Cyano acids

A related reaction sequence, which proceeds through a Curtius rearrangement, allows the transformation of a-cyano acids into hydantoins (66) ... 

Cyan-saure, /. cyanic acid cyano acid, -schlamm, m. cyanide sludge, -senf l, n. cyanomustard oil. -silber, n. silver cyanide. -stickstoS, m. cyanonitride. -toluol, n. cyanotoluene. 

The methyl esters of aromatic cyano acids show intense molecular ions, but the intensity decreases as the length of the side chain increases. Losses from the molecular ion are 31 and 59 Daltons. 

Possibly loss of formic acid [e.g., C6H5CH2CH2C(0)0H] Cyano acids... 

GC separation of derivatized carboxylic acids, 46-52 bacterial fatty acids, 51-52 bile acids, 50-51 C6-C24 monocarboxylic acids and dicarboxylic acids, 51 cyano acids, 52 higher-boiling acids, 49 itaconic acid, citraconic acid, and mesaconic acid, 49... 

Here too there is an enol that tautomerizes to the product. The mechanism is illustrated for the case of P-keto acids, ° but it is likely that malonic acids, a-cyano acids, a-nitro acids, and P,y-unsaturated acids behave similarly, since similar six-membered transition states can be written for them. Some a,P-unsaturated acids are also decarboxylated by this mechanism by isomerizing to the p,y-isomers before... 

In a 500-ml. three-necked flask fitted with a sealed mechanical stirrer and a reflux condenser are placed 86 g. (1 mole) of 7-butyrolactone (Note 1) and 72 g. (1.1 moles) of potassium cyanide (Note 2). As the contents of the flask are stirred, the mixture is heated in an oil bath for 2 hours at a temperature of 190-195° (Note 3). There is an initial vigorous reaction which soon subsides. After the completion of the heating period the mixture is cooled to about 100°, and the potassium salt of the cyano acid is dissolved in about 200 ml. of hot water. The warm solution is cautiously acidified to Congo Red by the addition of about 90 ml. of concentrated hydrochloric acid. The resultant solution, which contains glutaric acid monoamide and potassium chloride, is used to prepare glutaric acid or glutarimide. 

The P-cyanodiester 4 was prepared by condensation of isovaleraldehyde with diethyl malonate followed by the addihon of potassium cyanide. The cyanodiester 4 was hydrolyzed and decarboxylated to give the P-cyano acid 5. Reduction with Raney nickel gave racemic pregabalin (6), which was resolved with (S)-mandelic acid. The diastereomeric salt was split with wet TH F under neutral conditions to give pregabalin, which was recrystallized from isopropanol (IPA) to give the final Active Pharmaceutical Ingredient (API). 

Alcoholysis of cyano acids 9-10 Oxidative cleavage of catechols... 

If the cyano acid obtained from the precipitated barium salt is worked up separately, it melts at 51-52°. 

Crystallization-induced asymmetric transformation has already been described by Leuchs in 1913 during the resolution of 2-(2-carboxybenzyl)-l-indanone with brucine.34 In this case spontaneous racemization occurred. More recently researchers at Sanofi observed spontaneous racemization during the resolution of 3-cyano-3-(3,4-dichlorophenyl)propionic acid (7), most likely as a result of the basic resolving agent [>-(-)-N-1 n etli y I g I near nine [d-(-)-MGA] (8) (Scheme 7.6).35 The enantiopure cyano acid, obtained in 91% overall yield, is subsequently reduced to (+)-4-amino-3-(3,4-dichlorophenyl)-l-butanol (9), a key intermediate in the phase 2 synthesis of tachykinin antagonists. 

The phenanthrenequinone oxime 54 was built in four steps from the two benzenoid precursors 52 and 53. Beckmann rearrangement of 54 furnished the cyano-acid 55. The latter, after reduction to the corresponding cyano-aldehyde, was homologated by Knoevenagel condensation with malonic acid to give, after reduction, hydrolysis and esterification, the diester 56. This compound underwent Dieckmann condensation, installing the seven-membered C-7 ketone 57 in 69% yield after hydrolysis and decarboxylation of the intermediate (3-ketoester. 

Base treatment of isoxazoIin-5-ones produced the cyano acids (70JOC3130), while ethoxide treatment of N- alkyl-A3-5-ones gave, after H20 treatment, a malonyl monoamide monoester (69JOC2981) and not an oximoacrylate as was reported earlier (Scheme 61) (23HCA102). The base treatment of a 4-bromoisoxazolin-5-one generated a ring-opened oxime (Scheme 62) (79JOC873). 

The thermal decompositions of a number of azolidines have been studied (Scheme 32). Thus 1,2,4-dioxazolidines, e.g. (138), rearrange to cyano acids (69JCS(C)267i) while their... 

Simple saturated nitriles are seldom prepared by the decarboxylation of cyano acids derived from the cyanoacetic ester synthesis (cf. method 265). However, difunctional compounds are frequently obtained by this route, as in the preparation of a-methyl-y-phenoxybutyronitrile from /3-phenoxy-ethyl bromide and ethyl methylcyanoacetate (52% over-all). ... 

The heating of lactones with powdered alkali cyanides leads to salts of cyano acids. The procedure is illustrated (above equation) by the synthesis of o-carboxybenzyl cyanide from phthalide and potassium cyanide (67-83%). In another instance, the reaction of potassium Cyanide with y-anisyl-y-butyrolactone involves a rearrangement thereby forming a /3-cyano acid instead of the anticipated y-cyano acid, ... 

A similar rearrangement has been observ ed in the treatment of y-methyl-y-valerolactone with potassium cyanide whereby y-methyl-yS-cyanovaleric acid is formed instead of the expected y-cyano acid. ... 

Cyano acetals, preparation, 598 Cyanoacetic ester condensation, 608 Cyanoacetic ester synthesis, 429, 601 Cyano acids, esterification, 481 preparation, 593, 607, 608 preparations listed in table 74, 622 a-Cyano acids, decarboxylation, 429, 601... 

Hydrolysis and Decarboxylation of Cl-Cyano Acids (Cyanoacetic Ester... 

Cyano acids are prepared by first neutralizing the corresponding halo acids with sodium carbonate and then treating the aqueous solutions with... 

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