NaBH4 in methanol to yield the chiral diol (IV). The selective monosilylation of (IV) by means of TipsCl and imidazole affords the secondary alcohol (V), which is protected with Mom-Cl and DIEA in dichloromethane to provide compound (VI). The debenzylation of (VI) by means of lithium di-t-butyl biphenylide (LiDBB) gives the primary alcohol (VII), which is oxidized with TPAP and NMO in dichloromethane to yield the carbaldehyde (VIII). The reductive allylation of (VIII) by means of allyl trimethoxy silane (IX), AgF and a chiral catalyst affords the secondary alcohol (X), which is esterified with acryloyl chloride (XI) and TEA to provide the acrylate ester (XII). Ester (XII) is submitted to a ring closing metathesis reaction, catalyzed by a Ru catalyst giving the dihydropyranone compound (XIII), which is desilylated by means of HF and TEA in THF to yield the primary alcohol (XIV). The oxidation of (XIV) with DMP in dichloromethane affords the aldehyde (XV), which is condensed with 4-(trimethylsilyl)-3-butyn-2-one (XVI), by means of a chiral La catalyst to provide the acetylenic hydroxyketone (XVII). The reaction of (XVII) with 2,2-dimethoxypropane (XVIII) by means of PPTS gives the acetonide (XIX), which is enantioselectively reduced and catalyzed by a chiral Ru catalyst to yield the secondary alcohol (XX). The reaction of (XX) with Tbdms-OTf affords the silyl ether (XXI), which is treated with NIS and AgNO3 to provide the iodoacetylene derivative (XXII). The diimide reduction of (XXII) using o-nitrobenzenesulfonyl hydrazide (NBSH) gives the cis-iodovinyl compound (XXIII).
| 【1】 Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M.; Formal catalytic asymmetric total synthesis of fostriecin. Org Lett 2003, 5, 5, 733. |
| 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) | 61446 | (E)-5-(benzyloxy)-3-penten-2-one | C12H14O2 | 详情 | 详情 | |
| (II) | 61447 | Trimethylsilyl cyanide; Cyanotrimethylsilane; TMSCN; Trimethylsilyl carbonitrile; Trimethylsilylnitrile; Cyantrimethylsilan; Trimethylsilylnitrile; Cyanotrimethylsilane; TRIMETHYLSILYLCYANIDE; Cyanotrimethylsilane; (CYANOTRIMETHYLSILANE) | 7677-24-9 | C4H9NSi | 详情 | 详情 |
| (III) | 61448 | (2R,3E)-5-(benzyloxy)-2-methyl-2-[(trimethylsilyl)oxy]-3-pentenenitrile | C16H23NO2Si | 详情 | 详情 | |
| (IV) | 61449 | (2R,3E)-5-(benzyloxy)-2-methyl-3-pentene-1,2-diol | C13H18O3 | 详情 | 详情 | |
| (V) | 61450 | (2R,3E)-5-(benzyloxy)-2-methyl-1-[(triisopropylsilyl)oxy]-3-penten-2-ol | C22H38O3Si | 详情 | 详情 | |
| (VI) | 61542 | (5R)-5-[(E)-3-(benzyloxy)-1-propenyl]-8,8-diisopropyl-5,9-dimethyl-2,4,7-trioxa-8-siladecane; benzyl (E,4R)-4-(methoxymethoxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-pentenyl ether | C24H42O4Si | 详情 | 详情 | |
| (VII) | 61543 | (E,4R)-4-(methoxymethoxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-penten-1-ol | C17H36O4Si | 详情 | 详情 | |
| (VIII) | 61544 | (E,4R)-4-(methoxymethoxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-pentenal | C17H34O4Si | 详情 | 详情 | |
| (IX) | 61545 | Allyltrimethoxysilane; Allyltrimethoxysilane | 2551-83-9 | C6H14O3Si | 详情 | 详情 |
| (X) | 61546 | (4R,5E,7R)-7-(methoxymethoxy)-7-methyl-8-[(triisopropylsilyl)oxy]-1,5-octadien-4-ol | C20H40O4Si | 详情 | 详情 | |
| (XI) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XII) | 61547 | (1R,2E,4R)-1-allyl-4-(methoxymethoxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-pentenyl acrylate | C23H42O5Si | 详情 | 详情 | |
| (XIII) | 61548 | (6R)-6-{(E,3R)-3-(methoxymethoxy)-3-methyl-4-[(triisopropylsilyl)oxy]-1-butenyl}-5,6-dihydro-2H-pyran-2-one | C21H38O5Si | 详情 | 详情 | |
| (XIV) | 61549 | (6R)-6-[(E,3R)-4-hydroxy-3-(methoxymethoxy)-3-methyl-1-butenyl]-5,6-dihydro-2H-pyran-2-one | C12H18O5 | 详情 | 详情 | |
| (XV) | 61550 | (2R,3E)-2-(methoxymethoxy)-2-methyl-4-[(2R)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-3-butenal | C12H16O5 | 详情 | 详情 | |
| (XVI) | 61551 | 4-Trimethylsilyl-3-butyn-2-one; 4-(TRIMETHYLSILYL)-3-BUTYN-2-ONE | 5930-98-3 | C7H12OSi | 详情 | 详情 |
| (XVII) | 61552 | (6R)-6-[(E,3R)-4-hydroxy-3-(methoxymethoxy)-3-methyl-6-oxo-8-(trimethylsilyl)-1-octen-7-ynyl]-5,6-dihydro-2H-pyran-2-one | C19H28O6Si | 详情 | 详情 | |
| (XVIII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XIX) | 61553 | (6R)-6-((E)-2-{(4R)-2,2,4-trimethyl-5-[2-oxo-4-(trimethylsilyl)-3-butynyl]-1,3-dioxolan-4-yl}ethenyl)-5,6-dihydro-2H-pyran-2-one | C20H28O5Si | 详情 | 详情 | |
| (XX) | 61554 | (6R)-6-((E)-2-{(4R,5R)-5-[(2R)-2-hydroxy-4-(trimethylsilyl)-3-butynyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl}ethenyl)-5,6-dihydro-2H-pyran-2-one | C20H30O5Si | 详情 | 详情 | |
| (XXI) | 61555 | (6R)-6-((E)-2-{(4R,5R)-5-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(trimethylsilyl)-3-butynyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl}ethenyl)-5,6-dihydro-2H-pyran-2-one | C26H44O5Si2 | 详情 | 详情 | |
| (XXII) | 61556 | (6R)-6-{(E)-2-[(4R,5R)-5-((2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-iodo-3-butynyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]ethenyl}-5,6-dihydro-2H-pyran-2-one | C23H35IO5Si | 详情 | 详情 | |
| (XXIII) | 61557 | (6R)-6-{(E)-2-[(4R,5R)-5-((2R,3Z)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-iodo-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]ethenyl}-5,6-dihydro-2H-pyran-2-one | C23H37IO5Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)In one strategy, bromination of 4-ethoxyacetophenone (I) with Br2 yields 2-bromo-1-(4-ethoxyphenyl)ethanone (II) along with the byproduct 2-bromo-1-(3-bromo-4-ethoxyphenyl)ethanone, which are separated using HPLC. Alkylation of propionaldehyde N,N-diisobutylenamine (III) with bromo ketone (II) and subsequent ketalization with neopentyl glycol (IV) using p-TsOH·H2O and, optionally, H2SO4 in MeCN gives monoprotected ketoaldehyde (V) (1). Finally, cyclization of ketoaldehyde derivative (V) with 4-aminobenzenesulfonamide (VI) in the presence of AcOH in PrOH/H2O at 90-100 °C furnishes apricoxib (1, 2).
Intermediate (V) can also be prepared by reaction of 1-(4-ethoxyphenyl)-2-buten-1-one (VII) with CH3NO2 in the presence of DBU in THF to produce nitro ketone (VIII). Subsequent treatment of nitro derivative (VIII) with neopentyl glycol (IV) and NaOMe and MeOH gives acetal (V) (2).
In an alternative strategy, condensation of 4-ethoxyacetaldehyde (IX) with 4-sulfamoylaniline (VI) in refluxing EtOH furnishes N-(4-ethoxybenzylidene)-4-sulfamoylaniline (X), which then condenses with trimethylsilyl cyanide (XI) in the presence of ZnCl2 in THF yielding α-amino nitrile (XII). Cyclization of this compound with methacrolein (XIII) using LiHMDS in THF affords apricoxib (3). Scheme 1.
| 【1】 Kojima, S., Ooyama, J. (Daiichi Sankyo Co., Ltd.). Process for production of brominated acetophenone. WO 2008020617. |
| 【2】 Fujimoto, K., Takebayashi, T., Noguchi, Y., Saitou, T. (Daiichi Sankyo Co., Ltd.). Production of 4-methyl-1,2-diarylpyrrole and intermediate for synthesizing the same. JP 2000080078. |
| 【3】 Kimura, T., Noguchi, Y., Nakao, A., Suzuki, K., Ushiyama, S., Kawara, A., Miyamoto, M. (Daiichi Sankyo Co., Ltd.). 1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses. CA 2201812, EP 0799823, JP 1997823971, US 5908858. |
| 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) | 66028 | 4'-Ethoxyacetophenone; 1-(4-Ethoxyphenyl)ethan-1-one | 1676-63-7 | C10H12O2 | 详情 | 详情 |
| (II) | 66029 | 2-Bromo-1-(4-Ethoxyphenyl)Ethanone; Zinc02649911 | 51012-63-6 | C10H11BrO2 | 详情 | 详情 |
| (III) | 66030 | 2-methyl-N-(2-methylpropyl)-N-prop-1-enylpropan-1-amine | 100334-82-5 | C11H23N | 详情 | 详情 |
| (IV) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (V) | 66031 | C18H26O4 | 详情 | 详情 | ||
| (VI) | 54719 | 4-Aminobenzenesulfonamide; p-Aminobenzene sulfonyl amide; p-Aminobenzenesulfonamide; p-Anilinesulfonamide; Sulfanilamide | 63-74-1 | C6H8N2O2S | 详情 | 详情 |
| (VII) | 66032 | C12H14O2 | 详情 | 详情 | ||
| (VIII) | 66033 | C13H17NO4 | 详情 | 详情 | ||
| (IX) | 66034 | 4-Ethoxybenzaldehyde; p-Ethoxybenzaldehyde | 10031-82-0 | C9H10O2 | 详情 | 详情 |
| (X) | 66035 | C15H16N2O3S | 详情 | 详情 | ||
| (XI) | 61447 | Trimethylsilyl cyanide; Cyanotrimethylsilane; TMSCN; Trimethylsilyl carbonitrile; Trimethylsilylnitrile; Cyantrimethylsilan; Trimethylsilylnitrile; Cyanotrimethylsilane; TRIMETHYLSILYLCYANIDE; Cyanotrimethylsilane; (CYANOTRIMETHYLSILANE) | 7677-24-9 | C4H9NSi | 详情 | 详情 |
| (XII) | 66036 | C16H17N2O3S | 详情 | 详情 | ||
| (XIII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |