2-(Diethylamino)-6-nitrobenzonitrile (72). To a mixture of 3.82 g (0.02 mol) of 2-(ethylamino)-6-nitrobenzonitrile (73) and 3.2 g (0.02 mol) of ethyl iodide in 100 mL of DMF was added 0.96 g (0.02 mol) of 50% NaH (in oil) in portions. The mildly exothermic reaction was stirred for 10 min, poured into ice-water, and extracted into methylene chloride. Evaporation gave an oil that was passed through a short column of silica gel (20 g) with methylene chloride. The bright orange oil was collected and triturated with hexane to give 3.1 g of pure product, mp 39-41 °C.2-Nitro-5-(dimethylamino)benzoic Acid (75). Sodium cyanoborohydride (57 g) was added to a mixture of 54.6 g (0.21 mol) of commercial (70%) 2-nitro-5-aminobenzoic acid and 240 mL of formalin in 1200 mL of acetonitrile. The reaction mixture was stirred overnight and evaporated to one-third volume. The product crystallized as the hemihydrate: mp 187-189 °C; yield 50 g (100%). Anal. (C9H10N2O4-0.5H2O) C, , N. 5-(Dimethylamino)anthranilic Acid (76). A mixture of 10.5 g (0.05 mol) of the nitrobenzoic acid 75,5 g of 10% Pd on charcoal, and 25 g (0.3 mol) of cyclohexene in 200 mL of ethanol was heated at reflux for 3 h. The hot reaction mixture was filtered through Celite, the Celite pad was extracted three times with hot ethanol, and the combined ethanol filtrates were evaporated to one-third volume. Water was added to cloudiness, whereupon the pure product crystallized: yield 8.0 g (93%); mp 234-238 °C (lit.28 234-236 °C).

A large number of oxanilic acid esters and N-heteroaryl oxamic acid esters were prepared and found to have antiallergic activity using the rat passive cutaneous anaphylaxis (PCA) test. Many of the oxanilic acid esters are active orally, with the most active species having an aryl 2'-carbamoyl group and a 3'-methoxy group. Hydrolysis of the ester from the oxanilic ester moiety causes a loss of oral activity.

We report herein the three-step enantioselective synthesis of beta-trifluoromethyl alpha-amino acids including trifluorovaline (TFV) using stereoselective hydrogenation with [((R)-trichickenfootphos)Rh(cod)]BF(4) catalyst as the key step.

dichloromethane (25 mL). The tan solid was filtered off and suspended in cold (0 °C) DMF (50 mL). Anhydrous ammonia was bubbled through for 10 min, and the resulting solution was allowed to stand at room temperature overnight. The DMF solution was evaporated to dryness under reduced pressure, and the residue was washed with CH2C12 and ether and dried: yield 3.0 g; mp 340-345 °C dec. Method M.7-Chloro-4,9-dihydro-4-methyl-9-oxopyrazolo[5,l-h]quinazoline-2-carbonitrile. 7-Chloro-4,9-dihydro-4-methyl-9-oxopyrazolo[5,l-6]quinazoline-2-carboxamide (3 g, 0.011 mol) was heated at 56 °C with thionyl chloride (1.6 mL, 0.022 mol) and DMF (35 mL) for 18 h. The resulting clear solution was evaporated to dryness, and the residue was treated with water (600 mL). After the solution was left standing for 1 h, the crude nitrile was filtered off, washed with water, and recrystallized from a DMF-EtOH mixture: yield 2.4 g (84%);

A suitable process for the preparation of kilogram quantities of a TNF-r converting enzyme (TACE) inhibitor (WAY-281418) was developed using isatin 13 as starting material and an efficient coupling step for the formation of sulfonamide 8 in a 15% overall yield. Process preparation of (+)-(1S,2R)-2-aminocyclopentane-1carboxylic acid (7, (+)-cispentacin), a chiral component for WAY-281418, was successfully scaled up via an asymmetric hydrogenation reaction. Crystallization allowed the isolation of all intermediates and the final product 9.