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Product Details of [ 5401-94-5 ]

CAS No. :5401-94-5 MDL No. :MFCD00005693
Formula : C7H5N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :WSGURAYTCUVDQL-UHFFFAOYSA-N
M.W : 163.13 Pubchem ID :21501
Synonyms :

Calculated chemistry of [ 5401-94-5 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 44.92
TPSA : 74.5 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.22 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.65
Log Po/w (XLOGP3) : 1.52
Log Po/w (WLOGP) : 1.47
Log Po/w (MLOGP) : 0.84
Log Po/w (SILICOS-IT) : -0.16
Consensus Log Po/w : 0.86

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.3
Solubility : 0.821 mg/ml ; 0.00503 mol/l
Class : Soluble
Log S (Ali) : -2.69
Solubility : 0.331 mg/ml ; 0.00203 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.28
Solubility : 0.852 mg/ml ; 0.00522 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.73

Safety of [ 5401-94-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5401-94-5 ]

* 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.

  • Upstream synthesis route of [ 5401-94-5 ]
  • Downstream synthetic route of [ 5401-94-5 ]

[ 5401-94-5 ] Synthesis Path-Upstream   1~49

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Reference: [1] Journal of the Chemical Society, 1955, p. 2412,2419
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YieldReaction ConditionsOperation in experiment
100% With hydrogen In tetrahydrofuran at 25℃; Autoclave; Inert atmosphere Preparation 4
1H-indazol-5-amine
To a 5000 mL autolcave equipped with a H2 inlet, a thermometer, and a mechanical stirrer is added a solution of 5-nitro-1H-indazole (500 g, 3.06 mol) in tetrahydrofuran (THF, 3500 mL), followed by palladium on carbon (10percent, 50 g, 141 mmol).
The resulting mixture is stirred overnight at 25° C. under H2 atmosphere (5 kg pressure).
After it is purged with N2, the mixture is filtered, and the filtrate is concentrated under vacuum to give the title compound (420 g, 100percent) as a brown solid. MS (m/z): 134.1 (M+H).
97% With hydrogen In methanol A mixture of 5-nitro-1H-indazole (25 g, 0.153 mmol, commercially available) and 10percent Pd/C (2.0 g) in MeOH was stirred under H2 (1 atm) overnight. After filtration, the filtrate was concentrated to yield 20 g (97percent) of 1H-indazol-5-amine as a yellow solid.
97% With hydrogen In methanol Example B16
A mixture of 5-nitro-1H-indazole (50 g, 0.31 mol) and 10percent Pd/C (5.0 g) in MeOH (400 mL) was heated under H2 (30 psi) atmosphere overnight.
After the mixture was filtered, the filtrate was concentrated to give 1H-indazol-5-ylamine as a yellow solid (40g, 97percent yield).
1H NMR (300 MHz, DMSO-d6) δ 12.50 (br s, 1H), 7.70 (s, 1H), 7.22 (d, J=6.6 Hz, 1H), 6.77 (d, J=6.6 Hz, 1H), 6.74 (s, 1H), 4.72 (br s, 1 H); MS (ESI) m/z: 134.2 (M+H+).
97% With palladium 10% on activated carbon; hydrogen In methanol A mixture of 5-nitro-lH-indazole (50 g, 0.31 mol) and 10 percent Pd/C (5.0 g) in MeOH (400 mL) was heated under H2 (30 psi) atmosphere overnight. After the mixture was filtered, the filtrate was concentrated to give lH-indazol-5-ylamine as a yellow solid (40 g, 97percent yield). 1H NMR (300 MHz, DMSO-i/6) δ 12.50 (br s, 1 H), 7.70 (s, 1 H), 7.22 (d, J= 6.6 Hz, 1 H), 6.77 (d, J= 6.6 Hz, 1 H), 6.74 (s, 1 H), 4.72 (br s, 1 H); MS (ESI) m z: 134.2 (M+H+).

Reference: [1] Patent: US2012/28984, 2012, A1, . Location in patent: Page/Page column 3
[2] Patent: WO2006/71940, 2006, A2, . Location in patent: Page/Page column 409
[3] Patent: US2008/90856, 2008, A1, . Location in patent: Page/Page column 45
[4] Patent: WO2013/36232, 2013, A2, . Location in patent: Paragraph 00321
[5] MedChemComm, 2016, vol. 7, # 5, p. 881 - 899
[6] Bioorganic Chemistry, 2019, vol. 82, p. 340 - 359
[7] Tetrahedron, 2008, vol. 64, # 28, p. 6711 - 6723
[8] Organic Letters, 2016, vol. 18, # 11, p. 2774 - 2776
[9] Tetrahedron Letters, 2017, vol. 58, # 49, p. 4632 - 4637
[10] Chemische Berichte, 1922, vol. 55, p. 1141,1157
[11] Justus Liebigs Annalen der Chemie, 1927, vol. 454, p. 306
[12] Journal of the Chemical Society, 1955, p. 2412,2419
[13] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 7, p. 925 - 930
[14] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2014, vol. 132, p. 733 - 742
[15] Patent: WO2016/57834, 2016, A1, . Location in patent: Paragraph 000325
[16] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2372 - 2380
  • 3
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Reference: [1] Patent: US2003/153596, 2003, A1,
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  • [ 55919-82-9 ]
Reference: [1] Patent: US2012/28984, 2012, A1,
  • 5
  • [ 27996-87-8 ]
  • [ 5401-94-5 ]
YieldReaction ConditionsOperation in experiment
90% With hydrazine hydrate In N,N-dimethyl-formamide at 23℃; for 2 h; Inert atmosphere General procedure: To a stirred solution of 5 or 6 (1.0 mmol) in DMF (5 mL) at 23 °C was added NH2NH2.H2O(3.0 mmol for 5, 2.0 mmol for 6). The solution was stirred at 23 °C for 2 h at which time thinlayer chromatography (TLC, 20percent EtOAc in hexanes) indicated complete consumption of the startingcarbonyl compound. The crude mixture was added to water and extracted with EtOAc (2 Χ 15 mL).The combined organic layers were washed with water and saturated aq NaCl, dried (MgSO4), filtered,and concentrated under vacuum to give the pure indazole products.
Reference: [1] Molecules, 2018, vol. 23, # 3,
[2] Organic Process Research and Development, 2011, vol. 15, # 3, p. 565 - 569
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Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2339 - 2352
[2] MedChemComm, 2016, vol. 7, # 5, p. 881 - 899
[3] Chemische Berichte, 1904, vol. 37, p. 2583
[4] Chemische Berichte, 1920, vol. 53, p. 1213,1216, 1227
[5] Organic Syntheses, 1940, vol. 20, p. 73
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  • [ 129488-09-1 ]
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Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 9, p. 1071 - 1074
[2] Synthetic Communications, 2006, vol. 36, # 14, p. 2069 - 2077
  • 8
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Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 39, p. 6890 - 6892
[2] Heterocycles, 2018, vol. 96, # 1, p. 74 - 85
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Reference: [1] Organic Process Research and Development, 2014, vol. 18, # 7, p. 886 - 890
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Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1928, vol. <2> 118, p. 74,90
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Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1928, vol. <2> 118, p. 74,90
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YieldReaction ConditionsOperation in experiment
92%
Stage #1: With sodium hydroxide In water
Stage #2: With sodium hypochlorite In water at 0℃; for 5.25 h;
Stage #3: With hydrogenchloride In water
EXAMPLE 112A
3-chloro-5-nitro-1H-indazole
A mixture of NaOH (5.00 g, 125 mmol) in H2O (150 mL) was added 5-nitroindazole (5.00 g, 30.7 mmol), and the mixture was heated until a red solution formed.
The mixture was cooled in an ice-water bath for 15 minutes, NaClO (60.0 mL, 5.25percent, 45.0 mmol) was added and the mixture stirred at 0° C. for 5 hour after which the pH was adjusted to 7 with diluted HCl.
The mixture was extracted with ethyl acetate, and the combined organic layer washed with H2O and concentrated under reduced pressure.
The residue was purified by flash chromatography to provide the title compound (5.5 g, 92percent).
1H NMR (300 MHz, DMSO-d6) ppm 7.78 (m, 1H), 8.28 (m, 1H), 8.61 (m, 1H), MS (DCI/NH3) m/z 197[M+H]+.
92%
Stage #1: With sodium hydroxide In water at 0℃; for 0.25 h; Heating
Stage #2: With sodium hypochlorite In water at 0℃; for 5 h;
Stage #3: With hydrogenchloride In water
Example 112; 1-[3-chloro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-yl]-3-(4-phenoxy-phenyl)-urea; Example 112A; 3-chloro-5-nitro-1H-indazole; A mixture of NaOH (5.00 g, 125 mmol) in H2O (150 mL) was added 5-nitroindazole (5.00 g, 30.7 mmol), and the mixture was heated until a red solution formed. The mixture was cooled in an ice-water bath for 15 minutes, NaClO (60.0 mL, 5.25percent, 45.0 mmol) was added and the mixture stirred at 0° C. for 5 hour after which the pH was adjusted to 7 with diluted HCl. The mixture was extracted with ethyl acetate, and the combined organic layer washed with H2O and concentrated under reduced pressure. The residue was purified by flash chromatography to provide the title compound (5.5 g, 92percent). 1H NMR (300 MHz, DMSO-d6) ppm 7.78 (m, 1H), 8.28 (m, 1H), 8.61 (m, 1H), MS (DCI/NH3) m/Z 197[M+H]+.
Reference: [1] Patent: US2005/137243, 2005, A1, . Location in patent: Page/Page column 47
[2] Patent: US2005/277638, 2005, A1, . Location in patent: Page/Page column 48
[3] European Journal of Medicinal Chemistry, 1983, vol. 18, # 5, p. 469 - 470
[4] Journal of Chemical Research, Miniprint, 1990, # 11, p. 2601 - 2615
[5] European Journal of Medicinal Chemistry, 1986, vol. 21, # 4, p. 359 - 362
[6] Justus Liebigs Annalen der Chemie, 1927, vol. 451, p. 285,302
[7] Journal of Medicinal Chemistry, 2003, vol. 46, # 26, p. 5663 - 5673
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Reference: [1] Patent: US2004/9968, 2004, A1,
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  • [ 50593-68-5 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With sodium hydroxide In waterHeating / reflux
Stage #2: With sodium hypochlorite In water at 0℃; for 5.25 h;
Stage #3: With hydrogenchloride In water
EXAMPLE 115A
3-chloro-6-nitro-1H-indazole
A mixture of NaOH (5.0 g) in H2O (150 mL) was added 5-nitroindazole (5.0 g, 31 mmol), and the mixture heated until a red solution formed.
The mixture was placed in an ice-water bath for 15 minutes after which NaClO (60 mL, 5.25percent, 45 mmol) was added.
The mixture was stirred at 0° C. for 5 hours after which the pH was adjusted to 7 with diluted HCl.
The mixture was extracted with ethyl acetate, and the combined organic layer was washed with H2O and concentrated under reduced pressure.
The residue was purified by flash chromatography to provide the title compound (5.5 g, 92percent).1H NMR (300 MHz, DMSO-d6) ppm 7.93 (m, 1H), 8.02 (m, 1H), 8.50 (m, 1H), 14.01 (s, 1H); MS (DCI/NH3) m/Z 197[M+H]+.
Reference: [1] Patent: US2005/137243, 2005, A1, . Location in patent: Page/Page column 48
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YieldReaction ConditionsOperation in experiment
95% With bromine In N,N-dimethyl-formamide at -5 - 40℃; for 12 h; Inert atmosphere (1) 50 g of 5-nitro-lH-indazole was added to a three-necked reaction flask under nitrogen atmosphere; (2) Add 500 ml of N, N-dimethylformamide to the three-necked flask and stir the mixture; (3) The temperature of the entire reaction system in the three reaction vials was reduced to -5 ° C; (4) 55.8 g of liquid bromine was slowly added dropwise at -5 ° C and incubated for 1 hour at 0 to -5 ° C. (5) The reaction system was slowly warmed to 35 ° C to 40 ° C and maintained at this temperature for 11 hours; (6) The remaining amount of 5-nitro-1H-indazole was measured by high performance liquid chromatography (HPLC). When the remaining amount was less than 0.16percent, the reaction reached the end point. 300 ml of soft water was added to the system, The reaction product was filtered below 10 ° C and the filter cake was washed once again with 50 ml of soft water to give the crude product. (7) The filtered crude product was added to a 500 ml three-necked reaction flask and 250 ml of water and 200 ml of an ethanol mixed solution were added and the temperature was raised to reflux. When the solid in the bottle was completely dissolved, 1.5 g of activated charcoal and 1 g EDTA (Ethylenediamine tetraacetic acid), and then reflux for 30 minutes, stop heating, heat filtered out of activated carbon, then the filtrate transferred to a clean three bottles, the filtrate cooled to 5 ° C below, fully stirred for 90 minutes, the crystal completely precipitated , The crystals were filtered off to give the final product 3-bromo-5-nitro-1H-indazole (8) The product was dried and weighed to 70 g, and the product yield was 95percent.
77% With bromine In acetic acid Example 22
3-Bromo-5-nitroindazole:
5-Nitroindazole (10 g, 61.3 mmol) was dissolved in acetic acid (170 mL) and the mixture heated to 80° C. Bromine (3.1 mL, 60.7 mmol) was added slowly and the mixture heated to reflux.
After 2 hours, the reaction mixture was allowed to cool to room temperature, and the resulting precipitate filtered off.
Additional product was isolated by concentrating the filtrate, partitioning the residue between chloroform and saturated sodium bicarbonate solution, separating and drying the organic phase over sodium sulfate.
Concentration gave a solid which was combined with the original precipitate to give the title compound as a yellow solid (11.4 g, 77percent).
1H NMR δ 7.74 (1H, d), 8.21 (1H, dd), 8.40 (1H, d), 14.06 (1H, brs); MS (ES-) m/e=240.
55%
Stage #1: With sodium hydroxide In water
Stage #2: With pyridinium perbromide hydrobromide In methanol; water at 0℃; for 5.25 h;
Stage #3: With hydrogenchloride In water
EXAMPLE 113A
3-bromo-5-nitro-1H-indazole
A mixture of NaOH (2.0 g) in H2O (60 mL) was added 5-nitroindazole (2.0 g, 12 mmol), and the mixture was heated until a red solution formed.
The mixture was placed in an ice-water bath for 15 minutes after which pyridinium tribromide (4.7 g, 15 mmol) in methanol (15 mL) was added.
The mixture was stirred at 0° C. for 5 hours, the pH adjusted to 7 with diluted HCl and the mixture extracted with ethyl acetate.
The combined organic layers were washed with H2O, concentrated under reduced pressure and purified by flash chromatography to provide the title compound (1.6 g, 55percent yield).
1H NMR (300 MHz, DMSO-d6) ppm 7.80 (m, 1H), 8.28 (m, 1H), 8.50 (m, 1H), 14.09 (s, 1H), MS (DCI/NH3) m/z 243[M+H]+.
55%
Stage #1: With sodium hydroxide In water at 0℃; for 0.25 h; Heating
Stage #2: With pyridinium hydrobromide perbromide In methanol; water at 0℃; for 5 h;
Stage #3: With hydrogenchloride In water
Example 113; 1-[3-bromo-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-yl]-3-(4-phenoxy-phenyl)-urea; Example 113A; 3-bromo-5-nitro-1H-indazole; A mixture of NaOH (2.0 g) in H2O (60 mL) was added 5-nitroindazole (2.0 g, 12 mmol), and the mixture was heated until a red solution formed. The mixture was placed in an ice-water bath for 15 minutes after which pyridinium tribromide (4.7 g, 15 mmol) in methanol (15 mL) was added. The mixture was stirred at 0° C. for 5 hours, the pH adjusted to 7 with diluted HCl and the mixture extracted with ethyl acetate. The combined organic layers were washed with H2O, concentrated under reduced pressure and purified by flash chromatography to provide the title compound (1.6 g, 55percent yield). 1H NMR (300 MHz, DMSO-d6) ppm 7.80 (m, 1H), 8.28 (m, 1H), 8.50 (m, 1H), 14.09 (s, 1H), MS (DCI/NH3) m/z 243[M+H]+.
19% With sodium hydroxide; bromine In 1,4-dioxane; water at 0 - 20℃; for 4 h; A solution of bromine (0.75 ml, 14.6 mmol) in a 2N-aqueous sodium hydroxide solution (20 ml) was added dropwise to a mixed solution of 5-nitro-1H-indazole (3.26 g, 20.0 mmol), dioxane (60 ml) and a 2N-aqueous sodium hydroxide solution (30 ml) at 0°C and stirred at 0°C for 30 minutes and then at room temperature for 3.5 hours. An aqueous sodium hydrogensulfite solution was added thereto until a solid was precipitated, to terminate the reaction, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous sodium thiosulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was suspended in ethyl acetate and extracted with a 0.1N-aqueous sodium hydroxide solution. After 6 times of the extraction, the combined aqueous layer was acidified with hydrochloric acid and then re-extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 3-bromo-5-nitro-1H-indazole (0.93 g, 19percent) was obtained.1H-NMR (DMSO-d6) δ; 7.79 (1H, d, J=9.2Hz), 8.26 (1H, dd, J=2.2, 9.4Hz), 8.48 (1H, d, J=2.2Hz), 14.03 (1H, br).

Reference: [1] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 12, p. 1258 - 1263
[2] Patent: CN103570624, 2016, B, . Location in patent: Paragraph 0019-0029
[3] Patent: US2002/103229, 2002, A1,
[4] Patent: US2004/127536, 2004, A1,
[5] Patent: US2005/9876, 2005, A1,
[6] European Journal of Medicinal Chemistry, 1986, vol. 21, # 4, p. 359 - 362
[7] Synthesis, 2011, # 16, p. 2651 - 2663
[8] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 11, p. 2029 - 2034
[9] Patent: US2004/9968, 2004, A1,
[10] Patent: US2005/137243, 2005, A1, . Location in patent: Page/Page column 47
[11] Patent: US2005/277638, 2005, A1, . Location in patent: Page/Page column 48
[12] Patent: EP1403255, 2004, A1, . Location in patent: Page 133
[13] Patent: EP1380576, 2004, A1, . Location in patent: Page 61
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  • [ 50593-24-3 ]
Reference: [1] Heterocycles, 2006, vol. 68, # 12, p. 2595 - 2605
[2] Heterocycles, 2006, vol. 68, # 12, p. 2595 - 2605
[3] Journal of Chemical Research, Miniprint, 1990, # 11, p. 2601 - 2615
[4] Justus Liebigs Annalen der Chemie, 1927, vol. 454, p. 306
[5] Patent: WO2013/100632, 2013, A1,
[6] Patent: US2014/371219, 2014, A1,
[7] Synthetic Communications, 2015, vol. 45, # 17, p. 2005 - 2013
[8] Patent: WO2016/57834, 2016, A1,
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  • [ 5228-49-9 ]
YieldReaction ConditionsOperation in experiment
58%
Stage #1: With caesium carbonate In tetrahydrofuran at 0℃; for 0.25 h;
Stage #2: at 0℃;
General procedure: Cesium carbonate (12.26mmol) was added to a solution of 5-nitroindazole 1 (6.13 mmol) in tetrahydrofuran (THF;25mL)cooledat 0°C. After 15 mn at 0°C, MeI or allyl bromide(6.13mmol) was added dropwise. Upon disappearance of the starting materialas indicated by TLC,the resulting mixture was evaporated.The crude material was dissolved with EtOAc(50mL),washed with water and brine,and dried over MgSO4; and the solvent was removed in vacuo.The resulting residue was purified by column chromatography on silica gel using EtOAc=hexane(3:7) to afford the desired products,1-alkyl-5-nitroindazole followed by2-alkyl-5-nitroindazole.
42%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃;
Stage #2: at 0 - 20℃; for 3 h;
NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0° C. Separately, 5-nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1-methyl added (Rf=0.3), 2-methyl added (Rf=0.1)) was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v)) to obtain the title compound (Rf=0.3, 2.29 g, 42percent). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 8.74 (d, 1H), 8.31 (dd, 1H), 8.20 (s, 1H), 7.47 (d, 1H), 4.15 (s, 3H) MS (ESI+, m/z): 178 [M+H]+
Reference: [1] Synthetic Communications, 2015, vol. 45, # 17, p. 2005 - 2013
[2] Tetrahedron, 2008, vol. 64, # 28, p. 6711 - 6723
[3] Patent: US2014/371219, 2014, A1, . Location in patent: Paragraph 0659; 0660; 0661
[4] Patent: WO2016/57834, 2016, A1, . Location in patent: Paragraph 000406
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YieldReaction ConditionsOperation in experiment
28%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃;
Stage #2: at 0 - 20℃; for 3 h;
General procedure: NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0° C. Separately, 5-nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1-methyl added (Rf=0.3), 2-methyl added (Rf=0.1)) was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v)) to obtain the title compound (Rf=0.3, 2.29 g, 42percent).
Reference: [1] Patent: US2014/371219, 2014, A1, . Location in patent: Paragraph 0659; 0668
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Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 13, p. 1661 - 1663
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  • [ 5228-48-8 ]
Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 10, p. 4093 - 4095
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  • [ 5228-49-9 ]
Reference: [1] Heterocycles, 2006, vol. 68, # 12, p. 2595 - 2605
[2] Journal of Chemical Research, Miniprint, 1990, # 11, p. 2601 - 2615
[3] Justus Liebigs Annalen der Chemie, 1927, vol. 454, p. 306
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Reference: [1] Chemische Berichte, 1904, vol. 37, p. 2583
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  • [ 74-88-4 ]
  • [ 5228-48-8 ]
  • [ 5228-49-9 ]
YieldReaction ConditionsOperation in experiment
58%
Stage #1: With caesium carbonate In tetrahydrofuran at 0℃; for 0.25 h;
Stage #2: at 0℃;
General procedure: Cesium carbonate (12.26mmol) was added to a solution of 5-nitroindazole 1 (6.13 mmol) in tetrahydrofuran (THF;25mL)cooledat 0°C. After 15 mn at 0°C, MeI or allyl bromide(6.13mmol) was added dropwise. Upon disappearance of the starting materialas indicated by TLC,the resulting mixture was evaporated.The crude material was dissolved with EtOAc(50mL),washed with water and brine,and dried over MgSO4; and the solvent was removed in vacuo.The resulting residue was purified by column chromatography on silica gel using EtOAc=hexane(3:7) to afford the desired products,1-alkyl-5-nitroindazole followed by2-alkyl-5-nitroindazole.
42%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃;
Stage #2: at 0 - 20℃; for 3 h;
NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0° C. Separately, 5-nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1-methyl added (Rf=0.3), 2-methyl added (Rf=0.1)) was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v)) to obtain the title compound (Rf=0.3, 2.29 g, 42percent). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 8.74 (d, 1H), 8.31 (dd, 1H), 8.20 (s, 1H), 7.47 (d, 1H), 4.15 (s, 3H) MS (ESI+, m/z): 178 [M+H]+
Reference: [1] Synthetic Communications, 2015, vol. 45, # 17, p. 2005 - 2013
[2] Tetrahedron, 2008, vol. 64, # 28, p. 6711 - 6723
[3] Patent: US2014/371219, 2014, A1, . Location in patent: Paragraph 0659; 0660; 0661
[4] Patent: WO2016/57834, 2016, A1, . Location in patent: Paragraph 000406
  • 24
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  • [ 74-88-4 ]
  • [ 5228-49-9 ]
YieldReaction ConditionsOperation in experiment
83%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h;
Stage #2: at 0 - 20℃; for 18 h;
Sodium hydride (55.0 mmol) was added to a solution of 5-nitro-1H-indazole (18.40 mmol) inN,N-dimethylformamide (50 mL) and the mixture was maintained for 60 min at 0 °C. To the mixture was added Methyl iodide (22.12 mmol) was added and the reaction mixture was allowed to warm to rt and was maintained for 18 h. The reaction mixture was quenched with water (60 mL), filtered through Celite, and the filtrate was concentrated to provide l-methyl-5-nitro-1H-indazole in 83percent yield as a yellow solid.
83%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h;
Stage #2: at 0 - 20℃;
Intermediate 40: Synthesis of l-methyl-lH-indazole-5-sulfonyl chloride.1. Synthesis of 1 -methγl-5-nitro- lH-indazole.Sodium hydride (55.0 mmol) was added to a solution of 5-nitro-lH-indazole (18.40 mmol) in N.jV-dimethylformamide (50 mL) and the mixture was maintained for 60 min at 0 0C. To the mixture was added Methyl iodide (22.12 mmol) was added and the reaction mixture was allowed to warm to rt and was maintained for 18 h. The reaction mixture was quenched with water (60 mL), filtered through Celite, and the filtrate was concentrated to provide l-methyl-5- nitro-1/f-indazole in 83percent yield as a yellow solid.
83%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h;
Stage #2: at 20℃; for 18 h;
Intermediate 40: Synthesis of l-methyl-l//-indazole-5-sulfonyl chloride. 1. Synthesis of l-methyl-5-nitro-lH-indazole.Sodium hydride (55.0 mmol) was added to a solution of 5-nitro-lH-indazole (18.40 mmol) in N,N-dimethylformamide (50 mL) and the mixture was maintained for 60 min at 0 0C. To the mixture was added Methyl iodide (22.12 mmol) was added and the reaction mixture was allowed to warm to rt and was maintained for 18 h. The reaction mixture was quenched with water (60 mL), filtered through Celite, and the filtrate was concentrated to provide l-methyl-5- nitro-l//-indazole in 83percent yield as a yellow solid.
55%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5 h;
Stage #2: at 20℃;
Step 1: Preparation of l-methyl-5-nitro-lH-indazoleSodium hydride (5.40 g, 0.135 mol) is added portionwise to a solution of 5- nitroindazole (20.0 g, 0.122 mol) in DMF (250 mL) at room temperature. The reaction is <n="20"/>stirred for 30 minutes, iodomethane (8.40 mL, 0.135 mol) added dropwise, and the mixture allowed to react overnight at room temperature. The solvent is then removed in vacuo and the residue diluted with ethyl acetate, washed with water and brine, the organic layer dried (Mg2SO4) and evaporated. The residue is purified by flash chromatography (20percent EtOAc/Hexanes) to give the title compound (12.0 g, 55percent); HPLC (SYMMETRY C18 3.5 μM, 4.6 x 30 mm column; gradient elution 2percent-98percent MeCN with 0.1percent TFA over 10 min; 2 mL/min rate): retention time = 4.29 min; MS for C8H7N3O2 m/z 178.2(M+H)+.
42% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 3 h; NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0°C. Separately, 5- nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1 -methyl added (Rf = 0.3), 2-methyl added (Rf = 0.1)) was purified using silica gel chromatography (ethyl acetate:hexane = 1 : 1 (v/v)) to obtain the title compound (Rf = 0.3, 2.29 g, 42percent). -NMR Spectrum (300 MHz, DMSO- ): δ 8.74 (d, 1H), 8.31 (dd, 1H), 8.20 (s, 1H), 7.47 (d, 1H), 4.15 (s, 3H) MS(ESI+, m/z): 178 [M+H]+

Reference: [1] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 132
[2] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 97
[3] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 114; 115
[4] Journal of Organic Chemistry, 2014, vol. 79, # 16, p. 7286 - 7293
[5] Patent: WO2007/88478, 2007, A1, . Location in patent: Page/Page column 18-19
[6] Patent: WO2013/100632, 2013, A1, . Location in patent: Page/Page column 94; 95
[7] Journal of Chemical Research, 2014, vol. 38, # 4, p. 202 - 207
[8] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2015, vol. 136, # PC, p. 1484 - 1490
[9] Journal of Molecular Structure, 2016, vol. 1119, p. 151 - 156
  • 25
  • [ 5401-94-5 ]
  • [ 74-88-4 ]
  • [ 6850-23-3 ]
  • [ 5228-49-9 ]
Reference: [1] Russian Journal of General Chemistry, 2018, vol. 88, # 3, p. 425 - 429[2] Zh. Obshch. Khim., 2018, vol. 88, # 3, p. 397 - 401,5
  • 26
  • [ 77-78-1 ]
  • [ 5401-94-5 ]
  • [ 5228-48-8 ]
  • [ 5228-49-9 ]
Reference: [1] Heterocycles, 2006, vol. 68, # 12, p. 2595 - 2605
[2] Journal of Chemical Research, Miniprint, 1990, # 11, p. 2601 - 2615
[3] Justus Liebigs Annalen der Chemie, 1927, vol. 454, p. 306
  • 27
  • [ 5401-94-5 ]
  • [ 78155-76-7 ]
Reference: [1] Monatshefte fur Chemie, 2017, vol. 148, # 2, p. 305 - 314
  • 28
  • [ 5401-94-5 ]
  • [ 23856-21-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 4, p. 1107 - 1131
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1401 - 1405
[3] Chinese Chemical Letters, 2011, vol. 22, # 11, p. 1277 - 1280
[4] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 316 - 336
  • 29
  • [ 100-39-0 ]
  • [ 5401-94-5 ]
  • [ 23856-20-4 ]
YieldReaction ConditionsOperation in experiment
44% With potassium carbonate In acetonitrile at 70℃; To a solution of 5-nitroindazole (10.0 g, 61.3 MMOL) in acetonitrile (100 mL) was added potassium carbonate (16.9 g, 122.6 MMOL) and benzyl bromide (13.6 g, 79.7 MMOL). The resulting yellow reaction mixture was heated with stirring at 70°C overnight. Upon cooling down, the solid was filtered off and washed with methylene chloride. The filtrate was concentrated to dryness and the resulting residue was purified by flash chromatography eluting with 17-25percent ethyl acetate in hexanes (v/v) yielding 7.0 g (44percent) of the corresponding 1-Benzyl-5-nitro-1 H-indazole as a yellow solid. 7.61g (136 MMOL, 5 equiv) of Iron powder (4.03 g, 72.1 MMOL) was added slowly to the solution of 1-BENZYL-5-NITRO-1 H-INDAZOLE (6. 9 g, 27.2 MMOL) in acetic acid (200 mL). After stirring at room temperature overnight, the reaction mixture became milky with formation of a white precipitate. The precipitate was filtered off and the filtrate was concentrated to ca. 20 mL. The residue was diluted with water (200 mL) and neutralized by slow addition of sodium hydroxide. The mixture was then extracted with ethyl acetate (500x5 mL). The organic layer were combined, dried over sodium sulfate, filtered and concentrated to dryness to afford 1-BENZYL-1 H-INDAZOL-5-YLAMINE (5.23 g, 82percent) as a brown SOLID. H NMR (DMSO-D6) : 8 7.72 (s, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.24-7. 14 (m, 5H), 6.74 (m, 2H), 5.49 (s, 2H), 4.80 (br, 2H). ES-LCMS: RT = 0.93 min; [M+H] + = 224.2.
Reference: [1] Patent: WO2005/10008, 2005, A1, . Location in patent: Page/Page column 117-118
  • 30
  • [ 100-39-0 ]
  • [ 5401-94-5 ]
  • [ 187668-23-1 ]
  • [ 23856-20-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 4, p. 1107 - 1131
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1401 - 1405
[3] Patent: US9199973, 2015, B2, . Location in patent: Page/Page column 39
  • 31
  • [ 5401-94-5 ]
  • [ 187668-23-1 ]
  • [ 23856-20-4 ]
Reference: [1] Patent: US2003/139416, 2003, A1,
  • 32
  • [ 100-44-7 ]
  • [ 5401-94-5 ]
  • [ 23856-20-4 ]
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 316 - 336
  • 33
  • [ 100-44-7 ]
  • [ 5401-94-5 ]
  • [ 23856-20-4 ]
Reference: [1] Chinese Chemical Letters, 2011, vol. 22, # 11, p. 1277 - 1280
  • 34
  • [ 5401-94-5 ]
  • [ 41330-49-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 26, p. 5663 - 5673
[2] Journal of Chemical Research, Miniprint, 1990, # 11, p. 2601 - 2615
  • 35
  • [ 5401-94-5 ]
  • [ 74626-47-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 7, p. 925 - 930
  • 36
  • [ 5401-94-5 ]
  • [ 478837-59-1 ]
Reference: [1] Patent: EP1403255, 2004, A1,
  • 37
  • [ 456-41-7 ]
  • [ 5401-94-5 ]
  • [ 529508-58-5 ]
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
  • 38
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  • [ 529508-58-5 ]
  • [ 884874-01-5 ]
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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  • [ 529508-58-5 ]
  • [ 884874-01-5 ]
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
  • 40
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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
  • 41
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  • [ 5401-94-5 ]
  • [ 529508-58-5 ]
  • [ 833474-48-9 ]
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
  • 42
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  • [ 529508-58-5 ]
  • [ 202197-31-7 ]
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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  • [ 529508-58-5 ]
Reference: [1] Chinese Chemical Letters, 2011, vol. 22, # 11, p. 1277 - 1280
  • 44
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  • [ 129488-10-4 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen In ethanol for 23 h; A suspension of 10percent Pd-C (0.054 g, 0.051 mmol in Pd) and the above carbamate Example 105 (2.647 g, 10.1 mmol) in 95percent EtOH was degassed under reduced pressure then reacted under hydrogen. After 23 h the solvent was evaporated on a rotary evaporator. EtOAc (20 mL) was added and the reaction filtered then slowly EPO <DP n="125"/>concentrated on a rotary evaporator yielding 2.335 g (100percent) of a tan solid.LC- MS (ESI) m/z 134 [M-Boc+H]+.
Reference: [1] Patent: WO2006/135383, 2006, A2, . Location in patent: Page/Page column 123-124
[2] Patent: WO2012/146724, 2012, A2,
[3] Patent: US2014/57942, 2014, A1,
[4] Patent: WO2014/68035, 2014, A1,
[5] Asian Journal of Chemistry, 2014, vol. 26, # 22, p. 7539 - 7543
  • 45
  • [ 24424-99-5 ]
  • [ 5401-94-5 ]
  • [ 129488-10-4 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: With dmap; triethylamine In dichloromethane for 17 h;
Stage #2: With citric acid; sodium chloride In dichloromethane; water
A soln of di-tert-butyl dicarbonate (6.719 g, 30.8 mmol) in DCM (20 mL) was added over 5 min to a suspension of 5-nitro-lH-indazole (5.009 g, 30.7 mmol), Et3N (4.30 mL, 30.9 mmol) and DMAP (0.751 g, 6.15 mmol) in DCM (60 mL). After 17 h the solution was washed with water (1 x 50 mL), 1 M citric acid (3 x 10 mL) and satd NaCl (1 x 20 mL), then dried (MgSO4), filtered through silica, washed with DCM and concentrated to give 7.75 g (96percent) an off-white solid. LC-MS (ESI) m/z 162 [M- Boc-H]-.
Reference: [1] Patent: WO2006/135383, 2006, A2, . Location in patent: Page/Page column 123
[2] Patent: WO2016/57834, 2016, A1,
  • 46
  • [ 68-12-2 ]
  • [ 5401-94-5 ]
  • [ 677702-36-2 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: at 0 - 5℃; for 0.5 h;
Stage #2: at 0 - 20℃; for 3 h;
POCl3 (67.43 mmol) was added dropwise to a stirred solution of 40 cm3 DMF at 0–5 C over a period of15 min. The reaction mixture was allowed on stirring for half an hour at the same temperature. 5-Nitroazaindole(10 g, 61.3 mmol) was dissolved in 10 cm3 DMF and added dropwise to the above Vilsmeier reagent at 0–5 C.Now the reaction mixture was allowed to stand for 3 h at room temperature. The completion of the reaction was known by monitoring the HPLC. The oily residue was poured into crushed ice and NaOH solution was added to this reaction mixture. Yellow color solid was precipitated,filtered, and recrystalized from hot ethanol. Yellow colorsolid; 92 percent yield (10.77 g); m.p.: 215–217 C; IR (neat):m = 3545, 1624, 1537, 1488, 1337, 949, 786,744 cm-1; 1HNMR (DMSO-d6, 400 MHz): d = 13.74 (bs, 1H, NH),8.84 (s, 1H), 8.41 (s, 1H), 8.21–8.18 (d, 1H, J = 10.4 Hz),7.74–7.72 (d, 1H, J = 9.2 Hz) ppm; 13C NMR (DMSO-d6,100 MHz): d = 110, 118, 120, 121, 136, 141, 168 ppm;MS (ESI): m/z = 192 ([M+H]+).
Reference: [1] Monatshefte fur Chemie, 2017, vol. 148, # 2, p. 305 - 314
  • 47
  • [ 76-83-5 ]
  • [ 5401-94-5 ]
  • [ 942189-39-1 ]
YieldReaction ConditionsOperation in experiment
10%
Stage #1: With bromine In methanol
Stage #2: With sodium hydride In N,N-dimethyl-formamide
(S)-N-(3-(6-isopropoxypyridin-3-yl)- 1H-indazol-5-yl)- 1 -(2-(4-(4-(1 -methyl-1H- 1 ,2,4-triazol-3 -yl)phenyl)-3 , 6-dihydropyridin- 1 (2H)-yl)-2-oxoethyl)-3 -(methylthio)pyrrolidine3-carboxamide free base synthesis is a 19 step process. Compound preparation is divided into three intermediate preparations A, B and C followed by coupling of the intermediates. Allintermediates start with commercially available compounds. Compound 5 is prepared by reaction of the commercially available bromo-4-cyanobenzene with methyl hydrazine under acidic conditions to form the hydrazinoimidate 2 in modest yield. After reaction with formic acid in two steps the bromophenyl-N-methyl triazole intermediate 3 is obtained. The tetrahydropyridine ring is introduced by a Suzuki reaction of the commercially available Bocprotected tetrahydropyridine-boronate to obtain the tricyclic ring system 4. Chloroacetamide 5 is obtained in excellent yield by reaction of the deprotected 4 with chloroacetylchloride. The pyrrolidine core lOa is obtained in good yield in 5 steps starting from commercially available 6. Reaction with thionylchloride gave the thiomethyl olefin 7. Cycloaddition (2+3) gives 8 followed by removal of the benzyl protection group to give 9. L-Tartaric acid resolution of thepyrrolidine core gives the pure (5) enantiomer 9 after filtration from methanol. After protection as the Boc derivative and hydrolysis of the methyl ester, 10 is obtained in overall 50percent yield. Compound 17 is obtained from commercially available indazole 11. Bromination at the 3- position of indazole 11 proceeds in excellent yield without chromatography to obtain 12. Suzuki reaction of the bromo compound 12 with 14 gives the nitro indazole 16 after chromatography.Reduction of 16 gives aniline 17 as an oil in quantitative yield without chromatography. The final coupling of the intermediates proceeded by coupling 17 with lOa to obtain 18 in good yield. After deprotection of the Boc and Trityl groups the final coupling with 5 gave (S)-N-(3-(6- isopropoxypyridin-3-yl)- 1H-indazol-5-yl)-1 -(2-(4-(4-(1 -methyl-1H- 1 ,2,4-triazol-3-yl)phenyl)- 3 ,6-dihydropyridin- 1 (2H)-yl)-2-oxoethyl)-3 -(methylthio)pyrrolidine-3 -carboxamide afterchromatography. Final purification is carried out by crystallization from methanol/diethylether.This synthetic route has been conducted on a scale that delivered (S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)- 1 -(2-(4-(4-(1 -methyl-1H- 1 ,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1 (2H)-yl)-2-oxoethyl)-3 -(methylthio)pyrroli dine-3 -carboxamide free base (Compound I).
Reference: [1] Patent: WO2016/100152, 2016, A1, . Location in patent: Page/Page column 8; 10
[2] Patent: WO2016/100147, 2016, A1, . Location in patent: Page/Page column 5; 8
[3] Patent: WO2017/40362, 2017, A1, . Location in patent: Page/Page column 4; 6
  • 48
  • [ 5401-94-5 ]
  • [ 1150617-94-9 ]
Reference: [1] Patent: US2012/28984, 2012, A1,
  • 49
  • [ 5401-94-5 ]
  • [ 1357072-61-7 ]
Reference: [1] Patent: US2012/28984, 2012, A1,
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