Amide route

As illustrated in Figure A8.3 nitrilases catalyse conversions of nitriles directly into the corresponding carboxylic adds (route A), while other nitrile converting enzymes, die nitrile hydratases, catalyse the conversion of nitriles into amides (route B) which, by the action of amidases usually present in the whole cell preparations, are readily transformed into carboxylic adds (route C). 

During the course of our investigations we found that various tantalum sil-sesquioxanes are readily accessible via a versatile amide route. Commercially available tantalum diethylamide, Ta(NMe2)5, was chosen as the key starting material for the development of a salt-free route leading to tantalum silsesquioxane derivatives. Clean protonation and liberation of three equivalents of dimethylamine took place upon reaction of Ta(NMe2)5 with 3 in a 1 1 molar ratio. Pale yellow... 

In 2006, Yamamoto and Nakashima picked np on this and designed a chiral A -triflyl phosphoramide as a stronger Brpnsted acid catalyst than the phosphoric acids based on this concept. In their seminal report, they disclosed the preparation of new chiral BINOL-derived A -triflyl phosphoramides and their application to the asymmetric Diels-Alder (DA) reaction of a,p-unsaturated ketones with sily-loxydienes [83], As depicted in Scheme 59, chiral A-triflyl phosphoramides of the general type 4 are readily synthesized from the corresponding optically active 3,3 -substituted BINOL derivatives 142 through a phosphorylation/amidation route. 

Second-Ceneration Chiral Auxiliarf Route. The PC A Enamine-amide Route 115... 

Second-Ceneration Chiral Auxiliary Route. The PGA Enamine-amide Route... 

With the (S)-PGA enamine-amide route, sitagliptin was prepared in 65% overall yield from 2,4,5-trifluorophenylacetic acid (9) in 4 chemical steps [18]. Two addi-honal crystallization steps are required for enanhomeric purity upgrade and final salt formation. The (S)-PGA enamine-amide hydrogenahon approach eliminated the ester hydrolysis and amide formation steps of the (S)-PGA enamine-ester route by incorporating the newly developed Meldrum s acid chemistry, which enabled direct amidahon with triazole 3. 

More general solutions come from the replacement of alkylations by reactions with carbonyl compounds. These generally occur once only and in many cases cannot occur twice as the products—amides 12 or imines 15 for example—are much less nucleophilic than the starting amine. The products are reduced to the target amines. The amide route is restricted to amines with a CH2 group next to nitrogen 13 but the imine route is very general and is known as reductive animation.1 It is the most important way to make amines and a recent survey showed that the majority of amines made in the pharmaceutical industry are made this way. 

An example that has been made by the amide route is the cyclic amine 24. Putting the carbonyl group on the side chain 25 allows us to use readily available piperidine 26 as a starting material. The synthesis4 uses catalytic reduction to give 24 in 92% yield from the amide 25. 

An early synthesis of water-free Nd carboxylates was reported by Roberts in 1961 [210]. Nd203 is reacted with an excess of carboxylic acid to yield the Nd carboxylate trihydrate by recrystalhzation in water. Subsequent dehydration is achieved by storage of the trihydrate over anhydrone (i.e. magnesium perchlorate) in vacuo. Dehydration of the trihydrate is also achieved by heating it at 150-180 °C for 2-3 h under a flow of dry nitrogen at reduced pressure [176]. Today, the amide route is the most commonly used laboratory method for the preparation of anhydrous Nd-carboxylates. In this route... 

As for the preparation of Nd carboxylates, in the laboratory, the amide route is the most convenient route to various Nd alcoholates. In this synthesis... 

The normal-propylamine NPT has been made by the oxalyl amide route, with the amide having a mp 179-181 °C (75%) from benzene and NPT hydrochloride mp 186-187 °C (33%) from MeOH/benzene. An attempt to make NPT by the alkyl halide procedure failed. Using these same ratios of reactants, there was the formation of a sizable quantity of DPT with appreciable unreacted tryptamine presence (T NPT DPT/1 5 4). A recycling under the same conditions gave T NPT DPT/0 3 7 and a third cycle gave only DPT, but with a loss of almost 90% of the material, presumably to quaternary salt formation. Interestingly, NPT is less toxic than DPT in experimental mice, but has not yet been assayed in man. 

You should find yourself quite restricted in choice the amide route clearly works only if there is a CH2 group next to the nitrogen (this comes from the C=0 reduction), so we have to use an imine. 

PREPARATION OF Mg ALKOXIDES, THIOLATES AND AMIDES route to the halomagnesium salt ... 

Synthesis of the bispidines can be tuned to select for 189 by promoting the Mannich-amidation route via the use of /-B11CO2H or 190 by promoting the Mannich-Mannich cascade via the use of MeSO.dl. 

Compound 3.117 was reacted with 3.114, then transformed on SP as seen for 3.107 and diversified with amines R3R4NH to give 3.125 (twenty amides, route a) ... 

The /feq for proton transfer is 10 -, which slightly favors reactants. If the amidate anion were to act as a nucleophile, the only site for attack would be another amide, and then it would just be kicked right back out again since it would be the best leaving group. If the amidate acts as a base, it returns to the reactants. This short exploration down the amidate route reveals it as a dead end. Hydroxide as a nucleophile looks more promising. 

An alternative route to dialkyl 2-oxoalkylphosphonates is based on the use of Nahm-Weinreb amides. Condensation of Nahm-Weinreb amides with dimethyl 1-lithiomethylphosphonate proceeds readily at low temperature. Compared with the ester route (Section 7.1.2.5.1), the Nahm-Weinreb amide route possesses significant synthetic advantages because only a slight excess of phosphonate carbanion is necessary to afford the P-ketophosphonates in good yields (66-85%). - This approach has been developed in the production of the optically active dimethyl 2-oxo-4-(tert-butyldimethylsilyloxy)-5-(methoxycarbonyl)pentylphosphonate (Scheme 7.30). ... 

Route A (chiral sultam amide) Route B (resolution with DAA) Route C (epoxide) Route D (asymmetric cyclopropanation)... 

The free-base form of sunitinib malate (2) contains a highly substituted pyrrole core bearing an amide side chain at the 3-position and an indolinone substituent at the 5-position. Two routes were originally evaluated for the synthesis of free base 2. These were the early and late amidation routes. In the early amidation route, the pyrrole core is assembled after the amide side chain is installed, and the late amidation route involves amidation after the pyrrole core is assembled. These two approaches are depicted in Figure 4.2. 

The early amidation route commenced with the synthesis of p-ketoamide 6. Reaction of diketene with Al,Al-diethylethylenediamine in t-butyl methyl ether afforded 6 in excellent yield (Scheme... 

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