- Development of an efficient and stereoselective manufacturing route to idoxifene
-
A literature route to 1-(2-{4-[(E)-1-(4-iodophenyl)-2-phenyl-but-1-enyl]phenoxy}ethyl)pyrrolidine (idoxifene) has been modified to tackle various scale-up issues and provide initial supplies. A new highly efficient, robust, and stereoselective manufacturing route is described in detail. This route involves diastereoselective synthesis of tertiary alcohol (1RS,2SR)-1-(4-iodophenyl)-2-phenyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]butan- 1-ol by Grignard addition to the ketone 1-(4-iodophenyl)-2-phenyl-1-butanone followed by derivatisation and stereoselective syn elimination to provide idoxifene in excellent yield and geometric purity. Evaluation of a more direct route to idoxifene using a McMurry low-valent titanium coupling reaction is also described.
- Ace, Karl W.,Armitage, Mark A.,Bellingham, Richard K.,Blackler, Paul D.,Ennis, David S.,Hussain, Nigel,Lathbury, David C.,Morgan, David O.,O'Connor, Noah,Oakes, Graham H.,Passey, Stephen C.,Powling, Laurence C.
-
p. 479 - 490
(2013/09/07)
-
- Derivatives of Tamoxifen. Dependence of Antiestrogenicity on the 4-Substituent
-
A range of tamoxifen derivatives substituted in the 4-position of the 1-phenyl ring are described.The key steps in the synthesis of 4-iodo-, 4-bromo-, and 4-(methylthio)tamoxifen were reactions of 1,2-diarylbutanones with the (4-halogenophenyl)lithium or magnesium bromide.Oxidized precursors of 4-(methylthio)tamoxifen were used to prepare the methylsulfinyl and methylsulfonyl derivatives.Further derivatives (formyl, hydroxymethyl, oxirane, mercapto) were prepared from 4-bromotamoxifen via the 4-lithio derivative.Several of the derivatives (Br, I, SMe, SoMe, SO2Me, oxirane, CHO, CH2OH) displayed a higher affinity for estrogen receptors (ER) of calf uterine cytosol than did tamoxifen, but there was no relationship between affinity to ER and the ability to inhibit the growth of the MCF-7 breast cancer cell line in vitro.
- McCague, Raymond,Leclercq, Guy,Legros, Nicole,Goodman, Joyce,Blackburn, G. Michael,et al.
-
p. 2527 - 2533
(2007/10/02)
-
