Methyl orthobenzoate

A mixture of 50 g of betamethasone, 50 cc of dimethylformamide, 50 cc of methyl orthobenzoate and 1.5 g of p-toluenesulfonicacid Is heated for 24 hours on oil bath at 105°C while a slow stream of nitrogen is passed through the mixture and the methanol produced as a byproduct of the reaction is distilled off. After addition of 2 cc of pyridine to neutralize the acid catalyst the solvent and the excess of methyl orthobenzoate are almost completely eliminated under vacuum at moderate temperature. The residue Is chromatographed on a column of 1,500 g of neutral aluminum oxide. By elution with ether-petroleum ether 30 g of a crystalline mixture are obtained consisting of the epimeric mixture of 170 ,21 -methyl orthobenzoates. This mixture is dissolved without further purification, in 600 cc of methanol and 240 cc of methanol and 240 cc of aqueous 2 N oxalic acid are added to the solution. The reaction mixture is heated at 40°-50°C on water bath, then concentrated under vacuum. The residue, crystallized from acetone-ether, gives betamethasone 17-benzoate, MP 225°-231°C. 

The observation of very pronounced inhibition of the sodium dodecyl sulfate-catalyzed hydrolysis of methyl orthobenzoate by inorganic cations is also consistent with the proposed mechanism for the micelle catalyzed reaction (Romsted et al., 1967 Dunlap and Cordes, 1968). For alkali-metal cations, the inhibition was found to increase with increasing ion size, i.e. ionic radius, but for alkaline-earth cations the inhibitory effectiveness was observed to be relatively independent of the ion. For... 

Second-order rate coefficients, kH (= rate/[S] [H30+]), for the hydrolyses of some typical acetals, ketals, and orthoesters in purely aqueous solutions are collected in Table 12. In a compilation of data from one single source [162], ftH values can be found for the reactions of a large number of diethyl acetals and ketals in 50 % dioxane—water at 25 °C. In more recent studies, kH values have been determined for the hydrolyses of substituted benzaldehyde diethylacetals [163] and benzophenone diethyl-ketal [164] in the same solvent (Table 13). The hydrolyses of para-substituted methyl orthobenzoates have been studied in 70 % methanol-water [169]. A large amount of other work is concerned with various special examples. 

The rate coefficients for the hydrolyses of substituted methyl orthobenzoates in 70 % methanol—water obey Hammett s rule with p = —2.0 [169]. There are no positive deviations for substituents with electronreleasing resonance effects, and it is not necessary to apply a + values and the Yukawa—Tsuno equation. 

In the NMR experiments carried out by Wenthe and Cordes [187] with methyl orthobenzoate and methyl orthocarbonate in CD3OD—D20 solutions, the rate coefficients for the disappearance of orthoester and those for the formation of CH3OD and of carboxylic ester have been found identical within experimental error (Table 15). This indicates that there is no exchange of methoxy groups prior to hydrolysis. The same result has been obtained from product analysis studies of the carboxylic esters formed. Consequently, the rate-determining step must be carbonium ion formation or a previous step. The findings do not support an A2 mechanism, for the following reason. As the nucleophilic reactivities of water and methanol are similar, the A2 reaction with attack of water... 

If the hydrolysis of methyl orthobenzoate in weakly acidic solution is carried out in the presence of various amounts of added nucleophiles, such as hydroxylamine or semicarbazide, a considerable fraction of the orthoester is transformed to the product of the reaction with the amine rather than to methyl benzoate, while the rate coefficient remains unchanged [183]. Similarly, the rate of hydrolysis of ethyl orthocarbonate in aqueous cacodylic acid buffer is the same in the presence of 0.04 M NaC104 and of 0.04 M Nal [192]. Thus, nucleophilic catalysis is absent even under conditions when general acid catalysis is effective. 

This reaction is similar to the Williamson synthesis of ethers (method 115). Otthofotmates in which the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and isoamyl have been prepared from chloroform. The yield of ethyl orthoformate is 45%. Mixed esters are obtained from a mixture of sodium alkoxides and chloroform. Benzotrichloride, C,HjCClj, is converted to methyl orthobenzoate in 86% yield by sodium methoxide in methanol, ... 

The effect of the chain length of sodium alkyl sulfates on the acid-catalyzed hydrolysis of methyl orthobenzoate (65) is illustrated in Fig. 6. It can be seen that up to a given concentration there seems to be... 

FlO. 6, Acid-catalyzed hydrolysis of methyl orthobenzoate in the presence of sodium alkyl sulfates as a function of the number of carbon atoms in the alkyl chain and of detergent concentration 0.008 M sodium acetate, 0.002 M aeetio acid, 6x 10" JIf methyl orthobenzoate, temperature 25°. 

Reaction of Betamethasone (125) with trimethyl orthobenzoate and toluene-p-sulphonic acid in DMF gave a mixture of the expected 17,21-(methyl orthobenzoate) (126) and the 17,21-(hydrogen orthobenzoate) (127). The unusual stability of the latter compound is attributed to intramolecular hydrogen-bonding between the free hydroxy- and 20-oxo-groups. 

Reaction of the l,2-(methyl orthobenzoate) (42) with 1,2,3,4-tetra-O-benzyl-L-ribitol and removal of the protecting groups from the product gave 1-0-P-D-... 

In the very early phase of the kinetic studies on the effects of [micelles] on the reaction rates, it has been observed that an empirical kinetic equation similar to Equation 7.48 with replacement of [M X ] by [Smflj - CMC (where [Smflj and CMC represent total surfactant concentration and critical micelle concentration, respectively) is applicable in many micellar-mediated reactions. But the plots of kobs vs. ([Surf]j - CMC) for alkaline hydrolysis of some esters reveal maxima when surfactants are cationic in nature. - - Similar kinetic plots have also been observed in the hydrolysis of methyl orthobenzoate in the presence of anionic micelles. Bunton and Robinson suggested a semiempirical equation similar to Equation 7.49, which could explain the presence of maxima in the plots of ko s vs. ([Surflj - CMC). In Equation 7.49), J, is an empirical constant. 

Dunlap, R.B., Cordes, E.H. Secondary valence force catalysis. Vni. Catalysis of hydrolysis of methyl orthobenzoate by anionic surfactants. J. Phys. Chem. 1969, 73(2), 361-370. 

---