Ammonolysis side reactions

We have already encountered alkylation of amines as a side reaction in the preparation of primary amines by the ammonolysis of halides (Sec. 22.10), and as a method of synthesis of secondary and tertiary amines (Sec. 22.13). Let us look at one further aspect of this reaction, the formation of quaternary ammonium salts. 

The vapor-phase ammonolysis of alcohol is much more complicated, because of side reactions. Although much information is available concerning operating conditions, effect of flow rates, and the effects of catalysts, there is little to be found in the literature on actual mechanism. 

The strategy described here explains the different possibilities of enzymatic ammonolysis and aminolysis reaction for resolution of esters or preparation of enantiomerically pure amides, which are important synthons in organic chemistry. This methodology has been also applied for the synthesis of pyrrolidinol derivatives that can be prepared via enzymatic ammonolysis of a polyfunctional ester, such as ethyl ( )-4-chloro-3-hydroxybutanoate [30]. In addition, it is possible in the resolution of chiral axe instead of a stereogenic carbon atom. An interesting enzymatic aminolysis of this class of reaction has been recently reported by Aoyagi et al. [31[. The side chain of binaphthyl moiety plays an important role in the enantiodis-crimination of the process (Scheme 7.14). 

Asymmetrization of a prochiral dicarboxylic acid diester catalyzed by lipases, where the stereo center of the product is located on the acyl side, becomes a single-step process because the polar carboxylic acid and/or amide formed are not well accepted as substrates by the Upase. One example is the enantioselective hydrolysis or ammonolysis of diethyl 3-hydroxyglutarate, as shown in Scheme 7.4, a reaction which leads to the formation of a precursor for the important chiral side chain of atorvastatin, lipitor [40, 41]. The S-enantiomer was formed with high e.e. (98%), but unfortunately this is the undesired enantiomer for the production of the pharmaceutically important product. Only a-chymotrypsin gave a predominance of the... 

The synthesis of DPP-IV inhibitor Saxagliptin 5 also required (55)-5-amino-carbonyl-4,5-dihydro-lH-pyrrole-l-carboxylic acid, l-(l,l-dimethylethyl)ester 10 (Figure 16.3C). Direct chemical ammonolyses were hindered by the requirement for aggressive reaction conditions, which resulted in unacceptable levels of amide race-mization and side-product formation, while milder two-step hydrolysis-condensation protocols using coupling agents such as 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) [41] were compromised by reduced overall yields. To address this issue, a biocatalytic procedure was developed based on the Candida antartica lipase B (CALB)-mediated ammonolysis of (55)-4,5-dihydro-lH-pyrrole-l,5-dicarboxylic acid, l-(l,l-dimethylethyl)-5-ethyl ester 9 with ammonium carbamate to furnish 10 without racemization and with low levels of side-product formation. 

Screening experiments utilized process stream ester feed, which consisted of about 22% w/v (0.91M) of the ester in toluene. Since toluene precluded the use of free ammonia due to its low solubility in toluene, solid ammonium carbamate was employed. Reactions were performed using a mixture of neat process feed, ammonium carbamate (71 g/L, 2 mol eq of ammonia), and biocatalyst (25 g/L), shaken at 400 rpm, 50°C. Under these conditions, CALB and its immobilized forms Novozym 435 and Chirazyme L2 provided racemization-free amide with yields of 69%, 43%, and 40%, together with 21%, 18%, and 22% of side products (by HPLC), respectively, while all other biocatalysts (lipases) furnished less than 5% of the desired product [42]. The ammonolysis reaction with free CALB was then optimized with regard to the temperature and the CALB and ammonium carbamate loads to increase yield from 56% to 71%, with side products varying from 7% to 19%. 

Resins incorporating spacer arms for peptide fragment coupling or stepwise peptide synthesis. The nonbenzylic resin-ester is cleaved by reactions other than protolysis, i.e., ammonolysis, hydrazinolysis, or mild alkaline saponification. Acid-labile side-chain protecting groups are not cleaved, so that the protected peptides can subsequently be used for fragment condensation by solution methods... 

Preparation of para-acetylaminobenzensulfonyl chloride (PAS) was described in Example 7.2. Sulfonation of 2-aminothiazole is performed in aqueous medium under controlled addition of hydroxide according to the already-discussed Schotten-Baumann process. As the result, double-sulfonated amine is formed, which does not represent a serious technological issue since on heating with ammonia to the reaction pot, selective ammonolysis is achieved and one mole of sulfonamide obtained. This is a useful side product that on separation is recycled in the production of biologically active sulfonamides. The ammonium salt of the sulfathiazole precursor is submitted to hydrolysis of the A-acetyl group and sulfathiazole isolated by crystallization. 

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