Methyl retinoate, preparation

Retinol Derivatives. Aryl sulphones have been used in two new syntheses in the vitamin A series. Reaction of /8-cyclocitryl phenyl sulphone (102) with the bromo-compound (103) gives the intermediate sulphone (104), which on base-catalysed elimination affords methyl retinoate (98). Alternatively retinol (99) has been prepared in high yield by condensation of the C15 bromide (105) with the C5 hydroxy-sulphone (106), followed by elimination of sulphinic acid. The syntheses... 

The C15 + C5 route is effective for preparing the sterically hindered (7Z)-isomer of methyl retinoate (19) (Scheme 6) [7]. Upon irradiation under selective sensitization (benzanthrone as sensitizer), the (all-E)-C2o-sulphone 20, which has been prepared by the Julia method, is converted into the (7Z)-isomer. Exposure of this isomer to methanolic KOH furnishes methyl (7Z)-retinoate [(7Z)-/9] together with a minor amount of the (7Z,9Z)-isomer. Analogously, the (7Z, 13Z)-retinoate is accessible starting from the (13Z)-C2o-sulphone. This strategy, starting from the Ci -sulphone 7, is also useful for preparing 13-substituted retinoates [8]. 

Didehydro compounds have been prepared from derivatives of the natural retinoids (2) and (3) (Henbest et aL, 1955) and from methyl retinoate (43). 

Wolf et al, (1954, 1957). The key intermediate retinoic-14-acid (preparation described in Section II,A,l,a,i) purified by crystallization was esterified with diazomethane. The ester was reduced with lithium aluminum hydride at low temperature to furnish the labeled retinol. Garbers (1956) isolated three isomers of retinoic-14-acid (see Section II,A,l,a,i) and reduced each to its corresponding retinol, thereby obtaining M-trans-, 3-cis-, and 9-c/5-retinol-14- C. Retinol labeled with carbon-14 in position 10 was obtained by Bu Lock et al. (1973) by direct reduction of purified methyl retinoate-lO- C. Labeling in positions 6, 7, and 15 has been reported (Mayer and Isler, 1971). 

Preparation of Methyl Retinoate from Retinoic Acid and Diazomethane... 

Methyl retmoate may also be prepared by refluxing retinoic acid in ethyl-acetate solution with anhydrous K2CO3 and CH3I for 2 h (ratio of methyl retmoate/ K2CO3/CH31,1/2/3, w/w/v). After allowing the solution to cool, wash It three times with water, dry it over anhydrous sodium sulfate, and evaporate the solvent. Purify the methyl retinoate product as appropriate (by TLC or HPLC or by crystallization from pentane at -20°C). 

Base-induced elimination of sulphinate from homoallylic sulphones , from y-ketosulphones , and from 1,2-bissulphones has been used in synthetic sequences ranging from the preparation of retinoic acid and of its methyl ester , to a novel pentannulation sequence that leads to a range of cross-conjugated dienes , as exemplified by equation (69). The overall yield for the two steps was 63%. 

Experimental studies showed antitumoral effects of raloxifene in different in vitro preparations and animal models. Raloxifene has been able to inhibit the mitogenic effect induced by estrogens on ZR-75-1 cells, an estrogen responsive human breast cancer cell line (Poulin et al. 1989). In a well-accepted rat model of breast cancer induced by nitroso-methyl urea (NMU) raloxifene significantly suppressed the development of breast tumors and acted synergistically with 9 cis-retinoic acid (Anzano et al. 1996). 

A concise preparation of retinoids via new enaminodiesters synthons was described by Valla et al. [41]. For example, all -retinoic acid was synthesized within one day by a one-pot process. The enaminodiester synthon was prepared from methyl isopropylidenemalonate and dimethylformamide dimethylacetal (DMF-DMA) and then condensed with the lithium enolate of (3-ionone. A Grignard reaction with the obtained ketodiester led to the retro carbomethoxyretinoate. Saponification and concomitant decarboxylation, provided mainly all E retinoic acid (all E/ 3Z 90/10, 72% from P-ionone), Fig. (17). 

A range of polyenes has been prepared from crocetin dialdehyde and various benzylidenephosphoranes. Among labelled compoimds synthesized using ylides are [2- C]abscisic acid, methyl /ranj -[10- C]retinoate, and trcois-[10- CJretinol. ... 

Several papers have described the synthesis of epoxyretinoids. The 5,6-epoxides of fmns-retinal (88) and its (9Z)-, (IIZ)-, and (13Z)-isomers were prepared by direct epoxidation of retinal with w-chloroperbenzoic acid. The 7,8-epoxides (89) of retinal, retinol, and retinoic acid and its methyl esters were synthesized from the jS-ionone epoxide (90). The exceedingly labile methyl 13,14-epoxy-13,14-dihydroretinoate (91) was made by addition of the epoxyaldehyde (92) to the phosphorane (93). Chromogen 574 , a product of the epoxidation of retinol first described in 1945, has now been identified as the... 

A good example of the preparative use of HPLC is the following Methyl (all- )-retinoate (43) in heptane, acetonitrile, or dimethyl sulfoxide was iso-merized by exposure to fluorescent light, and 11 isomers were then purified from the mixture by preparative HPLC (McKenzie et aL, 1978a Halley and Nelson, 1979a,b). The stmctures of these compounds were assigned by spectroscopic analyses. 

The preparation of all-rran -retinoic acid labeled with carbon-14 in positions 13 and 14 has been described (Kaegi et aL, 1980) and is depicted in Fig. 4. The methyl senecioate-2,3- C was prepared from acetone-2- C and the labeled phosphonoacetate (XIV) by a Homer-Emmons reaction. The preparation of the methyl diethyl phosphonoacetate-2- C (XIV) was simplified by using a novel... 

In the past, retinyl acetate has been prepared from labeled retinoic acid by the following procedure. Esterification of crystallized al -trans-Tciinoic acid with diazomethane and subsequent reduction of the methyl all-fraw -retinoate with lithium aluminum hydride at low temperature yielded M-trans-rctinol, which was acetylated in situ with acetyl chloride and pyridine in ether to give M-trans-retinyl acetate. 

Tosukhowong and Olson (1978) have described the synthesis, as shown in Fig. 16, and metabolism of 15-methylretinone, 15-methyl retinol, and 15-di-methyl retinol. The labeled compounds needed for the metabolic study were prepared in the following way. Starting with retinoic acid-6,7- 2, 15-meth-ylretinone-6,7- C (LX) was prepared by treatment with lithium and methyl... 

Retinoic acid and other retinoid carboxylic acids, however, can be readily converted to derivatives that are suitable for gas chromatography. Many of these applications have used mass spectrometry for detection (see below). Diazomethane is used, at room temperature, to prepare the methyl esters without apparent isomerization. Pentafluorobenzyl esters of retinoic acid and its analogs have also been prepared for GC-MS (280) or HPLC-MS (281). Deuterated analogs of retinoic acid or other retinoid carboxylic acids have been used as internal standards, with mass spectrometric detection (88,282) (reviewed by Napoli [283] and by De Leenheer and Lambert [89]). The pentafluorobenzyl ester of a synthetic retinoid, Ro 13-7410, was analyzed by column switching the peak of interest from a SE54 colunm was cut to an OV 240 column, with subsequent detection by negative ion chemical ionization mass spectrometry (280). 

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