Diketene acetal

An entirely different class of poly(ortho esters) has also been described (11). These polymers are prepared by the addition of polyols to diketene acetals. Principally due to the relative ease of... 

Because this diketene acetal is so susceptible to cationic polymerization, acids cannot be used to catalyze its condensation with diols because the competing cationic polymerization of the diketene acetal double bonds leads to a crosslinked product. Linear polymers can, however, be prepared by using iodine in pyridine (11). Polymer structure was verified by 13c nmR spectroscopy as shown in Fig. 

When one hydrogen in the diketene acetal is replaced with a methyl group, the resulting steric hinderance about the double bond... 

Because the condensation between a diketene acetal and a diol proceeds without the evolution of volatile byproducts, this method allows the preparation of dense, crossUnked materials by using reagents having a functionality greater than 2 (15). Even though either or both the ketene acetal and alcohol could have functionalities greater than 2, only triols were investigated because the synthesis of trifunctional ketene acetals is extremely difficult. 

To prepare crosslinked material, 2 eq of the diketene acetal is reacted with 1 eq of the diol and the resulting prepolymer is then reacted with a triol or a mixture of diols and triols. 

Initial polymer hydrolysis products are the diol or mixture of diols used in the reaction with the diketene acetal, and pentaerythritol dipropionate, or diacetate if 3,9-bis(methylene-2,4,8,10-tetraoxaspiro-[5,5Jundecane) was used. These pentaerythritol esters hydrolyze at a slower rate to pentaerythritol and the corresponding aliphatic acid (13). 

However, in subsequent work it was found that carboxylic acid groups readily add to ketene acetals to form carboxyortho ester linkages (24). These are very labile linkages and on hydrolysis regenerate the carboxylic acid group which then exerts its catalytic function. Because carboxylic acids add so readily to ketene acetals, very labile polymers can be prepared by the addition of diacids to diketene acetals. The utilization of such polymers is currently under investigation. 

A ketene acetal-terminated prepolymer was first prepared from 2 eq of the diketene acetal 3,9-bis(ethylidene-2,4,8,10-tetraoxaspiro-[5,5]undecane) and 1 eq of the diol 3-raethyl-l,5-pentanediol and. then 30 wt% levonorgestrel, 7 wt% Mg(OH)2j and a 30 mole% excess of 1,2,6-hexanetriol mixed into the prepolymer. This mixture was then extruded into rods and cured. Erosion and drug release from these devices was studied by implanting the rod-shaped devices subcutaneously into rabbits, explanting at various time intervals, and measuring weight loss and residual drug (15). 

Because acid excipients can be used to achieve rapid polymer erosion, the possibility of preparing devices useful for oral delivery was investigated (31). In one such system, 2 wt% phthalic anhydride was incorporated into a polymer prepared from the diketene acetal, trans-cyclohexanedimethanol and C-labeled 1,6-hexanediol and polymer erosion followed in a pH 7 buffer and in pH 1.5 canine... 

Ng, S. Y., Penhale, D. W. H., and Heller, J., Preparation of poly (ortho esters) by the reaction of diketene acetals and alcohols, Macromol. Synth. In Press. 

Diketene Acetic anhydride Sodium hydroxide 5-Methylisoxazole-4-... 

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. 

Poly(ortho esters) have also been produced by the addition of diols to diketene acetals (50). Principally because of ease of monomer synthesis, polymers were prepared by the addition of... 

J. Heller, D.W.H. Penhale and R.F. Helwing, Preparation of poly(ortho esters) by the reaction of diketene acetals and polyols, J. Polym. Sci., Polym. Letter Ed. 1980, 18, 619-624. 

Clearly, formation of polymers requires the availability of a bifunctional ketene acetal. One diketene acetal that has been described is 1,1,4,4-tetramethoxy-1,3-butadiene which can be prepared by the multistep synthesis shown in Scheme 5 [22],... 

Reaction between this diketene acetal and a diol should proceed as shown in Scheme 6. 

This facile crosslinking reaction is due to the extreme ease with which alkoxy groups on an ortho ester linkage transesterify. To prevent this transesterification, a scheme was used where the alkoxy groups were made part of a cyclic structure. In this particular case, two alkoxy groups in the final polymer were made part of a cyclic structure. To prepare such a polymer, the cyclic diketene acetal 3,9-bis (methylene 2,4,8,10-tetraoxaspiro [5,5] undecane) was used. It was prepared as shown in Scheme 8 [23]. 

However, because the addition of an alcohol to a ketene acetal is an acid-catalyzed reaction, formation of polymers by the addition of diols to this diketene acetal is greatly complicated by the extreme susceptibility of this monomer towards a competing cationic polymerization. Nevertheless, linear polymers could be prepared by using iodine in pyridine catalysis [24], This polymerization, illustrated for 1,6-hexanediol, is shown in Scheme 9. The polymer was characterized by 13C-NMR spectroscopy shown in Fig. 5 [24], The band assignments are shown in the figure. 

The facile cationic polymerization of the diketene acetal is due to the activation of the double bond by the two alkoxy electron donor groups. To convert this monomer to a more useful one, it is necessary to block this facile cationic polymerization and yet retain the reactivity of the ketene acetal group towards additions of alcohols. This was achieved by the introduction of steric hindrance about the double bond by replacing a hydrogen by a methyl group. The structure of the two compounds is compared in Scheme 10. 

The second diketene acetal, 3,9-bis (ethylidene 2,4,8,10-tetraoxaspiro [5,5] undecane) can be prepared as shown in Scheme 11. 

The increase in steric hindrance by the introduction of the methyl group was sufficient to prevent the facile cationic polymerization and linear polymers could be prepared by using acid catalysts such as p-toluenesulfonic acid. Further, this diketene acetal could be easily purified and analyzed and the synthesis readily scaled up. 

The addition of diols to diketene acetals is similar to the addition of diols to diisocyanates that leads to the formation of polyurethanes. And, like in polyurethanes, mechanical properties can be widely varied by using different diols. Further, because the condensation between a diketene acetal and a diol, just like... 

Vilsmeier reaction on ethyl benzothiazole-2-acetate gives an enamine (108), which reacts with diketen, acetic anhydride, NCCH2C02Et, etc. to give, e.g., (185 R = C02Et). The pyridine ring of (185 R = OH) may be cleaved by amines at ca 140 °C to give (186), ° but the ring is stable to this treatment in (185 R = OAc). 

POE II polymers are synthesized starting from3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane (a diketene acetal) and a diol another example is the addition of a diol with 1,1,4,4-tetramethoxy-13-butadiene. Their synthesis is simpler because it is only necessary to dissolve the monomers in a polar solvent and to add traces of an acidic catalyst (Fig. 1.13). Molecular weights... 

Polymers were prepared as described previously by condensation of equimolar amounts of a diketene acetal and a diol... 

Further effort resulted in the development of a second major famUy of POE polymers based on the addition of polyols to diketene acetals (HeUer et al, 1980), prepared by the procedure shown in Scheme n. 

Clearly, formation of polymers requires the use of a diketene acetal. Early work with this polymer system w as based on the reaction of the diketene acetal 3,9-bis(methylene) 2,4,8,10-tetraoxaspiro[5,5] undecane and 1,6-hexanediol as shown in Scheme 4 (Heller et al., 1980). 

However, the diketene acetal 3,9-bis (methylene) 2,4,8,10-tetraoxaspiro [5,5] undecane contains a double bond connected to two electron donor groups and is thus extremely susceptible to a cationic polymerization. For this reason, the synthesis of a more useful diketene acetal was evolved as shown in Scheme 5. In this diketene acetal, the cationic polymerization has been inhibited by the introduction of a methylene group which sterically hinders the facile cationic polymerization. This diketene acetal can be readily prepared by a rearrangement of the commercially available diallylpentaerythritol as shown in scheme 5 (Ng et al, 1992). 

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