ethyl 4-chloro-4-oxobutanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (48 mg, 0.072 mmol) in DCE (2 ml) was added Hunig's base (0.037 ml, 0.215 mmol), 3-carboethoxypropionyl chloride (21.54 mg, 0.143 mmol), and DMAP (1 mg, 8.19 mmol). The mixture was stirred at rt for 5 h then was loaded directly onto a silica gel column and was purified using a 0-5% MeOH in dichloromethane gradient to afford tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((N-(2-(dimethylamino)ethyl)-4-methoxy-4-oxobutanamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a white foam (53.8 mg, 0.051 mmol, 71.8% yield). LCMS: m/e 785.6 (M+H)+, 3.21 min (method 6). was purified

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-nitroindole (2.00 g, 12.3 mmol) in CH2Cl2 (60 mL) at 0° C. was added dimethylaluminum chloride (1 M in hexanes, 14.8 mL, 14.8 mmol) and the mixture was stirred for 30 min. Ethyl 4-chloro-4-oxobutyrate (2.44 g, 14.8 mmol) was added dropwise and the resulting mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction mixture was carefully quenched with 10% aqueous citric acid (150 mL) and extracted with CH2Cl2 (3×150 mL). stirred for 18 h The reaction mixture was carefully quenched with 10% aqueous citric acid (150 mL) extracted with CH2Cl2 (3×150 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 338 mg of triethylamine were added at ambient temperature to 583 mg of 1-methyl 7-ethyl 6-amino-3-heptenedioate prepared as in Example 5D in 50 ml of methylene chloride and after the mixture was cooled to +5° C., 483 mg of ethyl4-chloro-4-oxo-butanoate were added. The mixture was stirred for 1 hour at ambient temperature and 25 ml of water and 1 ml of 2N hydrochloric acid were added. Extraction was done with methylene chloride and the extract was washed with salt water, then with sodium bicarbonate solution, dried and the solvents were evaporated. The residue was chromatographed on silica and elution with cyclohexane - ethylene acetate (1-1) yielded 750 mg of the expected product. after the mixture was cooled to +5° C. Extraction the extract was washed with salt water with sodium bicarbonate solution, dried the solvents were evaporated The residue was chromatographed on silica and elution with cyclohexane - ethylene acetate (1-1)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Stir a mixture of diethyl 2-methyl-3-oxoadipate (2.3 g, b.p. 111°-112°C/0.2 mm), prepared from 2- methylacetoacetic ester and ethoxycarbonylpropionyl chloride by the method of Cardwell, J. Chem. Soc., 1949, 715, and the methiodide of 1-diethylamino-6-m-methoxyphenylhexan-3-one (4.6 g) in benzene (20 cc) in an ice bath and add a solution of potassium (0.4 g) in ethanol (10 cc) dropwise over one hour. After stirring for a further 4 hours add ether (50 cc) and evaporate the washed and dried ether extracts. Heat the residue at 160°C and 0.2 mm pressure to remove unchanged starting materials. The residual gum is diethyl 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methyl-3-oxoadipate (2.7 g); infrared absorption peaks at 5.78, 5.88, 6.25, 12.82, 14.49 μ. After stirring for a further 4 hours evaporate the washed 0.2 mm pressure to remove unchanged absorption peaks at 5.78, 5.88, 6.25, 12.82, 14.49 μ

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-piperidone monohydrate hydrochloride (7.68 g, 50 mmol) and triethylamine (21 ml) in methylene chloride (100 ml) was added 3-(ethoxycarbonyl)propionyl chloride (9.87 g, 60 mmol) at 0° C. over a period of 10 min. The mixture was stirred at room temperature for 16 h before being quenched with water (100 ml). The organic layer was separated and the aqueous layer was extracted with methylene chloride (100 ml). The combined organic layers were washed with 1M HCl (100 ml), saturated aqueous sodium bicarbonate (100 ml), and brine (100 ml), dried over sodium sulfate, and concentrated. Purification by flash chromatography (silica gel, 30% ether in hexanes) gave the desired ketone (3.80 g, 33%) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ1.27 (t, J=7.3 Hz, 3H), 2.48 (t, J=6.4 Hz, 2H), 2.53 (t, J=6.4 Hz, 2H), 2.68 (s, 4H), 3.82 (t, J=6.3 Hz, 2H), 3.82 (t, J=6.3 Hz, 2H), 4.16 (q, J=7.3 Hz, 2H). before being quenched with water (100 ml) The organic layer was separated the aqueous layer was extracted with methylene chloride (100 ml) The combined organic layers were washed with 1M HCl (100 ml), saturated aqueous sodium bicarbonate (100 ml), and brine (100 ml) dried over sodium sulfate concentrated Purification by flash chromatography (silica gel, 30% ether in hexanes)