5-methoxybenzene-1,3-diol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyldiphenylsilylchloride (TBDPSCl) (1.8 mL, 1.96 g, 7.14 mmol) was added to a suspension of 5-methoxyresorcinol 18 (1.0 g, 7.14 mmol) and imidazole (729 mg, 10.71 mmol) in dry DMF (5 mL) under argon at −22° C. and the mixture was stirred for 10 min. The reaction mixture was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with aq 1M of HCl (2×25 mL), and brine (2×25 mL). The organic layer was then dried (Na2SO4) and concentrated in vacuo. The crude silyl phenol 19 was purified by FCC on silica gel (5% ethyl acetate in hexane) to afford pure silyl phenol 19 (892 mg, 33%): 1H NMR (300 MHz, CDCl3) δ 7.89-7.75 (4H, m, HAr), 7.48-7.34 (6H, m, HAr), 5.98 (2H, t, J=2.1 Hz, HAr), 5.92 (1H, t, J=2.1 Hz, HAr), 5.13 (1H, br, s, HO—), 3.56 (3H, s, H3CO), 1.14 (9H, s, [(H3C)3C]; 13C NMR (75 MHz, CDCl3) δ 161.1, 157.3, 156.8, 135.4, 132.8, 129.9, 127.7, 100.1, 98.5, 95.0, 55.0, 26.4, 19.4; LRMS (CI), m/z (relative intensity): 378([M+1]+, 30), 321 (100), 243 (30), 213 (10), 199 (29). This material was employed directly in the next step. extracted with EtOAc (3×25 mL) The combined organic extracts were washed with aq 1M of HCl (2×25 mL), and brine (2×25 mL) The organic layer was then dried (Na2SO4) concentrated in vacuo The crude silyl phenol 19 was purified by FCC on silica gel (5% ethyl acetate in hexane)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyldiphenylsilylchloride (TBDPSCl) (1.8 mL, 1.96 g, 7.14 mmol) was added to a suspension of 5-methoxyresorcinol 18 (1.0 g, 7.14 mmol) and imidazole (729 mg, 10.71 mmol) in dry DMF (5 mL) under argon at −22° C. and the mixture was stirred for 10 min. The reaction mixture was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with aq 1M of HCl (2×25 mL), and brine (2×25 mL). The organic layer was then dried (Na2SO4) and concentrated in vacuo. The crude silyl phenol 19 was purified by FCC on silica gel (5% ethyl acetate in hexane) to afford pure silyl phenol 19 (892 mg, 33%): 1H NMR (300 MHz, CDCl3) δ 7.89-7.75 (4H, m, HAr), 7.48-7.34 (6H, m, HAr), 5.98 (2H, t, J=2.1 Hz, HAr), 5.92 (1H, t, J=2.1 Hz, HAr), 5.13 (1H, br, s, HO—), 3.56 (3H, s, H3CO), 1.14 (9H, s, [(H3C)3C]; 13C NMR (75 MHz, CDCl3) δ 161.1, 157.3, 156.8, 135.4, 132.8, 129.9, 127.7, 100.1, 98.5, 95.0, 55.0, 26.4, 19.4; LRMS (CI), m/z (relative intensity): 378([M+1]+, 30), 321 (100), 243 (30), 213 (10), 199 (29). This material was employed directly in the next step. extracted with EtOAc (3×25 mL) The combined organic extracts were washed with aq 1M of HCl (2×25 mL), and brine (2×25 mL) The organic layer was then dried (Na2SO4) concentrated in vacuo The crude silyl phenol 19 was purified by FCC on silica gel (5% ethyl acetate in hexane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A process of synthesizing 5-methoxy psoralene comprising methylating phloroglucinol with methanol to obtain the monomethyl ether of phloroglucinol; cyclizing the phloroglucinol monomethyl ether by first reacting with chloracetonitrile in the presence of gaseous HCl and zinc chloride then heating with postassium acetate to obtain 6-hydroxy-4-methoxy-3-coumaranone; reducing the 6-hydroxy-4-methoxy-3-courmaranone by direct reduction in the presence of a hydrazine hydrate catalyst to obtain 6-hydroxy-4-methoxy coumaran; cylizing the 6-hydroxy-4-methoxy-coumaran by reacting with acrylonitrile in the presence of HCl and zinc chloride to obtain 3,4,4',5'-tetra-hydro-5-methoxy psoralene and dehydrogenerating the 3,4,4',5' tetrahydro-5-methoxy psoralen to obtain 5-methoxy psoralene.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A process of synthesizing 5-methoxy psoralene comprising methylating phloroglucinol with methanol to obtain the monomethyl ether of phloroglucinol; cyclizing the phloroglucinol monomethyl ether by first reacting with chloracetonitrile in the presence of gaseous HCl and zinc chloride then heating with postassium acetate to obtain 6-hydroxy-4-methoxy-3-coumaranone; reducing the 6-hydroxy-4-methoxy-3-courmaranone by direct reduction in the presence of a hydrazine hydrate catalyst to obtain 6-hydroxy-4-methoxy coumaran; cylizing the 6-hydroxy-4-methoxy-coumaran by reacting with acrylonitrile in the presence of HCl and zinc chloride to obtain 3,4,4',5'-tetra-hydro-5-methoxy psoralene and dehydrogenerating the 3,4,4',5' tetrahydro-5-methoxy psoralen to obtain 5-methoxy psoralene.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The present invention also relates to a new synthesis of 5-methoxy-psoralen of the formula: ##STR3## starting from phloroglucinol of the formula: ##STR4## In this synthesis the phloroglucinol is methylated to obtain phloroglucinol mono-methyl ether, which is in turn cyclicized to obtain 6-hydroxy-4-methoxy-3-coumaranone; the coumaranone is reduced in one step to obtain 6-hydroxy-4-methoxy coumaran; the coumaran is then cyclicized to obtain 3,4,4',5'-tetrahydro-5 methoxy psoralen; and that product is hydrogenated to yield 5-methoxy-psoralen.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The present invention also relates to a new synthesis of 5-methoxy-psoralen of the formula: ##STR3## starting from phloroglucinol of the formula: ##STR4## In this synthesis the phloroglucinol is methylated to obtain phloroglucinol mono-methyl ether, which is in turn cyclicized to obtain 6-hydroxy-4-methoxy-3-coumaranone; the coumaranone is reduced in one step to obtain 6-hydroxy-4-methoxy coumaran; the coumaran is then cyclicized to obtain 3,4,4',5'-tetrahydro-5 methoxy psoralen; and that product is hydrogenated to yield 5-methoxy-psoralen.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.0 g (35.7 mmol) of 5-methoxybenzene-1,3-diol and then, after 10 minutes, 8.7 ml (78.5 mmol) of ethyl 2-bromoacetate are added to the suspension of 3.1 g (71.4 mmol) of sodium hydride (60% dispersion in oil) in 180 ml of 1-methyl-2-pyrrolidinone under argon. The mixture is stirred at ambient temperature for 3 hours. The reaction medium is diluted with ethyl acetate and washed with a saturated aqueous solution of potassium hydrogen sulphate and a saturated solution of sodium chloride and dried over sodium sulphate then concentrated to dryness. The crude product is purified by chromatography on silica gel (dichloromethane/ethyl acetate=95/5). 5.9 g (53%) of a colourless gum are obtained. washed with a saturated aqueous solution of potassium hydrogen sulphate a saturated solution of sodium chloride and dried over sodium sulphate then concentrated to dryness The crude product is purified by chromatography on silica gel (dichloromethane/ethyl acetate=95/5)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.0 g (35.7 mmol) of 5-methoxybenzene-1,3-diol and then, after 10 minutes, 8.7 ml (78.5 mmol) of ethyl 2-bromoacetate are added to the suspension of 3.1 g (71.4 mmol) of sodium hydride (60% dispersion in oil) in 180 ml of 1-methyl-2-pyrrolidinone under argon. The mixture is stirred at ambient temperature for 3 hours. The reaction medium is diluted with ethyl acetate and washed with a saturated aqueous solution of potassium hydrogen sulphate and a saturated solution of sodium chloride and dried over sodium sulphate then concentrated to dryness. The crude product is purified by chromatography on silica gel (dichloromethane/ethyl acetate=95/5). 5.9 g (53%) of a colourless gum are obtained. washed with a saturated aqueous solution of potassium hydrogen sulphate a saturated solution of sodium chloride and dried over sodium sulphate then concentrated to dryness The crude product is purified by chromatography on silica gel (dichloromethane/ethyl acetate=95/5)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N,N-diisopropylethylamine (3.15 mL, 18.1 mmol) was added to 5-methoxybenzene-1,3-diol (634 mg, 4.52 mmol) in anhydrous N,N-dimethylformamide (12.6 mL) over five minutes at room temperature. After 30 minutes, the solution was cooled to 0° C., methoxy methylchloride (3.02 mL, 18.1 mmol) was added, and the solution was warmed to room temperature over 12 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3 at 0° C. and extracted with EtOAc (3×10 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1→4:1 Hexane:EtOAc) to afford 8 as a yellow amorphous solid (441 mg, 43%): 1H NMR (CDCl3, 500 MHz) δ 6.29 (t, J=2.2 Hz, 1H), 6.21 (d, J=2.2 Hz, 2H), 5.07 (s, 4H), 3.69 (s, 3H), 3.40 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 161.394, 159.0 (2C), 97.2, 96.2 (2C), 94.5 (2C), 56.1, 55.4 (2C); IR (film) νmax 2997, 2955, 2903, 2827, 1601, 1475, 1400, 1215, 1194, 1146, 1032, 991, 924, 829, 685 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C11H16O5, 251.0895. found, 251.0910. the solution was warmed to room temperature over 12 hours The reaction was quenched by the addition of saturated aqueous NaHCO3 at 0° C. extracted with EtOAc (3×10 mL) Combined organic fractions were washed with saturated aqueous NaCl dried (Na2SO4) filtered concentrated The residue was purified via column chromatography (SiO2, 6:1→4:1 Hexane:EtOAc)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: One equivalent of 3,5-dihydroxyanisole was reacted with one equivalent of valeroyl chloride in pyridine as solvent for a period of one hour by the reaction scheme shown in FIG. 2. The solvent pyridine was removed from the reaction mixture to give 3-hydroxy-5-methoxyphenyl valerate (the monoester) and 5-methoxyphenyl-1,3-divalerate (the diester) in approximately equal amounts. The solvent pyridine was removed from the reaction mixture