* 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 N-benzyl-N,N-diethylethanaminium chloride; sodium hydroxide In dichloromethane; water at 0 - 20℃; Inert atmosphere
General procedure: General procedure for the synthesis of 3a–3t: Representative procedure for 3h: 50percent aqueous sodium hydroxide (0.42 mL, 5 equiv) was added dropwise to astirred mixture of o-phenylene diamine 1a (CAUTION: toxic) (200 mg, 1 equiv),4-(trichloromethyl)tetrahydro-2H-pyran-4-ol (812 mg, 2 equiv) and N-benzyl-N,N-diethylethanaminium chloride (42 mg, 0.1 equiv) in CH2Cl2 (0.1 M) cooledto 0 °C over a period of 10–20 s under nitrogen. The resulting mixture wasstirred at 0 °C and left to warm to room temperature with stirring over 18 h.The reaction was monitored by analytical HPLC–MS. When complete, thereaction mixture was diluted with water (10 mL) until any solid had dissolvedand the layers were separated. The aqueous layer was extracted with CH2Cl2(3 20 mL). The combined organic layers were dried (MgSO4), ltered andevaporated to afford the crude product which was puried by ash silicachromatography, elution gradient 0–50percent EtOAc in heptane. The resulting solidwas ltered through a Buchner funnel, rinsed with MTBE (2 10 mL), andcollected to afford 10,2,3,40,5,6-hexahydro-30H-spiro[pyran-4,20-quinoxalin]-30-one (310 mg, 77percent) as a pale yellow powder.
Reference:
[1] Roczniki Farm., vol. 2, p. 99[2] Chem. Zentralbl., 1924, vol. 95, # II, p. 304
6
[ 67-66-3 ]
[ 67-64-1 ]
[ 57-15-8 ]
Reference:
[1] Chemische Berichte, 1882, vol. 15, p. 2312[2] Chemische Berichte, 1887, vol. 20, p. 2448
7
[ 67-66-3 ]
[ 67-64-1 ]
[ 57-15-8 ]
Reference:
[1] Chemische Berichte, 1882, vol. 15, p. 2312[2] Chemische Berichte, 1887, vol. 20, p. 2448
8
[ 930-68-7 ]
[ 94-36-0 ]
[ 59992-07-3 ]
[ 57-15-8 ]
Reference:
[1] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 6, p. 1423 - 1429
9
[ 7664-41-7 ]
[ 594-65-0 ]
[ 57-15-8 ]
Reference:
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1912, vol. 155, p. 1252[2] Bulletin de la Societe Chimique de France, 1914, vol. <4>15, p. 730
10
[ 512-47-0 ]
[ 7664-93-9 ]
[ 75-87-6 ]
[ 57-15-8 ]
Reference:
[1] Patent: DE151188, , ,
11
[ 67-56-1 ]
[ 57-15-8 ]
[ 13836-62-9 ]
Yield
Reaction Conditions
Operation in experiment
48%
Stage #1: With potassium hydroxide In water at 0℃; for 5.15 h; Stage #2: With hydrogenchloride In water
The procedure of Weizmann, Sulzbacher, and Bergmann as written in JA CS 70,1153 (1948), which is hereby incorporated by reference, was used as follows: A solution of potassium hydroxide (8.96 g, 159.7 mmol) in 5 mL of water and 20 mL of methanol was stirred with ice bath cooling under nitrogen as l,l,l-trichloro-2- methylpropan-2-ol (7.10 g, 40.0 mmol) was carefully added dropwise over ten min. Vigorous bubbling was observed as a white precipitate formed. The ice bath was removed after 15 min. The reaction was stirred at room temperature for 2 h then refluxed for 3 h. The reaction was cooled to room temperature and the solids were then removed by filtration and rinsed with methanol (350 mL). The filtrate was concentrated under vacuum EPO <DP n="44"/>to remove methanol and the remaining aqueous layer was brought to pH 0 by the addition of aqueous HCl then extracted with ethyl acetate (300 mL). The extract was dried (Na2SO4) and concentrated in vacuo to yield 4.11 g of crude product, which was purified by vacuum distillation to yield 2.28 g (48percent) of the pure title compound as a colorless oil which was distilled at 105 0C (28 mm Hg). 1HNMR (CDCl3) δ 9.65 (s, IH), 3.20 (s, 3H) and 1.32 ppm (s, 3H).
48%
at 0 - 20℃; for 5.25 h; Heating / reflux
Intermediate N : Preparation of 7V-[4-(chloromethyl)pyridin-2-yl]-2-methoxy-2-methylpropanamide; Step 1 : Preparation of 2-methoxy-2-methylpropanoic acid; The procedure of Weizmann, Sulzbacher, and Bergmann as written in JACS 70,1153 (1948), which is hereby incorporated by reference, was used as follows: A solution of potassium hydroxide (8.96 g, 159.7 mmol) in 5 mL of water and 20 mL of methanol was stirred with ice bath cooling under nitrogen as l,l,l-trichloro-2-methylpropan-2-ol (7.10 g, 40.0 mmol) was carefully added dropwise over ten min. Vigorous bubbling was observed as a white precipitate formed. The ice bath was removed after 15 min. The reaction was stirred at room temperature for 2 h then refluxed for 3 h. The reaction was cooled to room temperature and the solids were then removed by filtration and rinsed with methanol (350 mL). The filtrate was concentrated under vacuum to remove methanol and the remaining aqueous layer was brought to pH 0 by the addition of aqueous HC1 then extracted with ethyl acetate (300 mL). The extract was dried (NaaSC^) and concentrated in vacuo to yield 4.1 1 g of crude product, which was purified by vacuum distillation to yield 2.28 g (48percent) of the pure title compound as a colorless oil which was distilled at 105 °C (28 mm Hg). 1HNMR (CDC13) 8 9.65 (s, 1H), 3.20 (s, 3H) and 1.32 ppm (s, 3H).
48%
With potassium hydroxide In water at 20℃; for 5 h; Heating / reflux
Preparation of 2-methoxy-2-methylpiOpanoic acid The procedure of Weizmann, Sulzbacher, and Bergmann as written in JACS 70,1153 (1948), which is hereby incorporated by reference, was used as follows: A solution of potassium hydroxide (8.96 g, 159.7 mmol) in 5 mL of water and 20 niL of methanol was stirred with ice bath cooling under nitrogen as 1,1 , l-trichloro-2- methylpropan-2-ol (7.10 g, 40.0 mmol) was carefully added dropwise over ten min. Vigorous bubbling was observed as a white precipitate formed. The ice bath was removed after 15 min. The reaction was stirred at room temperature for 2 h then refluxed for 3 h. The reaction was cooled to room temperature and the solids were then removed by filtration and rinsed with methanol (350 mL). The filtrate was concentrated under vacuum to remove methanol and the remaining aqueous layer was brought to pH 0 by the addition of aqueous HCl then extracted with ethyl acetate (300 mL). The extract was dried (Na2SO4) and concentrated in vacuo to yield 4.11 g of crude product, which was purified by vacuum distillation to yield 2.28 g (48percent) of the pure title compound as a colorless oil which was distilled at 105 C (28 mm Hg). 1HNMR (CDCl3) ? 9.65 (s, IH), 3.20 (s, 3H) and 1.32 ppm (s, 6H).
Reference:
[1] Patent: WO2006/96338, 2006, A1, . Location in patent: Page/Page column 42-43
[2] Patent: WO2006/2383, 2006, A2, . Location in patent: Page/Page column 50-51
[3] Patent: WO2006/133006, 2006, A2, . Location in patent: Page/Page column 47-48
[4] European Journal of Organic Chemistry, 2007, # 21, p. 3449 - 3462
[5] Journal of the American Chemical Society, 1948, vol. 70, p. 1157
[6] Patent: GB578082, 1943, ,
[7] Journal of the Chemical Society [Section] C: Organic, 1966, p. 2166 - 2176
12
[ 17356-08-0 ]
[ 57-15-8 ]
[ 13836-62-9 ]
[ 4695-19-6 ]
Reference:
[1] Canadian Journal of Chemistry, 1980, vol. 58, p. 2784 - 2788
13
[ 67-56-1 ]
[ 57-15-8 ]
[ 13836-62-9 ]
[ 4695-19-6 ]
Reference:
[1] Canadian Journal of Chemistry, 1980, vol. 58, p. 2784 - 2788
14
[ 124-41-4 ]
[ 57-15-8 ]
[ 13836-62-9 ]
Reference:
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 1157
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 2669
[3] Journal of the American Chemical Society, 1948, vol. 70, p. 1157
[4] Patent: GB578082, 1943, ,
15
[ 106-48-9 ]
[ 57-15-8 ]
[ 882-09-7 ]
Reference:
[1] Canadian Journal of Chemistry, 1989, vol. 67, p. 1472 - 1479
16
[ 57-15-8 ]
[ 108-95-2 ]
[ 943-45-3 ]
Yield
Reaction Conditions
Operation in experiment
38%
With sodium hydroxide In acetone at 0 - 20℃; for 4 h;
[0270] Step 1: 2-Methyl-2-phenoxypropionic acid 6 was prepared following the procedure of Corey et al., J. Am. Chem. Soc. 1969;91 :4782. To an ice-cold, stirred suspension of powdered NaOH (3.2 g, 80 mmol) in acetone (40 mL) was added phenol (1.88 g, 20 mmol) followed by 1, 1, 1-trichloro-2-methyl-2-propanol hydrate (7.82 g, 40 mmol). The mixture was stirred at 0° C. for 2 hours and then at room temperature for 2 hours. The mixture was diluted with H2O, acidified with 2N HCl, and extracted with EtOAc. The organic layer was washed with 2 N HCl, then extracted with saturated NaHCO3 (2.x.). The aqueous extracts were combined, washed once with EtOAc, acidified with 2N HCl, then extracted with EtOAc (2.x.). The combined organic layers were washed once with saturated NaCl, dried (MgSO4), and concentrated under reduced pressure. Purification by flash chromatography gave 6 (1.36 g, 38percent): 1H NMR (300 MHz, CDCl3) δ 7.28 (t, J=8 Hz, 2H), 7.08 (t, J=8 Hz, 1H), 6.96 (d, J=8 Hz, 2H), 1.52 (s, 6H).
With N-benzyl-N,N-diethylethanaminium chloride; sodium hydroxide; In dichloromethane; water; at 0 - 20℃;Inert atmosphere;
General procedure: General procedure for the synthesis of 3a-3t: Representative procedure for 3h: 50% aqueous sodium hydroxide (0.42 mL, 5 equiv) was added dropwise to astirred mixture of o-phenylene diamine 1a (CAUTION: toxic) (200 mg, 1 equiv),4-(trichloromethyl)tetrahydro-2H-pyran-4-ol (812 mg, 2 equiv) and N-benzyl-N,N-diethylethanaminium chloride (42 mg, 0.1 equiv) in CH2Cl2 (0.1 M) cooledto 0 C over a period of 10-20 s under nitrogen. The resulting mixture wasstirred at 0 C and left to warm to room temperature with stirring over 18 h.The reaction was monitored by analytical HPLC-MS. When complete, thereaction mixture was diluted with water (10 mL) until any solid had dissolvedand the layers were separated. The aqueous layer was extracted with CH2Cl2(3 20 mL). The combined organic layers were dried (MgSO4), ltered andevaporated to afford the crude product which was puried by ash silicachromatography, elution gradient 0-50% EtOAc in heptane. The resulting solidwas ltered through a Buchner funnel, rinsed with MTBE (2 10 mL), andcollected to afford 10,2,3,40,5,6-hexahydro-30H-spiro[pyran-4,20-quinoxalin]-30-one (310 mg, 77%) as a pale yellow powder.
With sodium hydroxide In acetone for 16h; Ambient temperature;
Stage #1: 4-bromo-phenol; 1,1,1-trichloro-2-methyl-2-propanol With sodium hydroxide In acetone at 20℃;
Stage #2: With hydrogenchloride In water
3
Example 3: Synthesis of 2-{ [4'-(2-{ [5-chloro-2-(4,4,4- trifluorobutoxy)benzoyl] amino } ethyl)-biphenyl-4-yl] oxy } -2-methylpropanoic acid(Compound 21); 4-Bromophenol (10 g, 57.8 mmol, 1 eq.) and l,l,l-trichloro-2-methyl-2-propanol hemihydrate (20.5 g, 115.6 mmol, 2 eq.) in 200 mL acetone is treated with solid NaOH (18.5 g, 462.4 mmol, 8 eq.) and the reaction mixture is stirred at ambient temperature overnight. The solvent is removed under reduced pressure and the resulting residue is dissolved in 10 mL water. The resulting solution is acidified with 3 N HCl and extracted with ether. The extracts are washed twice with brine and dried over anhydrous MgSO4. The filtered solvent is removed under reduced pressure to give 2.5 g crude product.
With sodium hydroxide; In acetone; at 0 - 20℃; for 4h;
[0270] Step 1: 2-Methyl-2-phenoxypropionic acid 6 was prepared following the procedure of Corey et al., J. Am. Chem. Soc. 1969;91 :4782. To an ice-cold, stirred suspension of powdered NaOH (3.2 g, 80 mmol) in acetone (40 mL) was added phenol (1.88 g, 20 mmol) followed by 1, 1, 1-trichloro-2-methyl-2-propanol hydrate (7.82 g, 40 mmol). The mixture was stirred at 0 C. for 2 hours and then at room temperature for 2 hours. The mixture was diluted with H2O, acidified with 2N HCl, and extracted with EtOAc. The organic layer was washed with 2 N HCl, then extracted with saturated NaHCO3 (2×). The aqueous extracts were combined, washed once with EtOAc, acidified with 2N HCl, then extracted with EtOAc (2×). The combined organic layers were washed once with saturated NaCl, dried (MgSO4), and concentrated under reduced pressure. Purification by flash chromatography gave 6 (1.36 g, 38%): 1H NMR (300 MHz, CDCl3) delta 7.28 (t, J=8 Hz, 2H), 7.08 (t, J=8 Hz, 1H), 6.96 (d, J=8 Hz, 2H), 1.52 (s, 6H).
Stage #1: 2,3-Dimethylphenol; 1,1,1-trichloro-2-methyl-2-propanol With sodium hydroxide In acetone at 0 - 20℃; for 49h;
Stage #2: With hydrogenchloride; water In acetone
25.A
Example 25A 2-(2,3-Dimethylphenoxy>2-methyl-propionic acid; To an ice cold solution of 2,3-dimethylphenol (136 mg, 1.0 mmol) and 1,1,1- trichloro-2-methyl-2-propanol hydrate (492 mg, 2.75 mmol) in acetone (2 mL) was added powdered sodium hydroxide (393 mg, 9.83 mmol) in three equal portions at 1 hour interval.After each addition reaction mixture was allowed to come to room temperature. Before last addition of sodium hydroxide, acetone (2 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 48 hours and concentrated in vacuo.The residue was diluted with water and acidified to pH 1 with aqueous HCl and extracted with diethyl ether (3x5 mL). The organic layers were pooled, dried (Na2SO4) and filtered.The filtrate was concentrated under reduced pressure to provide the crude that was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (40mm X 100mm,7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over12min (15min run time) at a flow rate of 70mL/min. to provide the title compound as a pale yellow solid (158 mg, 76%).
4-Amino-2-fluoro-benzoic acid (0.2 g, 1.29 mmol) and l,l,l-trichloro-2-methyl- propan-2-ol (0.593 g, 3.35 mmol) were dissolved in anhydrous acetone and the solution was cooled at 0 C. Powdered sodium hydroxide (0.2 g, 5.01 mmol) was added portion-wise after which the reaction mixture was warmed to and stirred at room temperature for 12 h.Volatiles were removed under reduced pressure and the residue was acidified with 1M aqueous HC1. The crude product obtained was purified by reverse phase HPLC to obtain 4- ( 1 -carboxy- 1 -methyl-ethylamino)-2-fluoro-benzoic acid.
ethyl N-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-methylalaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12 g
1,1,1 -Trichloro-2-methylpropan-2-ol (100 g, Formula III) was added todichloromethane (120 mL) and the reaction mixture was cooled to 0C to 5C. Sodium hydroxide (50 g) was added to the reaction mixture and the mixture was stirred for 30 minutes. N-Methyl 2-flouro-4-amino benzamide (10 g) and ethanol (30 mL) were added to the reaction mixture at 0C to 5C over 1 minute. The reaction mixture was stirred at 0C to 5C for 60 minutes. The reaction mixture was heated at 20C to 25C for 2 hoursto 3 hours. Water (100 mL) and dichloromethane (100 mL) were added to the reaction mixture and the mixture was stirred for 15 minutes. The layers obtained were separated, and then the organic layer was concentrated at 45C to 50C over 1 hour to 2 hours to obtain the title compound.Yield: 12g.
7-tert-butyl-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
6-tert-butyl-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-benzyl-N,N-diethylethanaminium chloride; sodium hydroxide; In dichloromethane; water; at 0 - 20℃;Inert atmosphere;
General procedure: General procedure for the synthesis of 3a?3t: Representative procedure for 3h: 50percent aqueous sodium hydroxide (0.42 mL, 5 equiv) was added dropwise to astirred mixture of o-phenylene diamine 1a (CAUTION: toxic) (200 mg, 1 equiv),4-(trichloromethyl)tetrahydro-2H-pyran-4-ol (812 mg, 2 equiv) and N-benzyl-N,N-diethylethanaminium chloride (42 mg, 0.1 equiv) in CH2Cl2 (0.1 M) cooledto 0 °C over a period of 10?20 s under nitrogen. The resulting mixture wasstirred at 0 °C and left to warm to room temperature with stirring over 18 h.The reaction was monitored by analytical HPLC?MS. When complete, thereaction mixture was diluted with water (10 mL) until any solid had dissolvedand the layers were separated. The aqueous layer was extracted with CH2Cl2(3 20 mL). The combined organic layers were dried (MgSO4), ltered andevaporated to afford the crude product which was puried by ash silicachromatography, elution gradient 0?50percent EtOAc in heptane. The resulting solidwas ltered through a Buchner funnel, rinsed with MTBE (2 10 mL), andcollected to afford 10,2,3,40,5,6-hexahydro-30H-spiro[pyran-4,20-quinoxalin]-30-one (310 mg, 77percent) as a pale yellow powder.
6-bromo-2,2-dimethyl-1,2-dihydropyrido[3,2-b]pyrazin-3(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With N-benzyl-N,N-diethylethanaminium chloride; sodium hydroxide; In dichloromethane; water; at 0 - 20℃;Inert atmosphere;
General procedure: General procedure for the synthesis of 3a-3t: Representative procedure for 3h: 50% aqueous sodium hydroxide (0.42 mL, 5 equiv) was added dropwise to astirred mixture of o-phenylene diamine 1a (CAUTION: toxic) (200 mg, 1 equiv),4-(trichloromethyl)tetrahydro-2H-pyran-4-ol (812 mg, 2 equiv) and N-benzyl-N,N-diethylethanaminium chloride (42 mg, 0.1 equiv) in CH2Cl2 (0.1 M) cooledto 0 C over a period of 10-20 s under nitrogen. The resulting mixture wasstirred at 0 C and left to warm to room temperature with stirring over 18 h.The reaction was monitored by analytical HPLC-MS. When complete, thereaction mixture was diluted with water (10 mL) until any solid had dissolvedand the layers were separated. The aqueous layer was extracted with CH2Cl2(3 20 mL). The combined organic layers were dried (MgSO4), ltered andevaporated to afford the crude product which was puried by ash silicachromatography, elution gradient 0-50% EtOAc in heptane. The resulting solidwas ltered through a Buchner funnel, rinsed with MTBE (2 10 mL), andcollected to afford 10,2,3,40,5,6-hexahydro-30H-spiro[pyran-4,20-quinoxalin]-30-one (310 mg, 77%) as a pale yellow powder.
Stage #1: (2E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-[4-(methylsulfanyl)phenyl]prop-2-en-1-one; 1,1,1-trichloro-2-methyl-2-propanol In acetone at 0 - 5℃; for 0.5h;
Stage #2: With sodium hydroxide In acetone at 20 - 25℃;
3; 4; 5 Example 4: Preparation of 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3- oxoprop-l-en-l-yl}phenoxy)-2-methylpropanoic acid (Elafibranor, I)
l,l,l-trichloro-2-methylpropan-2-ol (8.8g, 0.05mol) was added to a suspension of compound IV (10. Og, 0.033mol) in acetone (lOOml). The reaction mixture was stirred at about 0°C to about 5°C for about 30min and pulverized sodium hydroxide (6.6g, 0. l65mol) was added in lots over the course of about 3h. The reaction mixture was stirred overnight at about 20°C to about 25°C. After completion of the reaction, acetone was removed under vacuum to afford a residue which was dissolved in water; acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was separated and concentrated under vacuum to yield crude oil. The crude oil was dissolved in ethyl acetate, benzyl amine (3.94 g, 0.036mmol) was added to it, refluxed for about lh and stirred overnight. The solid obtained was filtered, washed with ethyl acetate and dried in air oven. The dry solid was added in water, basified using aq sodium hydroxide under stirring. The reaction mass was washed with dichloromethane, distilled to remove traces of dichloromethane and acidified using dil. Hydrochloric acid under stirring. The solid was filtered, washed with water and dried in an air oven to obtain 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3-oxoprop-l- en-l-yl}phenoxy)-2-methylpropanoic acid (elafibranor, I) as a pale yellow solid (7.6 g, 59% yield; purity >99.5%; Z-isomer less than 2% w/w) 1H NMR CDCh d ppm: 1.55 (s, 6H), 2.29 (s, 6H), 2.55 (s, 3H), 7.31 (d, J = 8.55Hz, 2H), 7.44 (s, 2H), 7.73 (d); , J = 15.5Hz, 1H), 7.97 (d, J = 8.55Hz, 2H), 12.97 (s, 1H).