[ CAS No. 1227628-78-5 ] {[proInfo.proName]}

Name: 1227628-78-5|5-Bromo-1H-pyrazolo[4,3-b]pyridine|95%
Brand: Ambeed
SKU: A170160
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Quality Control of [ 1227628-78-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1227628-78-5 ]

SDS Specification

Alternatived Products of [ 1227628-78-5 ]

Product Details of [ 1227628-78-5 ]

CAS No. :	1227628-78-5	MDL No. :	MFCD15526714
Formula :	C₆H₄BrN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QWLXNBNVCRSNEX-UHFFFAOYSA-N
M.W :	198.02	Pubchem ID :	71307620
Synonyms :

Calculated chemistry of [ 1227628-78-5 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.59
TPSA :	41.57 Å²

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) :	1.1
Log Po/w (XLOGP3) :	1.6
Log Po/w (WLOGP) :	1.72
Log Po/w (MLOGP) :	0.95
Log Po/w (SILICOS-IT) :	2.28
Consensus Log Po/w :	1.53

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.74
Solubility :	0.359 mg/ml ; 0.00181 mol/l
Class :	Soluble
Log S (Ali) :	-2.08
Solubility :	1.63 mg/ml ; 0.00823 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.4
Solubility :	0.0797 mg/ml ; 0.000403 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.89

Safety of [ 1227628-78-5 ]

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 [ 1227628-78-5 ]

* 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 [ 1227628-78-5 ]
Downstream synthetic route of [ 1227628-78-5 ]

[ 1227628-78-5 ] Synthesis Path-Upstream 1~3

1
[ 126325-47-1 ]
[ 1227628-78-5 ]

Reference： [1] Patent: WO2017/23993, 2017, A1, . Location in patent: Paragraph 0615; 0617
[2] Patent: WO2017/24004, 2017, A1, . Location in patent: Paragraph 0612
[3] Patent: WO2017/24025, 2017, A1, . Location in patent: Paragraph 0612
[4] Patent: WO2017/24003, 2017, A1, . Location in patent: Paragraph 0610; 0612

2
[ 22282-96-8 ]
[ 110-46-3 ]
[ 1227628-78-5 ]

Yield	Reaction Conditions	Operation in experiment
5 g	Stage #1: With potassium acetate; acetic anhydride In chloroform at 10 - 65℃; for 2 h; Stage #2: With 18-crown-6 ether In chloroform at 65℃; for 16 h; Stage #3: With potassium carbonate; potassium hydroxide In methanol; chloroform; water at 23℃; for 3 h;	To a stirred solution of 6-bromo-2-methyl-3-nitropyridine (5 g, 26.73 mmol) in chloroform was added potassium acetate (3.14 g, 32.08 mmol) and acetic anhydride (10.9 g, 106 mmol) at 10° C., the contents were stirred at 65° C. temperature for 2 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to room temperature, isoamylnitrite (3.75 g, 32.06 mmol) was added drop wise over a period of 15 min, followed by 18-crown-6 (0.7 g, 2.67 mmol) was added, reaction mixture was stirred at 65° C. for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to room temperature, methanol and water mixture 120 mL (1:1) was added to the reaction mixture followed by potassium carbonate (34.48 g, 24.99 mmol) and KOH (4.2 g, 74.97 mmol), reaction mixture was stirred for 3 h at room temperature. After completion of reaction, reaction mixture was added diluted with ethyl acetate and the organic layer was washed with water followed by brine. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain this title compound (5 g) as an off-white solid.

Reference： [1] Patent: US2016/347717, 2016, A1, . Location in patent: Paragraph 0595; 0596

3
[ 22282-96-8 ]
[ 1227628-78-5 ]

Reference： [1] Patent: WO2017/23993, 2017, A1,
[2] Patent: WO2017/24004, 2017, A1,
[3] Patent: WO2017/24025, 2017, A1,
[4] Patent: WO2017/24003, 2017, A1,

[ 1227628-78-5 ] Synthesis Path-Downstream 1~45

1
[ 1227628-78-5 ]
[ 1613639-39-6 ]
[ 1613638-99-5 ]

Yield	Reaction Conditions	Operation in experiment
5 mg	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 95℃; for 10h;Inert atmosphere;	To a solution of (R)-5-(2-hydroxy-l-phenylethyl)-amino)-pyridin-3-yl)-boronic acid (100 mg, 0.5 mmol) in DME/H20 (5 : 1, 6 mL) was added Pd(PPh3)4 (1 16 mg, 0.1 mmol), K2C03 (138 mg, 1.0 mmol) and 5-bromo-lH-pyrazolo[4,3-b]pyridine (125 mg, 0.5 mmol). The resulting mixture was degassed and then stirred for 10 hours at 95 C under an Ar atmosphere. After cooling, the mixture was diluted with water (30 mL) and then extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water and brine, and then dried. The solvent was concentrated and the residue was purified by Prep-HPLC to give (R)-2-phenyl-2-[5-(lH- pyrazolo[4,3-b]pyridin-5-yl)-pyridin-3-ylamino]-ethanol (5 mg).

Reference： [1]Patent: WO2014/90692,2014,A1 .Location in patent: Page/Page column 58

2
[ 22282-96-8 ]
[ 1227628-78-5 ]

Reference： [1]Patent: WO2017/23993,2017,A1
[2]Patent: WO2017/24004,2017,A1
[3]Patent: WO2017/24025,2017,A1
[4]Patent: WO2017/24003,2017,A1

3
[ 22282-96-8 ]
[ 110-46-3 ]
[ 1227628-78-5 ]

Yield	Reaction Conditions	Operation in experiment
5 g		To a stirred solution of <strong>[22282-96-8]6-bromo-2-methyl-3-nitropyridine</strong> (5 g, 26.73 mmol) in chloroform was added potassium acetate (3.14 g, 32.08 mmol) and acetic anhydride (10.9 g, 106 mmol) at 10 C., the contents were stirred at 65 C. temperature for 2 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to room temperature, isoamylnitrite (3.75 g, 32.06 mmol) was added drop wise over a period of 15 min, followed by 18-crown-6 (0.7 g, 2.67 mmol) was added, reaction mixture was stirred at 65 C. for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to room temperature, methanol and water mixture 120 mL (1:1) was added to the reaction mixture followed by potassium carbonate (34.48 g, 24.99 mmol) and KOH (4.2 g, 74.97 mmol), reaction mixture was stirred for 3 h at room temperature. After completion of reaction, reaction mixture was added diluted with ethyl acetate and the organic layer was washed with water followed by brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain this title compound (5 g) as an off-white solid.

Reference： [1]Patent: US2016/347717,2016,A1 .Location in patent: Paragraph 0595; 0596

4
[ 110-87-2 ]
[ 1227628-78-5 ]
5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With toluene-4-sulfonic acid; In dichloromethane; at 20℃;	: To a solution of <strong>[1227628-78-5]5-bromopyrazolo[4,3-b]pyridine</strong> (0.4395 g, 2.22 mmol) and 3,4-dihydro-2H-pyran (0.25 mL, 2.66 mmol) in CH2Cl2 (4.1 mL) was added 4-methylbenzenesulfonic acid (38 mg, 0.222 mmol). The mixture was stirred at rt overnight. The mixture was diluted with DCM (20 mL) and washed with water (3 x 8 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified via flash column chromatography to give E11A (527 mg, 84%).1H NMR (500 MHz, chloroform-d) delta 8.19 (d, J = 1.0 Hz, 1H), 7.89 (dd, J = 8.8, 0.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 5.75 (dd, J = 8.7, 2.6 Hz, 1H), 3.99 (dtd, J = 11.7, 4.0, 1.4 Hz, 1H), 3.81 - 3.71 (m, 1H), 2.56 - 2.42 (m, 1H), 2.20 - 2.10 (m, 2H), 1.87 - 1.67 (m, 3H).
	With toluene-4-sulfonic acid; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide; at 25℃; for 6h;	j0618j To a solution of 5-bromo-1H-pyrazolo[4,3-bjpyridine (XVI) (200 g, 1.01 mol, 1.00 eq) in DCM (1.60 L), THF (1.60 L) and DMF (100 mL) at 2SC was added p-TsOH (19.2 g, 101 mmol, 0.10 eq). The reaction solution was stirred at 2SC for 6 h. The solvent was removed under vacuum. 10% NaHCO3 (1.S L) and EtOAc (1.S L) was added to the residue and the residue was washed with EtOAc (500 mL x 3). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5- bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-bjpyridine (XVII) (347 g, cmde) as yellow oil. The crude product was used for the next step without any purification. ESIMS found for CjiHi2BrN3O m/z 281.7 (M+H).
	With toluene-4-sulfonic acid; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide; at 25℃; for 6h;	To a solution of 5-bromo-lH-pyrazolo[4,3-b]pyridine (XVI) (200 g, 1.01 mol, 1.00 eq) in DCM (1.60 L), THF (1.60 L) and DMF (100 mL) at 25C was added p-TsOH (19.2 g, 101 mmol, 0.10 eq). The reaction solution was stirred at 25C for 6 h. The solvent was removed under vacuum. 10% NaHCC (1.5 L) and EtOAc (1.5 L) was added to the residue and the residue was washed with EtOAc (500 mL x 3). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5- bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-b]pyridine (XVII) (347 g, crude) as yellow oil. The crude product was used for the next step without any purification. ESIMS found for CnHi2BrN30 mlz 281.7 (M+H).

	With toluene-4-sulfonic acid; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide; at 25℃; for 6h;	To a solution of 5-bromo-lH-pyrazolo[4,3-b]pyridine (XVI) (200 g, 1.01 mol, 1.00 eq) in DCM (1.60 L), THF (1.60 L) and DMF (100 mL) at 25C was added p-TsOH (19.2 g, 101 mmol, 0.10 eq). The reaction solution was stirred at 25C for 6 h. The solvent was removed under vacuum. 10% NaHCC (1.5 L) and EtOAc (1.5 L) was added to the residue and the residue was washed with EtOAc (500 mL x 3). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-b]pyridine (XVII) (347 g, crude) as yellow oil. The crude product was used for the next step without any purification. ESIMS found for CnHnBrNsO mlz 281.7 (M+H).
	With toluene-4-sulfonic acid; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide; at 25℃; for 6h;	To a solution of 5-bromo-lH-pyrazolo[4,3-b]pyridine (XVI) (200 g, 1.01 mol, 1.00 eq) in DCM (1.60 L), THF (1.60 L) and DMF (100 mL) at 25C was added p-TsOH (19.2 g, 101 mmol, 0.10 eq). The reaction solution was stirred at 25C for 6 h. The solvent was removed under vacuum. 10% NaHC03 (1.5 L) and EtOAc (1.5 L) was added to the residue and the residue was washed with EtOAc (500 mL x 3). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5- bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[4,3-b]pyridine (XVII) (347 g, crude) as yellow oil. The crude product was used for the next step without any purification. ESIMS found for CnHi2BrN30 mlz 281.7 (M+H).

Reference： [1]Patent: WO2018/89357,2018,A1 .Location in patent: Page/Page column 111
[2]Patent: WO2017/23993,2017,A1 .Location in patent: Paragraph 0615; 0618
[3]Patent: WO2017/24004,2017,A1 .Location in patent: Paragraph 0613
[4]Patent: WO2017/24025,2017,A1 .Location in patent: Paragraph 0613
[5]Patent: WO2017/24003,2017,A1 .Location in patent: Paragraph 0610; 0613

5
[ 126325-47-1 ]
[ 1227628-78-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension <strong>[126325-47-1]6-bromo-2-methylpyridin-3-amine</strong> (XV) (186 g, 994 mmol, 1.00 eq) and KOAc (115 g, 1.17 mol, 1.18 eq) in CHC13 (3.50 L) was added Ac20 (405 g, 3.97 mol, 3.99 eq) and the suspension was stirred at 25C for 1 h and then heated at 60-70C to reflux for an additional 2 h. After cooling the suspension to 25C, isopentyl nitrate (233 g, 1.99 mol, 2.00 eq) and 18-crown-6 (21 g, 79.5 mmol, 0.08 eq) was added and the suspension heated to reflux for 12 h. After cooling to 25C, the suspension was filtered and the filtrate was concentrated under reduced pressure to yield a residue that was treated with a suspension of potassium carbonate (450 g) in a solution of methanol and water (450 mL) at 0C for 3 h. The suspension was concentrated under reduced pressure to yield a residue that was extracted with EtOAc (1000 mL x 3) and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give S -bromo- 1H-pyrazolo [4,3 -bjpyridine (XVI) (405 g, crude) as yellow solid. The crude product was used for the next step without any purification. ?H NMR (DM50-cl6, 400 MHz) ppm 7.49 (d, J=8.8Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 8.27 (s, 1H); ESIMS found for C6H4BrN3 mlz 198.1 (M+H).
		To a suspension 6-bromo-2-methylpyridin-3 -amine (XV) (186 g, 994 mmol, 1.00 eq) and KOAc (115 g, 1.17 mol, 1.18 eq) in CHC13 (3.50 L) was added Ac20 (405 g, 3.97 mol, 3.99 eq) and the suspension was stirred at 25C for 1 h and then heated at 60-70C to reflux for an additional 2 h. After cooling the suspension to 25C, isopentyl nitrate (233 g, 1.99 mol, 2.00 eq) and 18-crown-6 (21 g, 79.5 mmol, 0.08 eq) was added and the suspension heated to reflux for 12 h. After cooling to 25C, the suspension was filtered and the filtrate was concentrated under reduced pressure to yield a residue that was treated with a suspension of potassium carbonate (450 g) in a solution of methanol and water (450 mL) at 0C for 3 h. The suspension was concentrated under reduced pressure to yield a residue that was extracted with EtOAc (1000 mL x 3) and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5-bromo-lH-pyrazolo[4,3-b]pyridine (XVI) (405 g, crude) as yellow solid. The crude product was used for the next step without any purification. NMR (DMSO- tf, 400 MHz) delta ppm 7.49 (d, J=8.8Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 8.27 (s, 1H); ESIMS found for C6H4BrN3 mlz 198.1 (M+H).
		To a suspension <strong>[126325-47-1]6-bromo-2-methylpyridin-3-amine</strong> (XV) (186 g, 994 mmol, 1.00 eq) and KOAc (115 g, 1.17 mol, 1.18 eq) in CHC13 (3.50 L) was added Ac20 (405 g, 3.97 mol, 3.99 eq) and the suspension was stirred at 25C for 1 h and then heated at 60-70C to reflux for an additional 2 h. After cooling the suspension to 25C, isopentyl nitrate (233 g, 1.99 mol, 2.00 eq) and 18-crown-6 (21 g, 79.5 mmol, 0.08 eq) was added and the suspension heated to reflux for 12 h. After cooling to 25C, the suspension was filtered and the filtrate was concentrated under reduced pressure to yield a residue that was treated with a suspension of potassium carbonate (450 g) in a solution of methanol and water (450 mL) at 0C for 3 h. The suspension was concentrated under reduced pressure to yield a residue that was extracted with EtOAc (1000 mL x 3) and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5-bromo-lH-pyrazolo[4,3-b]pyridine (XVI) (405 g, crude) as yellow solid. The crude product was used for the next step without any purification. NMR (DMSO- e, 400 MHz) delta ppm 7.49 (d, J=8.8Hz, IH), 8.00 (d, J=8.8Hz, IH), 8.27 (s, IH); ESIMS found for C6H4BrN3 mlz 198.1 (M+H).

To a suspension <strong>[126325-47-1]6-bromo-2-methylpyridin-3-amine</strong> (XV) (186 g, 994 mmol, 1.00 eq) and KOAc (115 g, 1.17 mol, 1.18 eq) in CHC13 (3.50 L) was added Ac20 (405 g, 3.97 mol, 3.99 eq) and the suspension was stirred at 25C for 1 h and then heated at 60-70C to reflux for an additional 2 h. After cooling the suspension to 25C, isopentyl nitrate (233 g, 1.99 mol, 2.00 eq) and 18-crown-6 (21 g, 79.5 mmol, 0.08 eq) was added and the suspension heated to reflux for 12 h. After cooling to 25C, the suspension was filtered and the filtrate was concentrated under reduced pressure to yield a residue that was treated with a suspension of potassium carbonate (450 g) in a solution of methanol and water (450 mL) at 0C for 3 h. The suspension was concentrated under reduced pressure to yield a residue that was extracted with EtOAc (1000 mL x 3) and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5-bromo-lH-pyrazolo[4,3-b]pyridine (XVI) (405 g, crude) as yellow solid. The crude product was used for the next step without any purification. NMR (DMSO- 6, 400 MHz) delta ppm 7.49 (d, J=8.8Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 8.27 (s, 1H); ESIMS found for C6H4BrN3 mlz 198.1 (M+H).

Reference： [1]Patent: WO2017/23993,2017,A1 .Location in patent: Paragraph 0615; 0617
[2]Patent: WO2017/24004,2017,A1 .Location in patent: Paragraph 0612
[3]Patent: WO2017/24025,2017,A1 .Location in patent: Paragraph 0612
[4]Patent: WO2017/24003,2017,A1 .Location in patent: Paragraph 0610; 0612

6
[ 1227628-78-5 ]
5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine [ No CAS ]

Reference： [1]Patent: WO2017/23993,2017,A1

7
[ 1227628-78-5 ]
5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine [ No CAS ]

Reference： [1]Patent: WO2017/23993,2017,A1

8
[ 1227628-78-5 ]
5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-iodo-1H-pyrazolo[4,3-b]pyridine [ No CAS ]

Reference： [1]Patent: WO2017/23993,2017,A1

9
[ 1227628-78-5 ]
tert-butyl 5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-iodo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/23993,2017,A1

10
[ 1227628-78-5 ]
tert-butyl 3-(1-(tert-butoxycarbonyl)-4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-indol-2-yl)-5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/23993,2017,A1

11
[ 1227628-78-5 ]
N-(3-(2-(5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-indol-4-yl)-5-fluorobenzyl)methane sulfonamide [ No CAS ]

Reference： [1]Patent: WO2017/23993,2017,A1

12
[ 1227628-78-5 ]
1-(tetrahydro-2H-pyran-2-yl)-5-(tributylstannyl)-1H-pyrazolo[4,3-b]pyridine [ No CAS ]

Reference： [1]Patent: WO2017/23993,2017,A1
[2]Patent: WO2017/24004,2017,A1

13
[ 1227628-78-5 ]
5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine [ No CAS ]