2,2-dimethylpropanoyl 2,2-dimethylpropanoate

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: Pyridine (14 g, 0.18 Mol) and 4-nitrophenylacetic acid (32 g, 0.18 Mol) were stirred in toluene (100 ml) whilst trimethylacetylchloride (21 g, 0.18 Mol) was added. The toluene was evaporated to yield 4-nitrophenylacetic trimethylacetic anhydride. 3-Aminophenol (20 g, 0.18 Mol) was stirred in DMF (100 ml) and treated with the mixed anhydride and pyridine (14 g) in dimethylformamide (DMF) dropwise. The solution was diluted with water and the product isolated by filtration and dried (19 g, 39%). was added The toluene was evaporated

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

Procedure: To a solution of sodium ethoxide, prepared by reacting sodium (0.28 g, 12 mmol) with ethanol(6 ml), was added guanidine hydrochloride (1.2 g, 12 mmol) and the mixture was briefly stirred at reflux. A solution of methyl 5-(N-(4-cyanophenyl)-2,2,2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-1-naphthalene carboxylate (0.63 g, 1.5 mmol) in ethanol (6 ml) was added and the reaction mixture was stirred at reflux under nitrogen for 18 hours. The solution was diluted with water (50 ml), neutralized with acetic acid, and the resulting precipitate filtered and dried at 110° C. under reduced pressure. A solution of the solid in pivalic anhydride (10 ml) was refluxed for 5 minutes and then concentrated under high vacuum. The residue was eluted on silica gel (30 g) with ethyl acetate:methylene chloride (1:9) and the resulting solid recrystallized from diethyl ether, the slurry diluted with hexane, filtered, and the solid dried at 100° C. under reduced pressure to give N-(7-(4-cyanoanilino)-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.48 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.23 (s, 9H, t-butyl), 2.67 (s, 4H, ArCH2's), 6.68 (d, J=9 Hz, 2H, Ar), 7.10 (d, J=8 Hz, 1H, Ar), 7.26 (t, J=8 Hz, 1H, Ar), 7.50 (d, J=9 Hz, 2H, Ar), 8.38 (d, J=8 Hz, 1H, Ar), 8.53 (s, 1H, C7—NH), 11.28 (br s, 1H, N2H), 12.16 (br s, 1H, C3—NH). A solution of the pivalamide (0.15 g) and 10% palladium on carbon (70 mg) in diglyme (5 ml) was stirred at reflux under nitrogen for 10 hours. Pivalic anhydride (2×0.5 ml, 4.9 mmol) was added at 5 and 9 hours. The solution was diluted with diglyme (15 ml), filtered hot through celite, and concentrated under high vacuum. The residue was purified by chromatography on silica gel (15 g) eluting with ethyl acetate:methylene chloride (1:9) and then recrystallization from methanol. The solid was filtered and dried at 90° C. under reduced pressure to give N-(7-(4-cyanoanilino)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (86 mg). 1H NMR (DMSO-d6, 200 MHz) δ: 1.26 (s, 9H, t-butyl), 6.85 (d, J=9 Hz, 2H, Ar), 7.49-7.60 (m, 4H, Ar), 7.72 (t, J=8 Hz, 1H, Ar); 8.29 (d, J=9 Hz, 1H, Ar); 9.07 (s, 1H, C7—NH), 9.61 (d, J=9 Hz, 1H, Ar), 11.25 (br s, 1H, N2H), 12.32 (br s, 1H, C3—NH). Mass spectrum (CI—CH4) 412 (M+1, 100%). Anal. Calculated for C24H21N5O2.17/100H2O: C, 69.54; H, 5.19; N, 16.89. Found: C, 69.56; H, 5.23; N, 16.88. at reflux under nitrogen for 10 hours filtered hot through celite concentrated under high vacuum The residue was purified by chromatography on silica gel (15 g) eluting with ethyl acetate:methylene chloride (1:9) recrystallization from methanol The solid was filtered dried at 90° C. under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a chemical reactor for hydrogen addition (hydrogenation) under elevated pressure, 3-(3-hydroxy-4-methoxyphenyl) propionic acid (5.09 g, 25.9 mmol), pivalic acid anhydride (14.3 g, 76.6 mmol), and tetrahydrofuran (64 ml) were added, and thereafter the mixture was bubbled with nitrogen gas for 10 minutes. Palladium acetate (57 mg, 0.254 mmol) and triphenylphosphine (349 mg, 1.33 mmol) were added thereto, and thereafter the mixture was bubbled with nitrogen gas for 20 minutes to substitute nitrogen gas completely for the gas in the system of reaction, whereby the system was filled with nitrogen gas. Next, hydrogen gas was added thereinto to substitute hydrogen gas for the gas in the system, and then the mixture was stirred under hydrogen pressure of 5.4 MPa at 80° C. for 24 hours for reaction. Thus obtained reaction solution was concentrated under reduced pressure to remove tetrahydrofuran by vaporization. The remaining residue was subjected to a purification process with a silica gel column chromatography (eluting solvent: hexane/ethyl acetate=2/1). The thus eluted fractions containing the object compound were concentrated under reduced pressure to obtain crude 3-(3-hydroxy-4-methoxyphenyl) propionaldehyde (2.26 g, 12.5 mmol, yield: 48%) in the slightly yellow coloured solid. were added the mixture was bubbled with nitrogen gas for 10 minutes the mixture was bubbled with nitrogen gas for 20 minutes in the system of reaction, whereby the system was filled with nitrogen gas for reaction Thus obtained reaction solution was concentrated under reduced pressure to remove tetrahydrofuran by vaporization The remaining residue was subjected to a purification process with a silica gel column chromatography (eluting solvent: hexane/ethyl acetate=2/1) The thus eluted fractions containing the object compound were concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium acetate (58 mg, 0.257 mmol), tri(p-tolyl) phosphine (157 mg, 0.515 mmol), 3-hydroxy-4-methoxycinnamic acid (5.00 g, 25.7 mmol) and pivalic acid anhydride (14.4 g, 77.2 mmol) were added thereto, and thereafter the mixture was bubbled with nitrogen gas for 30 minutes to substitute nitrogen gas completely for the gas in the system of reaction, whereby the system was filled with nitrogen gas. Next, hydrogen gas was added thereinto to substitute hydrogen gas for the gas in the system, and then the mixture was stirred under hydrogen pressure of 3.4 MPa at 80° C. for 24 hours for reaction. Thus obtained reaction solution was concentrated under reduced pressure to remove tetrahydrofuran by vaporization. The remaining residue was subjected to a purification process with a silica gel column chromatography (eluting solvent: toluene/ethyl acetate=4/1) to obtain 3-hydroxy-4-methoxycinnamaldehyde (2.26 g, 12.7 mmol, yield: 49%). the mixture was bubbled with nitrogen gas for 30 minutes in the system of reaction, whereby the system was filled with nitrogen gas for reaction Thus obtained reaction solution was concentrated under reduced pressure to remove tetrahydrofuran by vaporization The remaining residue was subjected to a purification process with a silica gel column chromatography (eluting solvent: toluene/ethyl acetate=4/1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium acetate (58 mg, 0.257 mmol), tri(p-tolyl) phosphine (157 mg, 0.515 mmol), 3-hydroxy-4-methoxycinnamic acid (5.00 g, 25.7 mmol) and pivalic acid anhydride (14.4 g, 77.2 mmol) were added thereto, and thereafter the mixture was bubbled with nitrogen gas for 30 minutes to substitute nitrogen gas completely for the gas in the system of reaction, whereby the system was filled with nitrogen gas. Next, hydrogen gas was added thereinto to substitute hydrogen gas for the gas in the system, and then the mixture was stirred under hydrogen pressure of 3.4 MPa at 80° C. for 24 hours for reaction. Thus obtained reaction solution was concentrated under reduced pressure to remove tetrahydrofuran by vaporization. The remaining residue was subjected to a purification process with a silica gel column chromatography (eluting solvent: toluene/ethyl acetate=4/1) to obtain 3-hydroxy-4-methoxycinnamaldehyde (2.26 g, 12.7 mmol, yield: 49%). the mixture was bubbled with nitrogen gas for 30 minutes in the system of reaction, whereby the system was filled with nitrogen gas for reaction Thus obtained reaction solution was concentrated under reduced pressure to remove tetrahydrofuran by vaporization The remaining residue was subjected to a purification process with a silica gel column chromatography (eluting solvent: toluene/ethyl acetate=4/1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100 ml flask having a septum cap and magnetic stirrer was initially charged with palladium acetate (67.3 mg, 0.30 mmol), diphenylferrocenylphosphine (194 mg, 0.35 mmol), 3-phenylpropionic acid (1.50 g, 10 mmol) and benzeneboronic acid (1.46 g, 12 mmol). THF (40 ml), water (45 mg, 2.5 mmol) and pivalic anhydride (2.79 g, 15 mmol) were added in succession with the aid of syringes. The reaction vessel was then purged with inert gas and the reaction mixture was heated to 60° C. for a few hours. The progress of the reaction was followed with the aid of gas chromatography. As soon as complete conversion had been attained, the catalyst was removed by filtration through silica gel, the solvent was distilled off and the residue was recrystallized from hexane. The pivalic acid remained in the mother liquor and could be recovered. In this way, 1.73 g (83%) of 3-phenylpropyl phenyl ketone were obtained as colorless crystals. 1H NMR (200 MHz, CDCl3, 25° C., TMS): δ=7.95 (m, 2H), 7.61-7.19 (m, 8H), 3.32 (t, 3J(H,H)=6 Hz, 2H), 3.13 (t, 3J (H,H)=6 Hz, 2H) ppm; 13C NMR (50 MHz, CDCl3, 25° C., TMS): δ=198.8, 141.0, 136.5, 132.7, 128.3, 128.2, 128.1, 127.7, 125.8, 40.1, 29.8 ppm; MS (70 eV): m/z (%): 210(53) [M+], 105(100), 77(46), 51(17), HRMS: calc. for C15H14O [M+]: 210.104465; found: 210.10447; anal. calc. for C15H14O (210.3): C 85.68%; H 6.71%; N 0.00%; found: C 85.37; H 6.67; N 0.00%. A 100 ml flask having a septum cap The reaction vessel was then purged with inert gas the catalyst was removed by filtration through silica gel the solvent was distilled off the residue was recrystallized from hexane could be recovered

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

Procedure: A suspension of 19.5 g of 15α-hydroxy-4,9-estradiene-3,17-dione in 300 ml of toluene is mixed, under ice water cooling, successively with 26.5 g of pivalic acid anhydride and 18.6 g of 4-dimethylaminopyridine. Stirring is then performed for 72 hours at room temperature, then the reaction solution is poured into saturated sodium hydrogen carbonate solution, stirred for 30 more minutes at room temperature and extracted with ethyl acetate. The ethyl acetate extracts are washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried with sodium sulfate and concentrated in a water jet vacuum. The crude product, thus obtained, is filtered with aluminum oxide, Merck, neutral, step III, with hexane/ethyl acetate. The main fraction is crystallized from ethyl acetate. 14.4 g (79% of theory) of 4,9,15-estratriene-3,17-dione with a melting point of 182° to 183° C. are obtained. stirred for 30 more minutes at room temperature extracted with ethyl acetate The ethyl acetate extracts are washed with saturated ammonium chloride solution and saturated sodium chloride solution dried with sodium sulfate concentrated in a water jet vacuum The crude product, thus obtained is filtered with aluminum oxide, Merck The main fraction is crystallized from ethyl acetate

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

Procedure: A suspension of 19.5 g of 15α-hydroxy-4,9-estradiene-3,17-dione in 300 ml of toluene is mixed, under ice water cooling, successively with 26.5 g of pivalic acid anhydride and 18.6 g of 4-dimethylaminopyridine. Stirring is then performed for 72 hours at room temperature, then the reaction solution is poured into saturated sodium hydrogen carbonate solution, stirred for 30 more minutes at room temperature and extracted with ethyl acetate. The ethyl acetate extracts are washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried with sodium sulfate and concentrated in a water jet vacuum. The crude product, thus obtained, is filtered with aluminum oxide, Merck, neutral, step III, with hexane/ethyl acetate. The main fraction is crystallized from ethyl acetate. 14.4 g (79% of theory) of 4,9,15-estratriene-3,17-dione with a melting point of 182° to 183° C. are obtained. stirred for 30 more minutes at room temperature extracted with ethyl acetate The ethyl acetate extracts are washed with saturated ammonium chloride solution and saturated sodium chloride solution dried with sodium sulfate concentrated in a water jet vacuum The crude product, thus obtained is filtered with aluminum oxide, Merck The main fraction is crystallized from ethyl acetate

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

Procedure: A mixture of 5.1 g. 4-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-benzotriazole hydrochloride, 6.7 g. pivalic anhydride and 33.3 g. molten pivalic acid is stirred for 3 days at ambient temperature, then poured on to ice, neutralized with an aqueous solution of ammonia and extracted with methylene chloride. After evaporation of the extract, the oily residue obtained is taken up in methanol and rendered weakly acidic with dilute hydrochloric acid. Upon evaporating the solvent, there are obtained 2.53 g. (38% of theory) 4-[2-pivaloyloxy-3-(4-phenoxymethylpiperidino)-propoxy]-benzotriazole hydrochloride; m.p. 131°-133° C. A mixture of 5.1 g poured on to ice extracted with methylene chloride After evaporation of the extract the oily residue obtained Upon evaporating the solvent, there are obtained 2.53 g

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

Procedure: A mixture of 5.1 g. 4-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-benzotriazole hydrochloride, 6.7 g. pivalic anhydride and 33.3 g. molten pivalic acid is stirred for 3 days at ambient temperature, then poured on to ice, neutralized with an aqueous solution of ammonia and extracted with methylene chloride. After evaporation of the extract, the oily residue obtained is taken up in methanol and rendered weakly acidic with dilute hydrochloric acid. Upon evaporating the solvent, there are obtained 2.53 g. (38% of theory) 4-[2-pivaloyloxy-3-(4-phenoxymethylpiperidino)-propoxy]-benzotriazole hydrochloride; m.p. 131°-133° C. A mixture of 5.1 g poured on to ice extracted with methylene chloride After evaporation of the extract the oily residue obtained Upon evaporating the solvent, there are obtained 2.53 g