- An efficient commercial process for the preparation of isotretinoin
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We describe an efficient process for the preparation of isotretinoin (13-cis isomer of vitamin A acid) in a single step starting from β-ionylidene acetaldehyde (5). The process conditions are convenient to operate on a commercial scale and afford isotretinoin of excellent quality; levels of related isomeric impurities such as tretinoin (all trans retinoic acid) and 9,13-di-cis-retinoic acid are extremely low. Thus, condensation of dienolate of methyl 3,3-dimethylacrylate with β-ionylidene acetaldehyde (5) followed by aqueous acidic workup afforded isotretinoin in >95% purity. The condensation reaction proceeds via in situ formation of lactone (8); furthermore, the reaction conditions have been optimized to exploit in situ generated methoxide anion for lactone ring opening to afford the desired product. Distinct advantages of this process are that it does not require isolation of intermediate lactone and utilizes in situ generated methoxide for lactone ring opening, thus obviating the need for an additional step and base. We also describe an optimized process for the preparation of β-ionylidene acetaldehyde (5), a key intermediate for isotretinoin.
- Salman, Mohammad,Babu, Suresh J.,Kaul, Vijay K.,Ray, Purna C.,Kumar, Naresh
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Read Online
- Photocatalytic e → Z Isomerization of β-Ionyl Derivatives
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An operationally simple E → Z isomerization of activated dienes, based on the β-ionyl motif intrinsic to retinal, is reported using inexpensive (-)-riboflavin (vitamin B2) under irradiation at 402 nm. Selective energy transfer from photoexcited (-)-riboflavin to the starting E-isomer enables geometrical isomerization. Since the analogous process with the Z-isomer is inefficient, microscopic reversibility is circumvented, thereby enabling a directional isomerization to generate the contra-thermodynamic product (up to 99% yield, up to 99:1 Z/E). Prudent choice of photocatalyst enables chemoselective isomerization to be achieved in both inter- and intramolecular systems. The principles established from this study, together with a molecular editing approach, have facilitated the development of a regioselective isomerization of a truncated triene based on the retinal scaffold.
- Livingstone, Keith,Tenberge, Marius,Pape, Felix,Daniliuc, Constantin G.,Jamieson, Craig,Gilmour, Ryan
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p. 9677 - 9680
(2019/11/29)
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- Syntheses of 13C2-labelled 11Z-retinals
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To enable solid-state NMR investigations of the rhodopsin chromophore and its photointermediates, a series of 11Z-retinal isotopomers have been synthesised containing pairs of adjacent 13C labels at C9/C10, C10/C11 or C11/C12, respectively. The C9 labelled carbon atom was introduced through the Heck reaction of a 13C-labelled Weinreb acrylamide derivative, and the label at the C12 position derived from a 13C-containing ethoxy Bestmann-Ohira reagent. The 13C labels at C10 and C11 were introduced through the reaction of β-ionone with labelled triethyl phosphonoacetate.
- McLean, Neville J.,Gansmuller, Axel,Concistre, Maria,Brown, Lynda J.,Levitt, Malcom H.,Brown, Richard C.D.
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supporting information; experimental part
p. 8404 - 8410
(2011/11/12)
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- Effect of conjugates of all-trans-retinoic acid and shorter polyene chain analogues with amino acids on prostate cancer cell growth
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In the present work, a series of conjugates of amino acids with all-trans-retinoic acid (ATRA) and shorter polyene chain analogues were rationally designed, synthesized by coupling the succinimidyl active esters of the acidic retinoids with appropriately
- Sadikoglou, Eldem,Magoulas, George,Theodoropoulou, Christina,Athanassopoulos, Constantinos M.,Giannopoulou, Efstathia,Theodorakopoulou, Olga,Drainas, Denis,Papaioannou, Dionysios,Papadimitriou, Evangelia
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experimental part
p. 3175 - 3187
(2009/12/04)
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- All-Trans-Retinol: All-Trans-13,14-Dihydroretinol Saturase and Methods of Its Use
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Compositions of all-trans-retinol: all-trans-13,14-dihydroretinal saturase and methods of use thereof are provided.
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Page/Page column 2; 19; 22; Sheet 22/24
(2008/12/08)
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- Agents for use on skin and/or hair containing quadruply substituted cyclohexene compounds
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The invention relates to agents for use on skin or hair, particularly for increasing skin tanning and the synthesis of melanin in skin or hair. The invention contains, in particular, cosmetic or dermatological preparations containing quadruply substituted
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Page/Page column 12
(2010/11/28)
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- Total synthesis of capsanthin and capsorubin using Lewis acid-promoted regio- and stereoselective rearrangement of tetrasubsutituted epoxides
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The synthesis of capsanthin 1 and capsorubin 2 was accomplished via the C15-cyclopentyl ketone 6 prepared by Lewis acid-promoted regio- and stereoselective rearrangement of the epoxy dienal 5. The Royal Society of Chemistry.
- Yamano, Yumiko,Ito, Masayoshi
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p. 3207 - 3212
(2008/03/14)
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- Synthesis of 10,11,14,15-13C4- and 14,15-13C2-retinyl acetate
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The synthesis of 10,11,14,15-13C4- and 14,15-13C2-retinyl acetate is described. The procedure uses a modified Wittig-Horner synthesis. By using the 13C isotope, sensitive gas chromatography-combustion
- Tanumihardjo, Sherry A.
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p. 365 - 372
(2007/10/03)
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- Stereoselective synthesis and receptor activity of conformationally defined retinoid X receptor selective ligands
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Retinoid X Receptor (RXR) specific ligands are currently being investigated for the treatment of metabolic diseases such as type II diabetes. We report the synthesis of conformationally locked retinoids, which are potent RXR selective ligands, and the att
- Vuligonda, Vidyasagar,Garst, Michael E.,Chandraratna, Roshantha A.S.
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p. 589 - 594
(2007/10/03)
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- A Novel Method for a Stereoselective Synthesis of Trisubstituted Olefin Using Tricarbonyliron Complex: A Highly Stereoselective Synthesis of (all-E)- and (9Z)-Retinoic Acids
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In order to establish the stereoselective synthesis of retinoic acids, which are ligand molecules of the retinoic acid receptors (RARs, all-E-isomer) and the retinoid X receptors (RXRs, 9Z-isomer), the reaction of β-ionone-tricarbonyliron complex 7 with carbanions was investigated. Treatment of 7 with the lithium salt of acetonitrile afforded (7E,9E)-β-ionylideneacetonitrile-tricarbonyliron complex 8 exclusively, via addition, dehydration, and migration of tricarbonyliron complex. On the contrary, the reaction of 7 with the lithium enolate of ethyl acetate and subsequent dehydration by thionyl chloride afforded the ethyl (7E,9Z)-β-ionylideneacetate-tricarbonyliron complex 16b predominantly. These compounds (8 and 16b) were converted to the corresponding β-ionylidene-acetaldehyde-tricarbonyliron complexes (10 and 22) in excellent yields, respectively. The Emmons-Horner reaction of these compounds with C5-phosphonate followed by the sequence of decomplexation and alkaline hydrolysis gave the corresponding retinoic acids (26 and 29).
- Wada, Akimori,Hiraishi, Saeko,Takamura, Norio,Date, Tadamasa,Aoe, Keiichi,Ito, Masayoshi
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p. 4343 - 4348
(2007/10/03)
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- Thermal interconversions among 15-cis-, 13-cis-, and all-trans-β-carotene: Kinetics, arrhenius parameters, thermochemistry, and potential relevance to anticarcinogenicity of all-trans-β-carotene
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Rates of thermal, cis-trans rearrangement among all-trans-, 15-cis-, and 13-cis-β-carotene have been measured at temperatures in the range 37-69°C. From the resulting specific rate constants, Arrhenius and Eyring parameters are derived. Positions of equilibrium are estimated experimentally and by force field calculations based on the Allinger MM2 program as improved by Roth (MM2-ERW), while enthalpies of activation for cis-trans isomerization to 11-, 9-, and 7-cis-β-carotenes are estimated by application of the Roth program augmented by the inclusion of the quantum mechanical program of Malrieu et al., EVBH (effective valence-bond Hamiltonian), expanded to encompass longer polyenes. Implications of the interaction of strain and delocalization in the rotation about the 7,8 double bond are presented. A procedure has been developed for the small scale preparation of 13-cis-β-carotene by heating all-trans-β-carotene at 80°C for 8 h. Kinetically and thermodynamically accessible at 37°C, 15-cis- or 13-cis-β-carotene or both become candidates for the role of true anticarcinogenic agent, whereupon all-trans-β-carotene would be relegated to the role of reservoir for the active species.
- Doering, W. Von E.,Sotiriou-Leventis, Chariklia,Roth
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p. 2747 - 2757
(2007/10/02)
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