Process for the preparation of 3-(6-amino-pyridin-3yl)-2-acrylic acid derivatives

#The present invention relates to a process for the preparation of a compound of the formula I, which can be used in the preparation of compounds which inhibit the enzyme TAFIa (activated thrombin-activatable fibrinolysis inhibitor), and to the novel intermediate compounds used therein.

#The enzyme TAFIa is produced for example through thrombin activation from the thrombin-activatable fibrinolysis inhibitor zymogen (TAFI). The enzyme TAFI is also referred to as plasma procarboxypeptidase B, procarboxypeptidase U or procarboxypeptidase R and is a proenzyme similar to carboxypeptidase B (L. Bajzar, Arterioscler. Thromb. Vasc. Biol. 2000, pages 2511-2518).

#During formation of a clot, thrombin is generated as the final product of the coagulation cascade and induces conversion of soluble plasma fibrinogen to an insoluble fibrin matrix. At the same time, thrombin activates the endogenous fibrinolysis inhibitor TAFI. Activated TAFI (TAFIa) is thus produced during thrombus formation and lysis from the zymogen TAFI through the action of thrombin; thrombomodulin in a complex with thrombin increases this effect about 1250-fold. TAFIa cleaves basic amino acids at the carboxy end of fibrin fragments. The loss of carboxy-terminal lysines as binding sites for plasminogen then leads to inhibition of fibrinolysis. Efficient inhibitors of TAFIa prevent the loss of these high-affinity lysine binding sites for plasminogen and, in this way, assist endogenous fibrinolysis by plasmin: TAFIa inhibitors have profibrinolytic effects. In order to maintain hemostasis in the blood, mechanisms which lead to the clotting of blood and to the breaking up of clots have developed; these are in equilibrium. If a disturbed equilibrium favors coagulation, fibrin is produced in larger quantities, so that pathological processes of thrombus formation may lead to serious pathological states in humans.

#200 g (0.758 mol) 4-Cyclohexylamino-3-oxo-butyric acid ethyl ester hydrochloride were dissolved in 360 ml water and 120 ml tert-butanol and were heated to 90° C. Then 88.4 g (0.91 mol) KSCN were added and the mixture was heated for 20 s, thereby a phase separation occurred. After cooling to RT, the phases were separated and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with Brine, dried with MgSO4 and concentrated. The solid was digested in MTBE and filtered to yield 192 g (0.715 mol, 94%) of (1-Cyclohexyl-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)-acetic acid ethyl ester as a beige solid. HPLC: tR=1.16 min (YMC J′ sphere ODS H 80 20×2.1 mm, 4 μm, A: H2O+0.05% TFA, B: MeCN, 4%→95% B in 2 min, 1 ml/min, 30° C.); Mass (ES+) (C13H20N2O2S): calculated. 268. found 269 [M+H]+.

#80.0 g (0.298 mol) of (1-Cyclohexyl-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)-acetic acid ethyl ester, dissolved in 200 ml acetic acid, were slowly added to H2O2 in 400 ml acetic acid at 0° C. within 90 min at 10° C. After addition the cooling was removed and the mixture was allowed stirring for 1 h. The solution was carefully poured into 80 g Na2SO3 in 300 ml water and ice. The slurry was concentrated and the acidic residue was treated with saturated aqueous K2CO3 and saturated aqueous NaHCO3 (pH 8). The mixture was extracted with AcOEt (1×400 ml, 2×150 ml). The combined organic layers were washed with brine, dried with MgSO4, concentrated and dried under reduced pressure and gave 70.0 g (0.296 mmol, 99%) of (1-Cyclohexyl-1H-imidazol-4-yl)-acetic acid ethyl ester as a brown oil which could be used without further purification in step A of Example 1.

#HPLC: tR=0.77 min (YMC J′ sphere ODS H 80 20×2.1 mm, 4 μm, A: H2O+0.05% TFA, B: MeCN, 4%→95% B in 2 min, 1 ml/min, 30° C.);