(4aS,7aR)-1-[5-[(3-Fluorophenyl)ethynyl]pyridin-2-yl]hexahydrocyclopenta[d][1,3]oxazin-2(1H)-one

(4aS,7aR)-l-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[d] [l,3]oxazin-2-one

336.35

C20 H17 F N2 O2

F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc.

mgluR5 Positive Allosteric Modulators

Signal Transduction Modulators

http://www.google.com/patents/WO2014056710A1?cl=en

Example 1

(4aS,7aR)-l-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[d] [l,3]oxazin-2-one

Ste 1 : ((lR,2S)-2-Hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester

To a well stirred suspension of 0.94 g (24.7 mmol, 2 equiv.) of L1AIH₄ in 30ml of THF at 0°C was added dropwise at 0°C a solution of (lS,2R)-methyl 2-(tert-butoxycarbonylamino)- cyclopentanecarboxylate (CAS: 592503-55-4) (3.0 g, 12.3 mmol) (gas evolution, lightly exo therm). After 15 minutes at 0°C the reaction mixture was allowed to warm up to room temperature and was stirred for 2h. The mixture was cooled to 0°C and water was added dropwise. The precipitated inorganic salts were filtered through Celite and were washed with ethyl acetate. The filtrate was evaporated and the residue was purified by column

chromatography on silica gel eluting with a 0% to 50% ethyl acetate in heptane gradient to yield 1.99 g (75%) of the title compound as a crystalline white solid which was directly used in the next step. Ste 2: (4aS,7aR)-Hexahydro-cyclopenta[d][l,3]oxazin-2-one

To a solution of ((lR,2S)-2-hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester (1.6 g, 7.43 mmol) in THF (40 ml) was added potassium tert-butoxide (3.34 g, 29.7 mmol, 4.0 equiv.) at room temperature. After stirring for lh at 60°C the reaction was allowed to warm up to room temperature and after workup with Ethyl acetate/water, drying and concentration in vaccuo, the crude material mixture was adsorbed on silica and chromatographed over a prepacked silica column (50g, 50% to 100% EtOAc in Heptane gradient) to yield 950 mg (91%) of the title compound as a white solid, which was directly used in the next step. -Fluoro-5-phenylethynyl-pyridine

In an 100ml 2-necked round bottomed flask under Argon were dissolved 2-fluoro-5-iodopyridine (5.0 g, 22.4 mmol, 1.0 equiv.) in THF (30 ml). After 5 minutes at room temperature were added bis(triphenylphosphin)palladium(II)chloride (944 mg, 1.35 mmol, 0.06 equiv.), triethylamine (6.81 g, 9.32 ml, 67.3 mmol, 3.0 equiv.), phenyl acetylene (2.75 g, 2.95 ml, 26.9 mmol, 1.2 equiv.) and copper(I)iodide (128 mg, 0.67 mmol, 0.03 equiv.). The brown suspension was cooled with water (exothermic) to room temperature and stirred overnight. Then 200ml of diethylether were added, the mixture was filtered, washed with ether and concentrated in vacuum to yield 5.7g of a brown solid which was adsorbed on silica and was chromatographed in 2 portions over a lOOg prepacked silica column eluting with a 0-10% ethyl acetate in heptane gradient to yield 3.99g (91%) of the title compound as a light brown solid, MS: m/e = 198.1 (M+H⁺). Step 4: (4aS aR)-l-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[d][l,3]oxazin-2-one In a 10ml Round bottomed flask were dissolved (4aS,7aR)-hexahydro-cyclopenta[d]- [l,3]oxazin-2-one (80 mg, 0.57 mmol, 1.0 equiv.) and 2-fluoro-5-(phenylethynyl)pyridine (112 mg, 0.57 mmol, 1.0 equiv.) in 2ml of DMF. Sodium hydride (60%> suspension) (29.5 mg, 0.74 mmol, 1.3 equiv.) were added and the brown suspension was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic phases were dried, filtered and concentrated. The crude material was purified by flash chromatography over a prepacked silica column eluting with 0-50% ethyl acetae in heptane gradient to yield 42.5mg of the title compound as colorless amorphous solid, MS: m/e = 319.1 (M+H⁺).

Example 2

(4aS,7aR)- 1- [5-(3-Fluorophenylethynyl)-py ridin-2-yl] -hexahydro- cyclopenta[d] [l,3]oxazin-2-one

Step 1 : 2-Fluoro-5-(3-fluoro-phenylethynyl)-pyridine

The title compound was prepared in accordance with the general method of Example 1, step 3 using 3-flurorophenylacetylene instead of phenylacetylene to yield the title compound as a crystalline white solid, MS: m/e = 216.2 (M+H⁺).

Step 2 : (4aS ,7aR)- 1 – [5 -(3 -Fluorophenylethynyl)-pyridin-2-yl] -hexahydro- cyclopenta[d] [ 1 ,3]oxazin-2-one

The title compound was prepared in accordance with the general method of Example 1, step 4 using (4aS,7aR)-hexahydro-cyclopenta[d]-[l,3]oxazin-2-one (66 mg, 0.47 mmol) (Example 1, step 2) and 2-fluoro-5-((3-fluorophenyl)ethynyl)pyridine (100 mg, 0.47 mmol) to yield 48 mg (31%) of the title compound as a light yellow amorphous solid; MS: m/e = 337.3 (M+H⁺).