* 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.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 935 - 942
[3] Patent: WO2014/106763, 2014, A1,
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6018 - 6035
[5] Patent: WO2007/126964, 2007, A2,
2
[ 75-16-1 ]
[ 93777-26-5 ]
[ 552331-15-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: at 0℃; for 0.5 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; toluene
J. 1-(5-bromo-2-fluorophenyl)ethan-1-ol. To a solution of 5-Bromo-2-fluorobenzaldehyde (10.0 g., 49.26 mmol) in anhydrous ether (60 mL) at 0° C. was added 1.4M methyl magnesium bromide (THF/Tol. solution) (36.9 mL) dropwise. The solution stirred for 30 minutes and quenched with water (50 mL) followed by 1N HCl (10 mL). The organics were separated and dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (10.8 g., 100percent). MS (ESI) m/z 218 [M+1]+, 220 [M+2]+.
93%
Stage #1: for 1 h;
[00199] 5-Bromo-2-fluro-phenyl-methanol: 5-Bromo-2-fluorobenzaldehyde(commercially available from Aldrich)( 150.0 g, 739 mmol) was charged into a 2 liter round bottom flask. The reaction mixture in the flask was immersed in an ice-water bath. Methylmagnesium bromide (270 mL, 812 mmol) was added dropwise via an addition funnel. The reaction mixture was stirred for one hour following completion of the addition. After the reaction was completed, the mixture was slowly poured into 500 mL ice water and 250 mL saturated ammonium chloride. The resulting aqueous solution was extracted with ether (800 mL x2) in a separation funnel. The combined ether layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave the product (150 g, yield = 93percent). The product was used directly in the next step without further purification.
93%
at 0℃; for 1 h;
Commercially available 4a (150.0 g,</p> <p id="p0144" num="0144">739 mmol) was charged into a 2 liter round bottom flask. The reaction mixture in the flask was immersed in an ice-water bath. Methylmagnesium bromide (270 ml, 812 mmol) was added dropwise via an additional funnel. The reaction mixture was continually stirred for one more hour after the addition. After the reaction was completed, the mixture was slowly poured into 500 ml ice water plus 250 ml saturated ammonium chloride. The resulting aqueous solution was extracted with ether (800 ml x2) in a separation funnel. The combined ether layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave the product (4b) (150 g, yield = 93percent). The product was used directly for the next step without further purification.
53%
Stage #1: at 0 - 20℃; for 14.5 h; Stage #2: With water In tetrahydrofuran
Methylmagnesium bromide (3M solution in tetrahydrofuran, 18 ml, 54.2 mmol) was added to a solution of 5-bromo-2-fluorobenzaldehyde (10.0 g, 49.3 mmol) under nitrogen at 0° C. over 30 min. The resulting solution was allowed to warm to room temperature over 14 h, upon which TLC analysis showed no remaining starting material, and two new products. The mixture was quenched with water, diluted with ethyl acetate and the organic phase removed and dried over sodium sulfate. This was then concentrated and purified by column chromatography (120 g ISCO column eluting with hexanes and ethyl acetate; gradient 100percent hexanes to 50percent hexanes). The second fraction was collected as the product, providing the alcohol (5.8 g, 53percent) as an oil; 1H NMR (500 MHz, CDCl3) δ 7.65-7.63 (dd, J=6.5, 2.6 Hz, 1H), 7.36-7.33 (ddd, J=8.7, 4.6, 2.6 Hz, 1H), 6.93-6.89 (dd, J=9.9, 8.7 Hz, 1H), 5.17-5.16 (m, 1H), 1.91-1.90 (m, 1H), 1.51-1.49 (d, J=6.4 Hz, 3H).
46 g
at 0℃; for 0.5 h;
A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THF (500.0 mL) was cooled to 0°C. Then MeMgBr (3 M, 94.8 mL) was added. The mixture was stirred at 0°C for 0.5 h, quenched with H4C1 (500 mL) and extracted with ethyl acetate (500 mL χ 3). The combined organic layers were washed with brine (500 mL χ 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02) to afford compound 31-2 (46.0 g).
Reference：
[1] Patent: US2008/242694, 2008, A1, . Location in patent: Page/Page column 41
[2] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[3] Patent: WO2009/11880, 2009, A2, . Location in patent: Page/Page column 95
[4] Patent: WO2006/44860, 2006, A2, . Location in patent: Page/Page column 23
[5] Patent: US2006/142307, 2006, A1, . Location in patent: Page/Page column 24
[6] Patent: WO2006/81230, 2006, A2, . Location in patent: Page/Page column 68-69
[7] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 38
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 5, p. 1652 - 1656
[9] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6018 - 6035
[10] Patent: WO2018/102751, 2018, A1, . Location in patent: Paragraph 00260
[11] Patent: WO2007/126964, 2007, A2, . Location in patent: Page/Page column 89
3
[ 676-58-4 ]
[ 93777-26-5 ]
[ 552331-15-4 ]
Yield
Reaction Conditions
Operation in experiment
37%
Stage #1: at 0℃; Stage #2: With water; ammonium chloride In tetrahydrofuran
Acid Preparation 5; 3-Methyl-1 H-indazole-5-carboxvlic acid; To a cooled solution of 3-bromobenzaldehyde (42.5 g, 209 mmol) in THF (300 ml_) at 0 aC was added MeMgCI (17.2 g, 230 mmol) and the mixture was stirred for 2 hours. The reaction mixture was quenched with saturated NH4CI solution (100 ml_) and extracted with diethyl ether (2x250 ml_). The combined organic layers were washed with water (2x100 mL), saturated aqueous NaCI (100 mL), dried over anhydrous Na2SO4 and concentrated to give 1-(5-bromo-2-fluoro-phenyl)-ethanol (17 g, 37percent) as an oil. 1H NMR (CDCI3): δ 7.6-7.7 (d, 1 H), 7.3-7.4 (m, 1 H), 6.8-6.9 (t, 1 H), 5.1-5.2 (m, 1 H), 1.8-1.9 (br, 1 H), 1.46-1.55 (d, 3H).
14.51 g
at -78 - -5℃; for 1 h; Inert atmosphere
Step 1 [0200] 5-Bromo-2-fluorobenzaldehyde (1) (12.98 g) was dissolved in tetrahydrofuran (60 ml) under nitrogen atmosphere, and the solution was cooled in a dry ice-acetone bath. To the solution was added dropwise methylmagnesium chloride (3M in THF, 25.6 ml) at a temperature between −78° C. and −30° C. After completion of addition, the mixture was stirred at a temperature between −10° C. and −5° C. for 1 hour. To the reaction solution were added an aqueous saturated ammonium chloride solution and water, extracted with ethyl acetate and washed subsequently with water and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford Compound 2 (14.51 g). [0201] 1H-NMR (CDCl3) δ: 1.50 (d, J=6.4 Hz, 3H), 1.91 (d, J=4.2 Hz, 1H), 5.16 (dq, J=4.2, 6.4 Hz, 1H), 6.91 (dd, J=9.9, 8.7 Hz, 1H), 7.31-7.38 (m, 1H), 7.64 (dd, J=6.5, 2.5 Hz, 1H).
Reference：
[1] Patent: WO2009/144554, 2009, A1, . Location in patent: Page/Page column 43
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 935 - 942
[3] Patent: US2013/210839, 2013, A1, . Location in patent: Paragraph 0200; 0201
4
[ 552331-15-4 ]
[ 198477-89-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With chromium(VI) oxide; sulfuric acid In water; acetone at 0 - 20℃; for 14.5 h;
Chromium trioxide (2.6 g, 26.0 mmol) was dissolved in water (3.7 ml) and cooled in an ice bath. Concentrated sulfuric acid (2.2 ml) was added over 5 min, and the solution was diluted with water (7.4 ml). The mixture was then added dropwise to a solution of the product from Step A (5.7 g, 26.0 mmol) in acetone (17 ml) at 0-20° C. over 30 min. The resultant solution was allowed to warm to room temperature over 14 h. It was then partitioned between ether (300 ml) and water (300 ml) and the organic phase removed. The aqueous phase was washed with ether (100 ml) and the combined organic phases were dried over sodium sulfate then concentrated, providing the ketone (5.2 g, 92percent) as a dark liquid: 1H NMR (300 MHz, CDCl3) δ 8.01-7.98 (dd, J=6.2, 2.3 Hz, 1H), 7.64-7.59 (m, 1H), 7.08-7.02 (t, J=10.0 Hz, 1H), 2.65-2.63 (d, J=4.9 Hz, 3H).
84%
With dipyridinium dichromate In dichloromethane at 20℃; for 16 h;
[00200] 1 -(5-Bromo-2-fluro-phenyl)-ethanone: 5-Bromo-2-fluro-phenyl- methanol (50.0g, 228 mmol) along with 300 mL DCM was charged into 2 liter round bottom flask. Crushed pyridinum dichromate (171.Og, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 2O0C. The resulting reaction mixture was filtered through Celite and washed with ether (50OmL x 3). The combined filtrate was concentrated under reduced pressure. The crude product was eluted through a short silica <n="97"/>gel pad (3 inch in length) with 10percent EtOAc in hexane. The resulting product (42.0 g, yield=84percent) was used in the following step.
84%
With dipyridinium dichromate In dichloromethane at 20℃; for 16 h; Molecular sieve
Crushed pyridinum dichromate (171.Og, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 20 0C. The resulting reaction mixture was filtered through celite and washed with ether (500 ml x 3). The combined filtrate was concentrated under reduced pressure. The crude product was eluted through a short silica gel pad (3 inches in length) with 10percent EtOAc in hexane. The resulting product (42.0 g, yield=84percent) was used for the following step.
82%
With manganese(IV) oxide In 1,4-dioxane at 115℃; for 16 h;
I. 1-(5-bromo-2-fluorophenyl)ethan-1-one. To a solution of 1-(5-bromo-2-fluoro phenyl)ethan-1-ol (8.66 g., 39.54 mmol) in 1,4-dioxane (175 mL)was added MnO2 (20.0 g., 197.7 mmol). The solution was heated to 115° C. under a nitrogen atmosphere for 16 hours. The solution was filtered through celite and condensed under reduced pressure to afford the title compound (7.1 g., 82percent). MS (ESI) m/z 216 [M+1]+, 218 [M+2]+.
78%
With methylmagnesium bromide In 1,4-dioxane for 4 h; Heating / reflux
Example 102B 1-(5-Bromo-2-fluoro-phenyl)-ethanone A solution of Example 102A (26.6 g; 121 mmol) and manganese(IV) oxide (53 g; 610 mmol) in p-dioxane (500 mL) was heated at reflux for 4 hrs., cooled, filtered through Celite.(R)., evaporated, and purified by flash chromatography (5-10percent Et2O/hexane) to yield the desired product as a nearly colorless oil that solidified upon standing (20.5 g; 78percent).
63%
With dipyridinium dichromate In dichloromethane at 20℃; for 20 h; Molecular sieve
To a solution of 1-(5-bromo-2-fluoro-phenyl)-ethanol (37 g, 168mmol) in CH2CI2 (400 mL) and pyridinium dichromate (127 g, 337mmol) were added molecular sieves (10 g). The mixture was stirred at room temperature for 20 hours. The mixture was filtered through diatomaceous earth, washed with CH2CI2 (3x100 mL) and concentrated. The crude product was purified by column chromatography (60-120 mesh silica gel) using 10percent ethyl acetate in pet-ether to afford of 1-(5-bromo-2-fluoro-phenyl)-ethanone (23 g, 63percent) as pale brown oil. 1H NMR (CDCI3): δ 7.9-8.1 (d, 1 H), 7.5-7.7 (m, 1 H), 6.95-7.1 (t, 1 H), 2.6-2.7 (d, 3H).
13.66 g
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In ethyl acetate for 7 h; Reflux
Step 2 [0202] To a solution of Compound 2 (14.01 g) in ethyl acetate (150 ml) was added 2-iodoxybenzoic acid (35.8 g), and the mixture was refluxed for 7 hours. The reaction solution was cooled in an ice bath and the precipitated solid was removed by filtration. The filtrate was evaporated under reduced pressure to afford Compound 3 (13.66 g) [0203] 1H-NMR (CDCl3) δ: 2.64 (d, J=5.0 Hz, 3H), 7.05 (dd, J=10.2, 8.7 Hz, 1H), 7.58-7.64 (m, 1H), 7.98 (dd, J=6.4, 2.5 Hz, 1H).
Reference：
[1] Patent: US2006/142307, 2006, A1, . Location in patent: Page/Page column 24
[2] Patent: WO2009/11880, 2009, A2, . Location in patent: Page/Page column 95-96
[3] Patent: WO2006/44860, 2006, A2, . Location in patent: Page/Page column 23
[4] Patent: US2008/242694, 2008, A1, . Location in patent: Page/Page column 41
[5] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[6] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 38-39
[7] Patent: WO2009/144554, 2009, A1, . Location in patent: Page/Page column 43
[8] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 935 - 942
[9] Patent: WO2006/81230, 2006, A2, . Location in patent: Page/Page column 68-69
[10] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 5, p. 1652 - 1656
[11] Patent: US2013/210839, 2013, A1, . Location in patent: Paragraph 0202; 0203
[12] Patent: WO2014/106763, 2014, A1, . Location in patent: Page/Page column 11-12
[13] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6018 - 6035
[14] Patent: WO2007/126964, 2007, A2, . Location in patent: Page/Page column 89
5
[ 552331-15-4 ]
[ 552331-30-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
6
[ 552331-15-4 ]
[ 627463-25-6 ]
Yield
Reaction Conditions
Operation in experiment
24 g
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane at 0 - 25℃; for 2 h;
To a solution of compound 31-2 (46.0 g, 210.0 mmol) and triethylsilane (48.8 g, 420.0 mmol, 66.9 mL) in DCM (500.0 mL) was added BF3.Et20 (59.6 g, 420.0 mmol, 51.8 mL) at 0°C. The mixture was stirred at 25°C for 2 h, concentrated, quenched by addition of (0767) Sat.NaHC03 (200 mL) at 0°C, and extracted with ethyl acetate (200 mL χ 3). The combined organic layers were washed with brine (200 mL χ 3), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (Si02) to afford compound 31-3 (24.0 g). 1H MR (CHLOROFORM-^, 400MHz) δ 7.31 (dd, J= 2.2, 6.6 Hz, 1H), 7.27 - 7.21 (m, 1H), 6.87 (t, J= 9.2 Hz, 1H), 2.62 (q, J= 7.5 Hz, 2H), 1.20 (t, J= 7.6 Hz, 3H).
With chromium(VI) oxide; sulfuric acid; In water; acetone; at 0 - 20℃; for 14.5h;
Chromium trioxide (2.6 g, 26.0 mmol) was dissolved in water (3.7 ml) and cooled in an ice bath. Concentrated sulfuric acid (2.2 ml) was added over 5 min, and the solution was diluted with water (7.4 ml). The mixture was then added dropwise to a solution of the product from Step A (5.7 g, 26.0 mmol) in acetone (17 ml) at 0-20 C. over 30 min. The resultant solution was allowed to warm to room temperature over 14 h. It was then partitioned between ether (300 ml) and water (300 ml) and the organic phase removed. The aqueous phase was washed with ether (100 ml) and the combined organic phases were dried over sodium sulfate then concentrated, providing the ketone (5.2 g, 92%) as a dark liquid: 1H NMR (300 MHz, CDCl3) delta 8.01-7.98 (dd, J=6.2, 2.3 Hz, 1H), 7.64-7.59 (m, 1H), 7.08-7.02 (t, J=10.0 Hz, 1H), 2.65-2.63 (d, J=4.9 Hz, 3H).
84%
With dipyridinium dichromate; In dichloromethane; at 20℃; for 16.0h;
[00200] 1 -(5-Bromo-2-fluro-phenyl)-ethanone: 5-Bromo-2-fluro-phenyl- methanol (50.0g, 228 mmol) along with 300 mL DCM was charged into 2 liter round bottom flask. Crushed pyridinum dichromate (171.Og, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 2O0C. The resulting reaction mixture was filtered through Celite and washed with ether (50OmL x 3). The combined filtrate was concentrated under reduced pressure. The crude product was eluted through a short silica <n="97"/>gel pad (3 inch in length) with 10% EtOAc in hexane. The resulting product (42.0 g, yield=84%) was used in the following step.
84%
With dipyridinium dichromate; In dichloromethane; at 20℃; for 16.0h;Molecular sieve;
Crushed pyridinum dichromate (171.Og, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 20 0C. The resulting reaction mixture was filtered through celite and washed with ether (500 ml x 3). The combined filtrate was concentrated under reduced pressure. The crude product was eluted through a short silica gel pad (3 inches in length) with 10% EtOAc in hexane. The resulting product (42.0 g, yield=84%) was used for the following step.
82%
With manganese(IV) oxide; In 1,4-dioxane; at 115℃; for 16.0h;
I. 1-(5-bromo-2-fluorophenyl)ethan-1-one. To a solution of <strong>[552331-15-4]1-(5-bromo-2-fluoro phenyl)ethan-1-ol</strong> (8.66 g., 39.54 mmol) in 1,4-dioxane (175 mL)was added MnO2 (20.0 g., 197.7 mmol). The solution was heated to 115 C. under a nitrogen atmosphere for 16 hours. The solution was filtered through celite and condensed under reduced pressure to afford the title compound (7.1 g., 82%). MS (ESI) m/z 216 [M+1]+, 218 [M+2]+.
78%
With methylmagnesium bromide; In 1,4-dioxane; for 4.0h;Heating / reflux;
Example 102B 1-(5-Bromo-2-fluoro-phenyl)-ethanone A solution of Example 102A (26.6 g; 121 mmol) and manganese(IV) oxide (53 g; 610 mmol) in p-dioxane (500 mL) was heated at reflux for 4 hrs., cooled, filtered through Celite, evaporated, and purified by flash chromatography (5-10% Et2O/hexane) to yield the desired product as a nearly colorless oil that solidified upon standing (20.5 g; 78%).
72%
With Dess-Martin periodane; In tetrahydrofuran; at 0 - 20℃; for 0.25h;
Step-2: Synthesis of 1-(5-bromo-2-fluorophenyl)ethan-1-one To a stirred solution of <strong>[552331-15-4]1-(5-bromo-2-fluorophenyl)ethan-1-ol</strong> (5.3 g, 24.195 mmol, 1.0 eq) in THF (50 mL) was added Dess-martin peridionane (12.314 g, 29.034 mmol, 1.2 eq) at 0 C. The resulting mixture was stirred at rt for 15 min. The progress of reaction was monitored by LCMS. The resection mixture was quenched with saturated solution of NaHCO3 (50 mL) extracted with EtOAc (2*50 mL). The combined organic extracts were washed with water (50 mL), with brine (50 mL) dried over Na2SO4 and concentrated under reduced pressure and purified by flash chromatography [silica gel 100-200 mesh; elution 0-5% EtOAc in hexane] to afford the desired compound 1-(5-bromo-2-fluorophenyl)ethan-1-one (3.78 g, 72.00%) as yellow liquid. 1H NMR (400 MHz, CDCl3) delta 7.99 (dd, J=2.63, 6.58 Hz, 1H), 7.61 (ddd, J=2.63, 4.39, 8.77 Hz, 1H), 7.05 (dd, J=8.77, 10.09 Hz, 1H), 2.64 (d, J=4.82 Hz, 3H).
63%
With dipyridinium dichromate; In dichloromethane; at 20℃; for 20.0h;Molecular sieve;
To a solution of <strong>[552331-15-4]1-(5-bromo-2-fluoro-phenyl)-ethanol</strong> (37 g, 168mmol) in CH2CI2 (400 mL) and pyridinium dichromate (127 g, 337mmol) were added molecular sieves (10 g). The mixture was stirred at room temperature for 20 hours. The mixture was filtered through diatomaceous earth, washed with CH2CI2 (3x100 mL) and concentrated. The crude product was purified by column chromatography (60-120 mesh silica gel) using 10% ethyl acetate in pet-ether to afford of 1-(5-bromo-2-fluoro-phenyl)-ethanone (23 g, 63%) as pale brown oil. 1H NMR (CDCI3): delta 7.9-8.1 (d, 1 H), 7.5-7.7 (m, 1 H), 6.95-7.1 (t, 1 H), 2.6-2.7 (d, 3H).
With manganese(IV) oxide; In 1,4-dioxane; for 5.0h;Heating / reflux;
Preparation of 5-bromo-3-methyl-1/-/-indazole 104; Scheme 2 EPO <DP n="70"/>To a solution of 5-bromo-2-fluorobenzaldehydbeta 101 (100 g, 0.492 mol.) in ether (500 ml_), cooled in an ice bath, was added a 3 M solution of methyl magnesium bromide in ether (i.e., diethyl ether) (173 mL, 0.516 mol.) in a dropwise manner. The reaction mixture was stirred for 30 minutes in the ice bath. The reaction mixture was allowed to warm to room temperature and was stirred for 15 minutes. The reaction mixture was cooled in an ice bath and the reaction was quenched by addition of water in a dropwise manner. The reaction mixture was acidified with dilute hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with ether for two times. The combined organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford 1-(5-bromo-2-fluoro-phenyl)- ethanol 102 (106 g, 0.484 mol.) which was used in the next step without further purification. To a solution of 1 -(5-bromo-2-f luoro-phenyl)-ethanol 102 (105 g, 0.479 mol.) in dioxane (2 L) was added manganese dioxide (203 g, 2.35 mol.). The reaction mixture was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through Celite (i.e., diatomaceous earth) and the solid was washed with ether (1 L). The combined filtrate was evaporated under reduced pressure to afford the 1-(5-bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol.) which was used in the next step without further purification.
13.66 g
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione; In ethyl acetate; for 7.0h;Reflux;
Step 2 [0202] To a solution of Compound 2 (14.01 g) in ethyl acetate (150 ml) was added 2-iodoxybenzoic acid (35.8 g), and the mixture was refluxed for 7 hours. The reaction solution was cooled in an ice bath and the precipitated solid was removed by filtration. The filtrate was evaporated under reduced pressure to afford Compound 3 (13.66 g) [0203] 1H-NMR (CDCl3) delta: 2.64 (d, J=5.0 Hz, 3H), 7.05 (dd, J=10.2, 8.7 Hz, 1H), 7.58-7.64 (m, 1H), 7.98 (dd, J=6.4, 2.5 Hz, 1H).
With manganese(IV) oxide;
1 -(5-Bromo-2-fluorophenyl)ethanone was synthesized via the reaction where 1 -(5-bromo-2- fluorophenyl)ethanol was oxygenated with manganese dioxide. The reaction was carried out according to available literature28. 1H NMR (300 MHz, DMSO-d6) delta ppm 7.91 (dd, = 6.45 Hz, J2 = 2.61 Hz, 1 H), 7.84 (m, 1 H), 7.36 (dd, J, = 8.79 Hz, J2 = 10.74 Hz, 1 H), 2.59 (s, 3H).
With manganese(IV) oxide; In 1,4-dioxane; for 5.0h;Heating / reflux;
Step B; To a solution of 1-(5-Bromo-2-fluoro-phenyl)-ethanol 102 (105 g, 0.479 mol) in dioxane (2 L) was added manganese dioxide (203 g, 2.35 mol). The reaction mixture was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through Celite and the solid was washed with ether (1 L). The combined filtrate was evaporated under reduced pressure to afford the 1-(5-Bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol) which was used in the next step without further purification.
J. 1-(5-bromo-2-fluorophenyl)ethan-1-ol. To a solution of 5-Bromo-2-fluorobenzaldehyde (10.0 g., 49.26 mmol) in anhydrous ether (60 mL) at 0 C. was added 1.4M methyl magnesium bromide (THF/Tol. solution) (36.9 mL) dropwise. The solution stirred for 30 minutes and quenched with water (50 mL) followed by 1N HCl (10 mL). The organics were separated and dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (10.8 g., 100%). MS (ESI) m/z 218 [M+1]+, 220 [M+2]+.
98.51%
In diethyl ether; at 0℃; for 0.25h;
Step-1: Synthesis of 1-(5-bromo-2-fluorophenyl)ethan-1-ol To a stirred solution of 5-bromo-2-fluorobenzaldehyde (5.0 g, 24.63 mmol, 1.0 eq) in diethylether (50 mL) was dropwise added methylmagnesium bromide (12.3 mL, 36.94 mmol, 1.5 eq) at 0 C. The resulting mixture was stirred at 0 C. for 15 min. The progress of reaction was monitored by LCMS. The resection mixture was quenched with saturated solution of NH4Cl (50 mL) extracted with EtOAc (2*50 mL). The combined organic extracts were washed with water (50 mL), with brine (50 mL) dried over Na2SO4 and concentrated under reduced to afford the desired compound 1-(5-bromo-2-fluorophenyl)ethan-1-ol (5.31 g, 98.51%) as yellow liquid. 1H NMR (400 MHz, CDCl3) 7.64 (dd, J=2.41, 6.36 Hz, 1H), 7.35 (ddd, J=2.63, 4.60, 8.55 Hz, 1H), 6.91 (dd, J=8.77, 9.65 Hz, 1H), 5.16 (d, J=5.26 Hz, 1H), 1.88 (brs, 1H), 1.50 (d, J=6.14 Hz, 3H).
93%
[00199] 5-Bromo-2-fluro-phenyl-methanol: 5-Bromo-2-fluorobenzaldehyde(commercially available from Aldrich)( 150.0 g, 739 mmol) was charged into a 2 liter round bottom flask. The reaction mixture in the flask was immersed in an ice-water bath. Methylmagnesium bromide (270 mL, 812 mmol) was added dropwise via an addition funnel. The reaction mixture was stirred for one hour following completion of the addition. After the reaction was completed, the mixture was slowly poured into 500 mL ice water and 250 mL saturated ammonium chloride. The resulting aqueous solution was extracted with ether (800 mL x2) in a separation funnel. The combined ether layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave the product (150 g, yield = 93%). The product was used directly in the next step without further purification.
93%
at 0℃; for 1.0h;
Commercially available 4a (150.0 g,</p> <p id="p0144" num="0144">739 mmol) was charged into a 2 liter round bottom flask. The reaction mixture in the flask was immersed in an ice-water bath. Methylmagnesium bromide (270 ml, 812 mmol) was added dropwise via an additional funnel. The reaction mixture was continually stirred for one more hour after the addition. After the reaction was completed, the mixture was slowly poured into 500 ml ice water plus 250 ml saturated ammonium chloride. The resulting aqueous solution was extracted with ether (800 ml x2) in a separation funnel. The combined ether layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave the product (4b) (150 g, yield = 93%). The product was used directly for the next step without further purification.
53%
Methylmagnesium bromide (3M solution in tetrahydrofuran, 18 ml, 54.2 mmol) was added to a solution of 5-bromo-2-fluorobenzaldehyde (10.0 g, 49.3 mmol) under nitrogen at 0 C. over 30 min. The resulting solution was allowed to warm to room temperature over 14 h, upon which TLC analysis showed no remaining starting material, and two new products. The mixture was quenched with water, diluted with ethyl acetate and the organic phase removed and dried over sodium sulfate. This was then concentrated and purified by column chromatography (120 g ISCO column eluting with hexanes and ethyl acetate; gradient 100% hexanes to 50% hexanes). The second fraction was collected as the product, providing the alcohol (5.8 g, 53%) as an oil; 1H NMR (500 MHz, CDCl3) delta 7.65-7.63 (dd, J=6.5, 2.6 Hz, 1H), 7.36-7.33 (ddd, J=8.7, 4.6, 2.6 Hz, 1H), 6.93-6.89 (dd, J=9.9, 8.7 Hz, 1H), 5.17-5.16 (m, 1H), 1.91-1.90 (m, 1H), 1.51-1.49 (d, J=6.4 Hz, 3H).
Preparation of 5-bromo-3-methyl-1/-/-indazole 104.; Scheme 2 EPO <DP n="70"/>To a solution of 5-bromo-2-fluorobenzaldehydbeta 101 (100 g, 0.492 mol.) in ether (500 ml_), cooled in an ice bath, was added a 3 M solution of methyl magnesium bromide in ether (i.e., diethyl ether) (173 mL, 0.516 mol.) in a dropwise manner. The reaction mixture was stirred for 30 minutes in the ice bath. The reaction mixture was allowed to warm to room temperature and was stirred for 15 minutes. The reaction mixture was cooled in an ice bath and the reaction was quenched by addition of water in a dropwise manner. The reaction mixture was acidified with dilute hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with ether for two times. The combined organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford 1-(5-bromo-2-fluoro-phenyl)- ethanol 102 (106 g, 0.484 mol.) which was used in the next step without further purification. To a solution of 1 -(5-bromo-2-f luoro-phenyl)-ethanol 102 (105 g, 0.479 mol.) in dioxane (2 L) was added manganese dioxide (203 g, 2.35 mol.). The reaction mixture was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through Celite (i.e., diatomaceous earth) and the solid was washed with ether (1 L). The combined filtrate was evaporated under reduced pressure to afford the 1-(5-bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol.) which was used in the next step without further purification.
Example 102A A solution of 5-bromo-2-fluorobenzaldehyde (24.75 g; 122 mmol) in Et2O (125 mL) at 0 C. was treated with 3.0 M MeMgBr in Et2O (43 mL, 129 mmol), stirred for 30 min., carefully diluted with water then acidified with 10% HCl (aq). The aqueous was extracted with Et2O, rinsed successively with 10% HCl (aq), water, and brine, dried (MgSO4), and evaporated to give the desired product (26.6 g; 99%) of sufficient purity to carry on to the next step.
46 g
In tetrahydrofuran; at 0℃; for 0.5h;
A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THF (500.0 mL) was cooled to 0C. Then MeMgBr (3 M, 94.8 mL) was added. The mixture was stirred at 0C for 0.5 h, quenched with H4C1 (500 mL) and extracted with ethyl acetate (500 mL chi 3). The combined organic layers were washed with brine (500 mL chi 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02) to afford compound 31-2 (46.0 g).
Step A; To a solution of 5-bromo-2-fluorobenzaldehyde 101 (100 g, 0.492 mol) in ether (500 ml_), cooled in an ice bath, was added a 3 M solution of methyl magnesium bromide in ether (173 ml_, 0.516 mol) in a dropwise manner. The reaction mixture was stirred for 30 minutes in the ice bath. The reaction mixture was allowed to warm to room temperature and was stirred for 15 minutes. The reaction mixture was cooled in an ice bath and the reaction was quenched by addition of water in a dropwise manner. The reaction mixture was acidified with dilute hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with ether for two times. The combined organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford 1-(5-Bromo-2-fluoro-phenyl)-ethanol 102 (106 g, 0.484 mol) which was used in the next step without further purification.
In tetrahydrofuran; at 0℃; for 0.5h;
A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THF (500.0 mL) was cooled to 0C. Then MeMgBr (3 M, 94.8 mL) was added. The mixture was stirred at 0C for 0.5 h, quenched with H4C1 (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL chi 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02) to afford compound 2A-2 (46.0 g, crude).
In tetrahydrofuran; at 0℃; for 0.5h;
A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THE (500.0 mL) was cooled to 0C. Then MeMgBr (3 M, 94.8 mL) was added. The mixture was stirred at 0C for 0.5 h, quenched with NH4C1 (500 mL) and extracted with ethyl acetate (500 mL >< 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02) to afford compound 2A-2 (46.0 g, crude).
Acid Preparation 5; 3-Methyl-1 H-indazole-5-carboxvlic acid; To a cooled solution of 3-bromobenzaldehyde (42.5 g, 209 mmol) in THF (300 ml_) at 0 aC was added MeMgCI (17.2 g, 230 mmol) and the mixture was stirred for 2 hours. The reaction mixture was quenched with saturated NH4CI solution (100 ml_) and extracted with diethyl ether (2x250 ml_). The combined organic layers were washed with water (2x100 mL), saturated aqueous NaCI (100 mL), dried over anhydrous Na2SO4 and concentrated to give 1-(5-bromo-2-fluoro-phenyl)-ethanol (17 g, 37%) as an oil. 1H NMR (CDCI3): delta 7.6-7.7 (d, 1 H), 7.3-7.4 (m, 1 H), 6.8-6.9 (t, 1 H), 5.1-5.2 (m, 1 H), 1.8-1.9 (br, 1 H), 1.46-1.55 (d, 3H).
14.51 g
In tetrahydrofuran; at -78 - -5℃; for 1.0h;Inert atmosphere;
Step 1 [0200] 5-Bromo-2-fluorobenzaldehyde (1) (12.98 g) was dissolved in tetrahydrofuran (60 ml) under nitrogen atmosphere, and the solution was cooled in a dry ice-acetone bath. To the solution was added dropwise methylmagnesium chloride (3M in THF, 25.6 ml) at a temperature between -78 C. and -30 C. After completion of addition, the mixture was stirred at a temperature between -10 C. and -5 C. for 1 hour. To the reaction solution were added an aqueous saturated ammonium chloride solution and water, extracted with ethyl acetate and washed subsequently with water and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford Compound 2 (14.51 g). [0201] 1H-NMR (CDCl3) delta: 1.50 (d, J=6.4 Hz, 3H), 1.91 (d, J=4.2 Hz, 1H), 5.16 (dq, J=4.2, 6.4 Hz, 1H), 6.91 (dd, J=9.9, 8.7 Hz, 1H), 7.31-7.38 (m, 1H), 7.64 (dd, J=6.5, 2.5 Hz, 1H).
With phosphorus tribromide; In dichloromethane; at 0℃; for 1.0h;
Step A: 4-bromo-2-( 1 -bromoethyl)- 1 -fluorobenzene (30-2)To a stirred solution of <strong>[552331-15-4]1-(5-bromo-2-fluorophenyl)ethanol</strong> 30-1 (1.2 g, 5.48 mmol) in DCM (15 ml) was added tribromophosphine (0.26 mL, 2.74 mmol). The reaction mixture was stirred at 0C for lh, and then diluted with DCM (50 mL). Then saturated NaHCO3 solution was addeddropwise to the mixture, and the layers were separated. The organic layer was washed with saturated NaHCO3 solution (3OmL), brine (30 mL), and then dried over Na2SO4, and concentrated to give the crude product 30-2, which was used in the next step without purification.
With phosphorus tribromide; In dichloromethane; at 0℃; for 1.0h;
To a stirred solution of 1 -(5 -bromo-2-fluorophenyl)ethanol 30-1 (1.2 g, 5.48 mmol) in DCM (15 ml) was added tribromophosphine (0.26 mL, 2.74 mmol). The reaction mixture was stirred at 0C for lh, and then diluted with DCM (50 mL). Then saturated NaHCO3 solution was added dropwise to the mixture, and the layers were separated. The organic layer was washed with saturated NaHCO3 solution (3OmL), brine (30 mL), and then dried over Na2SO4, and concentrated to give the crude product 30-2, which was used in the next step without purification.
With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 1.0h;
[0856] Compound 455-2 was prepared essentially as described in PCT Publication No. WO 2012/057247, published May 3, 2012, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 455-2. To a solution of 455-2 (2.0 g. 9.17 mmol) in DCM (50 mL) was added DAST (6.0 g, 36 mmol) at 0 C, and the mixture was stirred at r.t. for 1 h. The reaction was quenched with water (50 mL). The organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by colomn chromatography (PE:EA 100: 1 ) to give 455-3 (1.2 g, 60%).
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; at 0 - 25℃; for 2.0h;
To a solution of compound 31-2 (46.0 g, 210.0 mmol) and triethylsilane (48.8 g, 420.0 mmol, 66.9 mL) in DCM (500.0 mL) was added BF3.Et20 (59.6 g, 420.0 mmol, 51.8 mL) at 0C. The mixture was stirred at 25C for 2 h, concentrated, quenched by addition of (0767) Sat.NaHC03 (200 mL) at 0C, and extracted with ethyl acetate (200 mL chi 3). The combined organic layers were washed with brine (200 mL chi 3), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (Si02) to afford compound 31-3 (24.0 g). 1H MR (CHLOROFORM-^, 400MHz) delta 7.31 (dd, J= 2.2, 6.6 Hz, 1H), 7.27 - 7.21 (m, 1H), 6.87 (t, J= 9.2 Hz, 1H), 2.62 (q, J= 7.5 Hz, 2H), 1.20 (t, J= 7.6 Hz, 3H).
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; at 0 - 25℃; for 2.0h;
To a solution of compound 2A-2 (46.0 g, 210.0 mmol) and triethylsilane (48.8 g, 420.0 mmol, 66.9 mL) in DCM (500.0 mL) was added BF3.Et20 (59.6 g, 420.0 mmol, 51.8 mL) at 0C. The mixture was stirred at 25C for 2 h, concentrated, quenched by addition of Sat.NaHC03 (200 mL) at 0C, and extracted with ethyl acetate (200 mL chi 3). The combined organic layers were washed with brine (200 mL chi 3), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (Si02) to afford compound 2A-3 (24.0 g, crude). 1H NMR (CHLOROFORM-d, 400MHz) delta 1 1 (dd, J= 2.2, 6.6 Hz, 1H), 7.27 - 7.21 (m, 1H), 6.87 (t, J= 9.2 Hz, 1H), 2.62 (q, J= 7.5 Hz, 2H), 1.20 (t, J= 7.6 Hz, 3H).
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; at 0 - 25℃; for 2.0h;
To a solution of compound 2A-2 (46.0 g, 210.0 mmol) and triethylsilane (48.8 g, 420.0 mmol, 66.9 mL) in DCM (500.0 mL) was added BF3.Et20 (59.6 g, 420.0 mmol, 51.8 mL) at 0C. The mixture was stirred at 25C for 2 h, concentrated, quenched by addition of Sat.NaHCO3 (200 mL) at 0C, and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (Si02) to afford compound 2A-3 (24.0 g, cmde). ?H NMR (CHLOROFORM-d, 400MHz) (5 7.31 (dd, J= 2.2, 6.6 Hz, 1H),7.27 - 7.21 (m, 1H), 6.87 (t, J 9.2 Hz, 1H), 2.62 (q, J= 7.5 Hz, 2H), 1.20 (t, J= 7.6 Hz, 3H).
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