* 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 tert.-butyl lithium In tetrahydrofuran; pentane at -78℃; for 2.5 h;
Step A: 1-Fluoro-3-methyl-benzene (compound 1g; 18.7 g, 170 mmol) was added to a three neck 500 mL flask and cooled to -78 C. Next, solution of potassium t-butoxide (11.0 g, 170 mmol) in THF was added slowly by syringe. After 10 minutes, t-BuLi (19.0 g, 170 mmol) in pentane was added slowly by cannula under nitrogen to the reaction. After 2.5 hours of stirring, the reaction was quenched with large amount of crushed fresh dry ice, taken off the -78 C. bath and manually stirred with a metal spatula to turn the dark brown material into a much lighter yellow slurry. After 20 minutes of mixing by hand, about 500 mL of water were added and reaction mixture was stirred. The reaction mixture was then washed With Et2O and then acidified with 6 N HCl to pH less than 3 and extracted with Et2O. The organic was washed with brine, dried over MgSO4 filtered and concentrated to yield 10 gm (45percent yield) of compound 2g. 1H NMR (400 MHz, CDCl3) d 7.90 (t, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 2.39 (s, 3H).
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 8124 - 8134
[3] Patent: WO2014/144380, 2014, A1, . Location in patent: Paragraph 0541
3
[ 5326-34-1 ]
[ 7697-23-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
4
[ 53078-85-6 ]
[ 7697-23-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
5
[ 612-45-3 ]
[ 7697-23-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
6
[ 696-01-5 ]
[ 7697-23-6 ]
Reference：
[1] Journal of Organic Chemistry, 1967, vol. 32, p. 134 - 136
7
[ 124-38-9 ]
[ 352-70-5 ]
[ 7697-23-6 ]
Reference：
[1] Chemistry - A European Journal, 1998, vol. 4, # 10, p. 1969 - 1973
8
[ 95-78-3 ]
[ 7697-23-6 ]
Reference：
[1] Journal of Organic Chemistry, 1967, vol. 32, p. 134 - 136
9
[ 67-56-1 ]
[ 7697-23-6 ]
[ 74733-29-2 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 20℃; for 18 h;
Method G; Example G-1; 2-Fluoro-4-r3-oxo-4-(2-tπfluoroιinethyl-benzyl)-3,4-clihvdro-2H-benzori ,41thiazin-2- ylmethyli-benzoic acid; Preparation of G-1 -a; 2-Fluoro-4-methyl-benzoic acid methyl ester; To a mixture of 2-fluoro-4-methylbenzoic acid (2.5g, 16mmol) in methyl alcohol (30ml_),thionyl chloride (1.36ml_, 18.9mmol) was added and the mixture was stirred at room temperature for 18h. The solvent was evaporated to provide the title compound (2.6g, 98percent yield). 1H NMR (400 MHz, METHANOL-^) δ ppm 7.79 (t, J=7.83 Hz, 1 H), 7.07 (d, J=8.08 Hz, 1 H), 7.02 (d, J=12.38 Hz, 1 H), 3.88 (s, 3 H), 2.39 (s, 3 H)
90%
Reflux
Method A: To a stirred mixture of 2-fluoro-4-methylbenzoic acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) in acetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After the reaction mixture was heated to reflux overnight, the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (1.73 g, 79percent), mp 51–53°C. 1H NMR (CDCl3): δ 7.83 (t, J=8.0Hz, 1H), 7.00 (dd, J=8.0, 1.0Hz, 1H), 6.95 (d, J=12.0Hz, 1H), 3.91 (s, 3H), 2.39 (s, 3H). Method B: To a stirred solution of 2-fluoro-4-methylbenzoic acid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuric acid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (6.88 g, 90percent). Analytical data were same as above.
90%
Reflux
(f) Methyl 2-fluoro-4-methylbenzoate (5): Method A: To a stirred mixture of 2-fluoro-4-methylbenzoic acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) inacetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After thereaction mixture was heated to reflux overnight, the solvent was removed invacuo. The residual was diluted with EtOAc, washed with water and brine,dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography with hexanes/EtOAc (6:1) toafford 5 as a white solid (1.73 g, 79percent), mp 51–53 C. 1H NMR (CDCl3): d 7.83 (t,J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.0 Hz, 1H), 6.95 (d, J = 12.0 Hz, 1H), 3.91 (s,3H), 2.39 (s, 3H). Method B: To a stirred solution of 2-fluoro-4-methylbenzoicacid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuricacid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; thesolvent was removed in vacuo. The residual was diluted with EtOAc, washedwith saturated NaHCO3 aqueous solution and brine, dried over anhydrousNa2SO4, filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid(6.88 g, 90percent). Analytical data were same as above.
77%
Stage #1: With thionyl chloride In toluene for 2.5 h; Heating / reflux Stage #2: at 20℃; for 2.5 h;
To a solution of 2-fluoro-4-methylbenzoic acid (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (65 ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50ml) and methanol (50 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentratedin vacuo to give a tan solid identified as methyl 2-fluoro-4-methylbenzoate (5.07 g, 77percent).
77%
Stage #1: With thionyl chloride In toluene for 2.5 h; Heating / reflux Stage #2: at 20℃; for 2.5 h;
To a solution of 2-fluoro-4-methylbenzoic acid from Example D1 (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (6.5 ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and methanol (50 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a tan solid; yield 5.07 g (77percent).
75%
for 24 h; Reflux
INTERMEDIATE 28 - PREPARATION OF Methyl 2-fluoro-4-methylbenzoate. Sulfuric acid (2 ml_) was added to the solution of 2-fluoro-4-methylbenzoic acid (0.848 g; 5.34 mmol) in methanol (30 ml_). The mixture was refluxed for 24 hours. After cooling, the solution was made alkaline by addition of an aqueous solution of sodium carbonate, concentrated under reduced pressure in order to remove methanol, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure to give 0.672 g (75percent) of methyl 2-fluoro-4-methylbenzoate as a solid.ESI/APCI(+) : 169 (M+H).
75%
for 24 h; Reflux
Sulfuric acid (2 mL) was added to the solution of 2-fluoro-4-methylbenzoic acid (0.848 g; 5.34 mmol) in methanol (30 mL). The mixture was refluxed for 24 hours. After cooling, the solution was made alkaline by addition of an aqueous solution of sodium carbonate, concentrated under reduced pressure in order to remove methanol, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure to give 0.672 g (75percent) of methyl 2-fluoro-4-methylbenzoate as a solid. [0609] ESI/APCI(+): 169 (M+H).
10.01 g
at 90℃;
In a 500 ml one-neck round bottom flask, equipped with a magnetic stir-bar and condenser was added 2-fluoro-4-methyl-benzoic acid (10.0 g, 64.88 mn1ol), 250 ml of methanol and 5 ml of sulfuric acid. The reaction was heated at 90°C overnight. The methanol was evaporated and residue was purified on 125g Filter Silica ISCO column using a hexane/ethyl acetate gradient to give 10.Olg of IXS-4-52-1. Overall yield is 91.75percent. ‘H NMR (CDcI3, 400 MHz) ö 7.80 (t, 1H), 6.95 (2d, 2K), 3.89 (s, 3H), 2.37 (s, 3H).
Reference：
[1] Patent: WO2010/116270, 2010, A1, . Location in patent: Page/Page column 55
[2] Organic Process Research and Development, 2011, vol. 15, # 3, p. 565 - 569
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1742 - 1747
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 24, # 7, p. 1742 - 1747
[5] Patent: EP1449844, 2004, A1, . Location in patent: Page 22
[6] Patent: US6664249, 2003, B1, . Location in patent: Page column 12
[7] Patent: WO2012/80221, 2012, A1, . Location in patent: Page/Page column 81
[8] Patent: US2013/274260, 2013, A1, . Location in patent: Paragraph 0608-0609
[9] Patent: WO2005/97762, 2005, A2, . Location in patent: Page/Page column 55
[10] Patent: US2008/318951, 2008, A1, . Location in patent: Page/Page column 47
[11] Patent: EP2305641, 2011, A1, . Location in patent: Page/Page column 16
[12] Patent: WO2014/144380, 2014, A1, . Location in patent: Paragraph 0542
[13] Journal of Medicinal Chemistry, 2017, vol. 60, # 18, p. 7703 - 7724
10
[ 74-88-4 ]
[ 7697-23-6 ]
[ 74733-29-2 ]
Yield
Reaction Conditions
Operation in experiment
79%
Reflux
Method A: To a stirred mixture of 2-fluoro-4-methylbenzoic acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) in acetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After the reaction mixture was heated to reflux overnight, the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (1.73 g, 79percent), mp 51–53°C. 1H NMR (CDCl3): δ 7.83 (t, J=8.0Hz, 1H), 7.00 (dd, J=8.0, 1.0Hz, 1H), 6.95 (d, J=12.0Hz, 1H), 3.91 (s, 3H), 2.39 (s, 3H). Method B: To a stirred solution of 2-fluoro-4-methylbenzoic acid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuric acid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (6.88 g, 90percent). Analytical data were same as above.
79%
With potassium carbonate In acetonitrileReflux
(f) Methyl 2-fluoro-4-methylbenzoate (5): Method A: To a stirred mixture of 2-fluoro-4-methylbenzoic acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) inacetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After thereaction mixture was heated to reflux overnight, the solvent was removed invacuo. The residual was diluted with EtOAc, washed with water and brine,dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography with hexanes/EtOAc (6:1) toafford 5 as a white solid (1.73 g, 79percent), mp 51–53 C. 1H NMR (CDCl3): d 7.83 (t,J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.0 Hz, 1H), 6.95 (d, J = 12.0 Hz, 1H), 3.91 (s,3H), 2.39 (s, 3H). Method B: To a stirred solution of 2-fluoro-4-methylbenzoicacid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuricacid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; thesolvent was removed in vacuo. The residual was diluted with EtOAc, washedwith saturated NaHCO3 aqueous solution and brine, dried over anhydrousNa2SO4, filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid(6.88 g, 90percent). Analytical data were same as above.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1742 - 1747
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 24, # 7, p. 1742 - 1747
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 17, p. 4804 - 4807
11
[ 7697-23-6 ]
[ 74733-29-2 ]
Yield
Reaction Conditions
Operation in experiment
77%
With thionyl chloride In methanol; dichloromethane; toluene
E2. Methyl 2-fluoro-4-methylbenzoate To a solution of 2-fluoro-4-methylbenzoic acid from Example E1 (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (65 ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and methanol (50 ml) was added. The mbture was stirred at room temperature for 2.5 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a tan solid; yield 5.07 g (77percent).
Reference：
[1] Patent: US2004/38962, 2004, A1,
12
[ 7697-23-6 ]
[ 85070-58-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1742 - 1747
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1742 - 1747
[3] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 24, # 7, p. 1742 - 1747
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 24, # 7, p. 1742 - 1747
[5] Patent: WO2011/28685, 2011, A1,
Step 2 2-fluoro-4-methylbenzoic Acid Compound of Step 1 (14 g, 105 mmol, 1 eq) was dissolved in 2-(2-ethoxyethoxy) ethanol (105 mL) and KOH (105 ml of a 8 M solution, 840 mmol, 8 eq) was added, the mixture was refluxed under nitrogen for 3 hours. The mixture was cooled and the pH set to 3. The product was extracted with EtOAc and the organic layer was washed 3 times with water and dried with sodium sulfate. The crude mixture was purified on silica using a 0-3% acetic acid/toluene gradient. 3.1 g of the desired compound (19%) was obtained. 1H NMR (400 MHz, CDCl3) delta 2.40 (3H, s), 7.00 (2H, m), 7.90 (1H, t).
Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 2-fluoro-4-iodobenzoic acid; 2-fluoro-5-iodobenzoic acid; 2-fluoro-6-iodobenzoic acid; 4-fluoro-2-iodobenzoic acid; 2-fluoro-4-methylbenzoic acid; 4-fluoro-2-methylbenzoic acid; 2-fluoro-6-nitrobenzoic acid; 3-fluoro-4-nitrobenzoic acid; ...
17
[ 352-70-5 ]
[ 865-47-4 ]
[ 7697-23-6 ]
Yield
Reaction Conditions
Operation in experiment
45%
With tert.-butyl lithium; In tetrahydrofuran; pentane; at -78℃; for 2.5h;
Step A: 1-Fluoro-3-methyl-benzene (compound 1g; 18.7 g, 170 mmol) was added to a three neck 500 mL flask and cooled to -78 C. Next, solution of potassium t-butoxide (11.0 g, 170 mmol) in THF was added slowly by syringe. After 10 minutes, t-BuLi (19.0 g, 170 mmol) in pentane was added slowly by cannula under nitrogen to the reaction. After 2.5 hours of stirring, the reaction was quenched with large amount of crushed fresh dry ice, taken off the -78 C. bath and manually stirred with a metal spatula to turn the dark brown material into a much lighter yellow slurry. After 20 minutes of mixing by hand, about 500 mL of water were added and reaction mixture was stirred. The reaction mixture was then washed With Et2O and then acidified with 6 N HCl to pH less than 3 and extracted with Et2O. The organic was washed with brine, dried over MgSO4 filtered and concentrated to yield 10 gm (45% yield) of compound 2g. 1H NMR (400 MHz, CDCl3) d 7.90 (t, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 2.39 (s, 3H).
In a 250 mL round-bottomed flask was dissolved <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong>acid (4 g, 26.0 mmol) in concentrated sulfuric acid (40 mL) at 0C (completelydissolved). A mixture of 12 N H2504 (1.69 mL, 31.1 mmol) and 70% nitric acid(2.485 mL, 38.9 mmol) was added dropwise. After stirring for 3 h at 0 C, an excessof ice water was added. The resulting solid was collected by vacuum filtration anddried to obtain the desired product (5.20 g, 100%) as a white solid. LCMS (ESI) m/e 200.4 [(M+H), calcd C8H7FNO4, 200.041; LC/MS retention time (method A): tR =0.72 mm.
88%
With sulfuric acid; nitric acid; at 0℃; for 1h;
2-Fluoro-4-methyl-benzoic acid (2.0g, 13mmol) was dissolved in 12N sulfuric acid solution (40ml). A mixture of 12N sulfuric acid solution (15.6mmol) and nitric acid solution (19.5mmol) was added dropwise thereto at 0. After stirring for 1 hour at 0, an excess of ice water was added. The resulting solid was filtered and dried to obtain the title compound (2.3g, 88%).
80%
With sulfuric acid; nitric acid; In water; at 0℃; for 3h;
Step B: Compound 2g (8.0 g, 52 mmol) was added to a 500 mL flask and cooled to salt water ice bath temp. H2SO4 (150 mL) was added and the mixture stirred. Next, a mixture of freshly prepared H2SO4 (6.11 g, 62.3 mmol) and HNO3 (5.2 g, 83 mmol) was dripped into the reaction mixture over 10 minutes. After 3 hours at 0 C., the reaction was complete and was added to 1500 ml of ice/ice water and stirred for 1 hour. The reaction was filtered and rinsed several times with cold water and dried under high vacuum, yielding 8 g (80% yield) of compound 3g. 1H NMR (400 MHz, CDCl3) d 8.74 (d, 1H), 7.20 (d, 1H), 2.69 (s, 3H).
With sulfuric acid; nitric acid; at 0℃; for 3h;
Step 1 : 2-Fluoro-4-methyl-5-nitrobenzoic acid<strong>[7697-23-6]2-Fluoro-4-methylbenzoic acid</strong> (1 g, 6.49 mmol) in H2S04 (19 ml, 356 mmol) was cooled to 0 C in an ice salt water bath and treated dropwise with mixture of H2S04 (0.763 ml, 14.31 mmol) and nitric acid (0.65 ml, 14.54 mmol) over 10 min. The reaction mixture was stirred at 0 C for 3 hrs and poured into ice/water (200 ml) and stirred for a further hour. The resulting suspension was collected by filtration, dried in vacuo and collected in EtOH, azeotroping to dryness to afford the title compound. Step 2: 5-Amino-<strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid
30 g
With sulfuric acid; nitric acid; at 0℃; for 3.75h;
To a stirred solution of 2-fluoro-4-methyl benzoic acid (26 g, 168 mmol) in concentrated H2SO4 (260 mL) is dropwise added freshly prepared nitration mixture [concentrated H2SO4 (10.7 mL)+70% HNO3 (11.9 mL)] at 0 C. over 45 min. The resultant solution is stirred for 3 h at 0 C. The reaction mixture is quenched with ice water. The resulting heterogeneous solution is extracted with ethyl acetate. The combined organic layer is washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford 30 g of crude 2-fluoro-4-methyl-5-nitro-benzoic acid (I-1-1).
With sulfuric acid; nitric acid; at 0℃; for 3.75h;
To a stirred solution of 2-fluoro-4-methyl benzoic acid (26 g, 168 mmol) in concentrated R2504 (260 mE) isdropwise added freshly prepared nitration mixture [concen trated R2504 (10.7 mE)+70% RNO3 (11.9 mE)] at 00 C. over 45 mm. The resultant solution is stirred for 3 h at 00 C. The reaction mixture is quenched with ice watet The resulting heterogeneous solution is extracted with ethyl acetate. The combined organic layer is washed with water, brine, dried over anhydrous Mg504, filtered and concentrated under reduced pressure to afford 30 g of crude 2-fluoro-4-methyl-5-nitro-benzoic acid (I-1-1).
Method G; Example G-1; 2-Fluoro-4-r3-oxo-4-(2-t?fluoroiotainethyl-benzyl)-3,4-clihvdro-2H-benzori ,41thiazin-2- ylmethyli-benzoic acid; Preparation of G-1 -a; 2-Fluoro-4-methyl-benzoic acid methyl ester; To a mixture of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (2.5g, 16mmol) in methyl alcohol (30ml_),thionyl chloride (1.36ml_, 18.9mmol) was added and the mixture was stirred at room temperature for 18h. The solvent was evaporated to provide the title compound (2.6g, 98% yield). 1H NMR (400 MHz, METHANOL-^) delta ppm 7.79 (t, J=7.83 Hz, 1 H), 7.07 (d, J=8.08 Hz, 1 H), 7.02 (d, J=12.38 Hz, 1 H), 3.88 (s, 3 H), 2.39 (s, 3 H)
90%
With sulfuric acid;Reflux;
Method A: To a stirred mixture of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) in acetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After the reaction mixture was heated to reflux overnight, the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (1.73 g, 79%), mp 51-53C. 1H NMR (CDCl3): delta 7.83 (t, J=8.0Hz, 1H), 7.00 (dd, J=8.0, 1.0Hz, 1H), 6.95 (d, J=12.0Hz, 1H), 3.91 (s, 3H), 2.39 (s, 3H). Method B: To a stirred solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuric acid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (6.88 g, 90%). Analytical data were same as above.
90%
With sulfuric acid;Reflux;
(f) Methyl 2-fluoro-4-methylbenzoate (5): Method A: To a stirred mixture of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) inacetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After thereaction mixture was heated to reflux overnight, the solvent was removed invacuo. The residual was diluted with EtOAc, washed with water and brine,dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography with hexanes/EtOAc (6:1) toafford 5 as a white solid (1.73 g, 79%), mp 51-53 C. 1H NMR (CDCl3): d 7.83 (t,J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.0 Hz, 1H), 6.95 (d, J = 12.0 Hz, 1H), 3.91 (s,3H), 2.39 (s, 3H). Method B: To a stirred solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong>acid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuricacid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; thesolvent was removed in vacuo. The residual was diluted with EtOAc, washedwith saturated NaHCO3 aqueous solution and brine, dried over anhydrousNa2SO4, filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid(6.88 g, 90%). Analytical data were same as above.
77%
To a solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (65 ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50ml) and methanol (50 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentratedin vacuo to give a tan solid identified as methyl 2-fluoro-4-methylbenzoate (5.07 g, 77%).
77%
To a solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid from Example D1 (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (6.5 ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and methanol (50 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a tan solid; yield 5.07 g (77%).
75%
With sulfuric acid; for 24h;Reflux;
INTERMEDIATE 28 - PREPARATION OF Methyl 2-fluoro-4-methylbenzoate. Sulfuric acid (2 ml_) was added to the solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (0.848 g; 5.34 mmol) in methanol (30 ml_). The mixture was refluxed for 24 hours. After cooling, the solution was made alkaline by addition of an aqueous solution of sodium carbonate, concentrated under reduced pressure in order to remove methanol, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure to give 0.672 g (75%) of methyl 2-fluoro-4-methylbenzoate as a solid.ESI/APCI(+) : 169 (M+H).
75%
With sulfuric acid; for 24h;Reflux;
Sulfuric acid (2 mL) was added to the solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (0.848 g; 5.34 mmol) in methanol (30 mL). The mixture was refluxed for 24 hours. After cooling, the solution was made alkaline by addition of an aqueous solution of sodium carbonate, concentrated under reduced pressure in order to remove methanol, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure to give 0.672 g (75%) of methyl 2-fluoro-4-methylbenzoate as a solid. [0609] ESI/APCI(+): 169 (M+H).
With thionyl chloride;
Example 24; Intermediate: 2-Fluoro-4-methyl-benzoic acid methyl ester; To a solution of <strong>[7697-23-6]2-fluoro-4-methyl-benzoic acid</strong> (1.1 g, 7.13 mmol) in methanol (20 mL) add thionyl chloride (1.02 g, 8.56 mmol). Stir the resulting mixture overnight then concentrate under vacuum to give the title compound (1.2 g) as a white solid. MS (ESI) m/z 169 (M+H); Hl NMR (DMSO-d6) 8 2.37 (s, 3H), 3.83 (s, 3H), 7.12-7.21 (m, 2H), 7.79 (t, J = 8.0 Hz, 1H).
With hydrogenchloride; In water; for 48h;Heating / reflux;
<strong>[7697-23-6]2-Fluoro-4-methylbenzoic acid</strong> methyl ester (6a): <strong>[7697-23-6]2-Fluoro-4-methylbenzoic acid</strong> (30.0 g, 195 mmol) was dissolved in MeOH (600 mL, 10 mol), and 12 M HCl (3.2 mL, 39 mmol) was added. The mixture was heated to reflux and stirred for 48 hours, then cooled and concentrated. The recovered material was dried in vacuo for 24 hours to obtain Intermediate (6a) as a white solid that was used without further purification.
With sulfuric acid;Reflux;
Preparative Example 8 15.4 g of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid was dissolved in 200 mL of methanol, and 10.0 mL of concentrated sulfuric acid was added thereto, followed by heating with reflux overnight. The reaction liquid was cooled to room temperature and then concentrated to about 50 mL, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate=95:5 to 90:10) to obtain 15.2 g of methyl 2-fluoro-4-methylbenzoate.
10.01 g
With sulfuric acid; at 90℃;
In a 500 ml one-neck round bottom flask, equipped with a magnetic stir-bar and condenser was added <strong>[7697-23-6]2-fluoro-4-methyl-benzoic acid</strong> (10.0 g, 64.88 mn1ol), 250 ml of methanol and 5 ml of sulfuric acid. The reaction was heated at 90C overnight. The methanol was evaporated and residue was purified on 125g Filter Silica ISCO column using a hexane/ethyl acetate gradient to give 10.Olg of IXS-4-52-1. Overall yield is 91.75%. ?H NMR (CDcI3, 400 MHz) oe 7.80 (t, 1H), 6.95 (2d, 2K), 3.89 (s, 3H), 2.37 (s, 3H).
With thionyl chloride; In toluene; for 2.5h;Heating / reflux;
To a solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid from Example El (6.04g, 39.18mmol) in toluene (80ml) was added thionyl chloride (65ml, 89.11mmol). The mixture was heated at reflux for 2.5h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50ml) and methanol (50ml) was added. The mixture was stirred at room temperature for 2.5h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100ml),washed with saturated sodium bicarbonate solution and brine, dried over MgS04, and concentrated in vacuo to give a tan solid; yield 5.07g (77%).
With thionyl chloride; In pyridine; hydrogenchloride; benzene;
A. 2'-Hydroxy-2-fluoro-p-toluanilide To a solution of 3.3 gm. o-aminophenol in 50 cc. of dry pyridine is added a solution of 4 gm. of 2-fluoro-p-toluyl chloride (prepared from 3.3 gm. of <strong>[7697-23-6]2-fluoro-p-toluic acid</strong> and 25 cc. of thionyl chloride) in 25 ml. of benzene. An exothermic reaction takes place and the reaction mixture is stirred overnight at ambient temperature. The reaction mixture is concentrated in vacuo and taken up between 2.5 N hydrochloric acid and a 1:1 mixture of chloroform-methylene chloride. The organic layer is separated and washed with a saturated NaHCO3 solution then with water. Concentration in vacuo followed by recrystallization from methanol gives 2'-hydroxy-2-fluoro-p-toluanilide, m.p. 181-183C.
With thionyl chloride; In methanol; dichloromethane; toluene;
E2. Methyl 2-fluoro-4-methylbenzoate To a solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid from Example E1 (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (65 ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and methanol (50 ml) was added. The mbture was stirred at room temperature for 2.5 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a tan solid; yield 5.07 g (77%).
Method A: To a stirred mixture of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) in acetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After the reaction mixture was heated to reflux overnight, the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (1.73 g, 79%), mp 51-53C. 1H NMR (CDCl3): delta 7.83 (t, J=8.0Hz, 1H), 7.00 (dd, J=8.0, 1.0Hz, 1H), 6.95 (d, J=12.0Hz, 1H), 3.91 (s, 3H), 2.39 (s, 3H). Method B: To a stirred solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuric acid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (6.88 g, 90%). Analytical data were same as above.
79%
With potassium carbonate; In acetonitrile;Reflux;
(f) Methyl 2-fluoro-4-methylbenzoate (5): Method A: To a stirred mixture of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) inacetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After thereaction mixture was heated to reflux overnight, the solvent was removed invacuo. The residual was diluted with EtOAc, washed with water and brine,dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography with hexanes/EtOAc (6:1) toafford 5 as a white solid (1.73 g, 79%), mp 51-53 C. 1H NMR (CDCl3): d 7.83 (t,J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.0 Hz, 1H), 6.95 (d, J = 12.0 Hz, 1H), 3.91 (s,3H), 2.39 (s, 3H). Method B: To a stirred solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong>acid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuricacid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; thesolvent was removed in vacuo. The residual was diluted with EtOAc, washedwith saturated NaHCO3 aqueous solution and brine, dried over anhydrousNa2SO4, filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid(6.88 g, 90%). Analytical data were same as above.
methyl 2-(trans-4-(cyclopropylamino)cyclohexyl)acetate[ No CAS ]
[ 7697-23-6 ]
methyl 2-(trans-4-(N-cyclopropyl-2-fluoro-4-methylbenzamido)cyclohexyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
To a mixture of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (0.153 g, 0.994 mmol), 1- hydroxybenzotriazole (0.0639 g, 0.473 mmol), and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (0.181 g, 0.947 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.396 ml, 2.84 mmol) and methyl 2-(trans-4-(cyclopropylamino)cyclohexyl)acetate (0.200 g, 0.947 mmol). The mixture was stirred at room temperature overnight, diluted with CH2Cl2 (50 mL), and then washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified through silica gel chromatography eluting with 18%-25% EtOAc- hexane. The desired amide product was obtained as a colorless oil (0.224g). MS: 348 (M+l), C20H26FNO3.
With N-Bromosuccinimide; sulfuric acid; at 20℃; for 16h;
l-Bromopyrrolidine-2,5-dione (NBS, 105 g, 584 mmol) was added to a solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (1, 90.0 g, 584 mol) in concentrated sulfuric acid (1.1 L) and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was then poured into ice-water (5 L). Resulting precipitate was filtered off, washed with water (1.5 L) and dissolved in ethyl acetate (1.2 L); dried over anhydrous sodium sulfate, filtered and evaporated to provide 5-bromo-2-fluoro-4- methylbenzoic acid (2) as white solid. Yield : 133.5 g (98%). JH NMR spectrum (300 MHz, CDCI3, deltaEta) : 8.20 (d, J = 6.9 Hz, 1 H); 7.11 (d, J= 11.4 Hz, 1 H); 2.47 (s, 3 H).
94%
With N-Bromosuccinimide; sulfuric acid;
5-Bromo-<strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid To a solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (0.154 g, 1 mmol) in concentrated sulfuric acid (2 mL) was added 1 -bromo-2,5-pyrolidinedione (0.178 g, 1 mmol). The resulting mixture was poured into ice-water (10 mL) after stirring for 20 minutes upon which the product precipitated as a white solid. The solid was collected by filtration and then was dissolved in dichloromethane (30 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 5-bromo-2-fluoro-4- methylbenzoic acid as a white solid (0.22 g, 94%). 1 H-NMR (300 MHz, CDCI3): delta = 2.38 (s, 3H), 7.40 (d, 1 H), 7.97 (d, 1 H), 13.42 (s, 1 H).
76%
With bromine; iron; at 0 - 20℃; for 1h;
5-Bromo-<strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid To a cold (0C) stirred solution of bromine (25.07 ml, 487 mmol) and iron powder (2.72 g, 48.7 mmol) was added <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (5.00 g, 32.4 mmol) portionwise and the resulting red solution was allowed to reach room temperature and stirred for 1 hour. The mixture was cooled to 0C and quenched with 250mL of aq. 1M sodium thiosulfate. The crude product was diluted with ethyl acetate, extracted, washed with water, brine, dried over magnesium sulfate, filtered and evaporated to a yellow solid. The crude solid was re-crystallized in 150mL of cyclohexane to give 6.65g (76% yield) of 5-bromo-2-fluoro-4- methylbenzoic acid. 1H NMR (500 MHz, DMSO-d6) delta ppm 13.44 (br. s., 1 H), 7.98 (d, J=7.09 Hz, 1 H), 7.41 (d, J=11.51 Hz, 1 H), 2.40 (s, 3 H). LCMS R, = 2.925 min., m/z 232.91 (M - H). The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+/-) at 220nm using the following set of conditions: Phenomenex Luna 3 m C 18, 2 x 50mm column, with a gradient of 0- 100%B (B = 95% HPLC grade methanol/ lOMm ammonium acetate/ 5% HPLC grade water), (A = 5% HPLC grade methanol/ lOMm ammonium acetate/ 95% HPLC grade water), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute.
71%
With bromine; iron; In dichloromethane; at 40℃; for 24h;Inert atmosphere;
To a solution of compound 1-a-1 (41.7 g, 0.271 mol) partially dissolved in dichloromethane (500 ml)Was added with liquid bromine (103.8 g, 0.65 mol)Iron powder (46.2 g, 0.82 mol) was added in portions under nitrogen protection,Heated to 40 C,Stirring for 24 hours,Cooled to room temperature,10%Of the insurance powderAqueous solution (200 ml * 3)Dispensing,The aqueous phase was extracted with EA (100 ml * 3)Saturated brine (50 ml)Sodium sulfate,filter,The filtrate was spin dried to give a black solid (45 g)Ethyl acetate was added to give compound 1-a-2 (45 g, yield: 71%) as a white solid;ESI-MS: 233.0 (M + H) +.
67%
With N-Bromosuccinimide; sulfuric acid; for 1h;
Step 1: 5-Bromo-<strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid To a solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (5.00 g, 32.44 mmol) in conc. H2SO4 (20.00 mL) was added NBS (6.06 g, 34.06 mmol). The resulting mixture was poured into ice-water (100 mL) after stirring for 1 h, the product precipitated as a white solid. The solid was collected by filtration and was dissolved in dichloromethane (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 5-bromo-<strong>[7697-23-6]2-fluoro-4-methyl-benzoic acid</strong> (5.10 g, 21.89 mmol, 67% yield). ESI-MS (EI+, m/z): 233.0 [M+H]+.
With bromine; iron; for 28h;
<strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (10 g, 64.9 mmol) was added in portions to a mixture of bromine (145 g, 908 mmol) and iron (1.812 g, 32.4 mmol), and the reaction mixture was stirred in a sealed vial for 28 h. The reaction mixture was then poured into aqueous saturated sodium thiosulfate and extracted with ethyl acetate (50 ml x 2). The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate and concentrated. The resulting residue was suspended in ethyl acetate and the insoluble impurity was filtered off. Then the filtrate was concentrated to dryness under vacuum to give the title compound as a yellow solid, which was used in the next step without further purification.
With bromine; iron; for 28h;
<strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (10 g, 64.9 mmol) was added in portions to a mixture of bromine (145 g, 908 mmol) and iron (1.812 g, 32.4 mmol) , and the reaction mixture was stirred in a sealed vial for 28 h. The reaction mixture was then poured into aqueous saturated sodium thiosulfate and extracted with ethyl acetate (50 ml x 2) . The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate and concentrated. The resulting residue was suspended in ethyl acetate and the insoluble impurity was filtered off. Then the filtrate was concentrated to dryness under vacuum to give the title compound as a yellow solid, which was used in the next step without further purification.
With N-Bromosuccinimide; trifluoroacetic acid; at 80℃; for 8h;
To a solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (2 g, 12.99 mmol) in CF3COOH (5OmL) was added NBS (6.9 g, 38.97 mmol). The mixture was stirred at 80C for 8 h. The resulting mixture was poured into water (300 mL) and stirred for 20 mm at rt. The precipitate was collected by filtration and dried to give 5-bromo-<strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (2 g, crude) as a white solid. ESI-MS (EI, m/z): 232.9 [M+H]t
With N-Bromosuccinimide; sulfuric acid; at 20℃; for 0.333333h;
N-bromosuccinimide (22.97 g, 129.75 mmol, 1.00 eq) was added to a mixture of WX004-1 (20.00 g, 129.75 mmol, 1.00 eq) and concentrated sulfuric acid (200.00 mL), and stirred at 20C for 20 minutes. The reaction solution was poured into ice water (1000 mL) while stirring, and a white solid was formed. After filtration, the filter cake was dissolved with 500 mL of dichloromethane, dried over magnesium sulfate, filtered and evaporated to dry to give WX004-2. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 2.45 (s, 3 H) 7.07 (d, J=11.17 Hz, 1 H) 8.16 (d, J=6.90 Hz, 1 H).
To a solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (2.62 g) in toluene (34 ml) were added N,N-dimethylformamide di-tert-butylacetal (16.3 ml), the mixed solution was stirred for 1 hour at 100 C. The solution was returned to room temperature, and water was added to the solution, which was then extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate/n-hexane=0 to 20%) to give tert-butyl 2-fluoro-4-methylbenzoate (2.87 g) as a pale yellow oily substance. 1H NMR (600 MHz, CHLOROFORM-d) delta ppm 1.59 (s, 9H), 2.37 (s, 3H), 6.89-7.77 (m, 3H)
(5aR,6S,6aS)-ethyl 3-((5-bromo-4-(difluoromethyl)-2-fluorobenzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
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