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[ CAS No. 1034667-22-5 ] {[proInfo.proName]}

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Chemical Structure| 1034667-22-5
Chemical Structure| 1034667-22-5
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Product Details of [ 1034667-22-5 ]

CAS No. :1034667-22-5 MDL No. :MFCD15526909
Formula : C6H5FN4 Boiling Point : -
Linear Structure Formula :- InChI Key :UFONWAPOQPJJLL-UHFFFAOYSA-N
M.W : 152.13 Pubchem ID :25181927
Synonyms :

Calculated chemistry of [ 1034667-22-5 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 38.25
TPSA : 67.59 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) : -6.82 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.61
Log Po/w (XLOGP3) : 0.57
Log Po/w (WLOGP) : 1.11
Log Po/w (MLOGP) : 0.83
Log Po/w (SILICOS-IT) : 1.27
Consensus Log Po/w : 0.88

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.75
Solubility : 2.72 mg/ml ; 0.0179 mol/l
Class : Very soluble
Log S (Ali) : -1.56
Solubility : 4.17 mg/ml ; 0.0274 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.44
Solubility : 0.55 mg/ml ; 0.00361 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.97

Safety of [ 1034667-22-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1034667-22-5 ]

* 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 [ 1034667-22-5 ]
  • Downstream synthetic route of [ 1034667-22-5 ]

[ 1034667-22-5 ] Synthesis Path-Upstream   1~8

  • 1
  • [ 791644-48-9 ]
  • [ 1034667-22-5 ]
YieldReaction ConditionsOperation in experiment
88% With hydrazine In butan-1-ol for 4 h; Heating / reflux To a solution of compound 4a (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol) , and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2x) and Et2O (2x) and dried in vacuo overnight to give compound 5a (44 g, 88percent) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz) : δ 5.53 (s, 2H); 7.94 (dd, IH); 8.35 (dd, IH); 12.02 (s, IH).
88% for 4 h; Heating / reflux To a solution of compound 4 (50 g, 321.7 mmol) in 1- butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol) , and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was <n="38"/>successively washed on filter with water (2x) and Et2<0 (2x) and dried in vacuo overnight to give compound 5 (44 g, 88percent) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 5.53 (s, 2H); 7.94 (dd, IH); 8.35 (dd, IH); 12.02 (s, IH).
88% With hydrazine hydrate In butan-1-ol for 4 h; Reflux To a solution of compound 4 (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol), and the mixture was refluxed for 4 h.
The mixture was cooled to room temperature and concentrated.
The precipitate was successively washed on filter with water (2*) and Et2O (2*) and dried in vacuo overnight to give compound 5 (44 g, 88percent) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 5.53 (s, 2H); 7.94 (dd, 1H); 8.35 (dd, 1H); 12.02 (s, 1H).
88% With hydrazine In butan-1-ol for 4 h; Heating / reflux To a solution of compound 4 (50 g, 321.7 mmol) in1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 <n="53"/>mol) , and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2x) and Et2<0 (2x) and dried in vacuo overnight to give compound 5 (44 g, 88percent) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 5.53 (s, 2H); 7.94 (dd, IH); 8.35 (dd, IH); 12.02 (s, IH).
88% With hydrazine In butan-1-ol for 4 h; Heating / reflux 5-Fluoro-lH-pyrazolo [3, 4-b]pyridin-3-amine (5) [00148] To a solution of compound 4 (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol) , and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2x) and Et2<0 (2x) and dried in vacuo overnight to give compound 5 (44 g, 88percent) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 5.53 (s, 2H); 7.94 (dd, IH); 8.35 (dd, IH); 12.02 (s, IH).
88% With hydrazine hydrate In butan-1-ol for 4 h; Reflux 5-Fluoro-lH-pyrazolo[3,4-b]pyridin-3-amine (5); [00189] To a solution of compound 4 (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol), and the mixture was refluxed for 4 hours. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2x) and Et2O (2x) and dried in-vacuo overnight to give compound 5 (44 g, 88percent) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 5.53 (s, 2H); 7.94 (dd, IH); 8.35 (dd, IH); 12.02 (s, IH).
84% With hydrogenchloride; hydrazine hydrate In butan-1-ol at 70℃; for 4 h; 2-Chloro-5-fluoro-3-pyridinecarbonitrile (15.3 g, 98 mmol) was dissolved in -butanol (300 mL), and thenhydrazine monohydrate (16.82 mL, 293 mmol) was added, followed by hydrochloric acid(4N in 1,4-dioxane) (0.244 mL, 0.977 mmol). The reaction mixture was maintained at70°C for 4 h, and the resulting yellow crystalline solid was collected by filtration (12.5 g, 84percent yield). MS (m/z) 153 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.56 (s, 2 H),7.97 (dd, 1 H), 8.39 (m, 1 H), 12.07 (s, 1 H).
84% With hydrogenchloride; hydrazine hydrate In 1,4-dioxane; butan-1-ol at 70℃; for 4 h; Dissolve 2-chloro-5-fluoro-3-pyridinecarbonitrile (15.3 g, 98 mmol) in 1-butanol (300 mL) and then add hydrazine monohydrate (16.82 mL, 293 mmol). Hydrochloric acid (4N in dioxane) (0.244 mL, 0.977 mmol) was then added. The reaction mixture was maintained at 70°C for 4 hours and the resulting yellow crystalline solid (12.5 g, 84percent yield) was collected by filtration.
84% With hydrogenchloride; hydrazine hydrate In 1,4-dioxane; butan-1-ol at 70℃; for 4 h; Step 3.
5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine
2-Chloro-5-fluoro-3-pyridinecarbonitrile (15.3 g, 98 mmol) was dissolved in 1-butanol (300 mL), and then hydrazine monohydrate (16.82 mL, 293 mmol) was added, followed by hydrochloric acid (4N in dioxane) (0.244 mL, 0.977 mmol).
The reaction mixture was maintained at 70 °C for 4 hours, and the resulting yellow crystalline solid was collected by filtration (12.5 g, 84 percent yield). MS (m/z) 153 (M+H+).
1H NMR (400 MHz, DMSO-d6) δ ppm 5.56 (s, 2 H), 7.97 (dd, 1 H), 8.39(m, 1 H), 12.07 (s, 1 H).
84% With hydrogenchloride; hydrazine In 1,4-dioxane; butan-1-ol at 70℃; for 4 h; 2-Chloro-5-fluoro-3-pyridinecarbonitrile (15.3 g, 98 mmol) was dissolved in 1-butanol (300 mL) ),And then added hydrazine monohydrate (16.82 mL, 293 mmol),Hydrochloric acid (4N in dioxane) (0.244 mL, 0.977 mmol) was then added.The reaction mixture was maintained at 70C for 4 hours.The resulting yellow crystalline solid (12.5 g, 84percent yield) was collected by filtration.
73% With hydrazine hydrate In butan-1-ol at 120℃; for 6 h; 2-Chloro-5-fluoronicotinonitrile (1.95 g, 12.50 mmol) was dissolved in n-butanol (30 mL).Then hydrazine hydrate (80percent, 8 mL, 125 mmol) was added thereto.The resulting mixture was warmed to 120 ° C and stirred for 6 hours.After cooling to room temperature, a small amount of solid was precipitated, and the mixture was allowed to stand in an ice water bath for 1 hour.A large amount of solid was precipitated, suction filtered, and the filter cake was washed with water (20 mL) at 0 ° C.Then vacuum dry,The title compound was obtained as a pale yellow solid (1. 36 g, 73percent).
73% With hydrazine hydrate In butan-1-ol at 120℃; for 6 h; To a solution of 2-chloro-5-fluoronicotinonitrile (1.95 g, 12.50 mmol) in n-butanol (30 mL) was added hydrazine hydrate (80percent, 8 mL, 125 mmol). The mixture was heated to 120 °C and stirred for 6 h, then cooled to rt and there was a little solid precipitated out. The mixture was placed in an ice-bath for 1 h, and there was a lot of solid precipitated out. Then the mixture was filtered by suction. The filter cake was washed with 0 °C water (20 mL) and dried in vacuo to give the title compound as a light yellow solid (1.36 g, 73percent).‘H NIVIR (400 MHz, CDC13) (ppm): 12.07 (s, 1H), 8.38 (dd, J 2.5, 1.8 Hz, 1H), 7.97 (dd, J 8.8, 2.7 Hz, 1H), 5.55 (s, 2H).
64% With hydrazine hydrate In 1,2-dimethoxyethane at 180℃; Weigh 2-chloro-5-fluoro-pyridine-3-carbonitrile (8.0 g, 51 mmol) in a 250 ml flask.Ethylene glycol (80 mL) and hydrazine hydrate (24 mL, 494 mmol) were added thereto.The temperature was raised to 180 ° C and refluxed overnight. Cool to room temperature and add water (50 mL).Stir at room temperature for 10 minutes and filter.The filter cake was washed with water (30 mL) and tetrahydrofuran (30 mL, -10 ° C).Dry in vacuo to a yellow solid (5.0 g, 64.0percent).
62% With hydrazine hydrate In ethanol at 100℃; for 2 h; A stirred solution of 2.-chloro.5-fluoro.-pyridine3..carbonitriie (50 g, 3.30 mo) and N2H4.H20(100 mL) in EtOH (500 mL) was heated at 100 °C for 2 h. After TLC (petroleum ether:EtOAc = 2:1) showed the completion of the reaction, the solvent was removed underreduced pressure. The residue, after being washed with EtOAc several times afforded thetitle compound (30.6 g, 62percent yield) as a solid. MS: 153.0 [M+H].
61% With hydrazine hydrate In ethylene glycol for 4 h; Reflux Example 4A5-Fluoro-lH-pyrazolo[3,4-b]pyridin-3-amineA suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was introduced in 1,2-ethanediol (380 ml) and subsequently admixed with hydrazine hydrate (1 19.6 ml, 2.459 mol) The mixture was heated at reflux with stirring for 4 h. On cooling, the product precipitated. The yellow crystals were admixed with water (380 ml) and subjected to extractive stirring at RT for 10 min. Then the suspension was filtered with suction over a frit, and the filter product was washed with water (200 ml) and with -10°C cold THF (200 ml). The residue was dried under a high vacuum over phosphorus pentoxide.Yield: 22.8 g (61percent of theory) .H NMR (400 MHz, DMSO-d6): δ = 5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07(m, 1H).
61% With hydrazine hydrate In ethylene glycol for 4 h; Reflux Example 4A
5-Fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine
A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1,2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml, 2.459 mol) was then added.
The mixture was heated under reflux with stirring for 4 h.
The product precipitated on cooling.
Water (380 ml) was added to the yellow crystals, and the mixture was subjected to extractive stirring at RT for 10 min.
The suspension was then filtered with suction over a frit, and the filter product was washed with water (200 ml) and with -10° C. cold THF (200 ml).
The residue was dried under high vacuum over phosphorus pentoxide.
Yield: 22.8 g (61percent of theory)
1H NMR (400 MHz, DMSO-d6): δ=5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).
61% With hydrazine hydrate In ethylene glycol for 4 h; Reflux Example 5A
5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine
A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1,2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml, 2.459 mol) was then added.
The mixture was heated under reflux while stirring for 4 h.
The product precipitated in the course of cooling.
Water (380 ml) was added to the yellow crystals, and the mixture was stirred at RT for 10 min.
The suspension was then filtered with suction through a frit and washed through with water (200 ml) and with THF at -10° C. (200 ml).
The residue was dried under high vacuum over phosphorus pentoxide.
Yield: 22.8 g (61percent of theory)
1H NMR (400 MHz, DMSO-d6): δ=5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).
61% With hydrazine hydrate In ethylene glycol for 4 h; Reflux 5-Fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine
A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1,2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml, 2.459 mol) was then added.
The mixture was heated under reflux with stirring for 4 h.
The product precipitated in the course of cooling.
Water (380 ml) was added to the yellow crystals, and the mixture was subjected to extractive stirring at RT for 10 min.
The suspension was then filtered with suction over a frit, and the filter product was washed with water (200 ml) and with -10° C. cold THF (200 ml).
The residue was dried under a high vacuum over phosphorus pentoxide.
Yield: 22.8 g (61percent of theory)
1H-NMR (400 MHz, DMSO-d6): δ=5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).
61% With hydrazine hydrate In ethylene glycol for 4 h; Reflux Example 5A
5-Fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine
A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile in 1,2-ethanediol (380 ml) was prepared and then hydrazine hydrate (119.6 ml) was added.
It was heated under reflux for 4 h, with stirring.
On cooling, the product was precipitated.
Water (380 ml) was added to the crystals and it was left to precipitate for 10 min at RT.
Then the suspension was filtered with suction on a frit, and washed again with water (200 ml) and with cold (-10° C.) THF (200 ml).
Drying over phosphorus pentoxide under high vacuum.
Yield: 22.8 g (61percent of theor.)
1H-NMR (400 MHz, DMSO-d6): δ=5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).
61% With hydrazine hydrate In ethylene glycol for 4 h; Reflux Example 22A
5-Fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine
A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1,2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml, 2.459 mol) was then added.
The mixture was heated under reflux while stirring for 4 h.
The product precipitated out in the course of cooling.
Water (380 ml) was added to the yellow crystals, and extraction was effected by stirring at RT for 10 min.
The suspension was then filtered with suction through a frit and washed through with water (200 ml) and with THF at -10° C. (200 ml).
The residue was dried under high vacuum over phosphorus pentoxide.
Yield: 22.8 g (61percent of theory)
1H NMR (400 MHz, DMSO-d6): δ=5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).
61% With hydrazine hydrate In ethylene glycol for 4 h; Reflux Example 4A
5-Fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine
A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was introduced in 1,2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml, 2.459 mol) was then added.
The mixture was heated under reflux with stirring for 4 h.
The product precipitated on cooling.
Water (380 ml) was added to the yellow crystals, and the mixture was subjected to extractive stirring at RT for 10 min.
The suspension was then filtered with suction over a frit, and the filter product was washed with water (200 ml) and with -10° C. cold THF (200 ml).
The residue was dried under a high vacuum over phosphorus pentoxide.
Yield: 22.8 g (61percent of theory)
2H NMR (400 MHz, DMSO-d6): δ=5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).
61% With hydrazine hydrate In ethylene glycol for 4 h; Reflux A suspension of 38.5 g (245.93 mmol) of 2-chioro- 5-fluoronicotinonitrile was initially charged in 1 ,2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml) was then added. With stirring, the mixture was heated at reflux for 4 h. On cooling, the product precipitated out. Water (380 ml) was added to the crystals, and the mixture was stirred at RT for 10 mm. The suspension was then filtered off with suction through a frit and washed with water (200 ml) and with —10° C-cold THF (200 ml). Drying under high vacuum over phosphorus pentoxide.10422] Yield: 22.8 g (61percent of theory)10423] ‘H NMR (400 MHz, DMSO-d5): ö=5.54 (s, 2H),7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).
18 g With hydrazine hydrate In butan-1-ol for 4.5 h; Reflux Formation of 5-fluoro-lH-pyrazolo[3,4-6]pyridin-3-amine (132a)To the mixture of 2-chloro-5-fiuoropyridine-3-carbonitrile, 131a, (29.6 g, 157.1 mmol) in n-butanol (492 mL) was added hydrazine hydrate (76.4 mL, 1.6 mol). This mixture was heated to reflux for 4.5 h and cooled down. n-Butanol was removed under reduced pressure and water (300 mL) was added resulting in a yellow precipitate. The suspension was filtered and washed with water twice, followed by a MTBE wash. The yellow solid was dried in a vacuum oven to give 18 g of the desired product: 1H NMR (300 MHz, DMSO- 6) δ 12.08 (s, 1H), 8.38 (dd, J = 2.7, 1.9 Hz, 1H), 7.97 (dd, J = 8.8, 2.7 Hz, 1H), 5.56 (s, 2H). LCMS Gradient 10-90percent, 0.1percent formic acid, 5 minutes, C18/ACN, Retention Time = 1.25 minutes (M+H) 152.95.
22.8 g With hydrazine hydrate In ethylene glycol for 4 h; Reflux A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1,2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml) was then added.
With stirring, the mixture was heated at reflux for 4 h.
The product precipitated on cooling.
Water (380 ml) was added to the crystals, and the mixture was subjected to extractive stirring at RT for 10 min.
The suspension was then filtered with suction over a frit, and the filter product was washed with water (200 ml) and with -10° C. cold THF (200 ml).
Drying under high vacuum over phosphorus pentoxide.
Yield: 22.8 g (61percent of theory)
1H NMR (400 MHz, DMSO-d6): δ=5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).

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[3] Patent: WO2013/19828, 2013, A1,
[4] Patent: TWI609011, 2017, B,
[5] Patent: EP2680844, 2016, B1,
[6] Patent: TW2018/8946, 2018, A,
[7] Patent: WO2012/83121, 2012, A1,
[8] Patent: WO2013/25958, 2013, A1,
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[10] Patent: WO2008/112646, 2008, A1,
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YieldReaction ConditionsOperation in experiment
55% With tert.-butylnitrite In Bromoform at 20 - 90℃; for 3 h; 5-Fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (1.87 g, 12.30 mmol)Dissolved in tribromomethane (20 mL), and the resulting solution was stirred at room temperature.Then tert-butyl nitrite (5.3 mL, 49.20 mmol) was added thereto.The resulting mixture was warmed to 60 ° C and stirred for 1 hour.Then, the temperature was raised to 90 ° C for 2 hours, the reaction was stopped, and the mixture was cooled to room temperature.The reaction solution was concentrated under reduced pressure, and the obtained residue was applied to silica gel column chromatography.(PE/EA(v/v)=10/1) was purified to give the title compound as a white solid.(1.45g, 55percent).
970 mg at 61 - 90℃; for 2 h; Formation of 3-bromo-5-fluoro-lH-pyrazolo[3,4-6]pyridine (133a)To a mixture of 5-fiuoro-lH-pyrazolo[3,4-¾]pyridin-3-amine, 132a, (0.88 g, 5.79 mmol) in bromoform (8.8 mL) was added fert-butyl nitrite (1.38 mL, 11.57 mmol). This mixture was heated to 61 °C for 1 h and then heated to 90 °C for an additional hour. The mixture was cooled to room temperature and bromoform was removed under reduced pressure. The resulting crude residue was purified by silica gel chromatography (5-50percent> ethyl acetate/hexanes) to afford 970 mg of the desired product as a white solid: 1H NMR (300 MHz, DMSO- 6) δ 14.22 (s, 1H), 8.67 (dd, J = 2.7, 1.9 Hz, 1H), 8.07 (dd, J = 8.2, 2.7 Hz, 1H); LCMS Gradient 10-90percent, 0.1percent formic acid, 5 minutes, C18/ACN, Retention Time = 2.42 minutes (M+H) 216.11.
Reference: [1] Patent: CN108276401, 2018, A, . Location in patent: Paragraph 0633; 0638; 0639
[2] Patent: WO2012/83121, 2012, A1, . Location in patent: Page/Page column 79
[3] Patent: WO2012/83117, 2012, A1, . Location in patent: Page/Page column 107
[4] Patent: WO2013/19828, 2013, A1, . Location in patent: Page/Page column 102-103
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