ethyl 4-oxocyclohexaneacetate

To a solution of acetone (720 mL) was added 10 G (43.8 MMOL, 1 equiv) of ethyl 1, 4-dioxaspiro [4.5] dec-8-ylacetate followed by 1 N Hydrochloric acid (180 mL) The reaction was heated at reflux for 2 h. Upon cooling the solution was diluted with EtOAc (100 mL) and washed with water (100 mL). The water layer was back extracted twice with EtOAc (100 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated to yield 7.57 g (94percent) of a clear OIL. H-NMR (CDCI3-D) 8 4.16 (q, 2H), 2.40 (m, 4H), 2.32 (m, 2H), 2.28 (m, 1H), 2.10 (m, 2H), 1.49 (m, 2H), 1.28 (t, 3H); TLC Rf = 0.32 (3: 7 EtOAc/Hex).Step 3; Preparation of ethyl (4-oxocvclohexyl)acetate; This material was prepared by either of two methods described below. Method A; To a solution of 10 g (43.8 mmol, 1 equiv) of ethyl l, 4-dioxaspiro[4.5]dec-8- ylacetate in acetone (720 mL) was added aqueous HCl (IN, 180 mL) The reaction was heated at reflux for 2 h. Upon cooling the solution was diluted with EtOAc (100 mL) and washed with water (100 mL). The water layer was back extracted with EtOAc (2 x 100 mL) and the organic layers were combined, dried (MgSOStep 1 : Synthesis of ethyl 2-(4-oxocyclohexyl)acetate. [00418] To a solution of ethyl 2-(l, 4-dioxaspiro[4.5]decan-8-yl)acetate (from Step 1, Example 77, 4.71 g, 19.44 mmol) in acetonitrile (45 mL) was added 6N HCl aqueous solution (45 mL). The resulting mixtures was stirred at rt for 2 h and neutralized with solid NaHC0A solution of reagent KR-47 (5 g, 21 .9 mmol) in HCI (6N, 10 mL) was stirred at 70°C overnight, then concentrated to give the crude product which was purified by the column to obtained pure reagent KR-48 (3 g, 75percent) as white solid. ESI-MS (Mi-i): 185.2 calc. for C10H1603: 184.1.In a 10 liter reactor was taken ethyl 2-(1, 4-dioxaspiro[4.5]decan-8-yl)acetate(67.5 g, 296 mmol) in acetone (5000 mL). To the reaction mixture was added 1 M HC1 solution (1183 mL, 1183 mmol) and the resulting mixture was heated under reflux for 2 h. The reaction mixture was concentrated to remove acetone. The residue was extractedwith ethyl acetate (3 x 1000 mL). Combined organic layer was washed with water andbrine. The organic layer was dried over sodium sulfate and concentrated in vacuo. Thecrude material was purified through flash column chromatography, eluting with 0-20percentethyl acetate in petroleum ether to give Intermediate 1 64C (pale yellow liquid, 40 g, 217mmol, 73.4percent yield). GC-MS Anal. Calc’d for C, 0H, 603, 184.11 found [M] 184. T =10.03 mm (Method J).In a 10 liter reactor was taken Intermediate 154B (67.5 g, 296 mmol) in acetone (5000 mL). To the reaction mixture was added 1 M HC1 solution (1 183 mL, 1 183 mmol) and the resulting mixture was heated under reflux for 2 h. The reaction mixture was concentrated to remove acetone. The residue was extracted with ethyl acetate (3 x 1000 mL). Combined organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified through flash column chromatography, eluting with 0-20percent ethyl acetate in petroleum ether to give Intermediate 154C (pale yellow liquid, 40 g, 217 mmol, 73.4percent yield). GC- MS Anal. Calc'd for CiIn a 10 liter reactor was taken Intermediate lB (67.5g. 296 mmol) in Acetone (5000 mL). To that FIC1 (1M) (1183 mL, 1183 mmol) was added and the reaction was heated to reflux for 2 hrs. After 2 hours, the reaction mixture was concentrated. The residue was then transferred to 10 liter separatory funnel and extracted with ethylacetate ( 3 x i000mi). The combined organic layers were washed with water (i000mi) and brine (l000mi), dried over sodium sulphate and concentrated in vacuo. The crude material was purified through silica gel flash column (750g coiunm using 0 to 20percent ethyl acetate in petether) to give Intermediate IC (40 g, 217 mmoi. 73percent). ‘HNMR (C1-TLOROFORM-d, 400 MHz) d: 4.15 (q, J=7.0 FIz. 2H), 2.35- 2.41 (m, 3H), 2.20-2.34 (in, 3H), 2.04-2.13 (m, 3H). 1.41-1.53 (m, 21-1), 1.24-1.30 (t. 31-1)Method B; Ethyl (4-hydroxyphenyl)acetate (5Og, 277 mmol) was dissolved in 150 niL of ethanol in a Parr bottle with Rh/Al4-Oxocyclohexaneacetic acid ethyl ester. To a solution of the unsaturated ester (2.50 g, 13.74 mmol) in ethanol (25 ml) was added Raney nickel (1.0 g). The mixture was stirred at room temperature under H2 (balloon) for 24 h. After the catalyst was removed by filtration, the filtrate was concentrated to give the alcohol ester, which was used for the Jones' oxidation without further purification. To a solution of the above residue in acetone (20 ml) at 0° C. was added Jones' reagent (6 ml), prepared by dissolving CrO3 (27.20 g) in concentrated sulfuric acid (25 ml) and further diluting the solution to 100 ml with water. The reaction was stirred at 0° C. for 2 h before being quenched with isopropanol (3 ml). The organic solvent was removed in vacuo and the residue was diluted with ether (100 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was dried over MgSO4 and concentrated to afford the ketone ester (1.80 g, 71percent) as a colorless oil. 1H NMR (500 MHz, CDCl3) delta1.26 (t, J=6.4 Hz, 3H), 1.44-1.48 (m, 3H), 2.08-2.10 (m, 2H), 2.29-2.31 (d, J=8.3 Hz, 2H), 2.39-2.40 (m, 4H), 4.18 (q, J=6.4 Hz, 2H).EXAMPLE Ba Ethyl 4-oxocyclohexaneacetate; bp05 100° C.Step 1. Ethyl 2-(4-(2, 6-dichlorophenyl)-4-hydroxycyclohexyl)acetate. To a solution of 2- bromo- 1, 3 -dichlorobenzene (22.6 g, 0.1 mol) in THE (200 mL) -78C was added H-BuLi (2.5 M in hexane, 40 mL, 0.1 mol) dropwise under N2. After stirring for 1 h, a solution of ethyl 2-(4- oxocyclohexyl)acetate (18.4 g, 0.1 mol) in THF (100 mL) was added and the resulting mixture was stirred at -78C for 2 h. The reaction was quenched with brine (100 mL) and extracted with EtOAc (300 mL x 2). The combined organic layer was dried over Na2S04, filtered and concentrated to give the title compound (31 g) as a crude yellow oil, which was used for the next step without further purification.Step 1. Ethyl 2-(4-(3-chloro-5-fluoropyridin-4-yl)-4-hydroxycyclohexyl)acetate. To a solution of 2-bromo-3-chloro-5-fluoropyridine (5.03 g, 23.9 mmol) in tetrahydrofuran (60 mL) at -78C was added a solution of H-butyllithium in hexanes (2.5 M, 10.4 mL, 26.1 mmol) dropwise. The reaction mixture was allowed to stir at -78C for 1 h before the addition of ethyl 2-(4- oxocyclohexyl)acetate (3.85 mL, 21.7 mmol) in one portion. The reaction allowed to warm to room temperature and stirred for 1 h, then was quenched with a saturated solution of ammonium chloride (100 mL) and extracted with EtOAc (3 x 50 mL), combined organics dried (Na2S04) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica, eluting with 0-40% EtOAc in hexanes to yield the unexpected product as a colorless oil (2.65 g, 39%). [M+H] = 316.1.

Molecular Weight:184.23
XLogP3:0.8
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:184.109944368
Monoisotopic Mass:184.109944368
Topological Polar Surface Area:43.4
Heavy Atom Count:13
Complexity:188
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes