Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment

Preparative Example 1

Preparation of: 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol

Step 1 Preparation of tert-butyl 4-[(4R)-5-(benzyloxy)-4-hydroxypent-1-yn-1-yl]piperidine-1-carboxylate

[0315]

[0316]Commercially available tert-butyl 4-ethynylpiperidine-1-carboxylate was dissolved in 40 ml of THF and cooled to −78° C. forming a white slurry. Titrated n-BuLi (2.2 M in hexanes, 23.9 ml, 52.6 mmol) was added drop wise with stirring. The clear colorless solution was stirred at −78° C. for 5 minutes. A solution of the R-(+) benzyl glycidyl epoxide (8.63 g, 52.6 mmol) in THF (20 ml) was added drop wise. BF3 etherate (8.43 g, 59.7 mmol) was then added drop wise with a syringe and the solution stirred at −78° C. for 1 hour. Saturated aqueous NH4Cl was added (100 ml), the mixture warmed to RT, diluted with water to dissolve any remaining solids, and extracted with iPrOAc (3×100 ml). The organic fractions were combined, washed with brine, dried over MgSO4, filtered and

Preparative Example 1b

Preparation of rac cis tert-Butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate, i.e. (tert-butyl 4-[(1S,2R)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate and tert-butyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate)

Step. 1. Preparation of tert-Butyl 4-[(1Z)-4-(benzyloxy)but-1-en-1-yl]piperidine-1-carboxylate

[0329]

(3-Benzyloxypropyl)triphenylphosphonium bromide (2.88 g, 5.86 mmol) was suspended in 15 mL THF and cooled to 0° C. Sodium bis(trimethylsily)amide (1M in THF, 5.63 mL, 5.63 mmol) was added drop wise. The mixture turned deep orange. tert-Butyl 4-formylpiperidine-1-carboxylate (1 g, 4.69 mmol) in 3 mL THF was added after 5 minutes. Color faded to slight yellow. The reaction was stirred at room temperature for 1.5 hours, before quenching with saturated aqueous ammonium chloride solution. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with water and brine, dried over

Preparative Example 2

Preparation of rac-trans-2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol

Step 1: tort-Butyl 4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]piperidine-1-carboxylate

[0333]

Lithium chloride (1.013 gram, 1.23 eq.) was suspended in 100 mL HPLC grade acetonitrile. Methyl (diethoxyphosphoryl)acetate (4.33 gram, 1.06 eq.) was added slowly at room temperature, followed by DBU (3.14 gram, 1.06 eq.) and the indicated commercially available aldehyde (4.14 gram, 1 eq.) in acetonitrile (10 mL). The mixture was stirred at room temperature for 3 hours. Excess solvent was removed in vacuum. The residue was diluted with water (100 mL) and was extracted with ether (50 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude ester as pale yellow oil, which was used in the next step without further purification.

Step 2: rac-trans-tert-Butyl 4-[(1E)-3-hydroxyprop-1-en-1-yl]piperidine-1-carboxylate

[0334]

1 M DiBAl-H in dichloro