propan-2-yl nitrate

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

Procedure: 17β-cyclopropyloxy-androst-4-en-3-one (9.70 g, 29.5 mM), potassium tert-butoxide (7.0 g, 62.4 mM), and isopropyl nitrate (2.99 ml) are reacted by the method of Example 1 to yield 17β-cyclopropyloxy-4-nitroandrost-4-en-3-one, m.p. 137°-38° C. (methanol) IR (CHCl3) , 1695, 1622(m) , 1535, 1373 cm-1MS(CI) 374(100%, M+10, 316(20%, M+1-c-C3H5 -O) 1H-NMR (CDCl3) 0.38-0.61(4H, m), 0.80(3H, s, C18 -Me), 1.29(s, C19 -Me), 3.25-3.33(1H, m, cyclopropyl-CHO), 3.44(1H, t, C17 -H) .

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

Procedure: Potassium tert-butoxide (109 g, 0.97 mol, 2.1 molar equivalents) is added to a stirred solution of 17β-(cyclopropyloxy)-androst-4-en-3-one (150 g, 0.46 mol) in tert-butanol (2 L) over 10 minutes at room temperature and under nitrogen. Continue stirring at room temperature for 18 hours, then add isopropylnitrate (48.2 g, 0.46 mol, 1.0 mol. equiv.) in tert-butanol (50 mL) over 30 minutes at room temperature. After an additional day of continuous stirring at room temperature, glacial acetic acid (130 mL) is added over 25 minutes and stirring is continued for an additional 18 hours. Subsequently, methylene chloride (1.5 L) and brine (saturated NaCl, 800 mL) is added and the solution is stirred an additional 10 minutes. The organic phase is then seperated and dried over magnesium sulfate. The resulting slurry is filered and the filtrate concentrated (35° C./40 Torr) to give a dark red oil. Purify by flash chromatography (SiO2, elution: EtOAc/hexane 5:95, EtOAc/hexane 1:9 and EtOAc/hexane 15:85). Combine and concentrate the fractions containing the desired product (30° C./40 Torr) to give a solid residue which is stirred under hexane (350 mL). Filter and dry the solids to give the title compound (68 g, 40%) as a yellow solid. Additional compound is obtained from the filtrate after concentration and rechromatography as above (8 g, 5%). mp 133°-134° C. After an additional day of continuous stirring at room temperature stirring is continued for an additional 18 hours the solution is stirred an additional 10 minutes The organic phase is then seperated dried over magnesium sulfate the filtrate concentrated (35° C./40 Torr) to give a dark red oil Purify by flash chromatography (SiO2, elution: EtOAc/hexane 5:95, EtOAc/hexane 1:9 and EtOAc/hexane 15:85) Combine and concentrate the fractions containing the desired product (30° C./40 Torr) to give a solid residue which is stirred under hexane (350 mL) Filter dry the solids

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

Procedure: 17β-cyclopropyloxy-androst-4-en-3-one (9.70 g, 29.5 mM), potassium tert-butoxide (7.0 g, 62.4 mM), and isopropyl nitrate (2.99 ml) are reacted by the method of Example 1 to yield 17β-cyclopropyloxy-4-nitroandrost-4-en-3-one, m.p. 137°-38° C. (methanol).

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

Procedure: By the method of example 1, testosterone (2.88 g, 10 mM), potassium tert-butoxide (3.40 g, 30 mM) and iso-propylnitrate (1.01 ml) are reacted to yield 17β-hydroxy-4-nitroandrost-4-en-3-one, m.p. 158°-160° C. (acetone-hexane)

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

Procedure: Potassium tert-butoxide (1.70 g, 15 mM), (20S)-20-hydroxymethylpregn-4-en-3-one (1.65 g, 5 mM) are mixed in tert-butanol and heated at reflux temperature, under argon atmosphere for 90 minutes. The combination is then cooled to room temperature and treated with one continuous portion of isopropylnitrate (0.51 mL, 5 mM). After 18 hours, the contents of the reaction vessel are acidified with 5 ml of acetic acid, and subsequently diluted with dichloromethane. The solids are then removed by filtration and further washed with additional dichloromethane. The filtrate and wash residue are purified as described in Example 1 to give a crystallized (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one. heated at reflux temperature After 18 hours The solids are then removed by filtration further washed with additional dichloromethane The filtrate and wash residue are purified

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

Procedure: Potassium tert-butoxide (1.70 g, 15 mM) and (20S)-20-hydroxymethylpregn-4-en-3-one (1.65 g, 5 mM) are mixed together in tert-butanol (25 mL), and heated at reflux temperature under argon atmosphere for 75 minutes. Iso-propylnitrate (0.51 mL, 5 mM) is then added to the refluxing reaction mixture, resulting in an exothermic reaction. After one minute, the reaction vessel is removed from heat and allowed to cool to room temperature. The cooled mixture is then made acidic by addition of acetic acid (5 mL), and stirred overnight. The mixture is then diluted with dichloromethane so as to form a separate phase sufficient to solubilize the synthesized product. Subsequently, the solids are removed by filtration and washed with dichloromethane. The materials in both the filtrate and wash(es) are combined together and concentrated. The residue is then redissolved in dichloromethane, then purified by flash chromatagraphy on silica gel to give (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one. The crystallization of this material from aqueous acetone gives white needles (m.p. 166°-168° C.). heated at reflux temperature under argon atmosphere for 75 minutes resulting in an exothermic reaction the reaction vessel is removed from heat made acidic by addition of acetic acid (5 mL) The mixture is then diluted with dichloromethane so as to form a separate phase sufficient Subsequently, the solids are removed by filtration washed with dichloromethane concentrated The residue is then redissolved in dichloromethane purified by flash chromatagraphy on silica gel

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

Procedure: Sulfuric acid (3.0 mL, 56 mmol) was added dropwise over 2 min to a solution of methyl 3-hydroxy-4-methoxybenzoate (3.64 g, 20 mmol), tetrabutylammonium hydrogensulfate (340 mg, 1.0 mmol), isopropyl nitrate (5.0 mL, 50 mmol), and dichloromethane (CH2Cl2) (40 mL) at 0° C. The reaction was allowed to warm to room temperature, maintained for 45 min, and then quenched with ice water (100 mL). This mixture was extracted with dichloromethane (250 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (4:1→3:7; hexanes:ethyl acetate) to give methyl 3-hydroxy-4-methoxy-2-nitrobenzoate: MS (ESI): 228.4. maintained for 45 min quenched with ice water (100 mL) This mixture was extracted with dichloromethane (250 mL×2) The combined extracts were dried filtered concentrated purified by silica gel chromatography (4:1→3:7; hexanes:ethyl acetate)

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

Procedure: Sulfuric acid (3.0 mL, 56 mmol) was added dropwise over 2 min to a solution of methyl 3-hydroxy-4-methoxybenzoate (3.64 g, 20 mmol), tetrabutylammonium hydrogensulfate (340 mg, 1.0 mmol), isopropyl nitrate (5.0 mL, 50 mmol), and dichloromethane (CH2Cl2) (40 mL) at 0° C. The reaction was allowed to warm to room temperature, maintained for 45 min, and then quenched with ice water (100 mL). This mixture was extracted with dichloromethane (250 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (4:1→3:7; hexanes:ethyl acetate) to give methyl 3-hydroxy-4-methoxy-2-nitrobenzoate: MS (ESI): 228.4. maintained for 45 min quenched with ice water (100 mL) This mixture was extracted with dichloromethane (250 mL×2) The combined extracts were dried filtered concentrated purified by silica gel chromatography (4:1→3:7; hexanes:ethyl acetate)

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

Procedure: To a stirred solution of 2,4-difluorophenol (0.65 g, 5 mmol) in dichloromethane (7 mL) at room temperature was added tetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed by isopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.65 mL) was then added dropwise to the mixture causing gentle reflux of the solvent. The reaction mixture was then stirred for fifteen minutes and then poured onto water (50 mL). The phases were separated and the aqueous phase was extracted by dichloromethane (10 mL). The combined organic layers were washed by brine, dried over anhydrous sodium sulphate and filtered through a short pad of silica gel. Evaporation of the solvent (40° C., water aspirator pressure) afforded a yellow solid, identified by NMR as the title compound (0.73 g, 83%). (ortho-selectivity 100%, no nitro-isomers detected). causing gentle reflux of the solvent poured onto water (50 mL) The phases were separated the aqueous phase was extracted by dichloromethane (10 mL) The combined organic layers were washed by brine dried over anhydrous sodium sulphate filtered through a short pad of silica gel Evaporation of the solvent (40° C., water aspirator pressure) afforded a yellow solid

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

Procedure: To a stirred suspension of salicylic acid (0.69 g, 5 mmol) in dichloromethane (10 mL) at room temperature was added tetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed by isopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.69 mL) was then added dropwise to the mixture which was allowed to stir at room temperature for thirty minutes (became a yellow solution, followed by formation of a yellow precipitate) and then poured onto water (50 mL). The yellow precipitate was filtered off and then triturated with water (10 mL). The insoluble material was filtered off and dried to afford yellow crystals, (0.42 g, 46%) of m.p. 121–122° C. identified by NMR as the title compound (lit. m.p. 123° C., Merck Index No. 6553). The mother liqours were concentrated on a rotary evaporator (60° C., water aspirator pressure) and recrystallised from a dichloromethane/petroleum ether mixture to give yellow/orange crystals (0.35 g, 39%) of m.p. 226–228° C., identified by NMR as 2-hydroxy-5-nitrobenzoic acid (5-nitrosalicylic acid) (lit. m.p. 228–230° C., Merck Index No. 6554). (85% combined yield, Ortho:Para selectivity, 1.2:1) then poured onto water (50 mL) The yellow precipitate was filtered off triturated with water (10 mL) The insoluble material was filtered off dried to afford yellow crystals, (0.42 g, 46%) of m.p. 121–122° C.

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

Procedure: To a stirred solution of 1-(3-hydroxy4-methoxyphenyl-2-phenyl-ethanone (8.57 g, 35.4 mmol) in dichloromethane (90 mL) at room temperature was added tetrabutylammonium sulphate (0.6 g, 5 mol %) followed by isopropyl nitrate (7.44 g, 70.8 mmol). Sulphuric acid (96%, 8.5 mL) was then added dropwise causing a gently exothermic reaction, and after stirring for forty minutes, the reaction mixture was poured onto water (250 mL). The phases were separated and the aqueous phase was extracted by dichloromethane (30 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent (40° C., water aspirator pressure) afforded a solid residue which was triturated with a small volume of diethylether (20 mL) to afford orange crystals, (6.9 g, 68%) of m.p. 176–177° C., identified by NMR as the ortho-nitrated title product. Concentration of the mother liquors and subsequent trituration with diethyl ether (15 mL) allowed the isolation of a small amount of a minor product, which was recrystallised from a dichloromethane/heptane mixture to give yellowish crystals of m.p. 142–143° C., corresponding (TLC) to a standard of the para-nitrated product, 1-(3-hydroxy-4-methoxy-6-nitrophenyl)-2-phenyl-ethanone (1.22 g, 12%). (80% combined yield, Ortho:Para selectivity, 5.7:1) a gently exothermic reaction the reaction mixture was poured onto water (250 mL) The phases were separated the aqueous phase was extracted by dichloromethane (30 mL) The combined organic phases were washed with brine dried over anhydrous sodium sulphate Filtration and evaporation of the solvent (40° C., water aspirator pressure) afforded a solid residue which was triturated with a small volume of diethylether (20 mL) to afford orange crystals, (6.9 g, 68%) of m.p. 176–177° C.

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

Procedure: To a stirred solution of 3-hydroxy-4-methoxybenzophenone (10.0 g, 43.8 mmol) in dichloromethane (100 mL) at room temperature was added tetrabutylammoniumhydrogen sulphate (0.74 g, 5 mol %) followed by isopropyl nitrate (11.5 g, 87.6 mmol). Sulphuric acid (96%, 10 mL) was then added dropwise causing a gently exothermic reaction, and, after stirring for forty minutes, the reaction mixture was poured onto water (300 mL). The phases were separated and the aqueous phase was extracted by dichloromethane (30 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent (40° C., water aspirator pressure) afforded a solid residue which was recrystallised from a small volume of ethanol (96%, 10 mL) to afford yellow crystals, (7.97 g, 67%) of m.p. 137–139° C., identified by NMR as the ortho-nitrated title product. Concentration of the mother liquors and subsequent chromatography on silica gel using a petroleum ether:ethyl acetate solvent mixture (2:1) allowed the isolation of a small amount of a minor product, corresponding (TLC) to a standard of the para-nitrated product, 3-hydroxy4-methoxy-6-nitrobenzophenone (1.43 g, 12%), m.p. 154–156° C. (79% combined yield, Ortho:Para selectivity, 5.6:1) a gently exothermic reaction the reaction mixture was poured onto water (300 mL) The phases were separated the aqueous phase was extracted by dichloromethane (30 mL) The combined organic phases were washed with brine dried over anhydrous sodium sulphate Filtration and evaporation of the solvent (40° C., water aspirator pressure) afforded a solid residue which was recrystallised from a small volume of ethanol (96%, 10 mL) to afford yellow crystals, (7.97 g, 67%) of m.p. 137–139° C.