[ CAS No. 153888-45-0 ]

Name: 153888-45-0|5-Bromo-1-methyl-3-nitropyridin-2(1H)-one|98%
Brand: Ambeed
SKU: A731007
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Quality Control of [ 153888-45-0 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 153888-45-0 ]

CAS No. :	153888-45-0	MDL No. :	MFCD09835081
Formula :	C₆H₅BrN₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	233.02 g/mol	Pubchem ID :	-
Synonyms :

Calculated chemistry of of [ 153888-45-0 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	48.49
TPSA :	67.82 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.13 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.15
Log Po/w (XLOGP3) :	0.84
Log Po/w (WLOGP) :	1.06
Log Po/w (MLOGP) :	0.28
Log Po/w (SILICOS-IT) :	-0.53
Consensus Log Po/w :	0.56

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.12
Solubility :	1.78 mg/ml ; 0.00762 mol/l
Class :	Soluble
Log S (Ali) :	-1.85
Solubility :	3.31 mg/ml ; 0.0142 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.73
Solubility :	4.3 mg/ml ; 0.0185 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.14

Safety of [ 153888-45-0 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 153888-45-0 ]

* 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 [ 153888-45-0 ]
Downstream synthetic route of [ 153888-45-0 ]

[ 153888-45-0 ] Synthesis Path-Upstream 1~1

1
[ 153888-45-0 ]
[ 910543-72-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: With hydrogenchloride; water; iron In ethanol at 60℃; for 2 h; Stage #2: With water; potassium carbonate In ethanol	3-Amino-5-bromo-1-methylpyridin-2-one (42); A 1-L three-neck round-bottomed flask equipped with a mechanical stirrer and reflux condenser was purged with nitrogen and charged with 41 (21.7 g, 93.3 mmol), ethanol (305 mL), iron powder (-325 mesh, 52.1 g, 933 mmol) and 2N hydrochloric acid (50 mL, 100 mmol), and the mixture was heated for 2 h at 60° C. After this time, the reaction was cooled to room temperature, and potassium carbonate was added to pH 8 as determined by a pH paper. The resulting suspension was filtered and the filter cake washed with ethanol (4.x.100 mL). The filtrate was concentrated under reduced pressure to yield a brown solid. This solid was purified by column chromatography on silica gel to afford 42 in 77percent yield (14.5 g) as an off-white powder: mp 104-105° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.15 (d, 1H, J=2.5 Hz), 6.46 (d, 1H, J=2.5 Hz), 5.45 (bs, 2H), 3.40 (s, 3H); MS (ESI+) m/z 203 (M+H).
34%	With iron; ammonium chloride In ethanol; water-d2 at 95℃; for 3 h; Inert atmosphere	Iron powder (1 g, 18 mmol, 4.2 equivalents) and ammonium chloride (0.964 g, 18 mmol, 4.2 equivalents) were added to a solution of 1-methyl-3-nitro-5-bromo-pyridin-2-one (1 g, 4.3 mmol, 1 equivalent) in ethanol (8 mL) and water (6 mL) and stirred at 95 °C for 3 hours. The solution was then filtered through a pad of celite and concentrated. The residue was then taken up in water (20 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were dried over magnesium sulfate and concentrated to give a brown oil that solidified upon standing. The residue was purified by SCX to give the desired product as a dark red solid (300 mg, 34percent).

Reference： [1] Organic Process Research and Development, 2014, vol. 18, # 1, p. 228 - 238
[2] Patent: US2009/82330, 2009, A1, . Location in patent: Page/Page column 39-41
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 11, p. 3021 - 3029
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 2, p. 755 - 758
[5] Patent: WO2006/99268, 2006, A2, . Location in patent: Page/Page column 69
[6] Patent: US2018/44335, 2018, A1, . Location in patent: Paragraph 0446-0447

[ 153888-45-0 ] Synthesis Path-Downstream 1~31

1
[ 15862-34-7 ]
[ 74-88-4 ]
[ 153888-45-0 ]

Yield	Reaction Conditions	Operation in experiment
85%		5-Bromo-1-methyl-3-nitropyridin-2-one (41); A 1-L round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 5-bromo-3-nitro-2-hydroxypyridine (24.0 g, 0.11 mol), anhydrous DMF (280 mL) and powdered potassium carbonate (-350 mesh, 33.4 g, 0.24 mol), and the suspension stirred for 15 min at ambient temperature. After this time methyl iodide (17.1 g, 0.124 mol) was added, and the mixture stirred at room temperature for 18 h. The reaction mixture was then diluted with water (750 mL) and extracted with ethyl acetate (3×1.0 L). The organic extracts were combined, washed with brine (500 mL) and dried over sodium sulfate. After removing the drying agent by filtration, the filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by flash chromatography on silica to afford an 85% yield (21.7 g) of 41 as a yellow solid: mp 122-123 C.; 1H NMR (300 MHz, CDCl3) delta 8.37 (d, 1H, J=2.7 Hz), 7.26 (s, 1H), 3.68 (s, 3H); MS (ESI+) m/z 234 (M+H).
	With caesium carbonate; In N,N-dimethyl-formamide; for 18h;	Cesium carbonate (44.6 g, 137 mmol) was added to a solution of 5-bromo-2-hydroxy-3- nitropyridine (20.0 g, 91.3 mmol) and iodomethane (19.4 g, 137 mmol) in NN-dimethylformamide (500 mL). After 18 h, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (3x), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. MS 233.1 (M).
		5-Bromo-1-methyl-3-nitro-1H-pyridin-2-one H A 1-L round-bottomed flask equipped with a magnetic stirrer is purged with nitrogen, then charged with 5-bromo-3-nitro-pyridin-2-ol G (20.0 g; 0.09 mol), DMF (200 mL) and K2CO3 (25.2 g; 0.18 mol). The suspension is stirred for 15 min at RT, MeI (14.3 g; 0.10 mol) is added and the mixture is stirred at RT for 18 h. The reaction mixture is diluted with water and extracted with EtOAc (3*200.0 mL). The combined extracts are washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography. HPLC-MS: (M+H)+=233/235; tRet=0.828 min; method M7

Reference： [1]Patent: US2009/82330,2009,A1 .Location in patent: Page/Page column 39-40
[2]Patent: WO2006/99268,2006,A2 .Location in patent: Page/Page column 69
[3]Patent: US2018/44335,2018,A1 .Location in patent: Paragraph 0443-0444

2
[ 153888-45-0 ]
[ 910543-72-5 ]

Yield	Reaction Conditions	Operation in experiment
77%		3-Amino-5-bromo-1-methylpyridin-2-one (42); A 1-L three-neck round-bottomed flask equipped with a mechanical stirrer and reflux condenser was purged with nitrogen and charged with 41 (21.7 g, 93.3 mmol), ethanol (305 mL), iron powder (-325 mesh, 52.1 g, 933 mmol) and 2N hydrochloric acid (50 mL, 100 mmol), and the mixture was heated for 2 h at 60 C. After this time, the reaction was cooled to room temperature, and potassium carbonate was added to pH 8 as determined by a pH paper. The resulting suspension was filtered and the filter cake washed with ethanol (4×100 mL). The filtrate was concentrated under reduced pressure to yield a brown solid. This solid was purified by column chromatography on silica gel to afford 42 in 77% yield (14.5 g) as an off-white powder: mp 104-105 C.; 1H NMR (500 MHz, DMSO-d6) delta 7.15 (d, 1H, J=2.5 Hz), 6.46 (d, 1H, J=2.5 Hz), 5.45 (bs, 2H), 3.40 (s, 3H); MS (ESI+) m/z 203 (M+H).
34%	With iron; ammonium chloride; In ethanol; water-d2; at 95℃; for 3h;Inert atmosphere;	Iron powder (1 g, 18 mmol, 4.2 equivalents) and ammonium chloride (0.964 g, 18 mmol, 4.2 equivalents) were added to a solution of 1-methyl-3-nitro-5-bromo-pyridin-2-one (1 g, 4.3 mmol, 1 equivalent) in ethanol (8 mL) and water (6 mL) and stirred at 95 C for 3 hours. The solution was then filtered through a pad of celite and concentrated. The residue was then taken up in water (20 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were dried over magnesium sulfate and concentrated to give a brown oil that solidified upon standing. The residue was purified by SCX to give the desired product as a dark red solid (300 mg, 34%).
	With tin(ll) chloride; In N,N-dimethyl-formamide; at 80℃; for 1.5h;	Tin(?) chloride dihydrate (53.3 g, 236 mmol) was added to a solution of 5-bromo-l- methyl-3-nitropyridin-2(lH)-one (11.0 g, 47.2 mmol) in ethyl acetate (400 mL) at 80 0C. After 1.5 h, the reaction mixture was quenched with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (3x), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. MS 203.1 (M).

With iron; ammonium chloride; In ethanol; water; at 60℃; for 2h;

3-Amino-5-bromo-1-methyl-1H-pyridin-2-one C-12 Iron powder (21.6 g; 0.39 mol) is added to a suspension of 5-bromo-1-methyl-3-nitro-1H-pyridin-2-one H (18.0 g; 0.08 mol) in EtOH (120.0 mL) and saturated aqueous NH4Cl (60.0 mL) at 60 C. The reaction is stirred at 60 C. for 2 h. The reaction mixture is then filtered and the solid residue on the filter is washed with EtOAc. The filtrate is concentrated under reduced pressure and extracted with EtOAc (3*100.0 mL). The combined extracts are washed with brine, dried with Na2SO4, filtered and concentrated. The residue is purified by column chromatography to afford the desired compound. HPLC-MS: (M+H)+=203/205; tRet=1.248 min; method M11

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 228 - 238
[2]Patent: US2009/82330,2009,A1 .Location in patent: Page/Page column 39-41
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3021 - 3029
[4]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 755 - 758
[5]Patent: WO2006/99268,2006,A2 .Location in patent: Page/Page column 69
[6]Patent: US2018/44335,2018,A1 .Location in patent: Paragraph 0446-0447

3
[ 15862-34-7 ]
methyl halide [ No CAS ]
[ 153888-45-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 755 - 758

4
[ 15862-34-7 ]
[ 33513-42-7 ]
[ 74-88-4 ]
[ 153888-45-0 ]

Yield	Reaction Conditions	Operation in experiment
89%		Example 1225-Bromo- l-methyl-3-nitropyridin-2(lH)-one 122a122aA 1-L round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 5-Bromo-3-nitropyridin-2(lH)-one (25.0 g, 114 mmol), anhydrous DMF (500 mL) and potassium carbonate (34.7 g, 251 mmol), and the suspension stirred for 15 min at ambient temperature. After this time, methyl iodide (17.8 g, 126 mmol) was added, and the mixture stirred at room temperature for 16 h. The reaction mixture was then diluted with water (500 mL) and extracted with methylene chloride (3 x 500 mL). The organic extracts were combined, washed with 10% aqueous lithium chloride (300 mL) and water (300 mL) and dried over sodium sulfate. After removing the drying agent by filtration, the filtrate was evaporated to dryness under reduced pressure. The resulting residue was flash chromatographed eluting with a gradient from 50% to 100% of ethyl acetate in hexanes, and the fractions containing 122a were collected to afford, after concentrating under reduced pressure, an 89% yield (23.6 g) of 122a as a yellow solid: mp 122-123 C; ]H NMR (300 MHz, CDC13) δ 8.37 (d, 1H, J = 2.7 Hz), 7.26 (s, 1H), 3.68 (s, 3H); MS (ESI+) m/z 234 (M+H).

Reference： [1]Patent: WO2012/31004,2012,A1 .Location in patent: Page/Page column 110

5
[ 153888-45-0 ]
[ 73183-34-3 ]
[ 1361941-27-6 ]

Yield	Reaction Conditions	Operation in experiment
73%		Example 122b l-Methyl-3-nitro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one 122bA 3-L three-neck round-bottomed flask equipped with a mechanical stirrer, reflux condenser and thermoregulator was purged with nitrogen and charged with 122a (23.6 g, 102 CGI PHARM6 0WO mmol), 4,4,4' ,4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (32.2 g, 127 mmol), potassium acetate (30.0 g, 306 mmol) and 1,4-dioxane (800 mL). A stream of nitrogen was passed through the resulting suspension for 30 min. Pd(dppf)C12»CH2C12 (4.17 g, 5.10 mmol) was then added, and the reaction was stirred at 80 C for 2 h. After this time, the mixture was cooled to ambient temperature and evaporated to dryness under reduced pressure at 40 C. The resulting black solid was charged into a 3-L three-neck round-bottomed flask equipped with a mechanical stirrer and reflux condenser. Toluene (640 mL) and magnesium sulfate (20 g) were added, and the resulting suspension was heated under nitrogen to 90 C over 15 min. The mixture was filtered hot through a pad of Cellpure P65, and the filter cake was washed with hot toluene (3 x 45 mL). The filtrate was evaporated on a rotary evaporator at 40 C until a thick suspension formed (weight of the residue was 97 g). This suspension was filtered using the filtrate to transfer the residual material from the walls of the flask. The filter cake was washed with toluene (15 mL) and dried for 2 h under vacuum at 40 C to afford a 73% yield (20.8 g) of 122b as a yellow solid: ]H NMR (300 MHz, DMSO-i¾) δ 8.48 (d, 1H, / = 2.0 Hz), 8.34 (d, 1H, / = 2.0 Hz), 3.60 (s, 3H), 1.30 (s, 12H).

Reference： [1]Patent: WO2012/31004,2012,A1 .Location in patent: Page/Page column 110-111

6
[ 153888-45-0 ]
[ 1361941-28-7 ]

Reference： [1]Patent: WO2012/31004,2012,A1

7
[ 153888-45-0 ]
[ 1361941-29-8 ]

Reference： [1]Patent: WO2012/31004,2012,A1

8
[ 153888-45-0 ]
[ 1361941-30-1 ]

Reference： [1]Patent: WO2012/31004,2012,A1

9
[ 15862-34-7 ]
[ 77-78-1 ]
[ 153888-45-0 ]