Mixed ortho ester

The mixed ortho ester formed from tri(2-chloroethyl) orthoformate (100°, 10 min-2 h, 16% yield) is more stable to acid than is the unsubstituted derivative, but can be cleaved with 80% AcOH (20°, 1 h). ... 

There are several variations of the Claisen rearrangement that make it a powerfid tool for the synthesis of y,<5-unsaturated carboxylic acids. The ortho ester modification of the Claisen rearrangement allows carboalkoxymethyl groups to be introduced at the /-position of allylic alcohols.157 A mixed ortho ester is formed as an intermediate and undergoes sequential elimination and sigmatropic rearrangement. 

Alcoholysis of nitriles, of ortho and thio ortho esters (transesterification), and of halides is the most common method of preparing the ortho ester functional groups (see Eqs. 2-7). A less practical method is the addition of alcohols to ketene acetals. The latter method is used only when the other methods are not found applicable to the synthesis of specially substituted mixed ortho esters. 

A useful method for the preparation of ortho esters was first reported by Pinner [12], who prepared simple and mixed ortho esters by the reaction of alkyl formimidate salts with an excess of alcohols at room temperature for example, see Eq. (10). With ethyl alcohol, the reaction was exothermic and... 

The addition of alcohols to ketene acetals allows the synthesis of mixed ortho esters [96, 120a-c, 121a, b, 124, 125a, b]. a-Haloaldehydes may be converted to ortho esters by the following process (a) acetal formation, (b) de-hydrohalogenation, and (c) reaction with alcohols via addition reaction (33). In general, the method above, using ketene acetals, is not practical since ketene acetals are not readily available and are difficult to prepare. However, the method is useful because it allows the synthesis of mixed ortho esters and other ortho esters more difficult to synthesize [122-127]. Recently a simple one-step synthesis of ketene acetals and ortho esters has been reported (see p. 56). 

Formation of mixed ortho esters by a disproportionation reaction between two ortho esters [35]. 

The Johnson rearrangement involves reaction of an allylic alcohol with ethyl orthoacetate to give a mixed ortho ester that loses ethanol and then undergoes... 

The ortho ester modification of the Claisen rearrangement allows carboalk-oxyalkyl groups to be introduced.A mixed ortho ester is formed as an intermediate which undergoes sequential elimination and rearrangement. 

Condensation of prednisone, 40 with tetraethyl orthocarbonate leads to the cyelie ortho-carbonate 41 liydrolysis proceeds by protonation on the most accessible ether oxygen (that on carbon 21) to give the 17 mixed carbonate ester 42. Acylation with propionyl chloride proceeds on the remaining hydroxyl group to afford prednicarbate (43) [10],... 

Intermediate 7, a viable precursor of intermediate 6, possesses a y,<5-unsaturated ester, the structural prerequisite, or retron, for the ortho ester Claisen transform.5 In the synthetic direction, the convergent union of intermediates 9 and 10 could give mixed-ketene acetal 8 the intermediacy of 8 should be brief, for it should readily... 

A prominent structural feature of 21 and its precursor 22 is the trans C16-C17 trisubstituted double bond. The particular relationship between the ethoxycarbonyl function and the A16 17 double bond in 22 is significant because it satisfies the structural prerequisite for the Johnson ortho ester Claisen rearrangement transform.2130 Mixed ketene acetal 23 thus emerges as the immediate... 

It will be recalled that lactone-derived enol triflate 102 was expected to serve as a substrate for a Murai coupling37 with the mixed cuprate reagent derived from iodo ortho ester 103 (see Scheme 17c). If successful, this C-C bond forming process would accomplish the introduction of the remaining carbon atoms needed for the annulation of the seven-membered D-ring lactone. 

Because the ketene acetal-terminated prepolymer is a viscous Liquid at room temperature, therapeutic agents and the triol can be mixed into the prepolymer at room temperature and the mixture crosslink id at temperatures as low as 40°C. This allows incorporation of heat-sensitive therapeutic agents into a solid polymer under very mild conditions of thermal stress. However, because the prepolymer con-tedns reactive ketene acetal groups, any hydroxyl groups present in the therapeutic agent will result in the covalent attachment of the therapeutic agent to the matrix via ortho ester bonds (16). 

TABLE 5 Comparing the Shaping of a Poly(ortho ester) Compound by Flux-Mixing with 5 wt% Stearic Acid... 

Crosslinked poly(ortho esters) are prepared by a reaction sequence in which an excess of the diketene acetal 3,9-bis(ethylidene 2,4,8,10-tetraoxaspiro [5,5] undecane) is reacted with a diol, and the ketene acetal terminated prepolymer is then crosslinked with a triol. Because the prepolymer is a viscous liquid at room temperature, the therapeutic agent and any excipients used are incorporated into the prepolymer by mixing at room temperature and then cured at temperatures that can be as low as 40°C. 

DIBALH, as well as with other reagents. Ortho esters are easily reduced to acetals by LiAlITj alone, offering a route to aldehydes, which are easily prepared by hydrolysis of the acetals (10-6). Mixed ketals [R(OMe)OR ] can be demethoxylated (to give RHOR ) with Bn3SnCl/NaCHBH3 in the presence of AIBN. ... 

Methanolysis of a C-20 mixed anhydride of gibberellin A13 gave the unusual 19-ortho-ester, the structure (71) of which was established by X-ray analysis.117 The formation of this compound and the corresponding 19-epimeric 20->19-lactols by sodium borohydride reduction of the mixed anhydrides reveals the facile participation of the 19-esters in the reactions of C-20. This feature may be of biosynthetic significance. 

Thus, chalcone (26), available via aldol condensation between the appropriate benzaldehyde and acetophenone, was transformed into the 1,3-diarylpropene (27) via a two-step sequence involving ethyl chloroformate and NaBH4, followed by protection of the phenolic hydroxy group as the TBDMS ether. Asymmetric dihydroxylation of olefin (2 7) with AD-mix-a gave an intermediate diol, which was converted into ortho-ester (28) with triethyl orthoformate in the presence of catalytic pyridinium -toluenesulfonate (PPTS), followed by deprotection of the TBDMS ether with TBAF in THE. Treatment of ortho-ester (28) with triethyl orthoformate and PPTS gave an intermediate (27( ,35)- w j -flavan-3-ol formate ester. De-esterification with K2CO3 in THF/methanol and oxidation of the... 

Release of hydrocortisone. Initial exploratory in vitro studies designed to ascertain the usefulness of this polymer system have been carried out with a polymer based on 1,2,6-hexanetriol and various alkyl ortho esters. In these studies 2 wt% hydrocortisone was physically mixed into the ointment and the mixture placed into an erosion cell. A pH 7.4 buffer solution was then pumped across the cell at 9.5 ml/h, samples collected using an automatic fraction collector and analyzed for hydrocortisone by HPLC. The same study was also carried out by mixing into the ointment 2 wt% hydrocortisone and 2 wt% adipic acid. Results of these studies are shown in Fig. 32 [49]. The data clearly shows that without the incorporation of an acidic excipient erosion rate of the polymer is so slow that no hydrocortisone is released for two days. However, when an acidic excipient is mixed into the polymer, a fairly constant release is obtained. 

Release of naltrexone. The release of naltrexone using poly (ortho ester) II has already been discussed in Sect. 4.2.5. Since it was not possible to form highly loaded devices that had useful mechanical properties due to an interaction between naltrexone and the polymer at the device fabrication temperatures, it was decided to use the ductile polymer since naltrexone could be mixed into the polymer at room temperature and with appropriate mechanical mixing, high drug loadings could be achieved. 

The poly(ortho ester), shown on the left-hand side of Equation A.2-8, can be synthesized under milder conditions those required for Alzamer. Since cross-linked polymeric drug delivery devices are usually fabricated by mixing a prepolymer and a diol with mild curing ( 40 °C), care must be taken when using drugs with reactive hydroxyl groups. Most recently, another group of poly-(ortho ester) materials was synthesized [22] ... 

The Claisen-Johnson rearrangement [7] is closely related to both Saucy vinyl allyl ether rearrangement and Eschenmoser rearrangement. The reaction proceeds via a ketene acetal, which results from the condensation between an ortho-ester and an aUylic alcohol giving rise to a mixed orthoester followed by the elimination of the low-boihng-point alcohol. This ketene intermediate forms after rearrangement of a y,d-unsaturated ester (Scheme 6.1). 

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