Urethans anhydrides

Hillshafer et al. reported that aromatic polyester urethanes based on orthoph-thalic anhydride had better hydrolysis resistance than polycaprolactone urethanes, despite high acid numbers [91]. 

The acylation of enamines derived from cyclic ketones, which can lead to the acyl ketone or ring expansion (692-694), was studied by NMR and mass spectroscopic analysis of the products (695,696). In a comparative study of the rates of diphenylketene addition to olefins, a pronounced activation was observed in enamines (697). Enamine N- and C-acylation products were obtained from reactions of Schiff s bases (698), vinylogous urethanes (699), cyanamides (699), amides (670,700), and 2-benzylidene-3-methylbenzothiazoline (672) with acid chlorides, anhydrides, and dithio-esters (699). 

Styrene acrylonitrile Styrene butadiene Styrene maleic anhydride Styrene methyl methacrylate Thermoplastic urethane, rigid... 

Polymers used in medicine fall into two main categories those that are sufficiently inert to fulfill a long-term structural function as biomaterials or membranes, and those that are sufficiently hydrolytically unstable to function as bioeradible materials, either in the form of sutures or as absorbable matrices for the controlled release of drugs. For the synthetic organic polymers widely used in biomedicine this often translates to a distinction between polymers that have a completely hydrocarbon backbone and those that have sites in the backbone that are hydrolytically sensitive. Ester, anhydride, amide, or urethane linkages in the backbone usually serve this function. 

Chemoenzymatic synthesis of alkyds (oil-based polyester resins) was demonstrated. PPL-catalyzed transesterification of triglycerides with an excess of 1,4-cyclohexanedimethanol mainly produced 2-monoglycerides, followed by thermal polymerization with phthalic anhydride to give the alkyd resins with molecular weight of several thousands. The reaction of the enzymatically obtained alcoholysis product with toluene diisocyanate produced the alkyd-urethane. 

Molecular weight may also affect the erosion rate. Table IX shows the degradation rate of a representative poly(anhydride-co-urethane), a poly(anhydride-co-amide), and a poly(anhydride-co-ester) of different molecular weights (Hartmann et al., 1993). For all of these polymers reported, the erosion rate decreases as the molecular weight increases. 

Maleate/vinyl ether formulations based on a model unsaturated polyester prepared from maleic anhydride and 1,5-pentane diol and triethylene glycol divinyl ether were studied. At molecular weights of less than about 10,000 the cured films were extremely brittle. When the equivalent weight of the unsaturated polyester was increased by replacing some of the maleic anhydride with succinic anhydride, measurable values for film elongation could be obtained but the cure speed was definitely slower. When either diethyl maleate or isobutyl vinyl ether were added as monofunctional diluents the cure dose needed to obtain 200 MEKDR was increased and the flexibility measured by pencil hardness increased as the amount of diluent was increased. A urethane vinyl ether was synthesized and used to replace DVE-3 and films with increased elongation were obtained at equivalent at dosages as low as 1 J/cm2. 

An additional minor source of urethane can be the reaction of unconsumed reagent with V-nucleophile (path C). Aminolysis of chloroformate occurs if there is an excess of reagent or if the anhydride-forming reaction is incomplete. The latter is more likely when the residues activated are hindered. This side reaction can be avoided by limiting the amount of reagent and extending the time of activation. A third side reaction that is of little consequence is disproportionation of the mixed anhydride to the symmetrical anhydride and dialkyl pyrocarbonate (see Section 7.5). 

FMF Chen, Y Lee, R Steinauer, NL Benoiton. Mixed anhydrides in peptide synthesis. Reduction of urethane formation and racemization using A-methylpiperidine as tertiary amine base. J Org Chem 48, 2939, 1983. 

FIGURE 2.27 More on additives. In a carbodiimide-mediated reaction between acid 1 and amine 2, addition of HOObt can lead to the side reaction of aminolysis at the carbonyl of the activating moiety of ester 3, generating addition product 4. Addition of HOBt to a mixed-anhydride reaction containing unconsumed chloroformate generates mixed carbonate 5, leading to production of urethane 6. 

There is a claim that HOBt suppresses undesired aminolysis at the carbonate carbonyl of a mixed anhydride (Figure 2.25, path F). It is rarely used for this purpose, but if it is, it must be added only after the chloroformate has been consumed otherwise, mixed carbonate 5 is formed, and it depletes the amino-containing component by acylating it, giving stable urethane 6 (Figure 2.27).2 UI 3477... 

FIGURE 7.4 The mixed-anhydride reaction (see Section 2.6). Preparation of mixed anhydride 4 followed by its aminolysis (A) producing peptide 6 and the major side reaction of aminolysis at the wrong carbonyl (B) generating urethane 7. 

SECONDARY REACTIONS OF MIXED ANHYDRIDES URETHANE FORMATION... 

The major side reaction associated with the use of mixed anhydrides is aminolysis at the carbonyl of the carbonate moiety (Figure 7.4, path B). The product is a urethane that resembles the desired protected peptide in properties, except that the amino-terminal substituent is not cleaved by the usual deprotecting reagents. Hence, its removal from the target product is not straightforward. The problem is serious when the residues activated are hindered (Val, lie, MeXaa), where the amounts can be as high as 10%. Other residues generate much less, but the reaction cannot be avoided completely, with the possible exception of activated proline (see Section 7.22). This is one reason why mixed anhydrides are not employed for solid-phase synthesis. 

There have been reports that urethane was produced when the mixed-anhydride method was employed for the coupling of segments. However, studies on urethane formation during the aminolysis of mixed anhydrides of peptides have never been carried out. The anhydrides are too unstable to be isolated. The activated moiety of the peptide cyclizes too quickly to the 2,4-dialkyl-5(4//)-oxazolonc (see Section 2.23), and since the time allowed to generate the anhydride in segment couplings is always limited to avoid epimerization, one cannot exclude the possibility that the urethane that was produced originated by aminolysis of unconsumed chloroformate. 

FIGURE 7.5 Preparation of a protected dipeptide by the mixed-anhydride method, employing a chloroformate that generates a cleavable urethane.13 The urethane impurity is destroyed by a P-elimination reaction. NMM = A-methylmorpholine, Msc = methane-sulfonylethoxycarbonyl. 

In fact, recent work indicates that less urethane is formed by aminolysis of an activated peptide than by aminolysis of an activated /V-al ko x y carbon y I am ino acid. Such results are consistent with the postulate that the intermediate undergoing aminolysis during the mixed anhydride reaction of a segment is the 2,4-dialkyl-5(4//)-oxazolonc, a tenet that is indicated by the high rate at which the activated peptide is converted to the oxazolone.10 13... 

WD Fuller, MP Cohen, M Shabankareh, RK Blair, M Goodman, FR Naider. Urethane-protected amino acid A-carboxy anhydrides and their use in peptide synthesis. J Am Chem Soc 112, 7414, 1990. 

FIGURE 7.34 Decomposition of the symmetrical anhydride of A-methoxycarbonyl-valine (R1 = CH3) in basic media.2 (A) The anhydride is in equilibrium with the acid anion and the 2-alkoxy-5(4//)-oxazolone. (B) The anhydride undergoes intramolecular acyl transfer to the urethane nitrogen, producing thelV.AT-fcwmethoxycarbonyldipeptide. (A) and (B) are initiated by proton abstraction. Double insertion of glycine can be explained by aminolysis of the AA -diprotected peptide that is activated by conversion to anhydride Moc-Gly-(Moc)Gly-0-Gly-Moc by reaction with the oxazolone. (C) The A,A -diacylated peptide eventually cyclizes to the IV.AT-disubstituted hydantoin as it ejects methoxy anion or (D) releases methoxycarbonyl from the peptide bond leading to formation of the -substituted dipeptide ester. 

RB Merrifield, AR Mitchell, JE Clarke. Detection and prevention of urethane acylation during solid-phase peptide synthesis by anhydride methods. J Org Chem 39, 660, 1974. 

Triethylamine (7) is a strong, hindered base originally employed for mixed-anhydride reactions. However, it reduces the rate of anhydride formation if the solvent is dichloromethane or chloroform (see Section 7.3) and promotes disproportionation of the anhydride under conditions in which /V-mcthylmorpholinc does not (see Section 7.5). It causes enantiomerization of urethane-protected amino-acid /V-carboxyanhydrides and reaction between two molecules with release of carbon dioxide (see Section 7.14). It is also used in the synthesis of Atosiban (see Section 8.9). There is no reaction for which it is recommended as superior to other tertiary amines, except possibly for coupling employing BOP-C1 (see Section 8.14). 

WD Fuller, M Goodman, FR Naider, Y-F Zhu. Urethane-protected a-amino acid N-carboxy-anhydrides and peptide synthesis. Biopolymers (Pept Sci) 40, 183-205, 1996. 

UNCA Urethane-protected a-amino acid A-carboxy anhydride... 

Cope and LeBel (60JA4656) prepared the cis laetone 81 from eyclo-pentane-c -l,2-dicarboxylic anhydride and converted it to the hydrazide 82. Curtius degradation of 82 gave the cyclic urethane 83. 

---