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【结 构 式】 
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【分子编号】24239 【品名】bromo(ethyl)magnesium；ethylmagnesium bromide 【CA登记号】925-90-6 |
【 分 子 式 】C2H5BrMg 【 分 子 量 】133.2707 【元素组成】C 18.02% H 3.78% Br 59.96% Mg 18.24% |
合成路线1
该中间体在本合成路线中的序号：(A)The synthesis of 3,4-bis(3'-methoxyphenyl)hexane (III) was accomplished in two different ways: 1) Reductive coupling of the 3-methoxypropiophenone (I) using the TiCl4/Zn reaction -- introduced by Mukaiyama et al. -- yields preferably the cis-stilbene (II). Catalytic hydrogenation of this alkene using palladium on activated carbon results in the isomerically pure meso-3,4-bis(3'-methoxyphenyl)hexane (III). 2) The reductive coupling of the 1-(3'-methoxyphenyl)-1-chloropropane (VI), obtained from 1-(3-methoxyphenyl)propanol (V) with dry HCl, according to Wilds and McCormack using COCl2 and ethylmagnesium bromide (A) yields mixture of the meso- and di-3,4-bis(3'-methoxyphenyl)hexanes (III). The meso-diastereomer (III) is separated by fractional crystallization from methanol. The ether cleavage of (III) to give 3,4-bis(3'-hydroxyphenyl)hexane is accomplished with BBr3.
| 【1】 Hitova, M.; Kouzeva, V.; J Org Chem 1949, 14, Suppl. 1, 45-58. |
| 【2】 Resende, C.; Barros, L.; Mota, A.; Barros, M.A.; Veloso, T.; Mesquita-Guimaraes, J.; Cunha, A.P.; J Cancer Res Clin Oncol 1982, 103, Suppl. 1, 165-180. |
| 【3】 El-Ashmawi, N.; Abdel-Samad, Z.; Sallam, F.; Nassar, S.; Gamae, M.; Chem Lett 1973, 16, Suppl. 1, 1041-44. |
| 【4】 Schonenberger, H.; Kranfelder, G.; Schmitt-Wallenborn, H. (Klinge Pharma GmbH); Novel di-(3'-hydroxyphenyl)-alkane cpds., process of preparation and their use in medicine. DE 2658307; US 4094994 . |
| 【5】 Schonenberger, H.; Engel, J.; Hartmann, R.W.; Metahexestrol. Drugs Fut 1983, 8, 5, 413. |
| 【6】 Picq, M.; et al.; Pentasubstituted quercetin analogues as selective inhibitors of particulate 3':5'-cyclic-AMP phosphodiesterase from rat brain. J Med Chem 1982, 24, 10, 1192-97. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (IIIa) | 36009 | 1-[(1S,2R)-1-ethyl-2-(3-methoxyphenyl)butyl]-3-methoxybenzene; 3-[(1R,2S)-1-ethyl-2-(3-methoxyphenyl)butyl]phenyl methyl ether | C20H26O2 | 详情 | 详情 | |
| (IIIb) | 36010 | 3-[(1S,2S)-1-ethyl-2-(3-methoxyphenyl)butyl]phenyl methyl ether; 1-[(1S,2S)-1-ethyl-2-(3-methoxyphenyl)butyl]-3-methoxybenzene | C20H26O2 | 详情 | 详情 | |
| (I) | 36007 | 1-(3-methoxyphenyl)-1-propanone | C10H12O2 | 详情 | 详情 | |
| (II) | 36008 | 1-[(Z)-1-ethyl-2-(3-methoxyphenyl)-1-butenyl]-3-methoxybenzene; 3-[(Z)-1-ethyl-2-(3-methoxyphenyl)-1-butenyl]phenyl methyl ether | C20H24O2 | 详情 | 详情 | |
| (V) | 36012 | 1-(3-methoxyphenyl)-1-propanol | C10H14O2 | 详情 | 详情 | |
| (VI) | 36011 | 3-(1-chloropropyl)phenyl methyl ether; 1-(1-chloropropyl)-3-methoxybenzene | C10H13ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The synthetic route from 8-aminopenicillanic acid (6-APA) to title compound is depicted in scheme. Diazotization of 6-APA (I) in the presence of Br2, followed by conventional esterification (MeI), gives the dibromopenicillanate (II), whose magnesium enolate (EtMgBr) is condensed with acetaldehyde to stereoselectively afford the bromohydrin (III). Debromination (Zn/MeOH) gives the trans-penicillanate (VI), which, via a two-step demolition of the thiazolidine ring [Hg(OAc)2, then KMnO4], is converted to the key azetidinone intermediate (IX). Acetate displacement with a suitable rhioacid (prepared trom glycolic acid after silylation of the hydroxy group) yields (XI). N-Oxalylation of the latter, followed by an original phosphite-mediated dicarbonyl coupling, gives the penem (XIV). Selective deblocking of the primary hydroxyl (Bu4NF) and exposure to trichloroacetylisocyanate results in the fully protected precursor (XVI), with is first unmasked in positions 2,8 (Bu4NF) and then in position 3 (Pd(0)-catalyzed deallylation in the presence of Na ethylhexanoate) to afford the sodium salt (FCE-22101).
| 【1】 Riva, F.; FCE-22101. Drugs Fut 1985, 10, 2, 119. |
| 【2】 Franceschi, G.; Foglio, M.; Alpegiani, M.; Battistini, C.; Bedeschi, A.; Perrone, E.; Zarini, F.; Arcamone, F.; Della Bruna, C.; Sanfilippo, A.; Synthesis and biological properties of sodium (5R,6S, 8R)-6alpha-hydroxyethyl-2-carbamoyloxymethyl-2-penem-3-carboxylate (FCE 22101) and its orally absorbed esters FCE 22553 and FCE 22891. J Antibiot 1983, 36, 7, 938-41. |
| 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) | 28871 | (2S,5R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | C8H12N2O3S | 详情 | 详情 | |
| (II) | 28872 | (2S,5R)-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | C8H9Br2NO3S | 详情 | 详情 | |
| (III) | 28873 | methyl (2S,5R)-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C9H11Br2NO3S | 详情 | 详情 | |
| (IV) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (V) | 28874 | methyl (2S,5R,6S)-6-bromo-6-[(1R)-1-hydroxyethyl]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H16BrNO4S | 详情 | 详情 | |
| (VI) | 28875 | methyl (2S,5R)-6-[(1R)-1-hydroxyethyl]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H17NO4S | 详情 | 详情 | |
| (VII) | 28876 | methyl (2S,5R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H31NO4SSi | 详情 | 详情 | |
| (VIII) | 28877 | methyl 2-[(2R)-2-(acetoxy)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-methyl-2-butenoate | C19H33NO6Si | 详情 | 详情 | |
| (IX) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (X) | 28878 | 2-[[tert-butyl(diphenyl)silyl]oxy]ethanethioic S-acid | C18H22O2SSi | 详情 | 详情 | |
| (XI) | 28879 | S-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl] 2-[[tert-butyl(diphenyl)silyl]oxy]ethanethioate | C29H43NO4SSi2 | 详情 | 详情 | |
| (XII) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (XIII) | 28880 | allyl 2-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(2-[[tert-butyl(diphenyl)silyl]oxy]acetyl)sulfanyl]-4-oxoazetidinyl]-2-oxoacetate | C34H47NO7SSi2 | 详情 | 详情 | |
| (XIV) | 28881 | allyl (5R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C34H47NO5SSi2 | 详情 | 详情 | |
| (XV) | 28882 | allyl (5R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-(hydroxymethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H29NO5SSi | 详情 | 详情 | |
| (XVI) | 28883 | allyl (5R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-7-oxo-3-[([[(2,2,2-trichloroacetyl)amino]carbonyl]oxy)methyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C21H29Cl3N2O7SSi | 详情 | 详情 | |
| (XVII) | 28884 | allyl (5R)-3-[[(aminocarbonyl)oxy]methyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C13H16N2O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The cyclization of methyl 5-oxo-6-heptenoate (I) with 2-methylcyclopentane-1-3-dione (II) by means of pyridine in refluxing toluene gives methyl 3-(1,5-dioxo-7a-methyl 5,6,7,7a-tetrahydroindan-4-yl)propionate (III), which is hydrolyzed with 5N HCl to the corresponding free acid (IV). Separation of the optical isomers with ephedrine affords the 3-(1,5-dioxo-7a-methyl-5,6,7,7a-tetrahydroindan 4-yl)propionic acid (V), which is reduced with NaBH4 in water to the 1beta-hydroxyacid (VI). Reduction of the double bond of (VI) with H2 over Pd/C in acetic acid gives the saturated ketoacid (VII), which is acetylated with acetic anhydride to the acetoxy Iactone (VIII). The Grignard reaction of (VIII) with propylmagnesium bromide (IX) and treatment with methanolic KOH affords 6-ethyl-3-hydroxy-3a-methyl-1,2,3,3a,4,5,8,9,9a,9b decahydro 7H benz[e]inden-7-one (X), which is finally acetylated with acetic anhydride as before.
| 【1】 Joly, R.; Warnant, J.; Goffinet, B.; Nouveaux composés tricycliques et procédé de préparation. FR 1359675 . |
| 【2】 Amiard, G.; Torelli, V.; Nomine, G.; Sur l'hydrogenation catalytique de structures tetrahydroindaniques, intermediaries de syntheses totales steroides. Bull Soc Chim France 1968, 9, 2, 3664. |
| 【3】 Cerede, J.; Amiard, G.; Velluz, L.; Nomine, G.; Torelli, V.; Pogres en synthese totale steroide. CR Hebd Seances Acad Sci 1963, 257, 3086. |
| 【4】 Morales-Alanis, H.; et al.; Antiandrogenic activity of a series of des-A-steroid derivatives. J Med Chem 1985, 28, 12, 1796. |
| 【5】 Bouton, M.-M.; Jacques, J.; Pierdet, A. (Aventis Pharma SA); Certain decahydro-7H-benz(e)-inden-7-ones, compositions containing same and method of use. EP 0059146; FR 2500441; JP 2243646; JP 57156430; US 4466971; US 4607054; US 4849454; US 4927975; US 5158981 . |
| 【6】 Castaner, J.; Prous, J.; RU-38882. Drugs Fut 1986, 11, 10, 856. |
| 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) | 24231 | methyl 5-oxo-6-heptenoate | C8H12O3 | 详情 | 详情 | |
| (II) | 24232 | 2-methyl-1,3-cyclopentanedione | 765-69-5 | C6H8O2 | 详情 | 详情 |
| (III) | 24233 | methyl 3-(7a-methyl-1,5-dioxo-2,3,5,6,7,7a-hexahydro-1H-inden-4-yl)propanoate | C14H18O4 | 详情 | 详情 | |
| (IV) | 24234 | 3-(7a-methyl-1,5-dioxo-2,3,5,6,7,7a-hexahydro-1H-inden-4-yl)propionic acid | C13H16O4 | 详情 | 详情 | |
| (V) | 24235 | 3-[(7aS)-7a-methyl-1,5-dioxo-2,3,5,6,7,7a-hexahydro-1H-inden-4-yl]propionic acid | C13H16O4 | 详情 | 详情 | |
| (VI) | 24236 | 3-[(1S,7aS)-1-hydroxy-7a-methyl-5-oxo-2,3,5,6,7,7a-hexahydro-1H-inden-4-yl]propionic acid | C13H18O4 | 详情 | 详情 | |
| (VII) | 24237 | 3-[(1S,3aS,4S,7aS)-1-hydroxy-7a-methyl-5-oxooctahydro-1H-inden-4-yl]propionic acid | C13H20O4 | 详情 | 详情 | |
| (VIII) | 24238 | (6aS,7S,9aS,9bS)-6a-methyl-3-oxododecahydrocyclopenta[f]chromen-7-yl acetate | C15H22O4 | 详情 | 详情 | |
| (IX) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (X) | 24240 | (3S,3aS,9aS,9bS)-6-ethyl-3-hydroxy-3a-methyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-cyclopenta[a]naphthalen-7-one | C16H24O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(A)By reaction of alpha,m-(dichloropropiophenone (I) with tert-butylamine (B) in refluxing acetonitrile or by reaction of alpha-bromo-m-chloropropiophenone (VI) with tert-butylamine (B) in acetonitrile at room temperature. The starting product (I) can be obtained in two different ways: 1) The Grignard condensation of m-chlorobenzonitrile (II) with ethyl magnesium bromide (A) in refluxing ether gives m-chloropropiophenone (III), which is then treated with SO2Cl2 in tetrachloroethane. 2) The reaction of propiophenone (IV) with SO2Cl2 in tetrachloroethane gives alpha-chloropropiophenone (V), which is then chlorinated in the ring by means of SO2Cl2 and AlCl3 in tetrachloroethane. The starting product (VI) is obtained by bromination of m-chloropropiophenone (III) with Br2 in methylene chloride
| 【1】 Mehta, N.B.; Yeowell, D.A.; Intermediates for biologically active ketones. CA 977778 . |
| 【2】 Mehta, N.B.; Yeowell, D.A.; Amino-propiophenones et medicaments contenant ces substances. DE 2059618; DE 2064934; FR 2081326; US 3819706 . |
| 【3】 Hopkins, S.J.; Castaner, J.; Bupropion. Drugs Fut 1978, 3, 10, 723. |
| 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) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
| (A) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (I) | 33569 | 2-chloro-1-(3-chlorophenyl)-1-propanone | C9H8Cl2O | 详情 | 详情 | |
| (II) | 33570 | 3-chlorobenzonitrile | 766-84-7 | C7H4ClN | 详情 | 详情 |
| (III) | 33571 | 3'-chloropropiophenone; 1-(3-chlorophenyl)-1-propanone | 34841-35-5 | C9H9ClO | 详情 | 详情 |
| (IV) | 33531 | propiophenone | 93-55-0 | C9H10O | 详情 | 详情 |
| (V) | 33572 | 2-chloro-1-phenyl-1-propanone | C9H9ClO | 详情 | 详情 | |
| (VI) | 33573 | 2-bromo-1-(3-chlorophenyl)-1-propanone | C9H8BrClO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The synthesis of the chiral 3-heptanone intermediate has been obtained as follows: The protection of the OH group of the chiral lactone (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is reduced with DIBAL to yield the lactol (III).The reaction of (III) with the Tebbe reagent affords the pentenol derivative (IV), which is oxidized with Dess-Martin periodinane (DMP), affording the aldehyde (V). The Grignard synthesis of (V) with ethylmagnesium bromide (VI) provides the 3-heptanol derivative (VII), which is hydroxylated at the terminal double bond by means of BH3/THF and H2O2, giving the diol (VIII). The selective protection of the primary OH group of (VIII) with Dmt-Cl, DIEA and DMAP yields the trityl ether (IX), which is finally oxidized with DMP to afford the desired chiral heptanone (X)
| 【1】 Martin, N.; Thomas, E.J.; Total syntheses of epothilones B and D: Applications of allylstannanes in organic synthesis. Tetrahedron Lett 2001, 42, 47, 8373. |
| 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) | 51427 | D-Pantolactone; R(-)-2-Hydroxy-3,3-dimethyl-gamma-butyrolactone | 599-04-2 | C6H10O3 | 详情 | 详情 |
| (II) | 51428 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyldihydro-2(3H)-furanone | C12H24O3Si | 详情 | 详情 | |
| (III) | 51429 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyltetrahydro-2-furanol | C12H26O3Si | 详情 | 详情 | |
| (IV) | 51430 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-4-penten-1-ol | C13H28O2Si | 详情 | 详情 | |
| (V) | 51431 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-4-pentenal | C13H26O2Si | 详情 | 详情 | |
| (VI) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (VII) | 51432 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-6-hepten-3-ol | C15H32O2Si | 详情 | 详情 | |
| (VIII) | 51433 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-1,5-heptanediol | C15H34O3Si | 详情 | 详情 | |
| (IX) | 51434 | (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol | C36H52O5Si | 详情 | 详情 | |
| (X) | 51435 | (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone | C36H50O5Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)The synthesis of the chiral 3-heptanone intermediate has been obtained as follows: The protection of the OH group of the chiral lactone (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is reduced with DIBAL to yield the lactol (III).The reaction of (III) with the Tebbe reagent affords the pentenol derivative (IV), which is oxidized with Dess-Martin periodinane (DMP), affording the aldehyde (V). The Grignard synthesis of (V) with ethylmagnesium bromide (VI) provides the 3-heptanol derivative (VII), which is hydroxylated at the terminal double bond by means of BH3/THF and H2O2, giving the diol (VIII). The selective protection of the primary OH group of (VIII) with Dmt-Cl, DIEA and DMAP yields the trityl ether (IX), which is finally oxidized with DMP to afford the desired chiral heptanone (X).
| 【1】 Martin, N.; Thomas, E.J.; Total syntheses of epothilones B and D: Applications of allylstannanes in organic synthesis. Tetrahedron Lett 2001, 42, 47, 8373. |
| 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) | 51427 | D-Pantolactone; R(-)-2-Hydroxy-3,3-dimethyl-gamma-butyrolactone | 599-04-2 | C6H10O3 | 详情 | 详情 |
| (II) | 51428 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyldihydro-2(3H)-furanone | C12H24O3Si | 详情 | 详情 | |
| (III) | 51429 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyltetrahydro-2-furanol | C12H26O3Si | 详情 | 详情 | |
| (IV) | 51430 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-4-penten-1-ol | C13H28O2Si | 详情 | 详情 | |
| (V) | 51431 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-4-pentenal | C13H26O2Si | 详情 | 详情 | |
| (VI) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (VII) | 51432 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-6-hepten-3-ol | C15H32O2Si | 详情 | 详情 | |
| (VIII) | 51433 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-1,5-heptanediol | C15H34O3Si | 详情 | 详情 | |
| (IX) | 51434 | (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol | C36H52O5Si | 详情 | 详情 | |
| (X) | 51435 | (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone | C36H50O5Si | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XVIII)Assembly of the target compound: The reaction of methyl 3-bromopropionate (XVII) with ethylmagnesium bromide (XVIII) and Ti(iPrO)4 gives 1-(2-bromoethyl)cyclopropan-1-ol (XIX), which is brominated by NBS in CCl4 to yield 1,5-dibromo-3-pentanone (XX). The reaction of (XX) with ethylene glycol (XXI), HC(OEt)3 and PPTS affords the cyclic ketal (XXII), which is cyclized with the indolinone intermediate (VII) by means of NaH in DMF to provide the spiro compound (XXIII). The deprotection of (XXIII) with PPTS in acetone/water gives the spiranic diketone (XXIV), which is selectively reduced with NaBH4 in methanol to yield the spiro cyclohexanol (XXV). The condensation of (XXV) with 4-(2-chloroethyl)morpholine (XXVI) by means of NaH in hot toluene affords the corresponding ether (XXVII), which is debenzylated by means of Li/NH3 to provide intermediate (XXVIII) with a free NH group. Finally, the sulfonation of (XXVIII) with intermediate chlorosulfonyl benzamide (XVI) by means of potassium tert-butoxide gives the target sulfonyl benzamide compound.
| 【1】 Venkatesan, H.; et al.; Total synthesis of SR 121463 A, a highly potent and selective vasopressin V2 receptor antagonist. J Org Chem 2001, 66, 11, 3653. |
| 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) | 50276 | 1-benzyl-5-ethoxy-1,3-dihydro-2H-indol-2-one | C17H17NO2 | 详情 | 详情 | |
| (XVI) | 50284 | 4-[(tert-butylamino)carbonyl]-2-methoxybenzenesulfonyl chloride | C12H16ClNO4S | 详情 | 详情 | |
| (XVII) | 50285 | 3-Bromopropionic acid methyl ester; Methyl 3-bromopropionate | 3395-91-3 | C4H7BrO2 | 详情 | 详情 |
| (XVIII) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (XIX) | 50286 | 1-(2-bromoethyl)cyclopropanol | C5H9BrO | 详情 | 详情 | |
| (XX) | 50287 | 1,5-dibromo-3-pentanone | C5H8Br2O | 详情 | 详情 | |
| (XXI) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XXII) | 50288 | 2,2-bis(2-bromoethyl)-1,3-dioxolane | C7H12Br2O2 | 详情 | 详情 | |
| (XXIII) | 50289 | C24H27NO4 | 详情 | 详情 | ||
| (XXIV) | 50290 | C22H23NO3 | 详情 | 详情 | ||
| (XXV) | 50291 | C22H25NO3 | 详情 | 详情 | ||
| (XXVI) | 27355 | 4-(2-chloroethyl)morpholine | 3647-69-6 | C6H12ClNO | 详情 | 详情 |
| (XXVII) | 50292 | C28H36N2O4 | 详情 | 详情 | ||
| (XXVIII) | 50293 | C21H30N2O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XVIII)The precursor 4-bromo-2,6-diethylpyridine (V) can be prepared by several methods. Condensation of 3-oxoglutaric acid (XIII) with propionic anhydride (XIV) in the presence of H2SO4, followed by cyclization with HCl at 100 °C leads to 2,6-diethyl-4-pyranone (XV). Subsequent treatment of pyranone (XV) with NH4OH at 50 °C yields 2,6-diethyl-4-pyridinol (XVI) , which is finally brominated with PBr5 in CHCl3 or POBr3 in DMF at 120 °C .
Alternatively, substitution of 2,6-dichloropyridine (XVII) with ethylmagnesium bromide (XVIII) in the presence of NiCl2(dppp) in Et2O gives 2,6-diethylpyridine (XIX), which can also be obtained by Wolff- Kishner reduction of 2,6-diacetylpyridine (XX) with NH2NH2 in the presence of NaOH in diethylene glycol at 120 °C. Oxidation of 2,6-diethylpyridine (XIX) with mCPBA in CHCl3, followed by nitration of the resulting 2,6-diethylpyridine-1-oxide (XXI) with HNO3 and H2SO4 at 90 °C provides the 4-nitro derivative (XXII). Substitution of nitropyridine (XXII) using AcBr in AcOH at 90 °C affords 4-bromo-2,6-diethylpyridin-1-oxide (XXIII), which is finally reduced with PBr3 in CH2Cl2 .
| 【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725. |
| 【2】 Li, H., Tatlock, J., Linton, A. et al. Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J Med Chem 2009, 52(5): 1255-8. |
| 【3】 Johnson, S., Drowns, M., Tatlock, J. et al. Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation. Synlett 2010(5): 796-800. |
| 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) | 68333 | 4-bromo-2,6-diethylpyridine | 877133-54-5 | C9H12BrN | 详情 | 详情 |
| (XIII) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (XIV) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (XV) | 68342 | 2,6-diethyl-4H-pyran-4-one | C9H12O2 | 详情 | 详情 | |
| (XVI) | 68343 | 2,6-diethyl-4-pyridinol;2,6-diethylpyridin-4-ol | C9H13NO | 详情 | 详情 | |
| (XVII) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (XVIII) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (XIX) | 68344 | 2,6-diethylpyridine | 935-28-4 | C9H13N | 详情 | 详情 |
| (XX) | 48515 | 2,6-Diacetylpyridine | 1129-30-2 | C9H9NO2 | 详情 | 详情 |
| (XXI) | 68345 | 2,6-diethylpyridine-1-oxide | C9H13NO | 详情 | 详情 | |
| (XXII) | 68346 | 2,6-diethyl-4-nitropyridine 1-oxide | C9H12N2O3 | 详情 | 详情 | |
| (XXIII) | 68347 | 4-bromo-2,6-diethylpyridin-1-oxide | C9H12BrNO | 详情 | 详情 |