* 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.
With palladium on activated charcoal; hydrogen In methanol at 50℃; for 4 h;
To a stirred suspension of ferulic acid (25g, 128.74mmol) in methnol (200ml), Pd/C (3.75g) was added and the mixture was hydrogenated in 1.2 Mpa of hydrogen pressure for 4h at 50oC. After cooled to room temperature, the mixture was filtered and vacuumed to get white solid (25g, 99percent). 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J = 7.8 Hz, 1H), 6.62 (m, 2H), 3.79 (s, 3H), 2.81 (t, J = 7.7 Hz, 2H), 2.58 (t, J = 7.7 Hz, 2H). ESI-MS m/z: 195.1 [M - H].
99%
With palladium on activated charcoal; hydrogen In methanol at 50℃; for 4 h;
Pd/C (3.75 g) was added to a stirred suspension of ferulic acid(25 g, 128.74 mmol) in methanol (200 ml), and the mixture was hydrogenated at a hydrogen pressure of 1.2 MPa for 4 h at 50 C. After cooling to room temperature, the mixture was filtered and vacuumed to obtain a white solid (25 g, 99percent). 1H NMR (400 MHz,CDCl3) d 6.76 (d, J 7.8 Hz, 1H), 6.62 (m, 2H), 3.79 (s, 3H), 2.81 (t,J 7.7 Hz, 2H), 2.58 (t, J 7.7 Hz, 2H). ESI-MS m/z: 195.1 [MH].
3.12 mmol
at 37℃; for 16 h; Microbiological reaction
Strains were reactivated in two subsequent growths (o/n, anaerobiosis, 37 °C) in 10 ml MRS freshly supplemented with 0.05percent cystein (MRS-Cys). MRS-Cys medium (10 ml) was supplemented with sterile filtered FA at a concentration of 3 mM and then inoculated at 2percent from the re-activated culture and grown at 37 °C under anaerobic conditions. After 16 h, the cultures were centrifuged and the supernatants filtered through a 0.22 μηη syringe filter and analyzed by Ultra-Performance Liquid Chromatography (UPLC). FA and DHFA were separated using a C18-column Acquity UPLC BEH C18 1.8 μιτι, 2.1 mm x 150 mm (Waters AG, Baden-Dattwil, Switzerland). The system consisted of an UPLC-PDA system, equipped with binary gradient pump and a Photodiode Array detector (PDA) (Waters AG, Baden-Dattwil, Switzerland). Samples were kept at 10 °C during the analysis and the chromatography was done at 40 °C. Elution was performed with a flow rate set at 0.5 ml/min and a gradient of solvent A (water) and B (acetonitrile), both acidified with 1percent acetic acid. UPLC analysis was started with 3percent of solvent B. This condition was maintained for 1.8 min and then the percentage of solvent B was linearly increased to 15percent within 5.4 min, to 21 percent within 2.7 min and finally to 90percent within 0.1 min; 90percent solvent B was maintained for 2 min, then initial conditions were reached within 0.1 min and the column equilibrated in 3percent solvent B for 3.9 min. The detection was monitored with the PDA set at 280 nm. (0037) As shown in table 1 below, other bacteria were able to completely metabolize FA, however, the maximum yield (100 percent) of DHFA production was reached only with Lactobacillus johnsonii CNCM 1-1225. Some strains were able to transform FA, but not exclusively to DHFA. It is expected (but not measured) that these strains converted at least some of the FA into other metabolites. Table 1 (0038) (0039) Lactobacillus johnsonii CNCM 1-1225 is more effective than other strains at converting ferulic acid to dihydroferulic acid, including the type strain of Lactobacillus plantarum which has previously been shown to nnetabolise ferulic acid into DHFA [Knockaert (2012)]
Reference：
[1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 1, p. 81 - 86
[2] Tetrahedron Letters, 2010, vol. 51, # 44, p. 5753 - 5756
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 13, p. 4462 - 4466
[4] European Journal of Medicinal Chemistry, 2014, vol. 87, p. 429 - 439
[5] Journal of the American Chemical Society, 2017, vol. 139, # 10, p. 3767 - 3773
[6] Advanced Synthesis and Catalysis, 2017, vol. 359, # 13, p. 2280 - 2287
[7] Synthesis, 2011, # 9, p. 1456 - 1464
[8] Pharmazie, 2010, vol. 65, # 12, p. 913 - 918
[9] Organic and Biomolecular Chemistry, 2010, vol. 8, # 22, p. 5199 - 5211
[10] European Journal of Medicinal Chemistry, 2009, vol. 44, # 1, p. 332 - 344
[11] Chemische Berichte, 1878, vol. 11, p. 656
[12] Journal of the Indian Chemical Society, 1962, vol. 39, # 10, p. 672 - 676
[13] Phytochemistry (Elsevier), 1981, vol. 20, # 6, p. 1543 - 1546
[14] Bulletin de la Societe Chimique de France, 1994, vol. 131, p. 575 - 578
[15] Patent: EP1609360, 2005, A1, . Location in patent: Page/Page column 12
[16] Journal of Agricultural and Food Chemistry, 2009, vol. 57, # 8, p. 3356 - 3362
[17] Patent: EP1640360, 2006, A1, . Location in patent: Page/Page column 58
[18] MedChemComm, 2015, vol. 6, # 7, p. 1318 - 1327
[19] Patent: WO2016/162227, 2016, A1, . Location in patent: Page/Page column 12-14
2
[ 1135-24-6 ]
[ 1135-23-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogen In tetrahydrofuran
a) 3-(4-hydroxy-3-methoxyphenyl)propanoic acid [Show Image] Trans-3-methoxy-4-hydroxycinnamic acid (4 mmol; 784 mg) was dissolved in THF (25 mL) under Argon. Palladium on charcoal (0.4 mmol; 899 mg) was added then the reaction was flushed twice with hydrogen, then left to stir overnight. The reaction mixture was then filtered on celite, then rinsed with ethyl acetate (3*5mL). Concentration yielded the title compound as a light brown solid (785 mg; 4.0 mmol; quantitative yield) used without further purification in the following reactions. MS (ES) m/e 197 (M+H)+ NMR1H (CDCl3) δ (ppm) : 6.84 (d, 1H, J= 7.6 Hz); 6.72 (s, 1H); 6.71 (d, 1H, J = 8.0 Hz); 3.87 (s, 3H); 2.90 (t, 2H, J = 7.6 Hz); 2.66 (t, 2H, J = 7.6 Hz).
100%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 12 h;
General procedure: To a 10mL round-bottom flask containing 5 (2.46g, 15mmol) was added MeOH (45mL), Pd/C (10percent, 750mg). The mixture was stirred at room temperature for 12h under H2 atmosphere. Pd/C was filtered and washed with MeOH. The filtrate was concentrated in vaccum to provide compound 6 as white solid (2.48mg, 99.6percent).
100%
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 20℃;
A catalytic amount of 10percent Pd/C (0.43 g) was added to a solution of ferulic acid (1, 6.0 g, 30.9 mmol)in degassed EtOAc (100 mL). The reaction flask was then sealed with a rubber septum and freedof air. The reaction mixture was stirred at room temperature (RT) overnight under H2 atmosphere.Upon completion, the reaction mixture was filtered through a bed of celite, and concentrated toafford the known compound 2 [26] (6.1 g, quant.) as an off-white solid: 1H-NMR (400 MHz, CDCl3,which matches the literature [26], Figure S1) 10.50 (very br s, 1H, CO2H), 6.82 (d, J = 7.6 Hz, 1H,aromatic), 6.69 (s, 1H, aromatic), 6.68 (d, J = 7.6 Hz, 1H, aromatic), 5.60 (very br s, 1H, OH), 3.85 (s, 3H,PhOCH3), 2.87 (t, J = 7.2 Hz, 2H, PhCH2CH2CO2H), 2.64 (t, J = 7.2 Hz, 2H, PhCH2CH2CO2H).
98%
With palladium on activated charcoal; hydrogen In ethyl acetate at 20℃; for 16 h;
To a solution of 6(ferulic acid, 1.00 g, 5.155 mmol) in ethyl acetate (20 mL) under H2was added Pd/C (excess). The progress of the reaction was monitored by analyticTLC (10: 1 petroleum ether: Et2O). The solution was stirred for 24hat room temperature. After the completion of reaction, the suspension wasfiltered and filtrate concentrated under reduced pressure to afford pureproduct 7 (0.990 g, 98percent yield) as a colorlesssolid: mp 91-92 oC. 1H NMR (CDCl3) δ 6.86 (d, J= 8.0, 1 H), 6.72 (m, 2 H), 3.89 (s, 3 H), 2.92 (t, J = 7.6, 2 H), 2.67 (t, J =7.6, 2 H); 13 C NMR (CDCl3) 179.3, 146.4, 144.0, 132.0,120.8, 114.4, 111.0, 56.0, 36.0, 32.2; MS:for C10H12O2 calcd 196.07, found 196.0(M+)
89.16%
With hydrogen In methanol; ethyl acetate for 5 h;
To a solution of 3-(4-Hydroxy-3-methoxy-phenyl)-acrylic acid (2Og, 103mmol) in EtOAc (100ml) and MeOH (100ml) was added carefully 10percent Pd/C (2.Og), the reaction mixture was shaken in Parr apparatus for 5hs under 30-40 psi of hydrogen, then the solution was passed through a celite pad and the catalyst was washed with methanol, the filtrate was concentrated and dried at 5O0C under reduced pressure to give product (18g, 89.16percent). LC-MS: m/e 195 (M-I).
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 20, p. 4724 - 4729
[2] Toxicology Letters, 2002, vol. 133, # 2-3, p. 141 - 151
[3] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 17, p. 3795 - 3805
[4] Patent: EP1845087, 2007, A1, . Location in patent: Page/Page column 19-20
[5] Tetrahedron Letters, 2018, vol. 59, # 42, p. 3810 - 3815
[6] Molecules, 2018, vol. 23, # 12,
[7] Journal of Natural Products, 2007, vol. 70, # 5, p. 779 - 782
[8] Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2181 - 2185
[9] Tetrahedron Letters, 2015, vol. 56, # 51, p. 7108 - 7111
[10] Journal of Chemical Ecology, 2008, vol. 34, # 4, p. 558 - 574
[11] Patent: WO2007/71348, 2007, A1, . Location in patent: Page/Page column 73
[12] Journal of Agricultural and Food Chemistry, 2007, vol. 55, # 26, p. 10635 - 10640
[13] Archiv der Pharmazie (Weinheim, Germany), 1931, vol. 269, p. 326,334
[14] Journal of the American Chemical Society, 1948, vol. 70, p. 57
[15] Journal of Organic Chemistry, 1959, vol. 24, p. 736,738
[16] Chemical & Pharmaceutical Bulletin, 1984, vol. 32, # 4, p. 1679 - 1682
[17] Phytochemistry (Elsevier), 1992, vol. 31, # 4, p. 1179 - 1184
[18] Journal of Agricultural and Food Chemistry, 2001, vol. 49, # 1, p. 177 - 182
[19] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 7, p. 2537 - 2546
[20] Journal of Organic Chemistry, 2002, vol. 67, # 9, p. 2954 - 2959
[21] Patent: EP1577290, 2005, A1, . Location in patent: Page/Page column 95
3
[ 61292-90-8 ]
[ 1135-23-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium hydroxide; water In tetrahydrofuran at 20℃;
To a stirred suspension of 2.00 g of palladium, 10 wt percent on activated carbon in methanol (30 ml) was added compound 35a (0.03 mol, 6.66 g) and then subjected to hydrogenation on Parr shaker at 60 psi for 15 hour. The reaction mixture was filtered through a Celite.(R). pad and the filtrate was concentrated under vacuum to give the title compound in 90percent (6.00 g) yield. The crude ester was subjected to saponification using 1N potassium hydroxide in THF at room temperature to get the corresponding carboxylic acid in nearly quantitative yield. The carboxylic acid was heated in concentrated sulfuric acid at 90° C. for 4 h to get the title compound as light brown solid in 70percent (3.50 g) overall yield. 1H NMR (300 MHz, CDCl3): δ 2.67 (2H, m); 3.08 (2H, m); 3.98 (3H, s); 6.89 (1H, s); 7.15 (1H, s); 7.32 (1H, s). 13C NMR (75 Hz, CDCl3): δ 24.59; 35.62; 55.04; 106.57; 106.86; 128.76; 145.58; 149.32; 153.85; 206.74.
Concentrated HCl (2 drops) was added to a solution of 3- methoxy-4-hydroxydihydrocinnamic acid (0.225 g, 1.15 iranol, 1.0 equiv) in anhydrous MeOH (10 mL) at 25 0C, and the resultant solution was stirred at 25 0C for 20 h. Upon completion, the reaction contents were concentrated directly and the resultant crude yellow oil was purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:2) to afford 16 (0.231 g, 96% yield) as a colorless oil. 16: Rf = 0.63 (silica gel, hexanes : EtOAc , 1:1); IR (film) {max 3445, 2951, 1731, 1606, 1515, 1434, 1364, 1290, 1234,. 1202, 1152, 1121, 1033, 818, 791, 732 cm-1; 1H NMR (400 MHz, CDCl3) delta 6.83 (d, J = 8.0 Hz, 1 H), 6.70 (s, 1 H), 6.69 (d, J = 9.6 Hz, 1 H), 5.51 (s, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 2.88 (t, J" = 7.8 Hz, 2 H), 2.60 (t, J" = 7.8 Hz, 2 H); 13C NMR (75 MHz, CDCl3) delta 173.4, 146.4, 144.0, 132.4, 120.8, 114.3, 110.9, 55.8, 51.6, 36.1, 30.7; HRMS (FAB) calcd for CuHi4O4+ [M+] 210.0892, found 210.0905.
93%
With sulfuric acid; for 16h;Reflux;
General procedure: According to a literature protocol.[1] Propanoic acid derivative (10 g) was dissolved inmethanol (80 ml) and H2SO4 (700mul, 6 mmol) added. The resulting solution was refluxed for16 h and then allowed to cool to room temperature. The reaction mixture was reduced todryness and re-dissolved in ethyl acetate (20 ml). The organic phase was washed withsaturated aqueous sodium hydrogen carbonate (10 ml), brine (10 ml) and dried over MgSO4.Removal of the solvent gave the desired methyl ester. (Note: column chromatography is oftennot required for the methyl ester starting materials).
With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃;Sealed tube;
To a solution of ferulic acid (6.0 g, 30.9 mmol) indegassed EtOAc (100 mL) was added a catalytic amount of 10% Pd/C (0.43 g). The reaction flask wasthen sealed with a rubber septum and freed of air. The reaction mixture was stirred at rt overnightunder H2 atmosphere. Upon completion, the reaction mixture was filtered through a bed of celite,and concentrated to aord the known compound 9 [70] (6.1 g, quant.) as an o-white solid: 1HNMR (400 MHz, CDCl3, Figure S27, which matches the lit. [70]) delta 10.50 (very br s, 1H, CO2H), 6.82(d, J = 7.6 Hz, 1H, aromatic), 6.69 (s, 1H, aromatic), 6.68 (d, J = 7.6 Hz, 1H, aromatic), 5.60 (very brs, 1H, OH), 3.85 (s, 3H, PhOCH3), 2.87 (t, J = 7.2 Hz, 2H, PhCH2CH2CO2H), 2.64 (t, J = 7.2 Hz, 2H,PhCH2CH2CO2H).
99%
With palladium on activated charcoal; hydrogen; In methanol; at 50℃; under 9000.9 Torr; for 4h;
To a stirred suspension of ferulic acid (25g, 128.74mmol) in methnol (200ml), Pd/C (3.75g) was added and the mixture was hydrogenated in 1.2 Mpa of hydrogen pressure for 4h at 50oC. After cooled to room temperature, the mixture was filtered and vacuumed to get white solid (25g, 99%). 1H NMR (400 MHz, CDCl3) delta 6.76 (d, J = 7.8 Hz, 1H), 6.62 (m, 2H), 3.79 (s, 3H), 2.81 (t, J = 7.7 Hz, 2H), 2.58 (t, J = 7.7 Hz, 2H). ESI-MS m/z: 195.1 [M - H].
99%
With palladium on activated charcoal; hydrogen; In methanol; at 50℃; under 9000.9 Torr; for 4h;
Pd/C (3.75 g) was added to a stirred suspension of ferulic acid(25 g, 128.74 mmol) in methanol (200 ml), and the mixture was hydrogenated at a hydrogen pressure of 1.2 MPa for 4 h at 50 C. After cooling to room temperature, the mixture was filtered and vacuumed to obtain a white solid (25 g, 99%). 1H NMR (400 MHz,CDCl3) d 6.76 (d, J 7.8 Hz, 1H), 6.62 (m, 2H), 3.79 (s, 3H), 2.81 (t,J 7.7 Hz, 2H), 2.58 (t, J 7.7 Hz, 2H). ESI-MS m/z: 195.1 [MH].
With hydrogen;5%-palladium/activated carbon; In tetrahydrofuran; ethanol;
Production Example 1 [production example for the compound (I-1)]; 50 g of 3-(4-hydroxy-3-methoxyphenyl)acrylic acid, 0.5 g of 5 % palladium charcoal, about 0.05 g of 36 % hydrochloric acid, 250 ml of ethanol and 100 ml of tetrahydrofuran were mixed and stirred under hydrogen atmosphere. After stopping absorption of hydrogen gas, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 52 g of 3-(4-hydroxy-3-methoxyphenyl)propionic acid. 3-(4-hydroxy-3-methoxyphenyl)propionic acid1H-NMR (CDCl3, TMS) delta (ppm): 6.83(1H, dd, J=7.3Hz, 0.8Hz), 6.70-6.81(2H, m), 3.86(3H, s), 2.88(2H, t, J=7.6Hz), 2.65(2H, t, J=7.6Hz) 50 g of 3-(4-hydroxy-3-methoxyphenyl)propionic acid, 50 ml of propargyl bromide, 88 g of potassium carbonate and 500 ml of acetonitrile were mixed and stirred at 80 C for 3 hours. Then the reaction mixture was cooled to about room temperature. Ethyl acetate was added to the reaction mixture, and filtered. The filtrate was concentrated under reduced pressure to obtain 67 g of 2-propynyl 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionate. 2-propynyl 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionate1H-NMR (CDCl3, TMS) delta (ppm):6.96(1H, d, J=7.8Hz), 6.68-6.75(2H, m), 4.73(2H, d, J=2.2Hz), 4.68(2H, d, J=2.2Hz), 3.87(3H, s), 2.93(2H, t, J=7.3Hz), 2.67(2H, t, J=7.3Hz), 2.47-2.50(2H, m) 67 g of 2-propynyl 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionate 8.08 g of lithium hydroxide, 400 ml of tetrahydrofuran and 200 ml of water were mixed and stirred at 65 C for 3 hours. Then the reaction mixture was cooled to room temperature. Water was added to the reaction mixture and concentrated under reduced pressure. 5 % hydrochloric acid was added to the residue and extracted with chloroform for three times. The organic layer was dried by magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to obtain 51 g of 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionic acid. 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionic acid1H-NMR (CDCl3, TMS) delta (ppm):6.96(1H, d, J=8.2Hz), 6.73-6.75(2H, m), 4.73(2H, d, J=2.4Hz), 3.85(3H, s), 2.91(2H, t, J=8Hz), 2.67(2H, t, J=8Hz), 2.49(1H, t, J=2.4Hz) 12.7 g of 3-{3-methoxy-4-(2-propynyloxy)phenyl}}propionic acid, 4.3 ml of thionyl chloride, 100 ml of toluene and about 0.05 g of N,N-dimethylformamide were mixed and stirred at 80 C for 30 minutes. Then the reaction mixture which was cooled to room temperature was concentrated under reduced pressure to obtain 14.6 g of 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionyl chloride. 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionyl chloride1H-NMR (CDCl3, TMS) delta (ppm):6.97(1H, d ,J=8.8Hz), 6.72-6.74(2H, m), 4.73(2H, d, J=2.4Hz), 3.87(3H, s), 3.19(2H, t, J=7.2Hz), 2.99(2H, t, J=7.2Hz), 2.49(1H, t, J=2.4Hz) 200 mg of 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionyl chloride, 99mg of 4-methylbenzylamine, 0.45 ml of triethylamine and 5 ml of tetrahydrofuran were mixed and stirred at room temperature for 1 hour. Then water was added to reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with 5 % hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride, dried by magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 204 mg of N-(4-methylbenzyl)-3-{3-methoxy-4-(2-propynyloxy)phenyl}pro panamide.1H-NMR (CDCl3, TMS) delta (ppm): 7.11 (2H, d, J=8.0 Hz), 7.05 (2H, d, J=8.0 Hz), 6.94 (1H, d, J=8.0 Hz), 6.71-6.75 (2H, m), 5.53 (1H, br.s), 4.73 (2H, d, J=2.4 Hz), 4.36 (2H, d, J=5.5 Hz), 3.82 (3H, s), 2.94 (2H, t, J=7.5 Hz), 2.46-2.50 (3H, m), 2.32 (3H, s)
With hydrogenchloride; hydrogen;5% palladium over charcoal; In tetrahydrofuran; ethanol; water;
Reference Example 1 50 g of 3-(4-hydroxy-3-methoxyphenyl)acrylic acid, 0.5 g of 5% palladium carbon, about 0.05 g of 36% hydrochloric acid, 250 ml of ethanol and 100 ml of tetrahydrofuran were mixed and stirred under a hydrogen atmosphere. After absorption of a hydrogen gas was stopped, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 52 g of 3-(4-hydroxy-3-methoxyphenyl)propionic acid. 1H-NMR (CDCl3, TMS) delta (ppm): 6.83 (1H, dd, J = 7.3 Hz, 0.8 Hz), 6.81-6.70 (2H, m), 3.86 (3H, s), 2.88 (2H, t, J = 7.6 Hz), 2.65 (2H, t, J = 7.6 Hz)
3.12 mmol
at 37℃; for 16h;Microbiological reaction;
Strains were reactivated in two subsequent growths (o/n, anaerobiosis, 37 C) in 10 ml MRS freshly supplemented with 0.05% cystein (MRS-Cys). MRS-Cys medium (10 ml) was supplemented with sterile filtered FA at a concentration of 3 mM and then inoculated at 2% from the re-activated culture and grown at 37 C under anaerobic conditions. After 16 h, the cultures were centrifuged and the supernatants filtered through a 0.22 muetaeta syringe filter and analyzed by Ultra-Performance Liquid Chromatography (UPLC). FA and DHFA were separated using a C18-column Acquity UPLC BEH C18 1.8 muiotatauiota, 2.1 mm x 150 mm (Waters AG, Baden-Dattwil, Switzerland). The system consisted of an UPLC-PDA system, equipped with binary gradient pump and a Photodiode Array detector (PDA) (Waters AG, Baden-Dattwil, Switzerland). Samples were kept at 10 C during the analysis and the chromatography was done at 40 C. Elution was performed with a flow rate set at 0.5 ml/min and a gradient of solvent A (water) and B (acetonitrile), both acidified with 1% acetic acid. UPLC analysis was started with 3% of solvent B. This condition was maintained for 1.8 min and then the percentage of solvent B was linearly increased to 15% within 5.4 min, to 21 % within 2.7 min and finally to 90% within 0.1 min; 90% solvent B was maintained for 2 min, then initial conditions were reached within 0.1 min and the column equilibrated in 3% solvent B for 3.9 min. The detection was monitored with the PDA set at 280 nm. (0037) As shown in table 1 below, other bacteria were able to completely metabolize FA, however, the maximum yield (100 %) of DHFA production was reached only with Lactobacillus johnsonii CNCM 1-1225. Some strains were able to transform FA, but not exclusively to DHFA. It is expected (but not measured) that these strains converted at least some of the FA into other metabolites. Table 1 (0038) (0039) Lactobacillus johnsonii CNCM 1-1225 is more effective than other strains at converting ferulic acid to dihydroferulic acid, including the type strain of Lactobacillus plantarum which has previously been shown to nnetabolise ferulic acid into DHFA [Knockaert (2012)]
With hydrogen;palladium on activated charcoal; In tetrahydrofuran;
a) 3-(4-hydroxy-3-methoxyphenyl)propanoic acid [Show Image] Trans-3-methoxy-4-hydroxycinnamic acid (4 mmol; 784 mg) was dissolved in THF (25 mL) under Argon. Palladium on charcoal (0.4 mmol; 899 mg) was added then the reaction was flushed twice with hydrogen, then left to stir overnight. The reaction mixture was then filtered on celite, then rinsed with ethyl acetate (3*5mL). Concentration yielded the title compound as a light brown solid (785 mg; 4.0 mmol; quantitative yield) used without further purification in the following reactions. MS (ES) m/e 197 (M+H)+ NMR1H (CDCl3) delta (ppm) : 6.84 (d, 1H, J= 7.6 Hz); 6.72 (s, 1H); 6.71 (d, 1H, J = 8.0 Hz); 3.87 (s, 3H); 2.90 (t, 2H, J = 7.6 Hz); 2.66 (t, 2H, J = 7.6 Hz).
100%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 12h;
General procedure: To a 10mL round-bottom flask containing 5 (2.46g, 15mmol) was added MeOH (45mL), Pd/C (10%, 750mg). The mixture was stirred at room temperature for 12h under H2 atmosphere. Pd/C was filtered and washed with MeOH. The filtrate was concentrated in vaccum to provide compound 6 as white solid (2.48mg, 99.6%).
100%
With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃;
A catalytic amount of 10% Pd/C (0.43 g) was added to a solution of ferulic acid (1, 6.0 g, 30.9 mmol)in degassed EtOAc (100 mL). The reaction flask was then sealed with a rubber septum and freedof air. The reaction mixture was stirred at room temperature (RT) overnight under H2 atmosphere.Upon completion, the reaction mixture was filtered through a bed of celite, and concentrated toafford the known compound 2 [26] (6.1 g, quant.) as an off-white solid: 1H-NMR (400 MHz, CDCl3,which matches the literature [26], Figure S1) 10.50 (very br s, 1H, CO2H), 6.82 (d, J = 7.6 Hz, 1H,aromatic), 6.69 (s, 1H, aromatic), 6.68 (d, J = 7.6 Hz, 1H, aromatic), 5.60 (very br s, 1H, OH), 3.85 (s, 3H,PhOCH3), 2.87 (t, J = 7.2 Hz, 2H, PhCH2CH2CO2H), 2.64 (t, J = 7.2 Hz, 2H, PhCH2CH2CO2H).
100%
With platinum on carbon; hydrogen; In methanol; water; at 20℃; for 24h;
Following literature procedure,1 trans-ferulic acid (10.0 g, 51.50 mmol, 1.0 equivalent) was dissolved in H2O (515 mL, 0.1 M), and methanol (515 mL, 0.1 M) in a 2.0 L round-bottom flask with a magnetic stir bar at room temperature (RT). CAUTION (flammability hazard): 5% Pd/C (2.0 g, 0.2 wt/wt equivalents) was then added carefully. The reaction vessel was topped with an H2 balloon, purged with H2 gas (3x), and stirred at RT under H2 balloon pressure for 24 hours. Once the reaction was complete (determined by TLC), the reaction slurry was concentrated and purified by column chromatography (50% EtOAc/hexanes, followed by 100% EtOAc flush). This procedure yielded 10.12 grams of 6 (quantitative yield) as an off-white solid. Melting point was 89 - 91 C. Data are: TLC Rf = 0.47 (streak, 60% EtOAc/hexanes); 1H NMR (DMSO-d6, 300 MHz) delta 12.09 (bs, 1H), 8.85 (bs, 1H), 6.59 (m, 2H), 3.70 (s, 3H), 2.68 (t, J=6 Hz, 2H), 2.44 (t, J=6Hz, 2H); 13C NMR (DMSO-d6, 75 MHz) delta 174.5, 147.9, 145.2, 132.2, 120.8, 115.8, 113.0, 56.0, 36.3, 30.6
98%
With palladium on activated charcoal; hydrogen; In ethyl acetate; at 20℃; for 16h;
To a solution of 6(ferulic acid, 1.00 g, 5.155 mmol) in ethyl acetate (20 mL) under H2was added Pd/C (excess). The progress of the reaction was monitored by analyticTLC (10: 1 petroleum ether: Et2O). The solution was stirred for 24hat room temperature. After the completion of reaction, the suspension wasfiltered and filtrate concentrated under reduced pressure to afford pureproduct 7 (0.990 g, 98% yield) as a colorlesssolid: mp 91-92 oC. 1H NMR (CDCl3) delta 6.86 (d, J= 8.0, 1 H), 6.72 (m, 2 H), 3.89 (s, 3 H), 2.92 (t, J = 7.6, 2 H), 2.67 (t, J =7.6, 2 H); 13 C NMR (CDCl3) 179.3, 146.4, 144.0, 132.0,120.8, 114.4, 111.0, 56.0, 36.0, 32.2; MS:for C10H12O2 calcd 196.07, found 196.0(M+)
89.16%
With hydrogen;palladium 10% on activated carbon; In methanol; ethyl acetate; under 1551.49 - 2068.65 Torr; for 5h;
To a solution of 3-(4-Hydroxy-3-methoxy-phenyl)-acrylic acid (2Og, 103mmol) in EtOAc (100ml) and MeOH (100ml) was added carefully 10% Pd/C (2.Og), the reaction mixture was shaken in Parr apparatus for 5hs under 30-40 psi of hydrogen, then the solution was passed through a celite pad and the catalyst was washed with methanol, the filtrate was concentrated and dried at 5O0C under reduced pressure to give product (18g, 89.16%). LC-MS: m/e 195 (M-I).
With hydrogenchloride; hydrogen;5%-palladium/activated carbon; In tetrahydrofuran; ethanol; water;
50 g of 3-(4-hydroxy-3-methoxyphenyl)acrylic acid, 0.5 g of 5 % of palladium charcoal, about 0.05 g of 36 % hydrochloric acid, 250 ml of ethanol and 100 ml of tetrahydrofuran were stirred under hydrogen atmosphere. After stopping absorption of hydrogen gas, it was filtered, and the filtrate was concentrated under reduced pressure to obtain 52 g of 3-(4-hydroxy-3-methoxyphenyl)propionic acid. [] 1H-NMR (CDCl3, TMS) delta (ppm): 6.83 (1H, dd, J=7.3 Hz, 0.8 Hz), 6.81-6.70 (2H, m), 3.86 (3H, s), 2.88 (2H, t, J=7.6 Hz), 2.65 (2H, t, J=7.6 Hz)
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 16h;
A mixture of ferulic acid 8 (19.4 g, 100 mmol)and 10% palladium on charcoal (1.0 g) in MeOH was stirred under hydrogen atmosphere for 16 h at rt.Filtration of the reaction mixture, followed by concentration gave carboxylic acid 9. To a solution ofcrude 9 in DMF (100 mL) were added potassium carbonate (34.5 g, 250 mmol) and benzyl bromide (26.4mL, 220 mmol), and the mixture was stirred for 3 h at rt. After being cooled, water was added, and thewhole was extracted with a mixture of toluene and hexane (4/1). Combined organic layers were washedwith brine, dried over sodium sulfate, filtered, and concentrated to give benzyl ester 10. To a solution ofcrude 10 in EtOH (50 mL) was added a solution of sodium hydroxide (8.0 g, 200 mmol) in water (50 mL),and the mixture was stirred for 1 h at rt. Reaction mixture was washed with Et2O, acidified with 10%hydrochloric acid, and then extracted with Et2O. Combined organic layers were washed with brine, driedover sodium sulfate, filtered, and evaporated. The residue was recrystallized from EtOAc to give 11 (24.8g, 87%) as colorless needles of mp 95-97 C. IR (Nujol) cm-1: 3500-3100, 1691. 1H-NMR (300 MHz,CDCl3) delta: 2.65 (2H, t, J = 7.7 Hz), 2.89 (2H, t, J = 7.7 Hz), 3.87 (3H, s), 5.12 (2H, s), 6.67 (1H, dd, J =8.2, 1.9 Hz), 6.75 (1H, d, J = 1.9 Hz), 6.81 (1H, d, J = 8.2 Hz), 7.26-7.45 (5H, m). 13C-NMR (75 MHz,CDCl3) delta: 30.4, 36.1, 56.2, 71.3, 112.4, 114.4, 120.3, 127.5, 128.0, 128.7, 133.6, 137.5, 146.9, 149.8,179.5
With methanesulfonic acid; at 90℃; for 0.166667h;Microwave irradiation;
The 3-(4-Hydroxy-3-methoxy-phenyl)-propionic acid ( 2gxlO) was dissolved in methanesulfonic acid (lOmlxlO) in microwave process vial (2OmIxIO), the mixture was heated at 9O0C for 10 minutes under microwave irradiation. The mixture was poured into ice (500g), and then stirred for 20 minutes. The precipitate was collected and dried to give 6-Hydroxy-5-methoxy-indan-l-one(15g, 82.6%). LC-MS: m/e 179 (MH+)
67%
With methanesulfonic acid; at 120℃; for 1.08333h;Cooling with ice;
A solution of compound 2 (6.3 g, 32.1 mmol) in methanesulfonic acid (50 mL) was refluxed at120 C for 1 h. After cooling to RT, the reaction mixture was poured into ice-water, stirred for 5 min,and filtered to afford a crude dark brown solid, which was recrystallized from EtOH to afford theknown compound 3 [20] (3.8 g, 67%) as a yellow solid: 1H-NMR (400 MHz, (CD3)2SO, which matchesthe lit. [20], Figure S2) 9.38 (s, 1H, OH), 7.03 (s, 1H, aromatic), 6.89 (s, 1H, aromatic), 3.83 (s, 3H,OCH3), 2.92 (t, J = 5.6 Hz, 2H, CH2CH2C=O), 2.49 (t, J = 5.6 Hz, 2H, CH2CH2C=O).
67%
With methanesulfonic acid; at 120℃; for 1h;
A solution of 9 (6.3 g, 32.1 mmol) inmethanesulfonic acid (50 mL) was refluxed at 120 C for 1 h. After cooling to rt, the reactionmixture was poured into ice-water, stirred for 5 min, and filtered to aord a crude dark brown solid,which was recrystallized from EtOH to aord the known compound 10 [71] (3.8 g, 67%) as a yellowsolid: 1H NMR (400 MHz, (CD3)2SO, Figure S28, which matches the lit. [71]) delta 9.38 (s, 1H, OH), 7.03 (s,1H, aromatic), 6.89 (s, 1H, aromatic), 3.83 (s, 3H, OCH3), 2.92 (t, J = 5.6 Hz, 2H, CH2CH2C=O), 2.49 (t,J = 5.6 Hz, 2H, CH2CH2C=O).
65%
With methanesulfonic acid; at 120℃; for 1h;
Compound 2 (25g, 127.4 mmol) was dissolved in a solution of methanesulfonic acid (250g) and the mixture was stirred at 120 for 1h. After the reaction finished (monitored by TLC), the mixture was poured into ice water, and filtered. The crude product was recrystallized in ethanol to afford a yellow solid (16g, 65%). 1H NMR (400 MHz, CDCl3) delta 7.25 (s, 1H), 6.88 (s, 1H), 5.73 (s, 1H), 3.99 (s, 3H), 3.04 (m, 2H), 2.66 (m, 2H). ESI-MS m/z: 179.1 [M+H]+.
65%
With methanesulfonic acid; at 120℃; for 1h;
Compound 2 (25 g, 127.4 mmol) was dissolved in a solution of methanesulfonic acid (250 g), and the mixture was stirred at 120 C for 1 h. After the reaction was completed (monitored by TLC), the mixture was poured into ice water and filtered. The crude product was recrystallized in ethanol to afford a yellow solid (16 g, 65%). 1HNMR (400 MHz, CDCl3) d 7.25 (s, 1H), 6.88 (s, 1H), 5.73 (s, 1H), 3.99(s, 3H), 3.04 (m, 2H), 2.66 (m, 2H). ESI-MS m/z: 179.1 [MH].
With sulfuric acid; at 90℃; for 4h;
To a stirred suspension of 2.00 g of palladium, 10 wt % on activated carbon in methanol (30 ml) was added compound 35a (0.03 mol, 6.66 g) and then subjected to hydrogenation on Parr shaker at 60 psi for 15 hour. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under vacuum to give the title compound in 90% (6.00 g) yield. The crude ester was subjected to saponification using 1N potassium hydroxide in THF at room temperature to get the corresponding carboxylic acid in nearly quantitative yield. The carboxylic acid was heated in concentrated sulfuric acid at 90 C. for 4 h to get the title compound as light brown solid in 70% (3.50 g) overall yield. 1H NMR (300 MHz, CDCl3): delta 2.67 (2H, m); 3.08 (2H, m); 3.98 (3H, s); 6.89 (1H, s); 7.15 (1H, s); 7.32 (1H, s). 13C NMR (75 Hz, CDCl3): delta 24.59; 35.62; 55.04; 106.57; 106.86; 128.76; 145.58; 149.32; 153.85; 206.74.
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 4h;
Following literature procedure,3 molecule 6 (2.40 g, 12.23 mmol, 1.0 equivalent) and K2CO3 (6.71 g, 48.55 mmol, 3.97 equivalents) were dissolved in N,N-dimethylformamide (DMF, 11.9 mL, 1.03 M) in a 250 mL round-bottom flask with a magnetic stir bar at room temperature (RT). CAUTION (caustic smell hazard): Benzyl bromide (9.5 mL, 79.73 mmol, 6.52 equivalents) was then added dropwise at RT. The flask was now warmed to 80 C and heated for 4.0 hours. Once complete (TLC), the mixture was cooled to RT and quenched with H2O (20 mL). The vessel was then cooled to 0 C in an ice bath, and the mixture was gradually brought to pH <4.0 by slow addition of 1N HCl. At this point, the mixture was transferred to a separatory funnel, where the layers were mixed and separated. The aqueous layer was then extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, concentrated, and purified by column chromatography (20% EtOAc/hexanes). This procedure yielded 4.73 g (quantitative yield) of the ester product as a light-yellow oil. When stored in a freezer overnight at -20 C, the compound converted to an off-white solid with a melting point of 35.5 - 37 C. Data are: TLC Rf = 0.36 (20% EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz) delta 7.46 (d, J=2.5Hz, 2H), 7.40-7.33 (m, 8H), 6.83-6.77 (m, 2H), 6.68 (d, J=2.5Hz, 1H), 5.15 (s, 2H), 5.14 (s, 2H), 3.87 (s, 3H), 2.94 (t, J=5Hz, 2H), 2.69 (t, J=5Hz, 2H); 13C NMR (CDCl3, 125 MHz) delta 172.8, 149.6, 146.7, 137.4, 135.9, 133.7, 128.6, 128.5, 128.2, 128.2, 127.8, 127.3, 120.2, 114.3, 112.2, 71.2, 66.3, 56.0, 36.1, 30.6.
With potassium carbonate; In acetonitrile; at 80℃; for 6h;
Reference Example 74 20 g of <strong>[1135-23-5]3-(4-hydroxy-3-methoxyphenyl)propionic acid</strong>, 55 g of benzyl bromide, 45 g of potassium carbonate and 300 ml of acetonitrile were mixed and stirred at 80C for 6 hours. After the reaction mixture was allowed to cool to around room temperature, ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was mixed with 46 g of a 20% aqueous sodium hydroxide solution. Then, ethanol was added to the mixture until a homogeneous solution was obtained, and the mixture was stirred under reflux for 1 hour. After the reaction mixture was allowed to cool to around room temperature, water was added and the mixture was concentrated under reduced pressure, and washed with tert-butyl methyl ether. To the residue was added 5% hydrochloric acid to adjust it to pH 2, followed by extraction with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was washed with hexane and then dried to obtain 62 g of 3-(3-methoxy-4-benzyloxyphenyl)propionic acid. 1H -NMR (CDCl3, TMS) delta (ppm): 7.42-7.44 (1H, m), 7.26-7.37 (4H, m), 6.80 (1H, d, J = 8.4 Hz), 6.75 (1H, d, J = 2.0 Hz), 6.67 (1H, dd, J = 8.4 Hz, 2.0 Hz), 5.12 (2H, s), 3.87 (3H, s), 2.89 (2H, t, J = 7.2 Hz), 2. 55 (2H, t, J = 7.2 Hz)
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
A mixture of ferulic acid 8 (19.4 g, 100 mmol)and 10% palladium on charcoal (1.0 g) in MeOH was stirred under hydrogen atmosphere for 16 h at rt.Filtration of the reaction mixture, followed by concentration gave carboxylic acid 9. To a solution ofcrude 9 in DMF (100 mL) were added potassium carbonate (34.5 g, 250 mmol) and benzyl bromide (26.4mL, 220 mmol), and the mixture was stirred for 3 h at rt. After being cooled, water was added, and thewhole was extracted with a mixture of toluene and hexane (4/1). Combined organic layers were washedwith brine, dried over sodium sulfate, filtered, and concentrated to give benzyl ester 10. To a solution ofcrude 10 in EtOH (50 mL) was added a solution of sodium hydroxide (8.0 g, 200 mmol) in water (50 mL),and the mixture was stirred for 1 h at rt. Reaction mixture was washed with Et2O, acidified with 10%hydrochloric acid, and then extracted with Et2O. Combined organic layers were washed with brine, driedover sodium sulfate, filtered, and evaporated. The residue was recrystallized from EtOAc to give 11 (24.8g, 87%) as colorless needles of mp 95-97 C. IR (Nujol) cm-1: 3500-3100, 1691. 1H-NMR (300 MHz,CDCl3) delta: 2.65 (2H, t, J = 7.7 Hz), 2.89 (2H, t, J = 7.7 Hz), 3.87 (3H, s), 5.12 (2H, s), 6.67 (1H, dd, J =8.2, 1.9 Hz), 6.75 (1H, d, J = 1.9 Hz), 6.81 (1H, d, J = 8.2 Hz), 7.26-7.45 (5H, m). 13C-NMR (75 MHz,CDCl3) delta: 30.4, 36.1, 56.2, 71.3, 112.4, 114.4, 120.3, 127.5, 128.0, 128.7, 133.6, 137.5, 146.9, 149.8,179.5
With potassium carbonate; In acetonitrile; at 80℃; for 3h;
50 g of 3- (4-hydroxy-3-methoxyphenyl)propionic acid, 50 ml of propargyl bromide, 88 g of potassium carbonate and 500 ml of acetonitrile were mixed, and stirred at 80 C for 3 hours. Then the reaction mixture was cooled to room temperature. Ethyl acetate was added to it, and filtered. The filtrate was concentrated under reduced pressure to obtain 67 g of (2-propynyl) 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionate. [] 1H-NMR (CDCl3, TMS) delta (ppm): 6.96 (1H, d, J=7.8 Hz), 6.68-6.75 (2H, m), 4.73 (2H, d, J=2.2 Hz), 4.68 (2H, d, J=2.2 Hz), 3.87 (3H, s), 2.93 (2H, t, J=7.3 Hz), 2.67 (2H, t, J=7.3Hz), 2.47-2.50 (2H, m)
With potassium carbonate; In acetonitrile; at 80℃; for 3h;
Production Example 1 [production example for the compound (I-1)]; 50 g of 3-(4-hydroxy-3-methoxyphenyl)acrylic acid, 0.5 g of 5 % palladium charcoal, about 0.05 g of 36 % hydrochloric acid, 250 ml of ethanol and 100 ml of tetrahydrofuran were mixed and stirred under hydrogen atmosphere. After stopping absorption of hydrogen gas, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 52 g of <strong>[1135-23-5]3-(4-hydroxy-3-methoxyphenyl)propionic acid</strong>. <strong>[1135-23-5]3-(4-hydroxy-3-methoxyphenyl)propionic acid</strong>1H-NMR (CDCl3, TMS) delta (ppm): 6.83(1H, dd, J=7.3Hz, 0.8Hz), 6.70-6.81(2H, m), 3.86(3H, s), 2.88(2H, t, J=7.6Hz), 2.65(2H, t, J=7.6Hz) 50 g of <strong>[1135-23-5]3-(4-hydroxy-3-methoxyphenyl)propionic acid</strong>, 50 ml of propargyl bromide, 88 g of potassium carbonate and 500 ml of acetonitrile were mixed and stirred at 80 C for 3 hours. Then the reaction mixture was cooled to about room temperature. Ethyl acetate was added to the reaction mixture, and filtered. The filtrate was concentrated under reduced pressure to obtain 67 g of 2-propynyl 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionate. 2-propynyl 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionate1H-NMR (CDCl3, TMS) delta (ppm):6.96(1H, d, J=7.8Hz), 6.68-6.75(2H, m), 4.73(2H, d, J=2.2Hz), 4.68(2H, d, J=2.2Hz), 3.87(3H, s), 2.93(2H, t, J=7.3Hz), 2.67(2H, t, J=7.3Hz), 2.47-2.50(2H, m) 67 g of 2-propynyl 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionate 8.08 g of lithium hydroxide, 400 ml of tetrahydrofuran and 200 ml of water were mixed and stirred at 65 C for 3 hours. Then the reaction mixture was cooled to room temperature. Water was added to the reaction mixture and concentrated under reduced pressure. 5 % hydrochloric acid was added to the residue and extracted with chloroform for three times. The organic layer was dried by magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to obtain 51 g of 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionic acid. 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionic acid1H-NMR (CDCl3, TMS) delta (ppm):6.96(1H, d, J=8.2Hz), 6.73-6.75(2H, m), 4.73(2H, d, J=2.4Hz), 3.85(3H, s), 2.91(2H, t, J=8Hz), 2.67(2H, t, J=8Hz), 2.49(1H, t, J=2.4Hz) 12.7 g of 3-{3-methoxy-4-(2-propynyloxy)phenyl}}propionic acid, 4.3 ml of thionyl chloride, 100 ml of toluene and about 0.05 g of N,N-dimethylformamide were mixed and stirred at 80 C for 30 minutes. Then the reaction mixture which was cooled to room temperature was concentrated under reduced pressure to obtain 14.6 g of 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionyl chloride. 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionyl chloride1H-NMR (CDCl3, TMS) delta (ppm):6.97(1H, d ,J=8.8Hz), 6.72-6.74(2H, m), 4.73(2H, d, J=2.4Hz), 3.87(3H, s), 3.19(2H, t, J=7.2Hz), 2.99(2H, t, J=7.2Hz), 2.49(1H, t, J=2.4Hz) 200 mg of 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionyl chloride, 99mg of 4-methylbenzylamine, 0.45 ml of triethylamine and 5 ml of tetrahydrofuran were mixed and stirred at room temperature for 1 hour. Then water was added to reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with 5 % hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride, dried by magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 204 mg of N-(4-methylbenzyl)-3-{3-methoxy-4-(2-propynyloxy)phenyl}pro panamide.1H-NMR (CDCl3, TMS) delta (ppm): 7.11 (2H, d, J=8.0 Hz), 7.05 (2H, d, J=8.0 Hz), 6.94 (1H, d, J=8.0 Hz), 6.71-6.75 (2H, m), 5.53 (1H, br.s), 4.73 (2H, d, J=2.4 Hz), 4.36 (2H, d, J=5.5 Hz), 3.82 (3H, s), 2.94 (2H, t, J=7.5 Hz), 2.46-2.50 (3H, m), 2.32 (3H, s)
With potassium carbonate; In acetonitrile; at 80℃; for 3h;
Reference Example 2 50 g of <strong>[1135-23-5]3-(4-hydroxy-3-methoxyphenyl)propionic acid</strong>, 50 ml of propargyl bromide, 88 g of potassium carbonate and 500 ml of acetonitrile were mixed and stirred at 80C for 3 hours. After the reaction mixture was allowed to cool to around room temperature, ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 67 g of 2-propynyl 3-{3-methoxy-4-(2-propynyloxy)phenyl}propionate. 1H-NMR (CDCl3, TMS) delta (ppm): 6.96 (1H, d, J = 7.8 Hz), 6.68-6.75 (2H, m), 4.73 (2H, d, J = 2.2 Hz), 4.68 (2H, d, J = 2.2 Hz), 3.87 (3H, s), 2.93 (2H, t, J = 7.3 Hz), 2.67 (2H, t, J = 7.3 Hz), 2.47-2.50 (2H, m)
N-(naphthalene-2-ylmethyl)-3-(4-hydroxy-3-methoxyphenyl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-[3-(diethylamino)propyl]-N'-ethylcarbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20℃; for 2h;
8 Reference Production Example 8
12.5 g of 3-(4-hydroxy-3-methoxyphenyl)propionic acid, 10.0 g of (C-naphthalene-2-yl)methylamine, 13.4 g of WSC and 100 ml of N,N-dimethylformamide were mixed, and stirred at room temperature for 2 hours. Then water was added to the reaction mixture and extracted with chloroform. The organic layer was washed successively with 5 % hydrochloric acid and saturated aqueous solution of sodium chloride, dried by magnesium sulfate, and concentrated under reduced pressure. The residue was washed by hexane to obtain 15.1 g of N-(naphthalene-2-ylmethyl)-3-(4-hydroxy-3-methoxyphenyl)pro panamide. [] 1H-NMR (CDCl3, TMS) δ (ppm): 7.73-7.84 (3H, m), 7.58 (1H, s), 7.43-7.51 (2H, m), 7.23-7.27 (1H, m), 6.82 (1H, d, J=7.6 Hz), 6.67-6.72 (2H, m), 5.67 (1H, br.s), 5.49 (1H, s), 4.56 (2H, d, J=5.9 Hz), 3.77 (3H, s), 2.94 (2H, d, J=7.5 Hz), 2.51 (2H, d, J=7.5 Hz)
sulfuric acid; In diethyl ether; at 20℃; for 24.0833h;
Compound 29. Butyric acid 4-{2-[4-(4-chloro-phenyl)-thiazol-2-ylcarbamoyl]-ethyl)-2-methoxy-phenyl ester (B241116) Butyric acid 4-(2-carboxy-ethyl)-2-methoxy-phenyl ester (B241028) 3-(4-Hydroxy3-methoxyphenyl)propionic acid (917 mg, 4.68 mmol) was mixed with butyric acid anhydride (3-5 mL) to form a suspension, followed by addition of H2SO4 (0.1 mL). It became a brown solution. After stirring for 5 min, ether (20 mL) was added to it. The color was turned to yellow. The reaction was continued for 24 hours at RT. The mixture was poured into 50 mL of ice-water and was extracted with EtOAc (50 mL). The EtOAc solution was dried over Na2SO4. After filtration and concentration, the oily residue was purified by chromatography eluted with hexane-chloroform-3% MeOH in chloroform to afford a yellowish solid (610 mg, Y=49%).
18.b
b) methyl 3-(4-hydroxy-3-methoxyphenyl)propanoate [Show Image] 3-(4-hydroxy-3-methoxyphenyl)propanoic acid (0.765 mmol ; 150 mg) was dissolved in a mixture of anhydrous CH2Cl2 (5 mL) and MeOH (3 mL), under argon. Triméthylsilyldiazométhane (2.2 mmol; 2M in diethyl ether; 1.1 mL) was added dropwise at 0°C, then the reaction mixture was stirred at room temperature overnight. After drying over MgSO4, concentration in vacuo, the residue was purified by preparative TLC (cyclohexane/ethyle acetate - 6/4), to yield the title compound as a white solid (0.29 mmol; 61 mg; 38%). NMR1H (CDCl3) δ (ppm) : 6.82 (d, 1 H, J = 7.6 Hz); 6.70 (s, 1H) ; 6.67 (d, 1H, J = 8.0 Hz); 3,84 (s, 3H); 3,66 (s, 3H); 2,87 (t, 2H, J = 7,6 Hz); 2,60 (t, 2H, J = 7.6 Hz) .
With potassium hydroxide; water; In tetrahydrofuran; at 20℃;
To a stirred suspension of 2.00 g of palladium, 10 wt % on activated carbon in methanol (30 ml) was added compound 35a (0.03 mol, 6.66 g) and then subjected to hydrogenation on Parr shaker at 60 psi for 15 hour. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under vacuum to give the title compound in 90% (6.00 g) yield. The crude ester was subjected to saponification using 1N potassium hydroxide in THF at room temperature to get the corresponding carboxylic acid in nearly quantitative yield. The carboxylic acid was heated in concentrated sulfuric acid at 90 C. for 4 h to get the title compound as light brown solid in 70% (3.50 g) overall yield. 1H NMR (300 MHz, CDCl3): delta 2.67 (2H, m); 3.08 (2H, m); 3.98 (3H, s); 6.89 (1H, s); 7.15 (1H, s); 7.32 (1H, s). 13C NMR (75 Hz, CDCl3): delta 24.59; 35.62; 55.04; 106.57; 106.86; 128.76; 145.58; 149.32; 153.85; 206.74.
With magnesium sulfate;novozyme 435; In toluene; at 50℃; for 16h;
8-Methyl-1-nonanol (752 mg, 4.74 mmol), <strong>[1135-23-5]3-(4-hydroxy-3-methoxyphenyl)propionic acid</strong> (977 mg, 4.98 mmol) and Novozyme 435 (100 mg) were measured and placed in a flask (25 ml). Toluene (5 ml) and anhydrous magnesium sulfate (1 g) were added, and the mixture was stirred with heating in an oil bath at 50 C. for 16 hr. The reaction mixture was allowed to cool to room temperature, toluene (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. Toluene (50 ml) was added, and the mixture was washed with 5% aqueous sodium hydrogen carbonate solution (25 ml×3) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (chloroform:n-hexane:ethyl acetate=1:1:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 8-methylnonyl 3-(4-hydroxy-3-methoxyphenyl)propionate (1.22 g, yield 76.2%) as a colorless oil.1H-NMR (CDCl3,delta): 0.86 (6H, d, J=6.62 Hz), 1.12-1.35 (10H, m), 1.45-1.65 (3H, m), 2.59 (2H, t, J=7.36 Hz), 2.28 (2H, t, J=7.56 Hz), 3.92 (3H, s), 4.06 (2H, t, J=6.76 Hz), 5.49 (1H, s), 6.65-6.71 (2H, m), 6.82 (1H, d, J=7.86 Hz).
With 1-iodo-propane; 3-chloro-benzenecarboperoxoic acid; In 2,2,2-trifluoroethanol; at 20℃; for 2h;
General procedure: 3-(4-Hydroxyphenyl)propionic acid (1a) (0.6 mmol), 1-iodopropane (0.12 mmol) and mCPBA (0.72 mmol, 75%) were added successively to 2,2,2-trifluoroethanol (1.5 mL). The suspension was vigorously stirredat r.t. for 2 h. Upon completion, the reaction was quenched by addition of saturated aqueous Na2S2O3 (2 mL), saturated aqueous Na2CO3 (8 mL) and H2O (5 mL). The mixture was extracted with CH2Cl2(3 × 5 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated at room temperature under reduced pressure. The residue was then purified by preparative TLC (silica gel) [5:1 (v/v) petroleum ether/ethyl acetate] to furnish 1-oxaspiro[4,5]deca-6,9-diene-2,8-dione (2a) in 72% yield.
With mercury(II) diacetate; toluene-4-sulfonic acid; In tetrahydrofuran; at 20℃;Molecular sieve;
General procedure: Method was modified according to procedure previously described by Gao et al.1 The phenolic acid (10 mmol) was dissolved in dry tetrahydrofuran (10 mL) and activated molecular sieves 4A (1g) were placed to the flask. Dry vinyl acetate (15 mL) and mercuric acetate (0.07 g) were added. After stirring the reaction mixture for 30 min, p-toluenesulfonic acid was added (0.02g). The reaction mixture was then stirred at room temperature overnight. Reaction was terminated by addition of sodium acetate, filtered and solvents were removed by evaporation. The residue was chromatographed on silica gel (toluene/ethyl acetate, 5:1) and the product was eventually crystallised.
(From 7): Toan ice-cooled solution of 7 (0.196g, 1.00 mmol) in DMF (2 mL) and DCM (2 mL), HOBt (0.135 g, 1.00 mmol) and EDC(0.192, 1.00 mmol) were added. After stirring the reaction mixture for 30 min,1,4-diaminobutane (0.044g, 0.50 mmol) in DCM (2 mL) was added slowly. Theresulting mixture was stirred for 18 h at room temperature. The volatiles of reactionmixture were directly evaporated under reduced pressure to give a viscousliquid. Acetone was added to afford natural product 1 as colorless solid (0.066 g, 15% yield). (From 10b): To a solution of 10b(0.200 g, 0.266 mmol) in methanol (10 mL) was added KOH (0.075 g, 1.33 mmol in2 mL water) at room temperature. The reaction mixture was stirred at reflux for16h. The reaction mixture was acidified by adding 3M HCl and a conventionalextractive workup (ethyl acetate) afforded pure product 1 as colorless solid (0.078 g, 66% yield). (From 10a): Following the same procedure described above (from 7b)afforded the product 1 (0.063 g, 63%yield). mp 179-180 oC; 1H NMR (CD3OD) delta 6.77(d, J = 1.6, 1H), 6.69 (d, J = 8.0, 1 H), 6.63 (dd, J = 1.6, 8.0, 1H), 3.82 (s,3H), 3.07 (br s, 2H), 2.81 (t, J = 7.5, 2H), 3.42 (t, J = 7.50, 2 H), 1.28 (brs, 2H); 13 CNMR (CD3OD) 175.4, 148.9, 145.9, 133.6,121.9, 116.2, 113.2, 56.3, 39.9, 39.4, 32.6, 27.6; HRMS: for C24H32O6N2 calcd444.2261, found 445.2334(M+ H)+
N-(3-methoxy-4-hydroxydihydrocinnamoyl)-3-methylanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pDRf1-(4-coumaroyl:CoA ligase 5 from Arabidopsis thaliana)-(hydroxycinnamoyl/benzoyl-CoA:anthranilate N-hydroxycinnamoyl/benzoyltransferase 1 from Dianthus caryophyllus) recombinant yeast In dimethyl sulfoxide at 30℃; for 24h;
Production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates
General procedure: An overnight culture from a single colony of the pDRf1-4CL5-HCBT1 recombinant yeast grown on 2X YNB medium without amino acids, supplemented with 6% glucose and 2X CSM-Ura, was used to inoculated 4 mL of fresh minimal medium at an OD600 = 0.15 and shaken at 200 rpm at 30°C. All precursors were prepared in DMSO and added 5 hours post inoculation at the concentrations indicated in S1, S2 and S3 Tables. The anthranilate acceptors were added to the medium at a final concentration of 300 μM (for anthranilate, 3-hydroxyanthranilate, 3-methylanthranilate, and 5-nitroanthranilate) or 50 μM (for 3-chloroanthranilate, 5-methylanthranilate, 3-methoxyanthranilate, 5-fluoroanthranilate, 5-iodoanthranilate, and 5-chloroanthranilate). These concentrations were selected to limit toxicity and growth inhibition due to either the supplied precursors or the metabolites produced. The cultures were shaken at 200 rpm at 30°C for 24 h in the presence of the precursors for the production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates. Yeast colonies harboring the pDRf1-HCBT1 or pDRf1-4CL5 control vectors were grown under similar conditions. For the detection of metabolites, an aliquot of the culture medium was collected and cleared by centrifugation (21,000xg for 5 min at 4°C), mixed with an equal volume of cold methanol:water (1:1, v/v), and filtered using Amicon Ultra centrifugal filters (3,000 Da MW cutoff regenerated cellulose membrane; Millipore, Billerica, MA) prior to LC-TOF MS analysis. The separation and identification of the metabolites were performed using high-performance liquid chromatography (HPLC), electrospray ionization (ESI), and time-of-flight (TOF) mass spectrometry (MS) as previously described [35]. For each compound, the measured masses agreed with the expected theoretical masses within less than 5 ppm mass error. Standard solutions of DHavnD and dianthramide B were prepared in methanol:water (1:1, v/v). Values obtained for the production of DHavnD and dianthramide B are the average of four replicates (n = 4). ESI-MS spectra of other cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates were obtained from single feeding experiments for each combination of precursors.
propyl 3-(3-methoxy-4-propoxyphenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
N,N-dimethylformamide solution (5 ml) containing 4-hydroxy-3-methoxypheny propionic acid (500 mg, 2.54 mmol) was added with potassium carbonate (881 mg, 6.37 mmol) and 1-bromopropane (692 mul, 7.65 mmol) and stirred over night at room temperature. After completion of the reaction, the solution was diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate-4/1) and 590 mg of propyl 3-(3-methoxy-4-propoxyphenyl)propanoate was obtained in a yield of 82%.
(6-methyl)-2-naphthylmethyl 3-(3-methoxy-4-hydroxyphenyl)propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
1) Weigh 1.10 mmol of 3- (3-methoxy-4-hydroxyphenyl) -propionic acid,Dissolved in 2 mL of DMSO,After adding 1.1 mmol of Li2CO3 for 1 h at room temperature,4.4 mmol of cesium iodide and 2.2 mmol of 2- (chloromethyl) - (5-methyl) -naphthalene are successively added.The reaction mixture was stirred at 60 C for 10 h (TLC end of the reaction).2) After the reaction was cooled to room temperature,5mL saturated sodium chloride solution and ethyl acetate 8mL,Homogenize after mixing;The aqueous phase was extracted twice with ethyl acetate (3 mL × twice)The combined organic phase,Then washed with saturated copper sulfate solution (3 mL × 3 times),And saturated sodium chloride solution (2 mL × 2 times),Dried over anhydrous sodium sulfate,The solvent was removed by rotary evaporation (-0.08 MPa, 45 C) to give a solid crude product.3) The crude product was purified by column chromatography,Column chromatography (total volume of solid to crude product mass multiple:Gradient I is 15 times,Gradient II is 10 times,(5-methyl) -methyl 3- (3-methoxy-4-hydroxyphenyl) -propionate (PN4 201 mg, 52% yield) was obtained after 10 times gradient III. Structure identification data as follows:
General procedure: To a solution or suspension of the respective acid (0.315 mmol,1.05 eq) in 5 mL of dichloromethane, 2 muL of dimethylformamideand 28.4 muL of oxalylchloride (0.33 mmol, 1.1 eq) were added. Theresulting mixture was stirred at room temperature for 1 h and wasadded to a solution of 146mg of silibinin (0.3 mmol, 1 eq) and 192 muL of triethylamine (1.35 mmol, 4.5 eq) in 10 mL tetrahydrofuran.The reaction mixture was stirred at room temperature for2-16 h. The reaction was quenched with 30 mL of water andextracted with ethyl acetate (3 x 30 mL). The combined organicphases were washed with 10 mL of 1M HCl-solution and 20 mL ofbrine, dried over sodium sulfate and the solvent was removed in vacuo.
With 5-carboxyvanilate decarboxylase from Sphingmonas paucimobilis SYK-6 species, protein 1; In aq. phosphate buffer; dimethyl sulfoxide; at 30℃; for 24h;pH 8.5;Enzymatic reaction;
General procedure: lyophilized whole cells (1g) were resuspended in phosphate buffer (30mL, pH 5.5, 100mM) and were rehydrated for 30min. The substrate was added as 600muL stock solution (DMSO) to yield a final concentration of 50mM, followed by addition of KHCO3 (3M, 9g, final pH 8.5). The mixture was shaken at 30C and 200rpm. After 24h the reaction mixture was centrifuged (13,000rpm, 15min). The aqueous phase was acidified with 5M HCl and extracted with EtOAc. The organic phase were combined and subjected to silica gel column chromatography to yield the compound 2P as white solid
4-(2-hydroxyethoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-N-oxide[ No CAS ]
[ 1135-23-5 ]
C20H20N2O9S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34.45%
With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 24h;
Take a 25 mL dry single-mouth flask.Compound 36 (50 mg, 0.18 mmol) was dissolved in 4 mL anhydrous THF.Compound 31a (34.34 mg, 0.18 mmol) was added in sequence with stirring.DCC (36.11 mg, 0.18 mmol) and DMAP (42.76 mg, 0.35 mmol),After reacting for 24 hours at room temperature,The reaction system was cooled to 0 C,The precipitated white solid was removed by suction filtration.The obtained filtrate was concentrated by rotary evaporation to give a crude product.Purified by silica gel column (PE: EA=2.5:1)A yellow viscous liquid product (28 mg, 34.45%) was obtained.
With dmap; triethylamine; In dichloromethane; at 0 - 20℃;
Following literature procedure,2 molecule 6 (253 mg, 1.29 mmol, 1.0 equivalent) was dissolved in CH2Cl2 (7.5 mL, 0.17 M) in a 25.0 mL round-bottom flask with a magnetic stir bar at room temperature (RT). Triethylamine (0.36 mL, 2.57 mmol, 2.0 equivalents) and 4-dimethylaminopyridine (DMAP, 4.4 mg, 0.036 mmol, 0.028 equivalents) were then added, and the flask was cooled to 0 C in an ice bath. At this point, acetic anhydride (Ac2O, 0.243 mL, 2.57 mmol, 2.0 equivalents) was added dropwise. The reaction was then warmed to RT, stirred for 20 minutes, and diluted with CH2Cl2 (20 mL) and H2O (20 mL). The suspension was now mixed and transferred to a separatory funnel, where the layers were separated. The organic (CH2Cl2) layer was then washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by column chromatography (20% EtOAc/hexanes). This procedure yielded 240 mg (78%) of 7a as a white powder. Melting point was 92 - 93 C. Data are: TLC Rf = 0.44 (streak, 50% EtOAc/hexanes); 1H NMR (DMSO-d6, 300 MHz) delta 12.02 (bs, 1H), 6.97-6.90 (m, 2H), 6.76 (d, J=4.5 Hz, 1H), 3.76 (s, 3H), 2.79 (t, J=9Hz, 2H), 2.50 (t, J=9Hz, 2H), 2.20 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) delta 174.3, 169.2, 151.1, 140.4, 138.0, 123.0, 120.6, 113.4, 56.2, 35.8, 30.8, 20.9.
N-((2S,3R)-4-((4-amino-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-3-(4-hydroxy-3-methoxyphenyl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: 3-(4-hydroxy-3-methoxyphenyl)propionic acid; 4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzenesulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere;
Stage #2: With dmap In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere;
4.1.23. (E)-3-(3, 4-dihydroxyphenyl)-N-((2S, 3R)-3-hydroxy-4-((Nisobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)acrylamide (35a)
General procedure: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt,0.15 g, 1.1 mmol) were sequentially added in batches to a stirredsolution of (E)-3-(3, 4-dihydroxyphenyl)acrylic acid (29, 0.18 g,1.0 mmol) and N-((2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl)-Nisobutyl-4- methoxybenzenesulfonamide (21, 0.43 g, 1.05 mmol) in3 mL dry DMF at 0 °C under an argon atmosphere. The reactionmixturewas stirred for 10 min at 0 °C and additional 1 h at 25 °C. 4-Dimethylaminopyridine (DMAP, 0.024 g, 0.20 mmol) was addedand the reaction mixture was stirred for another 2 h at 25 °C. Thesolvent was removed under reduced pressure. Water (6 mL) wasadded to the residue and extracted with CH2Cl2 (3 6 mL). Thecombined organic layers were dried over Na2SO4. Removal of solventunder reduced pressure, followed by column chromatographyover silica gel column. Elution with 5% CH3OH in CH2Cl2 gavecompound 35a (0.40 g, 78%) as white amorphous solid:
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