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【结 构 式】

【分子编号】39584

【品名】(E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one

【CA登记号】14901-07-6

【 分 子 式 】C13H20O

【 分 子 量 】192.3012

【元素组成】C 81.2% H 10.48% O 8.32%

与该中间体有关的原料药合成路线共 5 条

合成路线1

该中间体在本合成路线中的序号:(I)

The formylation of the beta-ionone (I) with methyl formate and NaOMe gives the enol (II), which by reaction with methanol and H2SO4 yields the dimethylacetal (III). The reaction of (III) with methylenetriphenylphosphorane (IV) affords the methylene compound (V), which is treated with formic acid to provide the aldehyde (VI). The condensation of (VI) with isopropylidenemalonic acid dimethyl ester (VII) by means of NaOH gives the polyenic malonic acid (VIII) as a mixture of isomers that is separated by crystallization in ethyl ether to yield the desired all-trans-isomer (IX). Finally, this malonic acid is selectively monodecarboxylated by means of refluxing 2,6-dimethylpyridine to afford the target (E,E,E,Z)-isomer.

1 Valia, A.; et al.; Stereoselective synthesis of 13 E retinoic and 13 Z retinoic acids via a new intermediate compound, C-15 beta-methylenealdehyde. Tetrahedron 2000, 56, 37, 7211.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIIIa),(IX) 49672 2-[(2E,4E,6E)-1,5-dimethyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6-heptatrienylidene]malonic acid C21H28O4 详情 详情
(VIIb) 49673 2-[(2E,4Z,6E)-1,5-dimethyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6-heptatrienylidene]malonic acid C21H28O4 详情 详情
(I) 39584 (E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one 14901-07-6 C13H20O 详情 详情
(II) 49667 (1E,4E)-1-hydroxy-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,4-pentadien-3-one C14H20O2 详情 详情
(III) 49668 (E)-5,5-dimethoxy-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-penten-3-one C16H26O3 详情 详情
(IV) 27301 methylene(triphenyl)phosphorane C19H17P 详情 详情
(V) 49669 (E)-1-methoxy-3-methylene-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-pentenyl methyl ether; 2-[(1E)-3-(2,2-dimethoxyethyl)-1,3-butadienyl]-1,3,3-trimethyl-1-cyclohexene C17H28O2 详情 详情
(VI) 49670 (E)-3-methylene-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-pentenal C15H22O 详情 详情
(VII) 49671 dimethyl 2-(1-methylethylidene)malonate 22035-53-6 C8H12O4 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 reaction of beta-ionon (X) with triethyl orthoformate (A) by means of H2SO4 in dioxane gives beta-ionon enolether (XI), which by reaction with NBS in CCl4 and hydrolysis with acetic acid is converted into 4-acetoxyonon (XII). The Grignard reaction of (XII) with vinylmagnesium bromide (B) in THF and hydrolysis with KOH in methanol gives 5-(3-hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)-3-methylpenta-1,4-dien-3-ol (XIII), which is oxidized with MnO2 in methylene chloride yielding 5-(3-oxo-2,6,6-trimethylcyclohex-1-en-1-yl)-3-methylpenta-1,4-dien-3-ol (XIV). Finally, this compound by reaction with triphenylphosphonium bromide (C) in DMF is converted into the phosphonium salt (VIII), which is finally condensed in a Wittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial (IX) by means of sodium methoxide in dichloromethane.

1 Rosenberg, M.; US 4000198 .
2 Serradell, M.N.; Blancafort, P.; Castaner, J.; Hillier, K.; Canthazanthin. Drugs Fut 1979, 4, 7, 477.
3 Rigassi, N.; Schwieter, U.; DE 2037935 .
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) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(A) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(VIII) 39582 [(2E,4E)-3-methyl-5-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)-2,4-pentadienyl](triphenyl)phosphonium bromide C33H36BrOP 详情 详情
(IX) 39583 (2E,4E,6E)-2,7-dimethyl-2,4,6-octatrienedial C10H12O2 详情 详情
(X) 39584 (E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one 14901-07-6 C13H20O 详情 详情
(XI) 39585 6-[(Z,2Z)-3-methoxy-2-butenylidene]-1,5,5-trimethyl-1-cyclohexene; methyl (Z)-1-methyl-3-(2,6,6-trimethyl-2-cyclohexen-1-ylidene)-1-propenyl ether C14H22O 详情 详情
(XII) 39586 2,4,4-trimethyl-3-[(E)-3-oxo-1-butenyl]-2-cyclohexen-1-yl acetate C15H22O3 详情 详情
(XIII) 39587 3-[(1E)-3-hydroxy-3-methyl-1,4-pentadienyl]-2,4,4-trimethyl-2-cyclohexen-1-ol C15H24O2 详情 详情
(XIV) 39588 3-[(1E)-3-hydroxy-3-methyl-1,4-pentadienyl]-2,4,4-trimethyl-2-cyclohexen-1-one C15H22O2 详情 详情
(C) 39589 triphenylphosphonium bromide 6399-81-1 C18H16BrP 详情 详情

合成路线3

该中间体在本合成路线中的序号:(XXVI)

The aldehyde intermediates (V) and (XII) are produced starting from β-ionone (XXVI) by several different methods. The lithium enolate of ketone (XXVI) is acylated with diethyl chlorophosphate to produce an enol phosphate intermediate, which undergoes regioselective β-elimination in the presence of LDA to furnish acetylene (XXVII). Deprotonation of (XXVII) with butyl lithium followed by treatment with phenyl cyanate gives nitrile (XXVIII), which undergoes conjugate addition of dimethyl cuprate in cold THF to afford the cis-trienenitrile (XXIX). Subsequent reduction of nitrile (XXIX) using DIBALH in hexane at –78 °C provides the target aldehyde (V) as the major isomer (4). Alternatively, Reformatsky reaction of β-ionone (XXVI) with the organo zinc reagent derived from ethyl bromoacetate followed by acidic dehydration produces a mixture of cis- and trans-ionylideneacetates (XXX), which, after saponification to the corresponding carboxylic acids, are separated by fractional crystallization from acetonitrile. The desired cis-isomer (XXXI) is then esterified by treatment with iodomethane and potassium carbonate under nonisomerizing conditions to furnish the cis-methyl ester (XXXIIa) (14). Reduction of ester (XXXIIa) with LiAlH4 in cold THF followed by re-oxidation of the resulting alcohol with MnO2 in CH2Cl2 affords aldehyde (V) (3, 14). The analogous tritium-labeled intermediate is similarly obtained utilizing [3H]-LiAlH4 in the reduction step (3). The tricarbonyliron complex of β-ionone (XXXIII) can be conveniently prepared by treatment of (XXVI) with dodecacarbonyltriiron(0) in boiling benzene. Condensation of (XXXIII) with the lithium enolate of ethyl acetate in cold THF gives the hydroxy ester adduct (XXXIV), which is dehydrated by means of SOCl2 in pyridine to produce the (9Z)-conjugated ester (XXXV) as the major isomer. Reduction of ester (XXXV) with DIBALH in Et2O at –45 °C yields the trienol derivative (XXXVI), which is converted to aldehyde (XII) without decomplexation by mild oxidation of the corresponding bromomagnesium alkoxide with azodicarbonyldipiperidine under Mukaiyama’s conditions. Alternatively, decomplexation of (XXXV) with CuCl2 provides the ethyl ester (XXXIIb), which is reduced to aldehyde (V) following known procedures (5). Scheme 3.

3 Boehm, M.F., McClurg, M.R., Pathirana, C. et al. Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties. J Med Chem 1994, 37(3): 408-14.
4 Bennani, Y.L. An efficient and stereoselective synthesis of 9-cis-retinoic acid. J Org Chem 1996, 61(10): 3542-4.
5 Wada, A., Hiraishi, S., Takamura, N., Date, T., Aoe, K., Ito, M. A novel method for a stereoselective synthesis of trisubstituted olefin using tricarbonyliron complex: A highly stereoselective synthesis of (all-E)- and (9Z)-retinoic acids. J Org Chem 1997, 62(13): 4343-8.
14 Robeson, C.D., Cawley, J.D., Weisler, L., Stern, M.H., Eddinger, C.C., Chechak, A.J. Chemistry of vitamin A. XXIV. The synthesis of geometric isomers of vitamin A via methyl beta-methylglutaconate. J Am Chem Soc 1955, 77(15): 4111.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIIa) 65506     C16H24O2 详情 详情
(XXXIIb) 65507     C17H26O2 详情 详情
(V) 65481 (2E,4E)-3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexenyl)Penta-2,4-Dienal 1209-68-3 C15H22O 详情 详情
(XII) 65488 complex of (2E,4E)-3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexenyl)Penta-2,4-Dienal with Fe(CO)3   C15H22O.Fe(CO)3 详情 详情
(XXVI) 39584 (E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one 14901-07-6 C13H20O 详情 详情
(XXVII) 65501   73395-75-2 C13H18 详情 详情
(XXVIII) 65502     C14H17N 详情 详情
(XXIX) 65503     C15H21N 详情 详情
(XXX) 65504 (2E,4E)-3-Methyl-5-(2,6,6-trimethyl-1-cyclohexenyl)penta-2,4-dienoic acid ethyl ester 5452-61-9 C17H26O2 详情 详情
(XXXI) 65505     C15H22O2 详情 详情
(XXXIII) 65508     C13H20O.Fe(CO)3 详情 详情
(XXXIV) 65509     C17H28O3.Fe(CO)3 详情 详情
(XXXV) 65510     C17H26O2.Fe(CO)3 详情 详情
(XXXVI) 65511     C15H24O.Fe(CO)3 详情 详情

合成路线4

该中间体在本合成路线中的序号:(I)

 

1 Abarbri M, Parrain J-L, Duchtne A, et aL. 2006, Stereoselective synthesis of trienoic acid: synthesis of retinoic acids and analogues. Synthesis, (17): 2951~2970
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) 39584 (E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one 14901-07-6 C13H20O 详情 详情
(II) 65501   73395-75-2 C13H18 详情 详情
(III) 66892 tributyl((1E,3E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)buta-1,3-dien-1-yl)stannane   C26H48Sn 详情 详情
(IV) 66893 (2E,4E)-5-iodo-3-methylpenta-2,4-dienoic acid   C6H7IO2 详情 详情

合成路线5

该中间体在本合成路线中的序号:(III)

 

1 Cartier D, Valla A, Le Guillou R, et al. 2003. New, regiaselective, one-pot synthesis of (all-E) -retinoic acid and analogues from enaminodiester synthons. Eur J Org Chem, (12). 2250~2253
2 Cartier D, Valla A, Labia R, et al. 2003. A new one-pot synthesis of all E-retinoic acid via a new enamin odiester synthon. Tetrahedrcm Lett, 44 (31): 5789~5790
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) 49671 dimethyl 2-(1-methylethylidene)malonate 22035-53-6 C8H12O4 详情 详情
(V) 66904 dimethyl 2-((2E,4E,6E,8Z)-6-methyl-8-(2,6,6-trimethylcyclohex-2-en-1-ylidene)octa-2,4,6-trien-2-yl)malonate   C23H32O4 详情 详情
(II) 66902 (E)-dimethyl 2-(4-(dimethylamino)but-3-en-2-ylidene)malonate   C11H17NO4 详情 详情
(III) 39584 (E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one 14901-07-6 C13H20O 详情 详情
(IV) 66903 dimethyl 2-((2E,4E,7E)-6-oxo-8-(2,6,6-trimethylcyclohex-1-en-1-yl)octa-2,4,7-trien-2-yl)malonate   C22H30O5 详情 详情
Extended Information