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[ CAS No. 875781-15-0 ] {[proInfo.proName]}

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Chemical Structure| 875781-15-0
Chemical Structure| 875781-15-0
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Product Details of [ 875781-15-0 ]

CAS No. :875781-15-0 MDL No. :MFCD09842440
Formula : C6H3BrFNO Boiling Point : -
Linear Structure Formula :- InChI Key :MUYVOGAJRCBWCY-UHFFFAOYSA-N
M.W : 204.00 Pubchem ID :45480192
Synonyms :

Calculated chemistry of [ 875781-15-0 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 37.28
TPSA : 29.96 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) : -6.52 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.47
Log Po/w (XLOGP3) : 1.44
Log Po/w (WLOGP) : 2.22
Log Po/w (MLOGP) : 1.0
Log Po/w (SILICOS-IT) : 2.61
Consensus Log Po/w : 1.75

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.39
Solubility : 0.831 mg/ml ; 0.00407 mol/l
Class : Soluble
Log S (Ali) : -1.67
Solubility : 4.31 mg/ml ; 0.0212 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.11
Solubility : 0.158 mg/ml ; 0.000776 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.66

Safety of [ 875781-15-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 875781-15-0 ]

* 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 [ 875781-15-0 ]
  • Downstream synthetic route of [ 875781-15-0 ]

[ 875781-15-0 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 875781-15-0 ]
  • [ 875781-17-2 ]
YieldReaction ConditionsOperation in experiment
46% With hydrazine In ethanolHeating / reflux Preparation of 5-bromo-1H-pyrazolo[3,4-b]pyridine (D-1-3). <n="101"/>D-1-2 D"1-3A solution of compound D-1-2 (20 g, 0.1 mol) and anhydrous hydrazine (18 g, 0.56 mol) in ethanol was heated to reflux overnight. TLC (petroleum ether/EtOAc 2:1 ) indicated complete consumption of starting material. The reaction mixture was concentrated in vacuo to a volume of about 50 ml_ and poured into water (500 ml_), the resulting mixture was filtered. The cake was washed with water (50 ml_χ3) and ether (20 ml_χ3), then dried in vacuo to yield compound D-1-3 (9.0 g, 46percent) as a yellow solid.
40% With hydrazine hydrate In ethanol at 100℃; for 8 h; 5-Bromo-2-fluoro-pyridine-3-carbaldehyde (4.1g, 20mmol) obtained from Preparation Example 129-1 was dissolved in ethanol (50ml). After adding hydrazine hydrate (5.0ml, 100mmol), the mixture was stirred for 8 hours at 100 and then distilled under reduced pressure. Water was added thereto and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.8g, 40percent).[1499] NMR:1H-NMR(400HMz, CDCl3); δ 11.29 (br s, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H)
135 g With hydrazine hydrate In ethanol at 75 - 80℃; for 12 h; To a stirred solution of 5-bromo-2-fluoronicotinaldehyde (XV) (250 g, 1.23 mol, 1.0 eq) in EtOH (2.50 L) was added hydrazine hydrate (221 g, 4.41 mol, 3.6 eq) at 25°C. The reaction was then heated to 75~80°C and stirred for 12 h. The solvent was removed under reduced pressure at 45°C. The residual crude solid was triturated in water (750 mL) and EtOH (250 mL). The resultant suspension was filtered and washed with ethanol to give 5 -bromo- lH-pyrazolo[3,4- b]pyridine (XVI) (135 g, 0.68 mol, 55.4percent yield) as yellowish solid which was used directly for the next step without further purification. ESIMS found for CeLLtBrNs mlz 199.1 (M+H).
135 g With hydrazine hydrate In ethanol at 25 - 80℃; for 12 h; To a stirred solution of 5-bromo-2-fluoronicotinaldehyde (XV) (250 g, 1.23mol, 1.0 eq) in EtOH (2.50 L) was added hydrazine hydrate (221 g, 4.41 mol, 3.6 eq) at 25°C. The reaction was then heated to 7580°C and stirred for 12 h. The solvent was removed under reduced pressure at 45°C. The residual crude solid was triturated in water (750 mL) and EtOH (250 mL). The resultant suspension was filtered and washed with ethanol to give 5-bromo-1H- pyrazolo[3,4-bjpyridine (XVI) (135 g, 0.68 mol, 55.4percent yield) as yellowish solid which was used directly for the next step without further purification. ESIMS found for C6H4BrN3 mlz 199.1 (M+H).

Reference: [1] Journal of Organic Chemistry, 2017, vol. 82, # 14, p. 7420 - 7427
[2] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 99-100
[3] Patent: WO2014/73904, 2014, A1, . Location in patent: Paragraph 1496-1499
[4] Patent: CN103980272, 2016, B, . Location in patent: Paragraph 0031; 0033
[5] Patent: WO2017/23987, 2017, A1, . Location in patent: Paragraph 0610; 0612
[6] Patent: WO2017/23981, 2017, A1, . Location in patent: Paragraph 0610; 0612
[7] Patent: WO2017/23973, 2017, A1, . Location in patent: Paragraph 0633
[8] Patent: WO2017/23996, 2017, A1, . Location in patent: Paragraph 0612
  • 2
  • [ 2591-86-8 ]
  • [ 766-11-0 ]
  • [ 875781-15-0 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃;
Stage #2: at -78℃;
Intermediate 1; Preparation of 5-bromo-1H-pyrazolo[3,4-b]pyridine; a) 5-bromo-2-fluoro-3-pyridinecarbaldehyde; Following the procedure described in WO2006015124 and trituration of the crude product in hexanes instead of crystallization from cyclohexane afforded the title compound as an off-white solid (68percent). MS (ES)+ m/e 203.8, 205.7 [M+H]+.
52%
Stage #1: With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; hexanes at -78℃; for 1.75 h;
Stage #2: at -78℃; for 0.0166667 h;
A solution of lithium di-iso-propylamine (5 mL, 35 mmol) in anhydrous THF (40 mL) was cooled to -78° C. under nitrogen and n-butyl lithium (2.5 M in hexanes, 12 mL, 30 mmol) was added. The mixture was then stirred at -78° C. for 15 min before 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added. The resulting mixture was then stirred at -78° C. for 90 min. N-formylpiperidine (4 mL, 36 mmol) was added very rapidly to the suspension at -78° C. and the mixture stirred vigorously for 60 sec. The reaction was immediately quenched by the addition of a 10percent (w/v) aqueous solution of citric acid. The mixture was warmed to room temperature and distributed between water and dichloromethane. The aqueous phase was extracted three times with dichloromethane and the organic phases were combined, dried over sodium sulfate, filtered and concentrated. Crystallization of the crude product from cyclohexane afforded 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2.993 g, 52percent yield) as pale beige flaky crystals. 1H-NMR (500 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.70 (dd, 1H), 8.55 (dd, 1H). MS: m/z 236, 238 [MNa+], 204, 206 [MH+], 176, 178 [MH-CO+].
Reference: [1] Patent: US2008/293706, 2008, A1, . Location in patent: Page/Page column 27; 85
[2] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 73-74
  • 3
  • [ 766-11-0 ]
  • [ 109-94-4 ]
  • [ 875781-15-0 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - 0℃; for 0.666667 h;
Stage #2: at -78℃; for 0.0333333 h;
Preparation of 3-Methyl-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazolo[3,4-b]pyridine (79) <n="54"/>7475 76 77Step 1 :7475To a stirred solution of diisopropyl-amine (50 g, 0.5 mol) in dry THF (1000 mL) was added dropwise n- BuLi (200 mL, 0.5 mol) at -780C under N2 atmosphere. After the addition, the resulting mixture was allowed to warm up to O0C, maintained for 10 minutes and cooled to -780C again. A mixture of compound 74 (80 g, 0.455 mol) in THF (1000 mL) was added dropwise to the LDA solution at -780C under N2 atmosphere. After the addition, the reaction mixture was stirred at -780C for 30 minutes. Then formic acid ethyl ester (50 g, 0.68 mol) was added portionwise to the mixture at -780C. After 2 minutes, the resulting mixture was quenched with a solution of 10percent citric acid in THF (400 mL) at -780C. The mixture was allowed to warmed up to room temperature and poured into H2O (500 mL), extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4 and concentrated in vacuo to give compound 75 (92 g, 99percent) as a yellow solid.
88%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78℃; for 0.166667 h;
Diisopropylamine (2.6ml, 25mmol) was dissolved in tetrahydrofuran (100ml), 2.5M solution of butyllithium in tetrahydrofuran (10ml, 25mmol) was slowly added dropwise at 0 and then the mixture was stirred for 1 minute. A solution of 5-bromo-fluoro-2-pyridine (4.0g, 22.7mmol) in tetrahydrofuran (20ml) was slowly added dropwise at -78 and stirred for 30 minutes. Ethylformate (2.8ml, 34mmol) was added dropwise and then the mixture was stirred for 10 minutes at -78. After completion of the reaction, 1N hydrochloric acid solution was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (4.1g, 88percent).
85%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -65 - 0℃; for 1.5 h;
Stage #2: for 0.166667 h;
Example D-1 : Preparation of (2S)-1-(4-(1-isopropyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4- yl)pyrimidin-2-ylamino)propan-2-ol <n="100"/>-J B-B; i/Pd(PPh3)2CI2, KOAc, DMF Preparation of 5-bromo-2-fluoronicotinaldehyde (D-1-2).D-1-1 D-1-2To a solution of diisopropylamine (17 mL, 0.17 mol) in dry THF (200 mL) was added 2.5 M n-BuLi in hexane (68 mL, 0.17 mol) dropwise at O 0C under N2 atmosphere. After the addition, the resulting mixture was cooled to -65°C. A solution of 5-bromo-2-fluoropyridine (25 g, 0.14 mol) in dry THF (100 mL) was then added dropwise. The resulting mixture was stirred at -65°C for 90 minutes. Then ethyl formate (15.6 g, 0.21 mol) was added dropwise to the mixture. After stirred for 10 minutes, the reaction mixture was quenched with a solution of 10percent citric acid in THF (100 mL) at -650C. The resulting mixture was warmed up to room temperature, poured into water (100 mL) and extracted with EtOAc (200 mL). The organic layer was separated and washed with saturated aqueous NaCI (100 mLχ2), dried over Na2SO4 and concentrated in vacuo to yield compound D-1-2 (25 g, 85percent) as a yellow solid.
Reference: [1] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 52-53
[2] Patent: WO2014/73904, 2014, A1, . Location in patent: Paragraph 1492-1494
[3] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 98-99
[4] Patent: CN103980272, 2016, B, . Location in patent: Paragraph 0031; 0032
[5] Patent: WO2017/23987, 2017, A1, . Location in patent: Paragraph 0610; 0611
[6] Patent: WO2017/23981, 2017, A1, . Location in patent: Paragraph 0610; 0611
[7] Patent: WO2017/23973, 2017, A1, . Location in patent: Paragraph 0632
[8] Patent: WO2017/23996, 2017, A1, . Location in patent: Paragraph 0611
  • 4
  • [ 766-11-0 ]
  • [ 875781-15-0 ]
YieldReaction ConditionsOperation in experiment
52%
Stage #1: With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1.75 h;
Stage #2: With N-Formylpiperidine In tetrahydrofuran; hexane at -78℃; for 0.0166667 h;
Stage #3: With citric acid In tetrahydrofuran; hexane; dichloromethane; water at -78 - 20℃;
Step 1: Synthesis of 5-bromo-2-fluoro-pyridine-3-carbaldehyde.[0217] A solution of lithium di-zso-propylamine (5 mL, 35 mmol) in anhydrous THF (40mL) was cooled to -78 °C under nitrogen and n-butyl lithium (2.5 M in hexanes, 12 mL, 30mmol) was added. The mixture was then stirred at -78 °C for 15 min before 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added. The resulting mixture was then stirred at -78 °Cfor 90 min. 7V-formylpiperidine (4 mL, 36 mmol) was added very rapidly to the suspensionat -78 °C and the mixture stirred vigorously for 60 sec. The reaction was immediately quenched by the addition of a 10 percent (w/v) aqueous solution of citric acid. The mixture waswarmed to room temperature and distributed between water and dichloromethane. Theaqueous phase was extracted three times with dichloromethane and the organic phases werecombined, dried over sodium sulfate, filtered and concentrated. Crystallization of the crudeproduct from cyclohexane afforded 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2.993 g,52percent yield) as pale beige flaky crystals.
Reference: [1] Patent: WO2006/15124, 2006, A2, . Location in patent: Page/Page column 57-58
  • 5
  • [ 875781-15-0 ]
  • [ 1111637-74-1 ]
Reference: [1] Patent: US2014/107109, 2014, A1,
[2] Patent: US2014/213581, 2014, A1,
[3] Patent: WO2016/123629, 2016, A1,
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6018 - 6035
  • 6
  • [ 875781-15-0 ]
  • [ 952182-02-4 ]
Reference: [1] Journal of Organic Chemistry, 2017, vol. 82, # 14, p. 7420 - 7427
  • 7
  • [ 875781-15-0 ]
  • [ 50-01-1 ]
  • [ 882670-89-5 ]
YieldReaction ConditionsOperation in experiment
60% With triethylamine In 1-methyl-pyrrolidin-2-one at 180℃; for 0.25 h; Microwave irradiation Synthesis of 6-bromopyrido [2,3-d]pyrimidin-2-amine. 5-bromo-2-fluoronicotinaldehyde (3.0 g, 14.78 mmol), guanidine hydrochloride (1.69 g,17.74 mmol) and triethylamine (4.48 g, 44.35 mmol) were dissolved in 1-methyl-2-pyffolidinone(15 mL), and the reaction mixture was stirred at 180 °C for 15 mm under microwave. Themixture was cooled to RT, quenched with water (200 mL) and extracted with ethyl acetate (2 x300 mL). The organic layers were combined, washed with water (3 x 50 mL) and brine (3 x 50mL), dried over sodium sulfate, filtered, and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 3 : 1) to afford 6- bromopyrido[2,3-d]pyrimidin-2-amine (2.0 g, 60 percent) as a yellow solid. MS (ES+) C7H5BrN4 requires: 224, 226, found: 225, 227 [M+H].
Reference: [1] Patent: WO2014/11900, 2014, A2, . Location in patent: Page/Page column 44; 45
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