Methyl esters ammonolysis

Mandelamide has been prepared by treating the ethyl ester with concentrated aqueous ammonia,12 and a saturated alcoholic solution of ammonia has been used to effect ammonolysis of the methyl ester.1 3 Esters of mandelic acid were treated with liquid... 

If the C-terminal residue is sterically hindered, anunonolysis may fail or be very slow. Yields may be improved by adding peroxide-free dioxane to the alcohol [up to 50% (v/v)] to improve resin swelling. If ammonolysis fails, the peptide can be converted into the methyl ester (see Section 4.3.5.1.14) and then ammonolyzed in solution. Ethers are not cleaved. If Ser(Bzl), Thr(Bzl), or Tyr(ether) are present, these must be subsequently cleaved by a suitable procedure. 

Dihydroxypyrrolidinones, which can be considered as cyclic GABA derivatives, are potential nootropic drug candidates. All four possible diastereomers 794—797, as shown in Scheme 174, can be prepared from tartaric acid. Treating L-tartaric acid sequentially with acetyl chloride, methyl glycinate, and then acetyl chloride provides in 81% overall yield the C2-symmetric succinimide 790. In order not to reduce the methyl ester, the very mild treatment with sodium borohydride at —40 °C is employed to prepare the cw-hydroxylactam 791 in an 80% isolated yield. Esterification of 791 with trifiuoroacetic anhydride followed by triethylsilane reduction yields to the extent of 79% the pyrrolidinone 792. This is deprotected with sodium methoxide to provide in 97% yield (3i ,45)-3,4-dihydroxy-A -methoxy-carbonylmethyl-2-pyrrolidinone (793). Ammonolysis of 793 affords (3i ,4 S)-3,4-dihydroxy-2-oxopyrrolidine-A -acetamide (794) in 60% yield. Subsequent modifications to 793 allow for the preparation of (35, 4S)-3,4-dihydroxy-2-oxopyrrolidine-A/-acetamide (795), (3R,4R)-3,4-dihydroxy-2-oxopyrrolidine-A -acetamide (796) and (35, 47 )-3,4-dihydroxy-2-oxopyrrolidine-7V-acetamide (797) [234]. 

The reaction of the methyl ester of the racemic epoxide 101 with acetone and aluminum chloride gave a 4,S-0-isopropylidene derivative 108. Michael addition of ammonia to the conjugated double bond of 108 with concomitant ammonolysis of the ester group afforded a mixture of 3-amino-2,3,6-trideoxy-4,5-0-isopro-pylidene-OL-arabino- and -r/Z o-hexonamides (109). For the purpose of isolation the mixture was N-acetylated. Acidic hydrolysis of the amide groupings gave a mixture of y- and 8-aminolactone hydrochlorides (110 and 111). Careful N-acetylation and reduction of the lactone carbonyl groups in 112 and 113 afforded N-acetyl-DL-acosamine (115) in 36% yield. The stereoisomeric potential partner of 115, N-acetyl-DL-ristosamine (116), was not isolated in this procedure. 

Without such activation simple esters, for instance methyl esters, react with nucleophiles at a low rate. The often applied ammonolysis of methyl esters... 

Scheme 8.6 Ammonolysis of phenylglycine methyl ester under DKR conditions.

The first chemical synthesis of TRF involved the ammonolysis of the methyl ester prepared from the free acid, C lu-His-Pro-OHl. Subsequently, many different kinds of total syntheses of TRF have appeared, employing classicall " and solid-phase methods >21 22 using chloromethyl resin or a benzhydrylamlne resin 2 latter method was used to synthesize TRF... 

The synthesis of peptide amides is Important for endocrinology. Recent reports describe cleavage of peptides from the standard SPPS resin by ammonolysis 9, or by transesterification to the methyl ester followed by ammonolysis In solution for C-termlnal valine peptides (a-melanotropln, MSH)70, Another synthesis of MSH was achieved by conversion of the standard resin to a hydroxypheny1 resin derivative, from which the peptide could be removed by amnxsnolysIs . In this case racemization was a problem if the ammonolysis was done at room temperature. Benzhydryl-amine resins71 offer much promise for the synthesis of amides, and have already been utilized in several syntheses7 73. 

The bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH4 furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. 

Workers at the India Orchid company have shown that the condensation of 2-pentanone with diethyl oxalate may be catalyzed by sodium methoxide which is cheaper than sodium ethoxide. After further condensation with hydrazine hydrate, the pyrazole 18 was obtained as a mixture of methyl and ethyl esters. Methylation with dimethyl sulfate was performed neat, as in the Pfizer medicinal chemistry synthesis. The mixture of the methylated pyrazoles 19 was then nitrated and subjected to ammonolysis to give the desired pyrazole intermediate 5 (Scheme 16.8). 

The effects of changes in structure, temperature, and reaction medium on the kinetics of alkaline hydrolysis of aryl esters of phosphinothioic acids (182 R = R = Me or Ph R = Me, R = Ph X = H, Br, Me, or NO2) have been investigated. The effect of the nature of the leaving group on the kinetics of alkaline hydrolysis of aryl diphenylphosphinates has also been reported on. Indirect evidence has been advanced for the participation of the azaphospholi-dines (183) in the solvolysis of A/-[amino(methyl)phosphinyl]-L-phenylalanine derivatives, and it includes the transfer of the P-amino group to the phenyl-alanyl carbonyl. The products from the hydrolysis or ammonolysis of fosfomycin have the threo structure and have been shown to possess no antibiotic activity. ... 

The syntiiesis of DPP-4 inhibitor, Saxagliptin 1 (Figure 4.21) required key intermediate (5S)-5-aminocarbonyl-4,5-dihydro-lH-pyrrole-l-carboxylic acid,l-(l,l-dimethyl ethyl)-ester 76 [22-24]. Direct chemical ammonolysis resulted in unacceptable levels of amide racemization and side-product formation. Milder, two-step hydrolysis-condensation protocols using coupling agents such as 4-(4,6-dimetiioxy-l,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMT-MM) were compromised by reduced overall yields [103]. 

---