* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
A mixture of 0.5 kg cinnamic acid, 0.401 kg p-cresol and 2.2 L xylene was stirred for 15 minutes. 0.132 kg cone, sulfuric acid was added under stirring. After completion of acid addition, reaction mixture was stirred at 140-1450C. After the completion of reaction, reaction was cooled at RT then washed with 1.0 L DM water. The reaction mixture was cooled at 10-150C solution of 0.5 N NaOH in DM water was added drop wise stirred reaction mixture at same temperature for 1 hr. The organic layer was separated washed with DM water. Organic layer was distilled out completely under reduced pressure (30-40 mm Hg) to obtain 3,4-dihydro-6-methyl - 4-phenyl-2H-benzopyran-2-one (Yield: 0.78 kg, 97percent).[151] HPLC Purity: > 95 percent.
94%
With 1-methyl-2-oxopyrrolidinium hydrogen sulfate In neat liquid at 120℃; for 2 h;
General procedure: Synthesis dihydrocoumarins: general procedure To a 25 mL round bottomed ask equipped with a reux condenser, phenol(1 mmol), cinnamic acid (1 mmol), and acidic ionic liquid N-methyl-2-pyrroli-donum hydrosulfate ([H-NMP]HSO4) (3 mmol) were placed. The reaction mixturewas heated at 120 °C for a period of time as indicated in Table 1 (2–5 h). Aftercompletion of the reaction (monitored by TLC), the reaction mixture was cooledand poured in water. The mixture was extracted with ethyl acetate (2 9 10 mL).The organic layer was separated, washed with water and brine and separated again,dried over anhydrous Na2SO4, and concentrated under reduced pressure to give thecrude product. This crude product was column chromatographed over silica gel(230–400 mesh) using ethyl acetate and petroleum ether as eluent to give the highlypure products in satisfactory yield (Table 1).
83%
at 120 - 130℃; for 1 h; Neat (no solvent)
General procedure for the synthesis of dihydrocoumarins: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over anhydrous sodium sulphate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent.
83%
With iodine In neat (no solvent) at 120 - 130℃; for 1 h;
General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120–130 °C for a period of time (1–4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent.
83%
With iodine In neat (no solvent) at 120 - 130℃; for 1 h;
General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent.
Reference：
[1] Patent: WO2010/46801, 2010, A2, . Location in patent: Page/Page column 15
[2] Research on Chemical Intermediates, 2016, vol. 42, # 7, p. 6407 - 6422
[3] Organic Process Research and Development, 2005, vol. 9, # 3, p. 314 - 318
[4] Tetrahedron Letters, 2012, vol. 53, # 33, p. 4469 - 4472
[5] Tetrahedron, 2014, vol. 70, # 34, p. 5221 - 5233
[6] Tetrahedron, 2014, vol. 70, # 34, p. 5221 - 5233
[7] Synthetic Communications, 2000, vol. 30, # 1, p. 39 - 42
2
[ 106-44-5 ]
[ 140-10-3 ]
[ 40546-94-9 ]
Yield
Reaction Conditions
Operation in experiment
77%
With Preyssler catalyst In neat (no solvent) at 130℃; for 2 h; Green chemistry
General procedure: The catalyst was dried overnight prior to use. A mixture of the correspondingphenol (1 mmol), cinnamic acid (1 mmol) and PA catalyst (0.5 mmol percent) wasplaced in an open glass tube (20 ml) and stirred at 130 C for the indicated time.When the reaction time was over, the reaction mixture was extracted with hottoluene (2 9 3 ml). The extract was washed with H2O (2 ml) and then dried withanhydrous sodium sulfate and filtered. Evaporation of the solvent under reducedpressure and recrystallization from methanol or ethanol gave the pure products.
70%
With iodine In neat (no solvent) at 130℃; for 3 h;
To a solution of trans-cinnamic acid (10.22 g, 69 mmol) in p-cresol (7.2 mL, 69 mmol, 1 equiv) was added I2 (3.5 g, 13.8 mmol, 20 mol percent). The solution was stirred at 130 °C for 3 h. It was then allowed to cool to room temperature, dissolved in ethyl acetate (300 mL) and washed with saturated aqueous sodium thiosulfate solution (2 * 100 mL), H2O (100 mL) and brine (200 mL). The organic layer was then passed through a silica plug and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/diethyl ether (5:1) to afford the pure product (+-)-5 (11.06 g, 70percent) as a white solid (mp 76-78 °C). νmax/cm-1 (ATR): 3028 (C-H), 1763 (C=O), 1493, 1126 (C-O). 1H NMR (300 MHz, CDCl3): δ 7.38-7.27 (m, 3H, ArH), 7.18-7.13 (m 3H, ArH), 7.09 (dd, J = 8.3 Hz, J = 1.8 Hz, 1H, ArH), 6.78 (s, 1H, ArH), 4.29 (app t, J = 6.9 Hz, CH), 3.10-2.93 (m, 2H, CH2), 2.25 (s, 3H, CH3); 13C NMR (75.5 MHz, CDCl3): δ 168.0 (C=O), 149.8, 140.7, 134.5, 129.5, 129.3, 128.8, 127.8, 127.7, 125.5, 117.0 (10 * ArC), 40.9 (CH), 37.3 (CH2), 20.9 (CH3).
Reference：
[1] Tetrahedron Letters, 2007, vol. 48, # 28, p. 4895 - 4898
[2] Tetrahedron Letters, 2008, vol. 49, # 23, p. 3790 - 3793
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 3, p. 372 - 375
[4] Research on Chemical Intermediates, 2015, vol. 41, # 12, p. 10109 - 10123
[5] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 9, p. 2157 - 2167
[6] Tetrahedron Asymmetry, 2017, vol. 28, # 4, p. 577 - 585
[7] Journal of the South African Chemical Institute, <N.S.> 2 <1949> 165, 168, 169,
[8] Journal of Organic Chemistry, 1952, vol. 17, p. 1122,1123, 1126
[9] Journal of the Chemical Society, 1956, p. 1382
[10] Patent: WO2005/61432, 2005, A1, . Location in patent: Page/Page column 11-12
[11] Patent: WO2012/137047, 2012, A1, . Location in patent: Page/Page column 9-10
[12] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 1, p. 653 - 659
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 25, p. 4347 - 4360
7
[ 99429-99-9 ]
[ 40546-94-9 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 1, p. 65 - 70
8
[ 99429-99-9 ]
[ 40546-94-9 ]
Reference：
[1] Journal of the South African Chemical Institute, <N.S.> 2 <1949> 165, 168, 169,
[2] Bulletin de la Societe Chimique de France, 1953, p. 573,577, 582
[3] Justus Liebigs Annalen der Chemie, 1954, vol. 587, p. 1,15
9
[ 106-44-5 ]
[ 40546-94-9 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 1, p. 65 - 70
10
[ 102-92-1 ]
[ 40546-94-9 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 1, p. 65 - 70
11
[ 106-44-5 ]
[ 103-26-4 ]
[ 40546-94-9 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1957, p. 776,777
12
[ 40546-94-9 ]
[ 851789-43-0 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 1 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water
A solution of 7-methyl-4-phenyl-3,4-dihydrocoumarin (compound of formula I) (9.52 g, 40.0 mmol) in dry tetrahydrofuran (50 ml) is added drop-wise to the cooled (0 °C) suspension of lithium aluminum hydride (3.04 g, 80 mmol) in 100 ml of dry tetrahydrofuran. The reaction mixture is stirred for 1 hour at room temperature under inert atmosphere and then the reaction is quenched by careful addition of 50 ml of a mixture tetrahydrofuran and water (1 :1) followed by acidification with 1 mol/l solution of hydrochloric acid (150 ml). The product is extracted with ethyl acetate. The combined organic phases are washed with water and brine, and dried over anhydrous magnesium sulphate. After removal of the solvents the compound of formula Il is obtained in 97 percent yield (9.68 g). It is recrystallized from diisopropylether yielding the product as white powder; mp = 112 - 115. 1H NMR (300MHz, DMSO-cfe): δ [ppm] = 2.08 - 2.17 (5H, m, CH3, CH2), 3.29 - 3.31 (2H, m, CH2), 4.38, 4.42 (2H, 2 x t, CH, OH), 6.63 (1 H, d, J = 8.0 Hz, 1 H-Ar), 6.76 (1 H, dd, J = 8.3, 1.7 Hz, 1 H-Ar), 7.00 (1 H, d, J = 1.7Hz, 1 H-Ar), 7.08 - 7.13 (2H, m, 1 H- Ph), 7.20 - 7.28 (3H, m, 4H-Ph), 9.04 (1 H, s, OH)13C NMR (300MHz, DMSO-Of6): δ [ppm] 20.5, 37.6, 39.1, 59.3, 115.0, 125.6, 127.0, 127.3, 127.9, 128.0, 130.9, 145.3, 152.4. ESI mass spectrum: 243 [M + H+]
86%
Stage #1: With sodium hydroxide; sodium tetrahydroborate In water; isopropyl alcohol at 20 - 60℃; for 5 h; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20℃; for 0.5 h;
EXAMPLE 1; Preparation of 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanol (VIII) A basic aqueous solution of sodium borohydride prepared beforehand by dissolving 23.8 g (0.630 moles) of NaBH4 at ambient temperature in 170 ml of H2O and 3.5 ml of 30percent wt./vol. NaOH was added dropwise to a suspension of 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of the formula (II) (100 g, 0.420 moles) in isopropanol (200 ml). Once addition was complete, the temperature was adjusted to 60° C. and the course of the reaction was monitored by TLC (eluent: cyclohexane/acetone: 70/30) until the substrate had completely disappeared. After 5 h, the reaction mixture was cooled to ambient temperature and HCl (2N) was added until a final pH of 7.0 was obtained. Stirring was continued for 30 min at ambient temperature, then the resultant suspension was filtered through a Buchner filter. The filtered solution was concentrated under reduced pressure and the crude residue was crystallised from toluene (280 ml) to yield 87.4 g (yield 86percent) of 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanol (VIII) as a white solid.
70%
Stage #1: With sodium tetrahydroborate In methanol at 0 - 20℃; for 5 h; Stage #2: With hydrogenchloride In methanol; water
Sodium borohydride (0.76 g, 20 mmol) is added in small portions to the cooled solution of 7-methyl-4-phenyl-3,4-dihydrocoumarin (compound of formula I) (0.48 g, 2 mmol) in 20 ml of methanol. The reaction mixture is stirred for 1 h at 0 °C and 4 h at room temperature. The reaction mixture is poured into 1 mol/l solution of hydrochloric acid (120 ml) and extracted with ethyl acetate (3 x 70 ml). The combined organic fractions are dried over anhydrous magnesium sulphate and the solvent evaporated to give the product in 70 percent yield (0.49 g).
Reference：
[1] Patent: WO2006/66931, 2006, A1, . Location in patent: Page/Page column 17
[2] Asian Journal of Chemistry, 2014, vol. 26, # 9, p. 2813 - 2814
[3] Tetrahedron Letters, 2008, vol. 49, # 23, p. 3790 - 3793
[4] Patent: US2006/79716, 2006, A1, . Location in patent: Page/Page column 7
[5] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 9, p. 2157 - 2167
[6] Patent: WO2006/66931, 2006, A1, . Location in patent: Page/Page column 17
[7] Patent: WO2005/61432, 2005, A1, . Location in patent: Page/Page column 13-14
[8] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 1, p. 653 - 659
With Preyssler catalyst; In neat (no solvent); at 130℃; for 2h;Green chemistry;
General procedure: The catalyst was dried overnight prior to use. A mixture of the correspondingphenol (1 mmol), cinnamic acid (1 mmol) and PA catalyst (0.5 mmol %) wasplaced in an open glass tube (20 ml) and stirred at 130 C for the indicated time.When the reaction time was over, the reaction mixture was extracted with hottoluene (2 9 3 ml). The extract was washed with H2O (2 ml) and then dried withanhydrous sodium sulfate and filtered. Evaporation of the solvent under reducedpressure and recrystallization from methanol or ethanol gave the pure products.
70%
With iodine; In neat (no solvent); at 130℃; for 3h;
To a solution of trans-cinnamic acid (10.22 g, 69 mmol) in p-cresol (7.2 mL, 69 mmol, 1 equiv) was added I2 (3.5 g, 13.8 mmol, 20 mol %). The solution was stirred at 130 C for 3 h. It was then allowed to cool to room temperature, dissolved in ethyl acetate (300 mL) and washed with saturated aqueous sodium thiosulfate solution (2 * 100 mL), H2O (100 mL) and brine (200 mL). The organic layer was then passed through a silica plug and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/diethyl ether (5:1) to afford the pure product (+-)-5 (11.06 g, 70%) as a white solid (mp 76-78 C). numax/cm-1 (ATR): 3028 (C-H), 1763 (C=O), 1493, 1126 (C-O). 1H NMR (300 MHz, CDCl3): delta 7.38-7.27 (m, 3H, ArH), 7.18-7.13 (m 3H, ArH), 7.09 (dd, J = 8.3 Hz, J = 1.8 Hz, 1H, ArH), 6.78 (s, 1H, ArH), 4.29 (app t, J = 6.9 Hz, CH), 3.10-2.93 (m, 2H, CH2), 2.25 (s, 3H, CH3); 13C NMR (75.5 MHz, CDCl3): delta 168.0 (C=O), 149.8, 140.7, 134.5, 129.5, 129.3, 128.8, 127.8, 127.7, 125.5, 117.0 (10 * ArC), 40.9 (CH), 37.3 (CH2), 20.9 (CH3).
With sulfuric acid; at 125 - 130℃; for 6h;
Intermediates; Intermediate 1; Synthesis of 6-methyl-4-phenyl-chroman-2-one; Cinnamic acid (100 gms) and p-cresol (76.6 gms) were charged to a clean and dry flask under nitrogen and stirred. Concentrated sulphuric acid was slowly charged and the reaction mixture heated to 125C-130C for 6 hours. After completion of reaction the mixture was cooled to about 60C and about 50 ml water and about 300 ml toluene were charged under stirring. The layers were separated. The toluene layer was washed with aqueous saturated solution of sodium bicarbonate and water. The organic layer was dried over sodium sulfate and concentrated under vacuum, at a temperature below 50C. The residue was stripped with 2 x 100 ml IPA. The residue was dissolved in 200 ml isopropanol, chilled to 5C and stirred for 2 hours. The solids obtained were filtered and dried at about 60C for 4-5 hours to give about 135 to 137 gms of the title product.
With sulfuric acid; at 120 - 125℃;Inert atmosphere;
Example-1; [40] Preparation of methyl 3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propionate: [41] Trans-cinammic acid (1.0 Kg) was added to a 1 L 4-neck round bottom flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet. Para-cresol (0.766 Kg) was preheated in a water bath at 60 C and added to the cinammic acid (II) followed by concentrated sulfuric acid (13.0 mL, 243 mmol). The reaction was immediately heated to a set point of 127 C and stirred at 120 C -125 C for 6-7hours. When the reaction was complete the mixture was cooled to 90 C and toluene (3.0L) and water (0.5 L) are added to the crude product. The layers are separated and the organic layer was concentrated under reduced pressure. Methanol (1.0L) was added and distillation is continued to give 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one as oily mass.
A reaction mixture of 0.75 kg 3,4-dihydro-6-methyl -4-phenyl-2H-benzopyran-2-one, 0.262 kg sodium hydroxide and 0.93 L DM water was stirred at 60-650C for 2 hrs. The reaction was cooled to RT. 0.825 kg dimethylsulphate was added drop wise to reaction mixture within 1 hr. After the completion of addition, reaction mixture was stirred at same temperature for 2 hrs. Again solution of 0.186 kg sodium hydroxide in 0.93 L DM water was added at RT within 1 hr. The reaction mixture was stirred at 800C for 4 hrs. After completion of reaction, reaction was cooled to RT. 0.3 L Cone, hydrochloric acid was added drop wise to the reaction mixture till washing is neutral. The reaction mixture was stirred for 2 hrs, then filtered & washed with 2.0 L DM water to obtain wet cake. The wet cake was dried at 60-650C for 10-12 hrs to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid (Yield: 0.71 kg, 83%).[159] HPLC Purity: > 95 %.
83%
Example 1[149] Preparation of 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid; [150](H) (HI)[152] [153] A reaction mixture of 0.75 kg <strong>[40546-94-9]3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one</strong>, 0.262 kg sodium hydroxide and 0.93 L DM water was stirred at 55-65C for 2-3 hrs. The reaction was cooled to RT. 0.825 kg dimethylsulphate was added drop wise to reaction mixture within 1-2 hr. After the completion of addition, reaction mixture was stirred at same temperature for 1-2 hrs. Again solution of 0.186 kg sodium hydroxide in 0.93 L DM water was added at RT within 1 hr. The reaction mixture was stirred at 70-800C for 3-5 hrs. After completion of reaction, reaction was cooled to RT. 0.3 L Cone, hydrochloric acid was added drop wise to the reaction mixture till washing is neutral. The reaction mixture was stirred for 1-2 hrs, then filtered &; washed with 2.0 L DM water to obtain wet cake. The wet cake was dried at 55-600C for 10-12 hrs to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid.[154] (Yield: 0.71 kg, 83%). [155] HPLC Purity: >; 95 %.
A mixture of 0.5 kg cinnamic acid, 0.401 kg p-cresol and 2.2 L xylene was stirred for 15 minutes. 0.132 kg cone, sulfuric acid was added under stirring. After completion of acid addition, reaction mixture was stirred at 140-1450C. After the completion of reaction, reaction was cooled at RT then washed with 1.0 L DM water. The reaction mixture was cooled at 10-150C & solution of 0.5 N NaOH in DM water was added drop wise & stirred reaction mixture at same temperature for 1 hr. The organic layer was separated & washed with DM water. Organic layer was distilled out completely under reduced pressure (30-40 mm Hg) to obtain 3,4-dihydro-6-methyl - 4-phenyl-2H-benzopyran-2-one (Yield: 0.78 kg, 97%).[151] HPLC Purity: > 95 %.
94%
With 1-methyl-2-oxopyrrolidinium hydrogen sulfate; In neat liquid; at 120℃; for 2h;
General procedure: Synthesis dihydrocoumarins: general procedure To a 25 mL round bottomed ask equipped with a reux condenser, phenol(1 mmol), cinnamic acid (1 mmol), and acidic ionic liquid N-methyl-2-pyrroli-donum hydrosulfate ([H-NMP]HSO4) (3 mmol) were placed. The reaction mixturewas heated at 120 C for a period of time as indicated in Table 1 (2-5 h). Aftercompletion of the reaction (monitored by TLC), the reaction mixture was cooledand poured in water. The mixture was extracted with ethyl acetate (2 9 10 mL).The organic layer was separated, washed with water and brine and separated again,dried over anhydrous Na2SO4, and concentrated under reduced pressure to give thecrude product. This crude product was column chromatographed over silica gel(230-400 mesh) using ethyl acetate and petroleum ether as eluent to give the highlypure products in satisfactory yield (Table 1).
83%
With iodine; at 120 - 130℃; for 1h;Neat (no solvent);
General procedure for the synthesis of dihydrocoumarins: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over anhydrous sodium sulphate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent.
83%
With iodine; In neat (no solvent); at 120 - 130℃; for 1h;
General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent.
83%
With iodine; In neat (no solvent); at 120 - 130℃; for 1h;
General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent.
6-methyl-4-phenyl-chroman-2-one (IIA) A glass cylinder placed in a steel autoclave was loaded with 6- methyl-4-phenyl-chromen-2-one (1 g; 4.2 mmol), [Rh (COD) CI] 2 (104.5 mg; 0.2 MMOL), (S, S) -Chiraphos (180.8 mg; 0.4 MMOL), CH30H (10 ml) and NAOH 4N (2.1 ml), then it was evacuated and the autoclave was pressurized to 12 bar with H2. The reaction mixture was stirred at 50C for 24 h, then cooled to room temperature and the gas was removed. The solvent was removed in a rotary evaporator and the raw product, absorbed in H20, was washed with CH2Cl2 (2 x 30 ML), the aqueous phase was then acidified with 6N HCI to pH = 1-2 and was then extracted with CH2CI2 (30 ml x 3). The organic phases were combined and dried over NA2SO4, filtered on celite and the solvent was evaporated at reduced pressure. GC of the raw product (DetTBuSilssCDX column 25 m, carrier gas N2, T initial = 100C, initial isotherm time = 1, heating rate = 2, T final = 200C, final isotherm time = 10, flow 2, N2 pressure = 30 psi) showed that conversion was 96% and e. e. = 80% enriched in the enantiomer at lower retention time to which the absolute (S) configuration was attributed [ (S) enantiomer retention time = 46.12 min, (R) enantiomer retention TIME = 48. 55 min, retention time of 6-methyl-4-phenyl- chromen-2-one = 53.05 MIN]. 1H NMR in CDC13 of the raw product showed that the product was a mixture of (IIA) and the corresponding uncyclized product (11 ; Y = T = OH and W = CO) in a ratio of 1: 6, approximately, and that in time the open form cyclizes spontaneously and that this cyclization is complete when operating under reflux for 4 h in toluene in the presence of catalytic amounts OF PTSOH acid. The raw 6-METHYL-4-PHENYL-CHROMAN-2-ONE (IIA) was purified by flash chromatography (SiO2, hexane:Et2O 7: 3) to give 850 mg of a white solid (yield : 84%). Dissolving the product in hot CH30H and then cooling, 170 mg (yield : 20%) of white needles of product (S) (LIA) were obtained, with e. e. > 99%
2-(3-hydroxy-5-methyl-phenyl)-propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In methanol; acetone; at 50 - 55℃; for 24h;
Intermediate 2; Synthesis of 2-(3-hvdroxy-5-methyl phenvl .-propionic acid methyl ester; Acetone (200 ml) and methanol (200 ml) were taken in a dry flask and 100 gms of Intermediate 1 were charged thereto under stirring. 71 gms of potassium carbonate and 66 ml dimethyl sulphate were charged thereto and the reaction mixture was heated to about 50C to 55C for 24 hours. After completion of reaction the reaction mass was cooled to room temperature and the inorganics filtered. The clear filtrate was concentrated under vacuum to obtain an oily residue. The residue was dissolved in methylene chloride and the organic layer was washed with water. The organic layer was concentrated under vacuum to obtain the title compound as an oil (117-119 gms).
A solution of 7-methyl-4-phenyl-3,4-dihydrocoumarin (compound of formula I) (9.52 g, 40.0 mmol) in dry tetrahydrofuran (50 ml) is added drop-wise to the cooled (0 °C) suspension of lithium aluminum hydride (3.04 g, 80 mmol) in 100 ml of dry tetrahydrofuran. The reaction mixture is stirred for 1 hour at room temperature under inert atmosphere and then the reaction is quenched by careful addition of 50 ml of a mixture tetrahydrofuran and water (1 :1) followed by acidification with 1 mol/l solution of hydrochloric acid (150 ml). The product is extracted with ethyl acetate. The combined organic phases are washed with water and brine, and dried over anhydrous magnesium sulphate. After removal of the solvents the compound of formula Il is obtained in 97 percent yield (9.68 g). It is recrystallized from diisopropylether yielding the product as white powder; mp = 112 - 115. 1H NMR (300MHz, DMSO-cfe): delta [ppm] = 2.08 - 2.17 (5H, m, CH3, CH2), 3.29 - 3.31 (2H, m, CH2), 4.38, 4.42 (2H, 2 x t, CH, OH), 6.63 (1 H, d, J = 8.0 Hz, 1 H-Ar), 6.76 (1 H, dd, J = 8.3, 1.7 Hz, 1 H-Ar), 7.00 (1 H, d, J = 1.7Hz, 1 H-Ar), 7.08 - 7.13 (2H, m, 1 H- Ph), 7.20 - 7.28 (3H, m, 4H-Ph), 9.04 (1 H, s, OH)13C NMR (300MHz, DMSO-Of6): delta [ppm] 20.5, 37.6, 39.1, 59.3, 115.0, 125.6, 127.0, 127.3, 127.9, 128.0, 130.9, 145.3, 152.4. ESI mass spectrum: 243 [M + H+]
86%
EXAMPLE 1; Preparation of 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanol (VIII) A basic aqueous solution of sodium borohydride prepared beforehand by dissolving 23.8 g (0.630 moles) of NaBH4 at ambient temperature in 170 ml of H2O and 3.5 ml of 30percent wt./vol. NaOH was added dropwise to a suspension of <strong>[40546-94-9]3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one</strong> of the formula (II) (100 g, 0.420 moles) in isopropanol (200 ml). Once addition was complete, the temperature was adjusted to 60° C. and the course of the reaction was monitored by TLC (eluent: cyclohexane/acetone: 70/30) until the substrate had completely disappeared. After 5 h, the reaction mixture was cooled to ambient temperature and HCl (2N) was added until a final pH of 7.0 was obtained. Stirring was continued for 30 min at ambient temperature, then the resultant suspension was filtered through a Buchner filter. The filtered solution was concentrated under reduced pressure and the crude residue was crystallised from toluene (280 ml) to yield 87.4 g (yield 86percent) of 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanol (VIII) as a white solid.
70%
Sodium borohydride (0.76 g, 20 mmol) is added in small portions to the cooled solution of 7-methyl-4-phenyl-3,4-dihydrocoumarin (compound of formula I) (0.48 g, 2 mmol) in 20 ml of methanol. The reaction mixture is stirred for 1 h at 0 °C and 4 h at room temperature. The reaction mixture is poured into 1 mol/l solution of hydrochloric acid (120 ml) and extracted with ethyl acetate (3 x 70 ml). The combined organic fractions are dried over anhydrous magnesium sulphate and the solvent evaporated to give the product in 70 percent yield (0.49 g).
Intermediate 6; 2-(3-hydroxy-1-phenyl-propy1 .-4-methyl-phenol; 6-methyl-4-phenyl-chroman-2-one, 250 gms was stirred in 1.25 liters methanol at room temperature. Sodium borohydride 70 gms was added slowly, whilst maintaining the temperature at room temperature. The reaction mixture was stirred for 18 hours. After completion of reaction, the pH of the reaction mass was adjusted to pH 5 using acetic acid. The reaction mixture was concentrated under vacuum and 2 liters of water were added. The reaction mass was stirred for 30 minutes and the solids filtered. The solids were dried at 55°C in a hot air oven for 20 hours. Weight 248 gms. Purification: Crude Intermediate I prepared as above was dissolved in 700 ml of toluene and heated to 85°C-87°C. The clear solution was gradually cooled to room temperature and stirred for 30 minutes. The solids were filtered and washed with toluene. The solids were dried in a hot air oven at 55°C-60°C. Yield: 222 gms. Mp (117-119°C)
methyl 3-(2-methoxy-5-methylphenyl)-3-phenylpropionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
e) Methyl 3-(2-methoxy-5-methylphenyl)-3-phenylpropionate (X) was obtained in a similar way from <strong>[40546-94-9]6-methyl-4-phenyl-3,4-dihydrocoumarin</strong> in 96% yield. NMR: delta 7.4 (m 8H), 5.0 (t 1H), 3.9 (s 3H), 3.7 (s 3H), 3.2 (d 2H), 2.4 (s 3H).
96%
e) Methyl 3-(2-methoxy-5-methylphenyl)-3-phenylpropionate (X) was obtained in a similar way from <strong>[40546-94-9]6-methyl-4-phenyl-3,4-dihydrocoumarin</strong> in 96% yield. NMR: delta 7.4 (m 8H), 5.0 (t 1H), 3.9 (s 3H), 3.7 (s 3H), 3.2 (d 2H), 2.4 (s 3H).
Following procedure similar to that described in patent US-A-5 922 914, a solution of 100 mg (0.42 MMOL) of (IIA), having [a] D20 =-2. 8 (CHC13, c = 1.44) and prepared according to the preceding Example 2, in anhydrous toluene (3 ML), was placed in a 100-MT two-necked flask that had been flamed beforehand. A solution of 1 M. DIBAL in toluene (440 ul, 0.44 MMOL) was added dropwise to this solution, under N2 and AT-25GC. The reaction was monitored by GC-MS and was stopped with 3 ml of ethyl acetate AT-25°C after 5 h, when GC-MS showed there was formation of 6-methyl-4-phenyl-chroman-2-ol at 89percent, together with unreacted starting product (7percent) and a product of further reduction [3- phenyl-3 (2'hydroxy, 5 METHYL) PHENYL-PROPAN-1-OL] (4percent). 3 ml of a 23percent citric acid solution was added. The solution was stirred at room temperature over night. The organic phase was separated and washed with H20, dried over NA2SO4, filtered and the solvent was removed by evaporation at reduced pressure. The raw product thus obtained was placed in a glass cylinder in an autoclave. CH30H (5 ML), Pd/C 5percent (20 mg), (PRI) 2NH (147 LUI, 1.05 MMOL) and H2 were added at 5 atmospheres. The reaction was continued for 12 h at 48°C. The temperature was brought back to room temperature and the autoclave was depressurized by eliminating the gas. After filtration of the catalyst on celite, a GC-MS analysis was carried out, which showed 6-methyl-4-phenyl-chroman-2-ol (2percent), (IIA) 5percent, [3-PHENYL-3 (2 HYDROXY, 5 METHYL) PHENYL-PROPAN-1-OL] (16percent), and (S)- TOLTERODINE (77percent). The raw product was purified by flash chromatography on SI02 (hexane: EtOAc (7: 3) /Et3N 98: 2) to give a colourless oil (100 mg; 73percent); [a] D20 =-23 (c = 1.5 ; CH30H).
methyl 3-(2-methoxy-5-methylphenyl)-3-phenylpropionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In methanol; at 55 - 60℃; for 10h;
Example 1: Preparation of 3-(2-methoxy-5-methylphenyl)-3-phenylpropyl methane sulfonate (Vb)This intermediate is of significant importance for use in the preparation of Tolterodine or salts thereof, or its derivatives according to the present invention.In a 3-necked round bottom flask, 6-methyl-4-phenyl-3,4-dihydro coumarin (II, 10Og, 0.420 mol) is charged into methanol (500 ml) at about 250C with stirring. To the resulting suspension, potassium carbonate (K2CO3, 87 g, 0.63 mol) and methyl iodide (MeI, 78 ml, 1.25 mol) are added and the mass is stirred at from about 550C to about 6O0C for 4 h. The reaction mass is cooled to from about 400C to about 450C and MeI (27 ml, 0.43 mol) and K2CO3 (29 g, 0.21 mol) are added. Re-heat the mass to 55~ 6O0C and stir for additional 6 h until the reaction completes. Then solvent is removed by distillation under vacuum. The residue is dissolved in 350 ml of toluene. This organic phase is washed once with 750 ml of DM water and twice with 450 ml of DM water.The organic layer thus obtained is charged into a 3-necked round bottom flask under N2 atmosphere and cooled at temperature from about -50C to about 5C. Toluene solution of sodium bis(2-methoxyethoxy) aluminum hydride (Red-Al, 200 ml, 70% w/v, 0.706 mol) is slowly added through a dropping funnel over a period of 120 min, maintaining the solution temperature within -5 ~ 50C. The mixture is stirred for an additional 1 h at this temperature until the reaction completes. Then aqueous solution of NaOH (80 ml, 10%) is added through a dropping funnel over a period of 45 min, maintaining the temperature at 0 ~ 100C, and continue stirring for an additional 45 min at the same temperature. Add 750 ml of DM water and stir for 30 min at 250C. The biphasic reaction mass is filtered through a celite bed (10 g). The organic layer is collected and dried over 20 g of anhydrous sodium sulfate (Na2SO4). The solids are filtered and washed with 50 ml of toluene. The toluene is distilled off completely and compound IV is obtained as slightly yellow thick oil.The thick oil is dissolved in 300 ml of dichloromethane (DCM) under N2 atmosphere. Triethylamine (Et3N, 90 ml, 0.647 mol) is added and the mass is cooled to 0 ~ 5C. Mesyl chloride (MsCl, 36 ml, 0.465 mol) is added slowly through a dropping funnel over a period of 120 min, keeping the solution temperature below 1O0C. Continue stirring the mixture for an additional 1 h at 0~5C until the reaction completes. 1 L of cold DM water (0~5C) was added and the mass is stirred for 30 ~ 60 min at this temperature. Cone. HCl (25 ml) is added and the mass is stirred until it reaches 25C. The organic layer is collected and washed with 200 ml of DM water. About 180 ~ 220 ml of DCM is distilled off from the organic layer under atmosphere pressure at 38 ~ 43C. 400 ml of cyclohexane is added to the residue and the mass is heated to reflux till a clear solution is obtained (70 ~ 800C). This solution is cooled slowly and compound Vb crystallized. The solid is filtered in Buchner funnel and spray washed with 100 ml of cold cyclohexane. The mass is dried under vacuum at 600C to give 90 ~ 110 g of title compound.
With potassium carbonate; In methanol; at 55 - 60℃; for 10h;
Example 1; Preparation of 3-(2-methoxy-5-methylphenyl)-3-phenylpropyl methane sulfonate (Vb); This intermediate is of significant importance for use in the preparation of Tolterodine or salts thereof, or its derivatives according to the present invention.In a 3-necked round bottom flask, 6-methyl-4-phenyl-3,4-dihydro coumarin (II, 100 g, 0.420 mol) is charged into methanol (500 ml) at about 25 C. with stirring. To the resulting suspension, potassium carbonate (K2CO3, 87 g, 0.63 mol) and methyl iodide (MeI, 78 ml, 1.25 mol) are added and the mass is stirred at from about 55 C. to about 60 C. for 4 h. The reaction mass is cooled to from about 40 C. to about 45 C. and MeI (27 ml, 0.43 mol) and K2CO3 (29 g, 0.21 mol) are added. Re-heat the mass to 5560 C. and stir for additional 6 h until the reaction completes. Then solvent is removed by distillation under vacuum. The residue is dissolved in 350 ml of toluene. This organic phase is washed once with 750 ml of DM water and twice with 450 ml of DM water.The organic layer thus obtained is charged into a 3-necked round bottom flask under N2 atmosphere and cooled at temperature from about -5 C. to about 5 C. Toluene solution of sodium bis(2-methoxyethoxy) aluminum hydride (Red-Al, 200 ml, 70% w/v, 0.706 mol) is slowly added through a dropping funnel over a period of 120 min, maintaining the solution temperature within -55 C. The mixture is stirred for an additional 1 h at this temperature until the reaction completes. Then aqueous solution of NaOH (80 ml, 10%) is added through a dropping funnel over a period of 45 min, maintaining the temperature at 010 C., and continue stirring for an additional 45 min at the same temperature. Add 750 ml of DM water and stir for 30 min at 25 C. The biphasic reaction mass is filtered through a celite bed (10 g). The organic layer is collected and dried over 20 g of anhydrous sodium sulfate (Na2SO4). The solids are filtered and washed with 50 ml of toluene. The toluene is distilled off completely and compound IV is obtained as slightly yellow thick oil.The thick oil is dissolved in 300 ml of dichloromethane (DCM) under N2 atmosphere. Triethylamine (Et3N, 90 ml, 0.647 mol) is added and the mass is cooled to 05 C. Mesyl chloride (MsCl, 36 ml, 0.465 mol) is added slowly through a dropping funnel over a period of 120 min, keeping the solution temperature below 10 C. Continue stirring the mixture for an additional 1 h at 05 C. until the reaction completes. 1 L of cold DM water (05 C.) was added and the mass is stirred for 3060 min at this temperature. Conc. HCl (25 ml) is added and the mass is stirred until it reaches 25 C. The organic layer is collected and washed with 200 ml of DM water. About 180220 ml of DCM is distilled off from the organic layer under atmosphere pressure at 3843 C. 400 ml of cyclohexane is added to the residue and the mass is heated to reflux till a clear solution is obtained (7080 C.). This solution is cooled slowly and compound Vb crystallized. The solid is filtered in Buchner funnel and spray washed with 100 ml of cold cyclohexane. The mass is dried under vacuum at 60 C. to give 90110 g of title compound.
675 g of 6-methyl-4 phenyl-3,4-dihydrocoumarin, 372 ml of benzyl bromide, and 513 g of potassium carbonate were charged into a round bottom flask containing a mixture of 2025 ml of acetone and 2025 ml of methanol. The contents were heated to reflux temperature for about 2-3 hours. Distilled off the solvent from the reaction mass at atmospheric conditions below 75 C. then under vacuum (about 600 mm Hg) at below 85 C. 6750 ml of water was added to the residue and stirred for 15 minutes for dissolution. Extracted the solution twice with ethyl acetate (4000 ml). Combined organic layers were washed with water (2*3375 ml) and distilled the solvent under vacuum (about 600 mm Hg) at below 85 C. 2025 ml of methanol was added to the residue at 50-55 C., then stirred the solution at 0-5 C. for about 2 hours. Filtered the formed solid and washed with 675 ml of methanol. Dried the solid at 50-55 C. for about 2-3 hours under vacuum (about 600 mm/Hg) to get 850 g of the title compound. 1H NMR (200 MHz, CDCl3, delta in ppm): 2.25 (s, 3H), 3.05 (d, J=3.4, 2H), 3.50 (s, 3H), 4.95 (te, 1H), 4.95 (se, 2H), 6.6-7.4 (m, Ar-H, 13H). Mass: m/z 360.
With potassium carbonate; In acetone;Reflux;
Benzyl bromide (1.372 Kg), potassium carbonate (1.275 Kg), acetone (5.0L) and methanol(5.0L)were loaded in to the mixture. The contents were heated to reflux temperature for about 4-5 hours and then distilled off the solvent from the reaction mass. 13L of water was added to the residue and extracted the solution twice with ethyl acetate (5.0L). Combined organic layers and distilled the solvent completely under vacuum. Methanol (5.3L) was added to the residue and heated for 30 to 45 min at 55+/-5C to get clear solution, then stirred the solution at 0-5 C for about 2 hours. The formed solid was filtered and washed with methanol (1.6 L) and the material was dried to give 1.8kg of methyl 3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propionate. Yield 74%.
Example 4AlCl3 (108 g, 0.81 mol) was dissolved in 250 ml chlorobenzene in a 1 L 3-neck flask at normal temperature, then the solution was cooled to 0 C. And diisopropylamine (152.9 g, 1.50 mol) was added into the solution of AlCl3 in dichloromethane, and the temperature was kept below 20 C. Then it was warmed to room temperature naturally. Compound 2 (40 g, 0.17 mol) was dissolved in 150 ml chlorobenzene, and the solution was added into the reaction flask. The reaction lasted for at least 16 hours. After the reaction was completed, it was quenched with 1 L water, then the reaction system was filtrated and separated. Then the organic phase was dried with anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, the residue was crystallized with methanol to obtain the subject product. Yield (37 g, 64.9%), purity (97.3%).
3,3-difluoro-6-methyl-4-phenyl-2-chromanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With potassium hexamethylsilazane; N-fluorobis(benzenesulfon)imide; In tetrahydrofuran; toluene; at -100 - 20℃;
Example 17 [0091] A solution of 0.50 g of 6-methyl-4-phenyl-2-chromanone, 2.65 g of N-fluorobenzenesulfonimide, 22 ml of THF and 6.5 ml of toluene, was cooled to -100 C., and 7.34 ml of a 1.0M THF solution of potassium hexamethyldisilazide was added. After raising the temperature to room temperature, an aqueous citric acid solution was added to terminate the reaction, followed by extraction with ethyl acetate, and the solvent was removed. 0.87 g of the obtained product was quantitatively analyzed by 19F NMR, whereby it was confirmed that 3,3-difluoro-6-methyl-4-phenyl-2-chromanone was formed in a yield of 25%. No formation of a monofluoro product was detected. The structural characteristics of the 3,3-difluoro-6-methyl-4-phenyl-2-chromanone are as follows. 19F-NMR (deuterated acetone): -96.5 (bs).
With diisobutylaluminium hydride; In hexane; toluene; at -78℃; for 2.5h;
General procedure: To a three-neck round-bottom flask equipped with nitrogen bubbler and dropping funnel were added dihydrocoumarin (5 g, 33.7 mmol) and dry toluene (100 mL). The solution was cooled to -78 C and DIBAL [1 M solution in hexanes, (37 mL, 37.0 mmol, 1.1 equiv)] was added dropwise over a period of 30 min. The reaction was stirred for 2 h, allowed to warm to room temperature and then quenched with H2O (30 mL). The resulting white suspension was filtered over Celite and washed through with diethyl ether (100 mL). The phases were separated and the aqueous phase was extracted with diethyl ether (200 mL). The combined organic phases were washed with H2O (200 mL) and brine (200 mL). The combined organic layers were dried, filtered and the solvent was removed under vacuum to give the product (4.83 g, 95%) as a colourless oil which was used without further purification. 4.3.3 (+-)-6-Methyl-4-phenylchroman-2-ol 1 18 This was prepared using the procedure for 3a from (+-)-6-methyl-4-phenylchromanone 5 (5.81 g, 24.38 mmol) and DIBAL solution (1 M in hexanes, 26.8 mL, 26.8 mmol, 1.1 equiv) in dry toluene (80 mL). The crude product was purified by column chromatography on silica gel using 100% DCM to give the pure product as a colourless oil which solidified overnight to give a white waxy solid (3.85 g, 66%) in a 4:1 mix of diastereomers. Mp 86-88 C. numax/cm-1 (ATR): 3433 (O-H), 3031 (Ar C-H), 2968 (C-H), 1493, 1202, 1012 (C-O). 1H NMR (300 MHz, CDCl3): delta 7.38-7.16 (m,5H, ArH), 6.94 (m, 1H, ArH), 6.81-6.76 (m, 1H, ArH), 6.58 (s, 0.79H, ArH), 6.54 (s, 0.21H, ArH), 5.63 (br s, 0.79H, CHOH), 5.48 (m, 0.21H, CHOH), 4.30 (dd, J = 10.8 Hz, J = 5.9 Hz, 0.79H, CHPh), 4.19 (dd, J = 10.9 Hz, J = 6.0 Hz, 0.21H, CHPh), 3.17-3.04 (m, 1H, OH), 2.49-2.40 (m, 2H, CH2), 2.30-2.22 (m, 0.79H, CH2), 2.19-2.06 (m, 4H, CH2 and CH3). 13C NMR (75.5 MHz, CDCl3): delta 151.1, 149.6, 144.0, 130.4, 130.3, 129.9, 129.7, 128.8, 128.7, 128.7, 128.6, 128.5, 129.6, 128.5, 126.9, 126.7, 124.9, 124.8, 116.7, 116.7 (20 * ArC), 94.3, 91.3 (2 * CHOH), 41.3 (CH), 38.9 (CH2), 37.0 (CH), 36.4 (CH2), 20.6 (CH3). Anal. Calcd for C8H8O: C, 79.97; H, 6.71. Found: C, 80.00; H, 6.71.
rac-methyl 3-(2-(allyloxy)-5-methylphenyl)-3-phenyl propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11.2 g
With potassium carbonate; In acetone;Reflux;
Into the suspension of rac-6-methyl-4-phenyl chroman-2-one (10 g) in MeOH (30 mL) and acetone (30 mL) was added potassium carbonate (9.4 g) and allyl bromide (7.6 g) at once. Refluxed the reaction mixture under stifling for 5-6 h. After completion of reaction cool the reaction mixture to room temperature and filtered off residual material. Filtrate was concentrated under reduced pressure and added EtOAc (150 mL) and water (100 mL). The separated organic layer was dried over sodium sulfate and solvent was distilled out under reduced pressure to get rac-methyl 3-(2-(allyloxy)-5- methylphenyl)-3-phenyl propanoate (11.2 g)
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