(trans-4-Aminocyclohexyl)acetic acid ethyl ester hydrochloride

Preparation of trans 4-amino-cyclohexyl-acetic acid ethyl ester HClA 2500 1 enamelled autoclave is charged with 1000 kg of deionizated water and 210 kg (1.16 kM) of 4-nitrophenyl-acetic acid at room temperature under nitrogen atmosphere. After inertisation by nitrogen to the mixture obtained a suspension of 21 kg of 10percent Pd/C in 20 kg of deionized water is added and the catalyst measuring gauge is rinsed by additional 20 kg of deionizated water. After rinsing the reaction vessel by hydrogen gas the hydrogenation is carried out at a temperature between 44-46°C and under up to 0, 6 bar overpressure until the hydrogen uptake is slowed. After reducing the nitro group the temperature is brought to 55- 58°C and the hydrogenation continued maintaining hydrogen pressure on max. 4.0 bar overpressures. After completion of the hydrogen uptake, the mixture is cooled to a temperature between 25-30°C, purged with nitrogen and the catalyst is filtered on a Spakler filter under pressurized nitrogen. The reaction vessel, the filter and the lines are washed additional 200 g of deionized water. The filtrates are combined and in a 2500 1 enamelled doubler 1200 kg of distillate is distilled at up to 80°C inner temperature in vacuum. The residue obtained is cooled to a temperature below 30°C and 430 kg of ethyl alcohol is added, then 500 1 of distillate is collected at up to 80°C under vacuum. After completion of the distillation the mixture is cooled to a temperature between 25-30°C, (water content is max. 10 wpercent, in terms of absolute value is about 32 kg), and 550 kg of ethyl alcohol, then 170 kg of 30percent hydrochloric ethyl alcohol are added and the reaction mixture is heated to reflux for approx. 2 hours. When the esterification is complete 800 1 of solvent is distilled off at up to 80°C, under vacuum. Additional 800 1 of ethyl alcohol is added and further 750-800 1 of solvent is distilled off at up to 80°C, under vacuum. To the residue obtained 700 kg of acetonitrile is added and 140 1 of distillate is collected at up to 80°C under vacuum. The vacuum is stopped by introducing nitrogen and the solution is cooled to a temperature between 0-(-)5°C. The crystals obtained is centrifuged, washed with 100 kg of acetonitrile in two portions during which the temperature is kept at 0-(-)5°C. The solid obtained is dried to a constant weight at up to 6OA mixture of 7-chloro-6-nitrothieno[3, 2-b]pyridine (97 mg, 0.45 mmol), To a solution of cyclohexyl-[5-fluoro-2-((_R)-methoxy-phenyl-methyl)-benzoimidazol-l- yl] -acetic acid (350 mg, 0.88 mmol, 1.0 equiv) in DMF (5 mL) was added triethylamine (179 mg, 240 muL, 1.77 mmol, 2.0 equiv) and HATU (403 mg, 1.06 mmol, 1.2 equiv) and the mixture stirred at 40 0C. After 15 min, trans- (4-amino-cyclohexyl) -acetic acid ethyl ester hydrochloride (235 mg, 1.06 mmol, 1.2 equiv; [CAS RN 76308-26-4]) was added and stirring continued at 50 0C for 2 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCtheta3 and the aqueous layer extracted with dichloromethane. The combined organic phases were dried over MgStheta4 and concentrated by evaporation under reduced pressure. The crude material was used in the consecutive step without further purification. MS (ISP): 564.7 [M+H]+.Step 2: Trans (4-Amino-cyclohexyl)-acetic acid ethyl ester hydrochloride A solution of the Trans-(4-amino-cyclohexyl)-acetic acid obtained (74 g, 476 mmol) was adjusted to pH 5 with 25% HCl. The mixture was evaporated to dryness and dried under vacuum overnight. The residue was suspended in 146 mL of a 6.5N ethanolic HCl solution and 0.6 L of ethanol was added to the mixture. After 4 h refluxing, the mixture was cooled and filtered and the filtrate was concentrated to dryness under vacuum. The residue was dissolved in ethanol, treated with ether and cooled overnight in the refrigerator, to give the Step 1: trans-(4-Acetylamino-cyclohexyl)-acetic acid ethyl ester Trans-(4-Amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (1.0 g, 4.51 mmol) (Example A, step 2) was dissolved in dichloromethane and triethylamine (1.89 ml, 13.5 mmol) was added. Acetyl chloride (0.35 ml, 4.96 mmol) was added drop wise and the reaction mixture stirred for 5 hours at room temperature. The reaction mixture was quenched with saturated NaHCO3-solution and extracted with dichloromethane. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product (804 mg, 78%) [MS: m/e=228.3/229.3 (M+H+)] was obtained as a white solid and used without any further purification for the next step.

Molecular Weight:221.72
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:221.1182566
Monoisotopic Mass:221.1182566
Topological Polar Surface Area:52.3
Heavy Atom Count:14
Complexity:162
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes