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[ CAS No. 444731-72-0 ] {[proInfo.proName]}

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Chemical Structure| 444731-72-0
Chemical Structure| 444731-72-0
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Product Details of [ 444731-72-0 ]

CAS No. :444731-72-0 MDL No. :MFCD09258896
Formula : C9H11N3 Boiling Point : -
Linear Structure Formula :- InChI Key :PVNVSSNARYHLRF-UHFFFAOYSA-N
M.W : 161.20 Pubchem ID :11542827
Synonyms :

Calculated chemistry of [ 444731-72-0 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.22
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 50.37
TPSA : 43.84 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) : -6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.44
Log Po/w (XLOGP3) : 1.29
Log Po/w (WLOGP) : 1.47
Log Po/w (MLOGP) : 1.16
Log Po/w (SILICOS-IT) : 1.15
Consensus Log Po/w : 1.3

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.21
Solubility : 1.0 mg/ml ; 0.00621 mol/l
Class : Soluble
Log S (Ali) : -1.81
Solubility : 2.49 mg/ml ; 0.0155 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.49
Solubility : 0.522 mg/ml ; 0.00324 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.54

Safety of [ 444731-72-0 ]

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 [ 444731-72-0 ]

* 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 [ 444731-72-0 ]
  • Downstream synthetic route of [ 444731-72-0 ]

[ 444731-72-0 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 444731-73-1 ]
  • [ 444731-72-0 ]
YieldReaction ConditionsOperation in experiment
96.7% With ammonium formate In methanol; water at 25 - 30℃; for 6 h; A 2-L 3-necked round bottom flask was fitted with nitrogen inlet and outlet and with mechanical stirring. A moderate nitrogen flow was initiated and the reactor was charged with 10 percent Pd/C (50percent water wet, 6.0 g). Stirring was initiated and the reactor was charged with methanol (750 ml_) and the product of Intermediate Example 1 (50 g). Ammonium formate (82.54 g) was dissolved in water (120 ml_). The water solution of ammonium formate was added to the reaction solution at an addition rate, which kept the reaction temperature at or between 25 and 300C. The reaction was allowed to proceed at 25°C. After 6 h the reaction was judged to be finished based on HPLC analysis. The mixture was filtered and the catalyst washed with methanol (50 ml_). The methanol layers were combined and the solvent removed under reduced pressure. The residue was dissolved in water (200 mL) and was extracted with methylene chloride (3 x 250 mL). The methylene chloride layers were combined and solvent removed under vacuum to remove approximately half the solvent. Heptane (400 mL) was added and the vacuum distillation continued until approximately 300 mL reaction product slurry remained. The product was isolated by filtration and dried under vacuum at 50°C for 4 h. to yield 2,3-dimethyl-6-amino-2H-indazole as the free base. (40.76 g, 96.7 percent). 1H NMR (300 MHz, DMSO-d6) δ 7.31 (d, J = 8.9 Hz, 1 H), 6.45 (d, J= 8.9 Hz, 1 H), 6.38 (s, 1 H), 4.95 (s, br, 2H), 3.85 (s, 3H), 2.44 (s, 3H) MS (ES+, m/z) 162 (M+H).
96.7% With ammonium formate In methanol; water at 25 - 30℃; for 6 h; A 2-L 3-necked round bottom flask was fitted with nitrogen inlet and outlet and with mechanical stirring. A moderate nitrogen flow was initiated and the reactor was charged with 10 [percent] Pd/C [(50percent] water wet, 6.0 g). Stirring was initiated and the reactor was charged with methanol (750 mL) and the product of Intermediate Example 1 (50 g). Ammonium formate (82.54 g) was dissolved in water (120 mL). The water solution of ammonium formate was added to the reaction solution at an addition rate, which kept the reaction temperature at or between 25 and 30 [C.] The reaction was allowed to proceed at [25 C.] After 6 h the reaction was judged to be finished based on HPLC analysis. The mixture was filtered and the catalyst washed with methanol (50 mL). The methanol layers were combined and the solvent removed under reduced pressure. The residue was dissolved in water (200 mL) and was extracted with methylene chloride (3 x 250 mL). The methylene chloride layers were combined and solvent removed under vacuum to remove approximately half the solvent. Heptane (400 mL) was added and the vacuum distillation continued until approximately 300 mL reaction product slurry remained. The product was isolated by filtration and dried under vacuum at 50 [C] for 4 h. to yield 2, 3-dimethyl-6-amino- 2H-indazole as the free base. (40.76 [G,] 96.7 [percent).APOS;H] NMR (300 MHz, [DMSO-D6)] 8 7.31 (d, [J =] 8.9 Hz, 1H), 6.45 (d, J = 8.9 Hz, [1 H),] 6.38 (s, 1H), 4.95 (s, br, 2H), 3.85 (s, [3H),] 2.44 (s, 3H) MS [(ES+,] m/z) 162 (M+H).
96.7% With ammonium formate In methanol; water at 25 - 30℃; for 6 h; A 2-L 3-necked round bottom flask was fitted with nitrogen inlet and outlet and with mechanical stirring. A moderate nitrogen flow was initiated and the reactor was charged with 10 percent Pd/C (50percent water wet, 6.0 g). Stirring was initiated and the reactor was charged with methanol (750 mL) and the product of Intermediate Example 1 (50 g). Ammonium formate (82.54 g) was dissolved in water (120 mL). The water solution of ammonium formate was added to the reaction solution at an addition rate, which kept the reaction temperature at or between 25 and 30 0C. The reaction was allowed to proceed at 25 0C. After 6 h the reaction was judged to be finished based on HPLC analysis. The mixture was filtered and the catalyst washed with methanol (50 mL). The methanol layers were combined and the solvent removed under reduced pressure. The residue was dissolved in water (200 mL) and was extracted with methylene chloride (3 x 250 mL). The methylene chloride layers were combined and solvent removed under vacuum to remove approximately half the solvent. Heptane (400 mL) was added and the vacuum distillation continued until approximately 300 mL reaction product slurry remained. The product was isolated by filtration and dried under vacuum at 50 0C for 4 h. to yield 2,3-dimethyl-6-amino-2H-indazole as the free base. (40.76 g, 96.7 percent). 1H NMR (300 MHz, DMSO-d6) δ 7.31 (d, J = 8.9 Hz, 1 H), 6.45 (d, J = 8.9 Hz, 1 H), 6.38 (s, 1 H), 4.95 (s, br, 2H), 3.85 (s, 3H), 2.44 (s, 3H) MS (ES+, m/z) 162 (M+H).
96.7% at 25 - 30℃; for 6 h; Procedure 2: A 2-L 3-necked round bottom flask was fitted with nitrogen inlet and outlet and with mechanical stirring. A moderate nitrogen flow was initiated and the reactor was charged with 10 percent Pd/C (50percent water wet, 6.0 g). Stirring was initiated and the reactor was charged with methanol (750 mL) and the product of Intermediate Example 1 (50 g). Ammonium formate (82.54 g) was dissolved in water (120 mL). The water solution of ammonium formate was added to the reaction solution at an addition rate, which kept the reaction temperature at or between 25 and 30 °C. The reaction was allowed to proceed at 25 °C. After 6 h the reaction was judged to be finished based on HPLC analysis. The mixture was filtered and the catalyst washed with methanol (50 mL). The methanol layers were combined and the solvent removed under reduced pressure. The residue was dissolved in water (200 mL) and was extracted with methylene chloride (3 x 250 mL). The methylene chloride layers were combined and solvent removed under vacuum to remove approximately half the solvent. Heptane (400 mL) was added and the vacuum distillation continued until approximately 300 mL reaction product slurry remained. The product was isolated by filtration and dried under vacuum at 50 OC for 4 h. to yield 2,3-dimethyl-6-amino-2H-indazole as the free base. (40.76 g, 96.7 percent).
96.7% With ammonium formate In methanol; water at 25 - 30℃; for 6 h; A 2-L 3-necked round bottom flask was fitted with nitrogen inlet and outlet and with mechanical stirring. A moderate nitrogen flow was initiated and the reactor was charged with 10 percent Pd/C (50percent water wet, 6.0 g). Stirring was initiated and the reactor was charged with methanol (750 mL) and the product of Intermediate Example 1 (50 g). Ammonium formate (82.54 g) was dissolved in water (120 mL). The water solution of ammonium formate was added to the reaction solution at an addition rate, which kept the reaction temperature at or between 25 and 300C. The reaction was allowed to proceed at 25°C. After 6 h the reaction was judged to be finished based on HPLC analysis. The mixture was filtered and the catalyst washed with methanol (50 mL). The methanol layers were combined and the solvent removed under reduced pressure. The residue was dissolved in water (200 mL) and was extracted with methylene chloride (3 x 250 mL). The methylene chloride layers were combined and solvent removed under vacuum to remove approximately half the solvent. Heptane (400 mL) was added and the vacuum distillation continued until approximately 300 mL reaction product slurry remained. The product was isolated by filtration and dried under vacuum at 500C for 4 h. to yield 2,3-dimethyl-6-amino-2H-indazole as the free base. (40.76 g, 96.7 percent). 1H NMR (300 MHz, DMSOd6) δ 7.31 (d, J = 8.9 Hz, 1 H), 6.45 (d, J = 8.9 Hz, 1 H), 6.38 (s, 1 H), 4.95 (s, br, 2H), 3.85 (s, 3H), 2.44 (s, 3H) MS (ES+, m/z) 162 (M+H).
95% With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 12 h; 10percent Palladium carbon (water content 51.7percent, 1 g) was added to a solution of 2a (7.50 g, 40 mmol) in ethanol (150 ml), and the mixture was stirred under hydrogen atmosphere at room temperature for 12 h. The catalyst was removed by filtration and washed with ethanol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure to give 3a as alight beige solid (6.05, 95.0percent yield).Mp: 149~150 C. 1HNMR (400MHz, DMSO-d6) δ: 2.44 (s, 3H), 3.85 (s, 3H), 4.93 (brs, 2H), 6.37 (s, 1H), 6.43 (d, J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H).
95% With hydrogen In methanol at 25 - 30℃; for 5 h; Autoclave Example 2a
Raney nickel (12.50 g) was added to a suspension of 2,3-dimethyl-6-nitro-2H-indazole (50 g, 0.26 mol) in methanol (500 mL).
The reaction mixture was stirred in an autoclave under hydrogen pressure of 3.5 kg/cm2-4.0 kg/cm2 at 25° C. to 30° C. for 5 hours.
Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed with methanol (100 mL*2).
The filtrates were combined, and the solvent was recovered completely. n-Heptane (250 mL) and dichloromethane (50 mL) were added to the residue, and the reaction mixture was stirred for 1 hour at 25° C. to 30° C.
The solid was collected by filtration, washed with n-heptane (50 mL*2), and dried under vacuum at 40° C. to 45° C. to afford 2,3-dimethyl-2H-indazol-6-amine as a light brown solid.
95.5% With palladium 10% on activated carbon; hydrogen In methanol at 50℃; for 2 h; 4 (15.3,0.08 mol) was suspended in 150 ml of methanol,10percent Pd / C (1.53 g) was added,Hydrogen at atmospheric pressure under stirring,The reaction was carried out at 50 ° C for 2 hours,filter,The residue was washed with methanol (10 ml x 2)The filtrate was concentrated to dryness,To give a light brown solid (12.3 g, 95.5percent).
94.1% With hydrogenchloride; tin(ll) chloride In ethanol; water at 20℃; for 0.5 h; Drops (89ml) at 0 ° C solution of stannous chloride (44.8g, 0.24mol) in concentratedhydrochloric acidwas added 2-3 (12.0g, 0.06mol) in ethanol (120ml) solution. It was removed and an ice bath, thereaction was stirred roomtemperature for 30min. And filtered togive a mixture of tin and 2-4 hydrochloride salt (25.1g). The crude product wasdissolved in water (150ml), add saturated aqueous sodium bicarbonate (150ml).Ethyl acetate (200ml × 2) and the combined organic phases were concentratedhydrochloric acid (20ml), stirred at room temperature 30min. Sub-phase water,evaporated under reduced pressure to give a yellow solid 11.2g, yield 94.1percent.

Reference: [1] Patent: WO2007/64753, 2007, A2, . Location in patent: Page/Page column 27
[2] Patent: WO2003/106416, 2003, A2, . Location in patent: Page 43
[3] Patent: WO2006/20564, 2006, A1, . Location in patent: Page/Page column 14-15
[4] Patent: WO2005/105094, 2005, A2, . Location in patent: Page/Page column 30
[5] Patent: WO2007/143483, 2007, A2, . Location in patent: Page/Page column 30
[6] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1108 - 1110
[7] Patent: US2015/329526, 2015, A1, . Location in patent: Paragraph 0035; 0036; 0037
[8] Patent: CN103373989, 2016, B, . Location in patent: Paragraph 0037; 0038
[9] Patent: CN103739550, 2016, B, . Location in patent: Paragraph 0125-0126; 0137-0138
[10] Patent: WO2009/62658, 2009, A1, . Location in patent: Page/Page column 34; 1/10
[11] Letters in Organic Chemistry, 2012, vol. 9, # 4, p. 276 - 279
[12] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 989 - 994
  • 2
  • [ 6494-19-5 ]
  • [ 444731-72-0 ]
YieldReaction ConditionsOperation in experiment
96.7% With ammonium formate In methanol; water at 25 - 30℃; for 6 h; Procedure 2:
A 2-L 3-necked round bottom flask was fitted with nitrogen inlet and outlet and with mechanical stirring.
A moderate nitrogen flow was initiated and the reactor was charged with 10percent Pd/C (50percent water wet, 6.0 g).
Stirring was initiated and the reactor was charged with methanol (750 mL) and the product of Intermediate Example 1 (50 g).
Ammonium formate (82.54 g) was dissolved in water (120 mL).
The water solution of ammonium formate was added to the reaction solution at an addition rate, which kept the reaction temperature at or between 25 and 30° C.
The reaction was allowed to proceed at 25° C.
After 6 h the reaction was judged to be finished based on HPLC analysis.
The mixture was filtered and the catalyst washed with methanol (50 mL).
The methanol layers were combined and the solvent removed under reduced pressure.
The residue was dissolved in water (200 mL) and was extracted with methylene chloride (3*250 mL).
The methylene chloride layers were combined and solvent removed under vacuum to remove approximately half the solvent.
Heptane (400 mL) was added and the vacuum distillation continued until approximately 300 mL reaction product slurry remained.
The product was isolated by filtration and dried under vacuum at 50° C. for 4 h. to yield 2,3-dimethyl-6-amino-2H-indazole as the free base. (40.76 g, 96.7percent).
1H NMR (300 MHz, DMSO-d6) δ 7.31 (d, J=8.9 Hz, 1H), 6.45 (d, J=8.9 Hz, 1H), 6.38 (s, 1H), 4.95 (s, br, 2H), 3.85 (s, 3H), 2.44 (s, 3H) MS (ES+, m/z) 162 (M+H).
Reference: [1] Patent: US2008/293691, 2008, A1, . Location in patent: Page/Page column 9
[2] Letters in Organic Chemistry, 2012, vol. 9, # 4, p. 276 - 279
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1108 - 1110
[4] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 989 - 994
[5] Patent: CN103739550, 2016, B,
[6] Patent: WO2005/105094, 2005, A2,
[7] Patent: WO2005/105094, 2005, A2,
[8] Patent: WO2005/105094, 2005, A2,
[9] Patent: WO2007/143483, 2007, A2,
[10] Patent: WO2007/143483, 2007, A2,
[11] Patent: WO2007/143483, 2007, A2,
  • 3
  • [ 20191-74-6 ]
  • [ 444731-72-0 ]
Reference: [1] Letters in Organic Chemistry, 2012, vol. 9, # 4, p. 276 - 279
[2] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 989 - 994
[3] Patent: CN103739550, 2016, B,
[4] Patent: CN103373989, 2016, B,
  • 4
  • [ 635702-59-9 ]
  • [ 444731-72-0 ]
Reference: [1] Patent: WO2005/105094, 2005, A2,
[2] Patent: WO2007/143483, 2007, A2,
  • 5
  • [ 578-54-1 ]
  • [ 444731-72-0 ]
Reference: [1] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 989 - 994
[2] Patent: CN103739550, 2016, B,
[3] Patent: CN103373989, 2016, B,
  • 6
  • [ 1313372-75-6 ]
  • [ 444731-72-0 ]
Reference: [1] Patent: CN103373989, 2016, B,
  • 7
  • [ 444731-72-0 ]
  • [ 444731-75-3 ]
Reference: [1] Letters in Organic Chemistry, 2012, vol. 9, # 4, p. 276 - 279
[2] Patent: WO2011/50159, 2011, A1,
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1108 - 1110
[4] Chemical Biology and Drug Design, 2014, vol. 83, # 3, p. 306 - 316
[5] Patent: US2015/329526, 2015, A1,
[6] Patent: CN103373989, 2016, B,
[7] Patent: CN107619407, 2018, A,
[8] Journal of Medicinal Chemistry, 2018, vol. 61, # 12, p. 5304 - 5322
[9] Pharmazie, 2018, vol. 73, # 9, p. 494 - 497
[10] Patent: US2008/293691, 2008, A1,
[11] Patent: US2008/293691, 2008, A1,
[12] Patent: WO2005/105094, 2005, A2,
[13] Patent: WO2007/143483, 2007, A2,
[14] Patent: WO2007/143483, 2007, A2,
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