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[ CAS No. 529508-58-5 ]

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2D
Chemical Structure| 529508-58-5
Chemical Structure| 529508-58-5
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Product Details of [ 529508-58-5 ]

CAS No. :529508-58-5MDL No. :MFCD09909402
Formula : C14H10FN3O2 Boiling Point : 447.697°C at 760 mmHg
Linear Structure Formula :-InChI Key :-
M.W :271.25Pubchem ID :21966490
Synonyms :

Computed Properties of [ 529508-58-5 ]

TPSA : 63.6 H-Bond Acceptor Count : 4
XLogP3 : 3.1 H-Bond Donor Count : 0
SP3 : 0.07 Rotatable Bond Count : 2

Safety of [ 529508-58-5 ]

Signal Word:WarningClass:N/A
Precautionary Statements:P261-P305+P351+P338UN#:N/A
Hazard Statements:H302-H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 529508-58-5 ]

  • Upstream synthesis route of [ 529508-58-5 ]
  • Downstream synthetic route of [ 529508-58-5 ]

[ 529508-58-5 ] Synthesis Path-Upstream   1~9

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YieldReaction ConditionsOperation in experiment
49% With caesium carbonate In N,N-dimethyl-formamide at 70 - 80℃; for 1.25 h; 5-nitro indazole (1 equiv. ), cesium carbonate (1. 1 equiv. ) and DMF (5 volumes) were charged to a vessel. The mixture was heated to 70-80 °C and 3-fluoro benzyl bromide was added over 75 mins. The reaction was assayed by HPLC for completion (<2 AP of nitro indazole vs combined isomers) and then cooled to 20 °C. The salts were filtered and the cake was washed with DMF (2.7 volumes). The product was crystallized by charging water (1.35 to 1.45 volumes) between 15-21 °C. The crystal slurry was held for 4 h, crystals were filtered and washed with 2: 1 DMF : water mix (2.1 volumes), water (2 volumes) and finally 3: 1 cold ACN: water mix (1.5 volumes). The wet cake was dried <45 °C to LOD <1percent and the yield was about 49percent lH NMR (CDC13) otilde; 5.64 (s, 2H), 6. 87 (d, 1H, J = 9.4 Hz), 6.95 (m, 2H), 7.30 (m, 1H), 7.42 (d, 1H, J = 9.2 Hz), 8.23 (d of d, 1H, J = 10 Hz and 2 Hz), 8.26 (s, 1H), 8. 72 (d, lH, J = 2 Hz); MS: 272 (M+H) + ; HPLC Ret Time: 6.99 min (YMC ODS-A 3 um, 4.6 x 50 mm column, 10 min gradient, 2.5 mL/min).
49% With caesium carbonate In N,N-dimethyl-formamide at 70 - 80℃; for 1.25 h; 5-nitro indazole (1 equiv. ), cesium carbonate (1. 1 equiv. ) and DMF (5 volumes) were charged to a vessel. The mixture was heated to 70-80 °C and 3-fluoro benzyl bromide was added over 75 mins. The reaction was assayed by HPLC for completion (<2 AP of nitro indazole vs combined isomers) and then cooled to 20 °C. The salts were filtered and the cake was washed with DMF (2.7 volumes). The product was crystallized by charging water (1.35 to 1.45 volumes) between 15-21 °C. The crystal slurry was held for 4 h, crystals were filtered and washed with 2: 1 DMF : water mix (2.1 volumes), water (2 volumes) and finally 3: 1 cold ACN: water mix (1.5 volumes). The wet cake was dried <45 °C to LOD <1percent and the yield was about 49percent lH NMR (CDC13) otilde; 5.64 (s, 2H), 6. 87 (d, 1H, J = 9.4 Hz), 6.95 (m, 2H), 7.30 (m, 1H), 7.42 (d, 1H, J = 9.2 Hz), 8.23 (d of d, 1H, J = 10 Hz and 2 Hz), 8.26 (s, 1H), 8. 72 (d, lH, J = 2 Hz); MS: 272 (M+H) + ; HPLC Ret Time: 6.99 min (YMC ODS-A 3 um, 4.6 x 50 mm column, 10 min gradient, 2.5 mL/min).
Reference: [1] Patent: WO2005/58245, 2005, A2, . Location in patent: Page/Page column 32-33
[2] Patent: WO2005/58245, 2005, A2, . Location in patent: Page/Page column 32-33
[3] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6527 - 6530
[4] Patent: WO2012/182, 2012, A1, . Location in patent: Page/Page column 11
[5] Patent: WO2012/356, 2012, A1, . Location in patent: Page/Page column 10-11
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YieldReaction ConditionsOperation in experiment
39% With potassium carbonate In tetrahydrofuran for 3 h; Heating / reflux 5-Nitroindazol (10.0 g, 61.3 mmol) was dissolved in TηF (100 mL). Potassium carbonate (25.4 g, 184 mmol) and 3-fluorobenzylbromide (12.7 g, 67.4 mmol) were added, and the mixture was heated to reflux for 3 h. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (150 mL) and extracted with water (200 mL). The aqueous layer was extracted twice with ethyl acetate (100 mL each). The combined organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to yield 6.55 g (39percent) of the title compound (less polar component) and 5.84 g (35percent) of the regioisomeric 2H-indazole derivative (more polar component).1H-NMR (400 MHz, DMSOd6): δ = 5.80 (s, 2H), 7.04-7.15 (m, 3H), 7.37 (dt, IH), 7.98 (d, IH), 8.25 (dd, IH), 8.48 (s, IH), 8.86 (d, IH).LC/MS (method 2): R, = 1.23 min; MS (ESIpos): m/z = 272 [M+H]+.
38% With potassium carbonate In DMF (N,N-dimethyl-formamide) at 75℃; for 4 h; A modified procedure from WO 99/35146, p. 61 WAS followed. 5-nitroindazole (3.915 g, 24 mmol) treated with potassium carbonate (3.65 g, 1.1 equiv. ), and 3-fluorobenzyl bromide (5 g, 1.1 equiv. ) in 41 ml of dry DMF under N2. Reaction mixture is stirred at 75 °C for 4 hours. The crude product (yellow solid, 5.536 g) is isolated as in the reference procedure. Acetone (26 ml) is added to the crude product, and the insoluble solids are filtered off. To filtered solution is added water dropwise (12 ml) upon which an oil forms. The mixture is store in freezer at-20 C for 15 min, upon which the oil solidifies and remains solid after warming to r. t. Chromatography of the solid (silica, 0-10percent ETOAC/HEXANES) afforded 2.49 g of high Rf material (1-H regioisomer, 9.2 mmol, 38percent), 0.7 g of the low Rf material. (2-H isomer, 11 percent) and mixed fractions (0.71 g, 3percent).
32% With potassium carbonate In acetonitrile at 70℃; for 12 h; 5-nitroindazole (15 g, 92 mmol, 1 eq), 3-fluorobenzylbromide (14.7 mL, 119.5 mmol, 1.3 eq) and potassium carbonate 25.4 g (184 mmol, 2 equiv) were suspended in 150 mL acetonitrile. The reaction mixture was stirred at 70° C. for 12 h, and then allowed to cool to rt. The resultant solid was filtered and washed with CH2Cl2, and the filtrate concentrated in vacuo. The crude mixture of regioisomeric products was purified by column:chromatography (5:1 to 4:1 Hex/EtOAc), yielding 5-nitro-1-N-(3-fluorobenzyl)indazole (7.9 g, 32percent) and 5-nitro-2-N-(3-fluorobenzyl)indazole (9.2 g, 37percent) as yellow solids.
Reference: [1] Patent: WO2009/33581, 2009, A1, . Location in patent: Page/Page column 61
[2] Patent: WO2004/46101, 2004, A2, . Location in patent: Page 43
[3] Patent: US2010/298297, 2010, A1, . Location in patent: Page/Page column 14; 15
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YieldReaction ConditionsOperation in experiment
46%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1 h;
Stage #2: at 0 - 20℃; for 12 h;
Sodium hydride (NaH) 95percent (0.81 g, 34.1 mmol) was added to a solution of 5-nitro-lH- indazole Compound 4a (5.3 g, 32.5 mmol) in DMF (33 mL) at 0 0C under nitrogen. The mixture was stirred for 1 hour at RT, then l-bromomethyl-3-fluoro-benzene Compound 4b(6.14 g, 32.5 mmol) was added dropwise at 0 0C. After stirring at RT for 12 hours, the reaction mixture was partitioned between ethyl acetate and icy water. The organic layer was washed with water, brine, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (100percent dichloromethane) to yield l-(3-fluoro-benzyl)-5-nitro-lH-indazole Compound 4c (4.02 g, 46percent) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.76-8.75 (IH, m), 8.27-8.23 (2H, m), 7.40-7.38 (IH, m), 7.33-2.27 (IH, m), 7.01-6.97 (2H, m), 6.89-6.86 (IH, m), 5.64 (2H, s); MS (ES+) m/z 272.1 (MH+).
Reference: [1] Patent: WO2006/118749, 2006, A1, . Location in patent: Page/Page column 96
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YieldReaction ConditionsOperation in experiment
38% With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 4 h; Step A:
1-(3-Fluoro-benzyl)-5-nitro-1 H-indazole
A modified procedure from WO 99/35146, p. 61was followed. 5-nitroindazole (3.915 g, 24 mmol) treated with potassium carbonate (3.65 g, 1.1 equiv.), and 3-fluorobenzyl bromide (5 g, 1.1 equiv.) in 41 ml of dry DMF under N2.
Reaction mixture is stirred at 75° C. for 4 hours.
The crude product (yellow solid, 5.536 g) is isolated as in the reference procedure.
Acetone (26 ml) is added to the crude product, and the insoluble solids are filtered off.
To filtered solution is added water dropwise (12 ml) upon which an oil forms.
The mixture is store in freezer at -20 C for 15 min, upon which the oil solidifies and remains solid after warming to r.t.
Chromatography of the solid (silica, 0-10percent EtOAc/hexanes) afforded 2.49 g of high Rf material (1-H regioisomer, 9.2 mmol, 38percent), 0.7 g of the low Rf material (2-H isomer, 11percent) and mixed fractions (0.71 g, 3percent).
Reference: [1] Patent: US2005/101617, 2005, A1, . Location in patent: Page/Page column 12-13
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YieldReaction ConditionsOperation in experiment
32% With potassium carbonate In acetonitrile at 70℃; for 12 h; Preparation of 5-amino-l-,/V-(3-fluorobenzyl) indazole; 5-nitroindazole (15 g, 92 mmol, 1 eq), 3-fluorobenzylbromide (14.7 mL,119.5 mmol, 1.3 eq) and potassium carbonate 25.4 g (184 mmol, 2 equiv) were suspended in 150 mL acetonitrile. The reaction mixture was stirred at 70 °C for 12h, and then allowed to cool to rt. The resultant solid was filtered and washed with CH2Cl2, and the filtrate concentrated in vacuo. The crude mixture of regioisomeric products was purified by column chromatography (5: 1 to 4: 1 Hex/EtOAc), yielding 5-nitro-1-N-(3-fluorobenzyl) indazole (7.9 g, 32percent) and 5-nitro-2-N-(3-fluorobenzyl) indazole (9.2 g, 37percent) as yellow solids.5-nitro-1-N-(3-fluorobenzyl) indazole (7.9 g, 29.1 mmol, 1 equiv) and iron (8.13 g , 145.6 mmol, 5 equiv) were mixed in 200 mL acetic acid and 50 mL EtOAc, and were stirred at rt for 36 h. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo to 10 mL volume. The contents were diluted with water (10 mL) and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc (3 x 500 mL), the combined organic layers dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography eluting with hexanes/EtOAC (4: 1 to 3: 1) to give 5-amino-1-N-(3-fluorobenzyl) indazole (5.32 g, 76percent) as a light brown solid. 1H-NMR (DMSO-d6) δ 7.72 (s, 1H), 7.22-7.36 (m, 2H), 6.87-7.05 (m, 3H), 6.70-6.77 (m, 2H), 5.48 (s, 2H), 4.78 (br s, 2H); LCMS RT = 1.66 min; [M+H]+ = 242.2.
Reference: [1] Patent: WO2006/44524, 2006, A1, . Location in patent: Page/Page column 42-43
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YieldReaction ConditionsOperation in experiment
32% With potassium carbonate In acetonitrile at 70℃; for 12 h; 5-nitroindazole (15 g, 92 mmol, 1 eq), 3-fluorobenzylbromide (14.7 mL, 119.5 mmol, 1.3 eq) and potassium carbonate 25.4 g (184 mmol, 2 equiv) were suspended in 150 mL acetonitrile. The reaction mixture was stirred at 70 °C for 12h, and then allowed to cool to rt. The resultant solid was filtered and washed with CH2Cl2, and the filtrate concentrated in vacuo. The crude mixture of regioisomeric products was purified by column chromatography (5:1 to 4:1 Hex/EtOAc), yielding 5-nitro-l-N-(3-fluorobenzyl) indazole (7.9 g, 32percent) and 5-nitro-2-N-(3-fluorobenzyl) indazole (9.2 g, 37percent) as yellow solids. 5-nitro-l-N-(3-fluorobenzyl) indazole (7.9 g, 29.1 mmol, 1 equiv) and iron (8.13 g , 145.6 mmol, 5 equiv) were mixed in 200 mL acetic acid and 50 mL EtOAc, and were stirred at rt for 36 h. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo to 10 mL volume. The contents were diluted with water (10 mL) and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc (3 x 500 mL), the combined organic layers dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography eluting with hexanes/EtOAC (4:1 to 3:1) to give 5-amino-l-N-(3- fluorobenzyl) indazole (5.32 g, 76percent) as a light brown solid. 1H-NMR (DMSO-O6) δ 7.72 (s, IH), 7.22-7.36 (m, 2H), 6.87-7.05 (m, 3H), 6.70-6.77 (m, 2H), 5.48 (s, 2H), 4.78 (br s, 2H); LCMS RT = 1.66 min; [M+H]+ = 242.2.
Reference: [1] Patent: WO2006/23843, 2006, A2, . Location in patent: Page/Page column 104-105
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YieldReaction ConditionsOperation in experiment
42% With potassium carbonate In acetoneReflux Step A: l-(3-fluorobenzyl)-5-nitro-lH-indazole (compound 16.1).[0157] A suspension of 5-nitrobenzoindazole (8.16 g, 50 mmol), 3-fluorobenzyl bromide (10.4 g, 55 mmol) and potassium carbonate (13.8 g, 100 mmol) in acetone (200 mL) was refluxed overnight. After reaction cooled to room temperature, the reaction mixture was diluted with dichloromethane (100 mL), filtered through silica gel (about 100 g), and rinsed with 1 :1 ethyl acetate : dichloromethane (about 100 mL). The residue after concentration was purified with column chromatography eluting with 0-30percent ethyl acetate in dichloromethane to give the title compound as a white crystalline solid (the first fraction, 5.69 g, 42percent). LCMS ESI(+) m/z: 272 (M+l).
Reference: [1] Patent: WO2011/2523, 2011, A1, . Location in patent: Page/Page column 63
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YieldReaction ConditionsOperation in experiment
33% With Ki; potassium carbonate In water; N,N-dimethyl-formamide E.
Preparation of 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine
A mixture of 5-nitro-1H-indazole (8.15 gm, 50 mmole), m-fluoro-benzyl chloride (7.95 gm, 1.1 equiv), K2CO3 (7.59 gm, 1.1 equiv), and KI (8.47 gm, 1.02 equiv) in dry DMF (75 mL) was heated at 70° C. overnight.
After cooling to RT, water (75 mL) was slowly added to give a precipitate that consisted of about a one to one mixture of isomers [HPLC Ret Time: 1.92 (1-substitued isomer vs. 2.03 (2-substituted isomer) YMC C18 S5 4.6*50 mm, 3 min gradient, 4 mL/min].
This was collected by filtration and washed with water.
The solid was crystallized twice from acetone/water to afford the desired 1-(3-fluoro-benzyl)-5-nitro-1H-indazole (4.47 gm, 33percent).
A suspension of this material (3.00 gm, 11.1) and 10percent Pd/C (3.00 gm) in EtOH (21 mL) was kept under an H2 atmosphere (balloon) for 24 hr.
The catalyst was removed by filtration and the solvent was evaporated to leave the product as a solid (2.4 gm, 90percent).
1H NMR (CDCl3): δ 3.61 (br s, 2H), 5.52 (s, 2H), 6.81-7.85 (m, 7H), 7.85 (s, 1H); MS: 242 (M+H)+; HPLC Ret Time: 1.03 min (YMC Xterra ODS S7, 3.0*50 mm column, 2 min gradient, 5 mL/min).
Reference: [1] Patent: US2003/186983, 2003, A1,
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Reference: [1] Chinese Chemical Letters, 2011, vol. 22, # 11, p. 1277 - 1280
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