2- -4-cyanopyridine

Ethyl nicotinate upon treatment with concentrated ammonia solution yields nicotinamide, which gives p-cyanopjTidine upon heating with phosphoric oxide  

Nicotinamide. Place 50 g. of pure ethyl nicotinate (Section V,23) in a 350 ml. bolt-head flask and add 75 ml. of concentrated aqueous ammonia saturated at 0°. Keep the flask loosely stoppered for 18 hours, after w)iich time the lower layer generally dissolves on shaking. Saturate the solution with ammonia and allow it to stand for a further 4 hours. Repeat the saturation with ammonia crystals of the amide commence to appear in the solution. Evaporate to drjmess in a dish on the steam bath and dry at 120°. The yield of nicotinamide, m.p. 130°, is usuallj quantitative. 

P-Cyanopyridine. Mix 25 g. of powdered nicotinamide with 30g. of phosphoric oxide in a 150 ml. distilling flask by shaking. Immerse the flask in an oil bath and arrange for distillation under a pressure of about 30 mm. Raise the temperature of the oil bath rapidly to 300°, then remove the oil bath and continue the heating with a free flame as long as a distillate is obtained. The nitrile crystallises on cooling to a snow-white solid. Redistil the solid at atmospheric pressure practically all of it passes over at 201° and crystallises completely on cooling. The yield of p-cyanopyridine, m.p. 49°, is 20 g. 

A mixture of 5 g. (0.031 mole) of 8-chloroquinoline (p. 85), 3.3 g. (0.019 mole) of cuprous cyanide, 10 ml. of pyridine, and 3-4 drops of acetonitrile is heated in a sealed tube at 200° for 18 hours. The resulting solution is treated with excess aqueous ammonia and extracted with a mixture of benzene and ether. The extracts are dried and distilled at 2 mm. The light-yellow solid distillate is recrystallized from an ether-hexane mixture to give 3.2 g. (67%) of 8-cyano-quinoline melting at 82-83.5°. 

A mixture of 10 g. (0.17 mole) of urea and 20 g. of freshly fused anhydrous zinc chloride is heated to 220°. Upon cooling and treating with hydrochloric acid, there is obtained a fine crystalline product which is separated and recrystallized from hot water. The resulting long needles of cyanuric acid are obtained in 62% yield. When heated cyanuric acid decomposes without prior melting. 

One gram of platinum oxide catalyst [Org. Syntheses Coll. Yol. 1, 463 (1941) ] is added to a solution of 42 g. (0.50 mole) of cyclopenta-none [Org. Syntheses Coll. Yol. 1, 192 (1941) ] in 150 ml. of methanol. The mixture is agitated under a hydrogen pressure of 2-3 atm. until the calculated amount of hydrogen has been absorbed (9-12 hours) [Org. Syntheses Coll. Vol. 1, 66 (1941)]. The catalyst is removed by filtration, and the solution is distilled through a fractionating column. The cyclopentanol is obtained in 93-95% yield (40-41 g.) and boils at 139-141°, 

Eighty grams (0.93 mole) of cyclopentanol (p. 93) is added to a solution of 272 g. of anhydrous zinc chloride in 190 g. of concentrated hydrochloric acid, and the mixture is heated on a steam bath for 1 hour. After the mixture has cooled, the upper layer is separated and washed in turn with water, dilute aqueous sodium bicarbonate 

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Cyanopyridines are usually manufactured from the corresponding picoline by catalytic, vapor-phase ammoxidation (eq. 7) in a fixed- or fluid-bed reactor (28). 3-Cyanopyridine (25) is the most important nitrile, as it undergoes partial or complete hydrolysis under basic conditions to give niacinamide... 

Hydrogenation of 3-cyanopyridine (25) in the presence of ammonia gives 3-pico1ylamine [3731 -52-0] (29) however, hydrogenation in the presence of hydrogen chloride affords the corresponding 3-carbinol (30) (31). 

Pyridinecarbonitriles, -carboxamides, and -carboxylic Acids. 3-Cyanopyridine (25) is used for the production of niaciu (27), or vitamin 4-Cyanopyridine (15) is used for making the antitubercular dmg isonia2id (31) (101). 

Cyanopyridine [100-54-9] M 104.1, m 50 , pK 1.38. Crystd to constant melting point from o-xylene/hexane. 

Yield % (reaction time h) [a] Anhydrous H202 in MluOH. [b] Aqueous H202 (30%), [c] Pyridine and 3-cyanopyridine (6 mol% of each). 

A major improvement regarding epoxidation of terminal olefins was achieved upon exchanging pyridine for its less basic analogue 3-cyanopyridine (p Krl pyridine = 5.4 pKa 3-cyanopyridine = 1.9) [105]. This improvement turned out to be general for a number of different terminal olefins, irrespective of the existence of steric hindrance at the a-position of the olefin or the presence of other functional groups in the substrate (Scheme 6.13 and Table 6.9). 

Corynebacterium glutamicum (CGMCC No. 1464) cells immobilized in calcium alginate beads cross-linked with polyethenimine and glutaraldehyde have been employed for the production of nicotinamide from 3-cyanopyridine [21], The reaction was mn at 10-15 °C,... 

Table 8.3 Dependence of Rhodococcus sp. FZ4, Rhodococcus sp. GF270, Amycolatopsis sp. NA40 and Rhodococcus rhodochrous J1 NHase activities on 3-cyanopyridine concentration ...

A thermally stable NHase from Comamonas testosteroni 5-MGAM-4D (ATCC 55 744) [22] was recombinantly expressed in Escherichia coli, and the resulting transformant cells immobilized in alginate beads that were subsequently chemically cross-linked with glutaraldehyde and polyethylenimine. This immobilized cell catalyst (at 0.5 % dew per reaction volume) was added to an aqueous reaction mixture containing 32wt% 3-cyanopyridine at 25 °C, and a quantitative conversion to nicotinamide was obtained. The versatility of this catalyst system was further illustrated by a systematic study of substrates, which included... 

Unimmobilized Corynebacterium propinquum (CGMCC No. 0886) cells containing a cobalt-dependent NHase were employed in either batch or continuous reactions for the production of nicotinamide from 3-cyanopyridine [24]. In the continuous process, membrane filtration separated precipitated product (>5 wt%) and the microbial cell catalyst from the reaction mixture, where the catalyst was then recovered and returned to the reactor using a continuous addition of aqueous 3-cyanpyridine to maintain substrate concentration at <20% (w/v), a final conversion of >99% was obtained. 

A novel nitrilase was purified from Aspergillus niger K10 cultivated on 2-cyanopyridine. It was found to be homologous to a putative nitrilase from Aspergillus fumigatus Af293. The nitrilase exhibited maximum activity at 45 °C and pH 8.0 with much less activity observed at slightly acid pH. Its substrate preference was for 4-cyanopyridine, benzonitrile, 1,4-dicyanobenzene, thio-phen-2-acetonitrile, 3-chlorobenzonitrile, 3-cyanopyridine, and 4-chlorobenzonitrile. ( )-2-Phenylpropionitrile was only poorly converted by this enzyme and with minimal enantioselectivity. The enzyme was shown to be multimeric (>650 kDa) and be stabilized in the presence of sorbitol and xylitol [57]. 

A process research investigation on p38 MAP kinase inhibitors examined the synthesis (on 7 mol scale) of a group of closely related pyrimidinones such as 37, by condensation of a number of arylacetic esters with 4-cyanopyridine and methyl isothiocyanate. Other nitriles were also examined but were much less successful than 4-cyanopyridine 3-cyanopyridine gave a much lower yield and both benzonitrile and 2-cyanopyridine failed completely <06T11714>. 

Surprisingly, aromatic nitriles were found not to yield 1-arylcyclopropylamines under these conditions. However, this deficit is compensated for by a complementary method developed by de Meijere et al. using diethylzinc in the presence of methyltitanium triiso-propoxide and lithium isopropoxide (Scheme 11.40). While aliphatic nitriles 152 gave primary cyclopropylamines 155 in only 12—16% yield with this reagent mixture, aromatic nitriles 156 and 158 furnished 1-arylcyclopropylamines 157 and 159 in moderate (28—40% for substituted benzonitriles 156) to good (70% for 3-cyanopyridine 158) yields (Scheme 11.40) [138],... 

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