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Chemical Structure| 19335-11-6
Chemical Structure| 19335-11-6
Structure of 19335-11-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 19335-11-6 ]

CAS No. :19335-11-6 MDL No. :MFCD00037975
Formula : C7H7N3 Boiling Point : -
Linear Structure Formula :- InChI Key :XBTOSRUBOXQWBO-UHFFFAOYSA-N
M.W : 133.15 Pubchem ID :88012
Synonyms :

Calculated chemistry of [ 19335-11-6 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 2.0
Molar Refractivity : 40.5
TPSA : 54.7 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.4 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.61
Log Po/w (XLOGP3) : 1.01
Log Po/w (WLOGP) : 1.15
Log Po/w (MLOGP) : 0.51
Log Po/w (SILICOS-IT) : 1.36
Consensus Log Po/w : 0.93

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.97
Solubility : 1.43 mg/ml ; 0.0108 mol/l
Class : Very soluble
Log S (Ali) : -1.75
Solubility : 2.38 mg/ml ; 0.0179 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.52
Solubility : 0.404 mg/ml ; 0.00303 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.21

Safety of [ 19335-11-6 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P301+P310+P330-P302+P352-P305+P351+P338 UN#:2811
Hazard Statements:H301-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 19335-11-6 ]

* 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 [ 19335-11-6 ]
  • Downstream synthetic route of [ 19335-11-6 ]

[ 19335-11-6 ] Synthesis Path-Upstream   1~14

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  • [ 15579-15-4 ]
Reference: [1] Journal of the Chemical Society, 1955, p. 2412,2419
[2] Bulletin de la Societe Chimique de France, 1950, p. 466,476
[3] Patent: US2006/58361, 2006, A1, . Location in patent: Page/Page column 34-35
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  • [ 5401-94-5 ]
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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
  • [ 5401-94-5 ]
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Reference: [1] Patent: US2003/153596, 2003, A1,
  • 4
  • [ 99-52-5 ]
  • [ 19335-11-6 ]
Reference: [1] MedChemComm, 2016, vol. 7, # 5, p. 881 - 899
[2] Bioorganic Chemistry, 2019, vol. 82, p. 340 - 359
  • 5
  • [ 7758-89-6 ]
  • [ 19335-11-6 ]
  • [ 698-26-0 ]
Reference: [1] Patent: US2002/161022, 2002, A1,
  • 6
  • [ 19335-11-6 ]
  • [ 55919-82-9 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With hydrogenchloride; sodium nitrite In water at -5 - 2℃; for 1.25 h;
Stage #2: With potassium iodide In water at 90℃; for 1.75 h;
SYNTHETIC PREPARATION 15-Aminoindazole (64.73 g, 486.13 mmol) was suspended in 600 mL water and ca. 600 mL ice, and cone. HCI ( 200 mL, 5759 mmol) was added. The mixture was cooled in an ice-salt bath to ca. -5 0C. To this mixture was added, dropwise, a solution of sodium nitrite (37.34 g, 541.2 mmol) in 200 mL water (took about 1 hr). The internal temperature was kept below ca. +2 0C. The resulting brown solution was stirred for a further 15 min at -5 0C, then a solution of potassium iodide (97 g, 584.34 mmol) in 250 mL water was slowly added dropwise (took about 30 min). After complete addition, the reaction was heated to 90 0C for 1.5 hr. After allowing to cool, the solution was filtered to give a fine black solid and the filtrate was allowed to sit overnight in the refrigerator. The next day the filtrate was filtered again and the two solids were combined and dried to give 5-iodoindazole (126.63 g, 106percent).
90% With hydrogenchloride; potassium iodide; sodium nitrite In water at 0 - 20℃; for 3 h; 6a) 5-Iodo- l H-indazole Sodium nitrite (2.7 g, 39.1 mmol) in water (40 ml) was added dropwise to a solution of 1 -H- indazol-5-amine (5.2 g, 39.1 mmol) in 6 N hydrochloric acid (73.7 ml) at 0 °C. The mixture obtained was in turn added dropwise to a solution of potassium iodide (26.9 g, 162 mmol) in water (60 ml) at 0 °C and the mixture was stirred at room temperature for 3 h. The reaction mixture was then extracted with ethyl acetate (4 x 30 ml) and the combined organic phases were washed with washed with 10percent w/v sodium thiosulfate solution (4 x 30 ml) and brine (2 x 30 ml), dried over magnesium sulfate and concentrated. Brown solid. Yield: 8.64 g (90 percent of theory) ,3C-NMR (101 MHz, CDC13, δ ppm): 84.4, 1 1 1.7, 125.6, 129.9, 133.4, 135.4, 139.0
75% With hydrogenchloride; potassium iodide; sodium nitrite In water at 0 - 20℃; for 3 h; To a solution of 1H-indazol-5-amine (1.41 g, 10.6 mmol) in 6 N HCl (20 mL) cooled to 0° C., a solution of NaNO2 (730 mg, 10.6 mmol) in water (10 mL) was added dropwisely. The resulting solution was added to a solution of Kl (7.3 g, 44 mmol) in water (15 mL), keeping the temperature at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h, then extracted with ethyl acetate. The combined layers were washed in sequence with 10percent Na2S2O3 and brine, then dried over Na2SO4 and concentrated under vacuum to afford product as a pale brown solid (1.90 g, 75percent), which was used without further purification in the next step.; To a solution of 1H-indazol-5-amine (1.41 g, 10.6 mmol) in 6 N HCl (20 mL) cooled to 0° C., a solution of NaNO2 (730 mg, 10.6 mmol) in water (10 mL) was added dropwisely. The resulting solution was added to a solution of KI (7.3 g, 44 mmol) in water (15 mL), keeping the temperature at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h, then extracted with ethyl acetate. The combined layers were washed in sequence with 10percent Na2S2O3 and brine, then dried over Na2SO4 and concentrated under vacuum to afford product as a pale brown solid (1.90 g, 75percent), which was used without further purification in the next step; To a solution of 1H-indazol-5-amine (1.41 g, 10.6 mmol) in 6 N HCl (20 mL) cooled to 0° C., a solution of NaNO2 (730 mg, 10.6 mmol) in water (10 mL) was added dropwisely. The resulting solution was added to a solution of KI (7.3 g, 44 mmol) in water (15 mL), keeping the temperature at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h, then extracted with ethyl acetate. The combined layers were washed in sequence with 10percent Na2S2O3 and brine, then dried over Na2SO4 and concentrated under vacuum to afford product as a pale brown solid (1.90 g, 75percent), which was used without further purification in the next step.
74.2%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 5℃;
Stage #2: With potassium iodide In water at 10 - 50℃; for 1.5 h;
Stage #3: With sodium carbonate In water
Preparation 5
5-iodo-1H-indazole
To a solution of concentrated HCl (1.3 L, 15.8 mol) in water (3.5 L) is added 1H-indazol-5-amine (500 g, 3.8 mol), followed by a solution of NaNO2 (285 g, 4.1 mol) in water (1 L) in portions at 0-5° C.
The resulting red suspension is added slowly to a solution of KI (3.1 kg, 18.7 mol) in water (3 L) at 50° C. to keep gas generation in control.
The resulting mixture is stirred at 50° C. for 1.5 h, cooled to 10° C. and basified to pH 8 with saturated aqueous Na2CO3 solution.
The solids are collected by filtration and redissolved in ETOAc (20 L).
The solution is washed with saturated aqueous Na2SO3 solution (3*5 L), dried over anhydrous Na2SO4 and filter through a short silica gel column.
The filtrate is concentrated under vacuum to provide the title compound (680 g, 74.2percent). MS (m/z): 244.9 (M+H).
25%
Stage #1: With hydrogenchloride; sodium nitrite In water at -5 - 0℃; for 0.25 h;
Stage #2: With potassium iodide In water at 90℃; for 25 h;
A suspected solution of compound 5-amino-i H-indazole in 20 ml water was cooled to0 ° C and then added con.HCI to the reaction mixture and cooled to -5 00, NaNO2 in water was added to the reaction mixture at same temperature and reaction mixture was stirred for 15 mm at the same temperature, then KI in water solution was added to the reaction mixture and Reaction mixture was heated to 90 ° C for 25h.Aftercooling reaction mixture basified with K2003 solution and extracted with Ethyl acetate and washed with water, brine, and dried with Na2SO4 under reduced pressure. To yield the title compound (0.900 g, 25percent as a off white solid. LCMS: (M+H) + = 245.0
18%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.166667 h;
Stage #2: With potassium iodide In water at 40 - 50℃; for 0.5 h;
A solution of 5-aminoindazole (5.0 g, 38 mmol) and ice (32 g) in water (16 mL) was further cooled with an ice bath. To this slurry was added concentrated hydrochloric acid (16 mL), followed immediately by sodium nitrite (2.9 g, 41 mmol in 11 mL water). After stirring for 10 min at 0°C, potassium iodide (7.5 g, 45 mmol) was added and the solution was slowly warmed to 40°C until gas evolution slowed. The reaction mixture was stirred in a 50°C oil bath for 30 min further, then cooled to room temperature and 3M aqueous sodium hydroxide solution (40 mL) was added, followed by 50percent aqueous sodium bicarbonate solution (40 mL). The solution was vacuum filtered and a brown solid was collected, taken up in 100 mL tetrahydrofuran and stirred with 100 mL of dry silica. To this slurry was added hexanes (66 mL), and the mixture was filtered through celite/fritted glass using 40percent tetrahydrofuran/hexanes to rinse the silica. Trituration from ethyl acetate gave 1.6g (18percent) of 5-iodo-lH-indazole. 1H NMR (400 MHz, CDC13): 10.55 (broad s, 1H), 8.14 (m, 1H), 8.02 (d, 1H), 7.61 (dd, 1H), 7.31 (m, 1H); MS (EI) for C7H5N2I: 245 (MH+).
13%
Stage #1: With hydrogenchloride In water; N,N-dimethyl-formamide for 0.333333 h;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 10℃; for 0.5 h;
(Referential Example 11)
Synthesis of 5-iodo-1H-indazole (referential compound 11-1)
At 0°C, 95 ml (570 mmol) of 6N hydrochloric acid was dropped into a solution of 25.0 g (188 mmol) of 5-amino-1H-indazole in 320 ml of N,N-dimethylformamide and the mixture was stirred for 20 minutes.
After that, a solution of 13.6 g (197 mmol) of sodium nitrite in 75 ml of water was dropped thereinto keeping the temperature of the reaction solution at below 10°C throughout.
After stirring for 30 minutes, 32.8 g (198 mmol) of potassium iodide was divisionally added thereto, then a cooling bath was removed to warm up the mixture gradually to room temperature.
After the reaction was finished, the reaction solution was poured into 1,000 ml of water and the mixture was neutralized with an aqueous solution of sodium hydroxide and extracted with 1,500 ml of toluene and then with each 500 ml of the same twice.
The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo.
The resulting residue was subjected to a silica gel column chromatography (eluding solvent: n-hexane: ethyl acetate = 2:1 (v/v)) and the fraction containing the aimed substance was concentrated in vacuo.
Ethyl acetate (50 ml) was added to the resulting crude crystals, the mixture was heated to dissolve it, 300 ml of n-hexane was added thereto and the resulting solid was filtered off to give 5.80 g of the title compound as white powder (yield: 13percent).
Rf value: 0.45 (n-hexane: ethyl acetate = 1:1 (v/v))
Mass spectrum (CI, m/z): 245 (M+ + 1)
1H-NMR spectrum (CDCl3, δ ppm): 7.30 (ddd, J1 = 8.8Hz, J2 = 1.1Hz, J3 = 0.7Hz, 1H), 7.63 (dd, J1 = 8.8Hz, J2 = 1.5Hz, 1H), 8.01 (d, J = 1.1Hz, 1H), 8.14 (dd, J1 = 1.5Hz, J2 = 0.7Hz, 1H), 10.17 (brs, 1H)
13%
Stage #1: With hydrogenchloride In water; N,N-dimethyl-formamide at 0℃; for 0.333333 h;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 10℃; for 0.5 h;
95 ml (570 mmol) of 6 N hydrochloric acid was added dropwise to a solution of 25.0 g (188 mmol) of 5-amino-1H-indazole in 320 ml of N,N-dimethylformamide at 0° C. and the mixture was stirred for 20 minutes.
Then, a solution of 13.6 g (197 mmol) of sodium nitrite in 75 ml of water was added dropwise thereto while keeping the temperature of the reaction solution at not higher than 10° C.
After the mixture was stirred for 30 minutes, 32.8 g (198 mmol) of potassium iodide was added thereto in divided portions, then a cooling bath was removed to warm up the mixture gradually to room temperature.
After the reaction was completed, the reaction solution was poured into 1000 ml of water and the mixture was neutralized with an aqueous solution of sodium hydroxide and extracted with 1500 ml of toluene and then with each 500 ml of toluene twice.
The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The resulting residue was subjected to silica gel column chromatography (eluding solvent: n-hexane:ethyl acetate=2:1 (v/v)) and the fraction containing the desired substance was concentrated under reduced pressure.
50 ml of ethyl acetate was added to the resulting crude crystals, the mixture was heated to dissolve them, 300 ml of n-hexane was added thereto and the resulting solid was collected by filtration, whereby 5.80 g of the title compound was obtained as white powder (yield: 13percent).
Rf value: 0.45 (n-hexane:ethyl acetate=1:1 (v/v))
Mass spectrum (CI, m/z): 245 (M++1)
1H-NMR spectrum (CDCl3, δppm): 7.30 (ddd, J1=8.8 Hz, J2=1.1 Hz, J3=0.7 Hz, 1H), 7.63 (dd, J1=8.8 Hz, J2=1.5 Hz, 1H), 8.01 (d, J=1.1 Hz, 1H), 8.14 (dd, J1=1.5 Hz, J2=0.7 Hz, 1H), 10.17 (brs, 1H)
13%
Stage #1: With hydrogenchloride In water; N,N-dimethyl-formamide at 0℃; for 0.333333 h;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 10℃; for 0.5 h;
Stage #3: With potassium iodide In water; N,N-dimethyl-formamide at 10 - 20℃;
(Reference Example 6)
Synthesis of 5-iodo-1H-indazole (Reference compound 6)
95 ml (570 mmol) of 6 N hydrochloric acid was added dropwise to a solution of 25.0 g (188 mmol) of 5-amino-1H-indazole in 320 ml of N,N-dimethylformamide at 0°C and the mixture was stirred for 20 minutes.
Then, a solution of 13.6 g (197 mmol) of sodium nitrite in 75 ml of water was added dropwise thereto while keeping the temperature of the reaction solution at not higher than 10°C.
After the mixture was stirred for 30 minutes, 32.8 g (198 mmol) of potassium iodide was added thereto in divided portions, then a cooling bath was removed to warm up the mixture gradually to room temperature.
After the reaction was completed, the reaction solution was poured into 1000 ml of water and the mixture was neutralized with an aqueous solution of sodium hydroxide and extracted with 1500 ml of toluene and then with each 500 ml of toluene twice.
The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The resulting residue was subjected to silica gel column chromatography (eluding solvent: n-hexane: ethyl acetate = 2: 1 (v/v)) and the fraction containing the desired substance was concentrated under reduced pressure.
50 ml of ethyl acetate was added to the resulting crude crystals, the mixture was heated to dissolve them, 300 ml of n-hexane was added thereto and the resulting solid was collected by filtration, whereby 5.80 g of the title compound was obtained as white powder
(yield: 13percent).
Rf value: 0.45 (n-hexane: ethyl acetate = 1: 1 (v/v))
Mass spectrum (CI, m/z): 245 (M++1)
1H-NMR spectrum (CDCl3, δppm): 7.30 (ddd, J1=8.8Hz, J2=1.1Hz, J3=0.7Hz, 1H), 7.63 (dd, J1=8.8Hz, J2=1.5Hz, 1H), 8.01 (d, J=1.1Hz, 1H), 8.14 (dd, J1=1.5Hz, J2=0.7Hz, 1H), 10.17 (brs, 1H)

Reference: [1] Patent: WO2008/71451, 2008, A1, . Location in patent: Page/Page column 47
[2] Patent: WO2014/170020, 2014, A1, . Location in patent: Page/Page column 50
[3] Patent: US2009/156590, 2009, A1, . Location in patent: Page/Page column 67; 69; 70
[4] Patent: US2012/28984, 2012, A1, . Location in patent: Page/Page column 3
[5] Patent: WO2014/202580, 2014, A1, . Location in patent: Page/Page column 164
[6] Patent: WO2005/112932, 2005, A2, . Location in patent: Page/Page column 76
[7] Patent: EP1679308, 2006, A1, . Location in patent: Page/Page column 36
[8] Patent: US2009/12123, 2009, A1, . Location in patent: Page/Page column 7
[9] Patent: EP1870099, 2007, A1, . Location in patent: Page/Page column 10-11
[10] Patent: US2002/161022, 2002, A1,
[11] Patent: WO2006/57922, 2006, A2, . Location in patent: Page/Page column 52-53
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Reference: [1] Organic Process Research and Development, 2014, vol. 18, # 7, p. 886 - 890
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  • [ 41330-49-8 ]
Reference: [1] Patent: WO2006/17443, 2006, A2, . Location in patent: Page/Page column 128
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  • [ 74626-47-4 ]
YieldReaction ConditionsOperation in experiment
91% With concentrated aqueous hydrochloric acid; sodium nitrite In water; ethyl acetate A.
1H-Indazole-5-Carbonitrile
To a 1-L beaker was added 20.0 g (150 mmol) of 5-aminoindazole, and 150 g of ice.
The mixture was stirred with a magnetic stir bar and cooled on an ice-water bath.
To this mixture was added 37.5 mL of concentrated aqueous hydrochloric acid, followed by a solution of 10.5 g (152 mmol, 1.01 equiv.) of sodium nitrite in 30 mL of H2O, dropwise over 15 min.
The mixture was vigorously stirred for 30 min. and then carefully neutralized to pH ca. 7.0 with 9.5 g of solid sodium carbonate (Na2CO3).
This mixture was transferred to a 1-L separatory funnel, kept cold by the addition of ice, and added dropwise to an ice cooled, magnetically stirred mixture of 16.8 g (188 mmol, 1.24 equiv.) of copper (1) cyanide (CuCN), 24.4 g (498 mmol, 3.32 equiv.) of sodium cyanide (NaCN), 112 mL H2O, and 250 mL of ethyl acetate (EtOAc) in a 2-L erlenmeyer flask over 20 min.
Nitrogen gas was evolved from the reaction.
The mixture turned dark quickly, and was stirred on ice for 30 min. and then the ice was removed.
Stirring was continued for 3.5 h.
The mixture was then heated on a hot plate until the internal temperature was 50° C.
The reaction was removed from the hot plate and allowed to cool to 35° C, and filtered through filter paper.
The layers were separated, and the organic layer was washed with saturated aqueous NaCl, and dried (Na2SO4).
The organic layer was poured directly onto a 65 mm column containing 200 g of silica gel and eluted with EtOAc.
Fractions of 500 mL were collected, and all product containing fractions were combined and concentrated to give the title compound (19.60 g, 91percent yield): ES-MS (m/z) 144 [M+1]+.
91% With concentrated aqueous hydrochloric acid; sodium nitrite In water; ethyl acetate A.
1H-Indazole-5-carbonitrile
To a 1-L beaker was added 20.0 g (150 mmol) of 5-aminoindazole, and 150 g of ice.
The mixture was stirred with a magnetic stir bar and cooled on an ice-water bath.
To this mixture was added 37.5 mL of concentrated aqueous hydrochloric acid, followed by a solution of 10.5 g (152 mmol, 1.01 equiv.) of sodium nitrite in 30 mL of H2O, dropwise over 15 min.
The mixture was vigorously stirred for 30 min. and then carefully neutralized to pH ca. 7.0 with 9.5 g of solid sodium carbonate (Na2CO3).
This mixture was transferred to a 1-L separatory funnel, kept cold by the addition of ice, and added dropwise to an ice cooled, magnetically stirred mixture of 16.8 g (188 mmol, 1.24 equiv.) of copper (I) cyanide (CuCN), 24.4 g (498 mmol, 3.32 equiv.) of sodium cyanide (NaCN), 112 mL H2O, and 250 mL of ethyl acetate (EtOAc) in a 2-L erlenmeyer flask over 20 min.
Nitrogen gas was evolved from the reaction.
The mixture turned dark quickly, and was stirred on ice for 30 min. and then the ice was removed.
Stirring was continued for 3.5 h.
The mixture was then heated on a hot plate until the internal temperature was 50° C.
The reaction was removed from the hot plate and allowed to cool to 35° C., and filtered through filter paper.
The layers were separated, and the organic layer was washed with saturated aqueous NaCl, and dried (Na2SO4).
The organic layer was poured directly onto a 65 mm column containing 200 g of silica gel and eluted with EtOAc.
Fractions of 500 mL were collected, and all product containing fractions were combined and concentrated to give the title compound (19.60 g, 91percent yield): ES-MS (m/z) 144 [M+1]+.
91% With concentrated aqueous hydrochloric acid; sodium nitrite In water; ethyl acetate A.
1H-Indazole-5-carbonitrile
To a 1-L beaker was added 20.0 g (150 mmol) of 5-aminoindazole, and 150 g of ice.
The mixture was stirred with a magnetic stir bar and cooled on an ice-water bath.
To this mixture was added 37.5 mL of concentrated aqueous hydrochloric acid, followed by a solution of 10.5 g (152 mmol, 1.01 equiv.) of sodium nitrite in 30 m]L of H2O, dropwise over 15 min.
The mixture was vigorously stirred for 30 min. and then carefully neutralized to pH ca. 7.0 with 9.5 g of solid sodium carbonate (Na2CO3).
This mixture was transferred to a 1-L separatory funnel, kept cold by the addition of ice, and added dropwise to an ice cooled, magnetically stirred mixture of 16.8 g (188 mmol, 1.24 equiv.) of copper (I) cyanide (CuCN), 24.4 g (498 mmol, 3.32 equiv.) of sodium cyanide (NaCN), 112 mL H2O, and 250 mL of ethyl acetate (EtOAc) in a 2-L erlenmeyer flask over 20 min.
Nitrogen gas was evolved from the reaction.
The mixture turned dark quickly, and was stirred on ice for 30 min. and then the ice was removed.
Stirring was continued for 3.5 h.
The mixture was then heated on a hot plate until the internal temperature was 50° C.
The reaction was removed from the hot plate and allowed to cool to 35° C., and filtered through filter paper.
The layers were separated, and the organic layer was washed with saturated aqueous NaCl, and dried (Na2SO4).
The organic layer was poured directly onto a 65 mm column containing 200 g of silica gel and eluted with EtOAc.
Fractions of 500 mL were collected, and all product containing fractions were combined and concentrated to give the title compound (19.60 g, 91percent yield): ES-MS (m/z) 144 [M+1]+.
Reference: [1] Patent: US2002/103229, 2002, A1,
[2] Patent: US2004/127536, 2004, A1,
[3] Patent: US2005/9876, 2005, A1,
  • 10
  • [ 19335-11-6 ]
  • [ 544-92-3 ]
  • [ 74626-47-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 7, p. 925 - 930
  • 11
  • [ 19335-11-6 ]
  • [ 821-48-7 ]
  • [ 478827-33-7 ]
YieldReaction ConditionsOperation in experiment
33%
Stage #1: Heating / reflux
Stage #2: for 8 h; Heating / reflux
A mixture of 5-aminoindazole (2.53 g, 19.0 mmol), bis (2- chloroethyl) amine hydrochloride (3.60 g, 20.1 mmol) and ethanol (30 mL) was heated at reflux overnight. The mixture was allowed to cool to room temperature. Na2C03 (2.14 g, 20.2 mmol) was added and the reaction mixture heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate evaporated in vacuo.-The residue was dissolved in 1 N HC1 (100 mL) and extracted with DCM (2 x 50 mL). The aqueous phase was made basic with 4 N NaOH (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (20: 1 DCM/MeOH to 20: 1: 0.5 DCM/MeOH/Et3N) to 5-Piperazin-l-yl-lH-indazole (1.26 g, 33percent) as a brown solid. 1H NMR (DMSO-d6, 400 MHz) 8 12.80 (s, 1H), 7.89 (s, 1H), 7.40 (d, J= 8.8 Hz, 1H), 7.16 (dd, J= 8. 8 Hz, J= 2. 0 Hz, 1H), 7.07 (s, 1H), 3.17 (s, 1H), 2.99 (m, 4H), 2. 89 (m, 4H). LCMS (APCI+) m/z 203 [M+H] + ; Rt = 1. 33 minutes.
Reference: [1] Patent: WO2005/51304, 2005, A2, . Location in patent: Page/Page column 76-77
[2] Patent: WO2005/51304, 2005, A2, . Location in patent: Page/Page column 76-77
  • 12
  • [ 19335-11-6 ]
  • [ 1072433-59-0 ]
Reference: [1] Patent: WO2014/202580, 2014, A1,
  • 13
  • [ 19335-11-6 ]
  • [ 1150617-94-9 ]
Reference: [1] Patent: US2012/28984, 2012, A1,
  • 14
  • [ 19335-11-6 ]
  • [ 1357072-61-7 ]
Reference: [1] Patent: US2012/28984, 2012, A1,
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