[ CAS No. 845305-87-5 ] {[proInfo.proName]}

Name: 845305-87-5|5-Bromo-N-methylpicolinamide|98%
Brand: Ambeed
SKU: A624180
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Quality Control of [ 845305-87-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 845305-87-5 ]

Product Details of [ 845305-87-5 ]

CAS No. :	845305-87-5	MDL No. :	MFCD07357421
Formula :	C₇H₇BrN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OHYCXPXWHPWYFX-UHFFFAOYSA-N
M.W :	215.05	Pubchem ID :	22831620
Synonyms :

Calculated chemistry of [ 845305-87-5 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	44.93
TPSA :	41.99 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) :	-6.6 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.98
Log Po/w (XLOGP3) :	1.43
Log Po/w (WLOGP) :	1.2
Log Po/w (MLOGP) :	0.68
Log Po/w (SILICOS-IT) :	1.55
Consensus Log Po/w :	1.37

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.35
Solubility :	0.97 mg/ml ; 0.00451 mol/l
Class :	Soluble
Log S (Ali) :	-1.92
Solubility :	2.6 mg/ml ; 0.0121 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.27
Solubility :	0.115 mg/ml ; 0.000535 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.48

Safety of [ 845305-87-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362-P403+P233-P501	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 845305-87-5 ]

* 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 [ 845305-87-5 ]
Downstream synthetic route of [ 845305-87-5 ]

[ 845305-87-5 ] Synthesis Path-Upstream 1~2

1
[ 845305-87-5 ]
[ 917-54-4 ]
[ 214701-49-2 ]

Reference： [1] Patent: WO2013/91096, 2013, A1, . Location in patent: Page/Page column 78-79

2
[ 845305-87-5 ]
[ 73183-34-3 ]
[ 945863-21-8 ]

Reference： [1] Patent: WO2010/8847, 2010, A2, . Location in patent: Page/Page column 125-126

[ 845305-87-5 ] Synthesis Path-Downstream 1~39

1
[ 845305-87-5 ]
[ 926036-39-7 ]
5-[2-methyl-5-(3-trifluoromethyl-phenylcarbamoyl)-phenylethynyl]-pyridine-2-carboxylic acid methylamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 627 - 640

2
[ 30766-11-1 ]
[ 593-51-1 ]
[ 845305-87-5 ]

Yield	Reaction Conditions	Operation in experiment
63%		S-Bromo-pyridine^-carboxylic acid (2.59 g, 12.8 mmol) and thionylchloride (2.79 ml) were heated at reflux in toluene (25 ml) for 16 hours. Excess reagents were removed in vacuo and the residue was diluted in dichloromethane (50 ml). A mixture of methyl amine hydrochloride (2.60 g, 38.5 mmol) and DIPEA (6.7 ml, 38.5 mmol) in dichloromethane (10 ml) was added dropwise to the stirred solution and the resulting mixture was maintained at room temperature for 5 hours. The solution was washed with saturated aqueous NaHCOs (25 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting brown solid was recrystallised (Heptane/EtOAc) to provide the title compound as off-white needles (1.74 g, 63%). LCMS data: Calculated MH+ (215/217); Found 100% (MH+) m/z 215/217, Rt = 1.36 min. 1H NMR data: (250MHz, MeOD) δ ppm 8.70 (1 H, d, J=2.3 Hz), 8.06 - 8.19 (1 H, m), 7.99 (1 H, d, J=8.4 Hz), 2.95 (3 H, s).
56.1%		General procedure: 5-bromopicolinic acid (100 mg, 0.5 mmol) and HATU (208 mg„ 0.54 mmol) were dissolved in DMF (2 mL), the mixture was stirred at room temperature for 30 min, DIPEA(129 mg, 1 mmol) and methylamine hydrochloride (20 mg, 0.64mmol) were added to the mixture, the mixture was stirred at room temperature over night. The reaction sample was diluted with water (5 mL), extracted with EtOAc (15x 3 mL), dried over Na2S04, concentrated under reduced pressure, the residue was purified by gradient elution on silica gel (0 to 20% EtOAc in petroleum) to afford the title compound (60 mg, 56.1%). LRMS (ES) calculated M + H for LRMS (ES) calculated M + H for C2iH2o 802: 215.0, found: 215.1
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃;	5-Bromo-2-pyridinecarboxylic acid (D10) (1g) was dissolved in dry DMF (50ml) and treated with methylamine hydrochloride (0.42g), EDC (1. 2g), HOBT (0. 56g) and Et3N (2. 4mi). The reaction was stirred at rt overnight then poured into water (200ml) and extracted with DCM (50ml). The organic extract was washed with brine (5x50ml), dried (magnesium sulfate) and evaporated to give the title compound (D11) as a yellow crystalline solid (0.45g). LCMS electrospray (+ve) 349 (MH+).

Reference： [1]Patent: WO2009/135842,2009,A1 .Location in patent: Page/Page column 76-77
[2]Patent: WO2014/81619,2014,A1 .Location in patent: Page/Page column 45
[3]Patent: WO2005/40144,2005,A1 .Location in patent: Page/Page column 13

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Cooling with ice;	General procedure: The compound 5-bromo-2-pyridinecarboxylic acid (404mg, 2.0mmol) was dissolved inDichloromethane (10mL),The corresponding amine (2.2mmol), HOBT (324mg, 2.4mmol), EDCI (575mg, 3.0mmol), DIPEA (383mg, 3.0mmol, 522μL) were added under ice bath stirring, and then moved to room temperature to react for 35h.After the reaction, the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography, using PE:EA (5:1-1:1) as the eluent to obtain a white or light yellow solid 1-5 to 1-11.Yield: 60 to 80%.

4
[ 845305-87-5 ]
[ 845305-85-3 ]
5-{4-[(1-cyclobutyl-4-piperidinyl)oxy]-1-piperidinyl}-N-methyl-2-pyridinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 250℃; for 0.5h;Microwave irradiation;Product distribution / selectivity;	Example 38 5- {4- [ (1-CYCLOBUTYL-4-PIPERIDINYL) OXY]-1-PIPERIDINYL}-N-METHYL-2- pyridinecarboxamide hydrochloride (E38) 1-Cyclobutyl-4- (4-piperidinyloxy) piperidine (D6) (0. 150g), 5-bromo-N-methyl-2- pyridinecarboxamide (D19) (0.203g) and anhydrous potassium carbonate (0. 174G) were added to a 5ML PERSONAL Chemistry microwave vial, to which DMSO (2ml) was added. The vial was sealed and heated at 250C for 30min in an EMRYS OPTIMIZER microwave reactor. The crude mixture was diluted with MeOH (5ML) and passed through an SCX cartridge [10g, MeOH (80ml) then 2N NH3 in MeOH (80ML)]. The eluted mixture was evaporated, then chromatography [silica gel, eluting with (10% NH3 in MeOH) /DCM, 0- 10%] and treatment of the free base product dissolved in DCM (5ML) with HCI (1 ML, 1 M in diethyl ether), followed by evaporation gave the title compound (E38) (0. 015G). MS ELECTROSPRAY (+ion) 373 (MH+). LHNMR8 (CDCI3) : 8.16 (1 H, D, J=2.8Hz), 8.02 (1 H, d, J=8.8Hz), 7.76 (1 H, d, J=5.6Hz), 7.21 (1H, dd, J=8.8Hz, J=2. 8HZ), 3.64 (3H, m), 3.46 (1H, m), 3.13 (2H, m), 2.99 (3H, d, J=5.2Hz), 2.68 (3H, m), 2.09-1. 78 (10H, m), 1.74- 1.52 (6H, m, obscured by H20).

Reference： [1]Patent: WO2005/14571,2005,A1 .Location in patent: Page/Page column 40

5
[ 845305-87-5 ]
(1R)-1'-{2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoyl}-3H-spiro[2-benzofuran-1,3'-pyrrolidin]-3-one [ No CAS ]
5-(4-{1,1-dimethyl-2-oxo-2-[(1R)-3-oxo-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1'-yl]ethyl}phenyl)-N-methylpyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; DMF (N,N-dimethyl-formamide); at 150℃; for 15h;	A stirred mixture of (1R)-1'-{2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoyl}-3H-spiro[2-benzofuran-1,3'-pyrrolidin]-3-one (750.0 mg, 0.001300 mol), 5-bromo-N-methylpyridine-2-carboxamide (559 mg, 0.00260 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (64 mg, 0.000078 mol) and potassium carbonate (539 mg, 0.00390 mol) in anhydrous N,N-dimethylformamide (3.0 mL, 0.039 mol) and 1,4-dioxane (3.5 mL, 0.045 mol) was heated at 150 C. (oil bath) for 15 h. The reaction mixture was filtered and purified by prep-HPLC to give the product as a solid (237.9 mg, 39% in yield for 2 steps). LCMS: (M+H)+=470.2.

Reference： [1]Patent: US2006/9471,2006,A1 .Location in patent: Page/Page column 47

6
[ 30766-11-1 ]
[ 845305-87-5 ]

Reference： [1]Patent: WO2012/162635,2012,A1
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 3228 - 3236

7
[ 845305-87-5 ]
1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-amine [ No CAS ]
5-({1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}amino)-N-methylpyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 16h;	To a solution of l-[(4-cyclo butyl- l,4-diazepan-l-yl)carbonyl]azetidin-3-amine (22 mg, 87 μmol) in degassed toluene (2 ml) was added 5-bromo-N-methylpyridine-2-carboxamide (19 mg, 87 μmol), racemic BINAP (8 mg, 13 μmol), 1BuOK (12 mg, 0.10 mmol), followed by Pd2(dba)3 (8 mg, 9 μmol). The reaction was heated at 100 0C for 16 hours, concentrated and purified by FCC (DCM/MeOH/NH3 gradient, 98:2:1 to 95:5:1) giving the title compound as colourless oil (26 mg, 78%). LCMS data: Calculated MH+ (387); Found 96% (MH+) m/z 387, Rt = 2.22 min (High pH method).NMR data: 1H NMR (500 MHz, MeOD) δ ppm 7.94 (1 H, d, J=2.4 Hz), 7.84 (1 H, d, J=8.6 Hz), 6.92 (1 H, dd, J=8.6, 2.6 Hz), 4.34 - 4.41 (2 H, m), 4.25 - 4.33 (1 H, m), 3.84 (2 H, dd, J=8.3, 5.0 Hz), 3.40 - 3.49 (4 H, m), 2.86 - 2.97 (4 H, m), 2.52 - 2.60 (2 H, m), 2.44 - 2.52 (2 H, m), 2.03 - 2.11 (2 H, m), 1.79 - 1.91 (4H, m), 1.59 - 1.75 (2 H, m).

Reference： [1]Patent: WO2009/135842,2009,A1 .Location in patent: Page/Page column 139-140

8
[ 845305-87-5 ]
[ 73183-34-3 ]
[ 945863-21-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 110℃; for 1h;Inert atmosphere; Microwave irradiation;	Example 6; Preparation of 5-(2-Acetamidothiazolo[5,4-Z>]pyridin-5-yl)-N- methylpicolinamide (6); PcIdPPfCI2-CH2CI2 KOAc, 1 ,4-dioxane microwave, 110 0C Example 1 ditbpfPdCI2, Cs2CO3 NaHCO3(Sat.), DMF, microwave, 110-120 0C[0381] A mixture of 5-bromo-N-methylpicolinamide (320 mg, 1.48 mmol), bispinacolatodiboron (752 mg, 2.96 mmol), PddppfCl2-DCM (cat.), KOAc (436 mg, 4.44 mmol) in 1,4-dioxane (5 mL, degassed) was heated at 110 0C in a microwave for 1 h. To this mixture was then added Example 1 (608 mg, 2.22 mmol), ditbpfPdC12 (cat.), Cs2CO3 (1.45 g, 4.44 mmol), NaHCO3 (sat., 1 mL) and DMF (dry, degassed, 1 mL). It was heated in a microwave at 1100C for 1 h, then at 120 0C for another hour. The reaction mixture was purified by HPLC to give the titled compound as a white solid. 1H NMR (400 MHz, DMSO-rfbeta) delta ppm 12.53 (s, IH), 9.28 (d, J=4 Hz, IH), 8.79 (m, IH), 8.61 (dd, J=8 Hz, IH), 8.18 (m, 2H), 8.08 (d, J=8 Hz, IH), 2.78 (d, J=4 Hz, IH), 2.18 (s, 3H); [M+H] calc'd for Ci5Hi3N5O2S, 328; found, 328.

Reference： [1]Patent: WO2010/8847,2010,A2 .Location in patent: Page/Page column 125-126

9
[ 1415143-76-8 ]
[ 124-40-3 ]
[ 845305-87-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 50℃; for 5h;	Example 4.2d. Synthesis of 5-bromo-N-methylpicolinamide To a solution of 5-bromopicolinic(ethyl carbonic) anhydride (1.2 g, 4.5 mmol) in THF (20 mL) was added 33% dimethylamine solution (3mL), then the reaction mixture was stirred at 50 C for 5 h. After cooling to room temperature, the mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2S04, and concentrated to give the desired product. MS (ESI): 215, 217 (MH+).

Reference： [1]Patent: WO2012/162635,2012,A1 .Location in patent: Page/Page column 70-71

10
[ 845305-87-5 ]
[ 1415143-77-9 ]

Yield	Reaction Conditions	Operation in experiment
	With Lawessons reagent; In tetrahydrofuran; at 20℃;	Example 4.2e. Synthesis of 5-bromo-N-methylpyridine-2-carbothioamideTo a solution of <strong>[845305-87-5]5-bromo-N-methylpicolinamide</strong> (1 equiv) in THF (0.11 M) was added Lawesson's reagent (0.42 equiv). The reaction was stirred at room temperature until the reaction was complete (approximately 6 hours), then the mixture was diluted with H20 and extracted with EtOAc. The combined organic layers was washed with brine and dried over Na2S04. Then the solution was concentrated and purified by flash chromatography. MS (ESI): 231, 233 (MH+).

Reference： [1]Patent: WO2012/162635,2012,A1 .Location in patent: Page/Page column 70-71

11
[ 845305-87-5 ]
[ 1415143-78-0 ]

Reference： [1]Patent: WO2012/162635,2012,A1

12
[ 30766-11-1 ]
[ 6638-79-5 ]
[ 845305-87-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 18 - 25℃; for 48h;	A solution of 5-bromo-pyridine-2-carboxylic acid (15.0 g, 74.3 mmol, Alfa), DIPEA (38.8 mL, 222.8 mmol), HOAt (1.01 g, 7.43 mmol), EDCI (21.4 g, 1 11.4 mmol) in DMF (150 mL) is treated with N-methyl-O-methylhydroxylamine hydrochloride (7.24 g, 74.3 mmol). The mixture is stirred at RT for 48 h, then water (100 mL) is added. The mixture is concentrated on high vaccum to about 50 mL and diluted with 300 mL of toluene. The layers are separated and the organic phase is washed with water (100 mL), 0.1 N HCI (100 mL) and 1.0 N NaOH (100 mL). The organic layer is dried (MgS04) and concentrated to provide 67a1 , which is used as such in the next step.

Reference： [1]Patent: WO2013/91096,2013,A1 .Location in patent: Page/Page column 78

13
[ 845305-87-5 ]
2-(1-hydroxyethyl)-5-bromopyridine [ No CAS ]

Reference： [1]Patent: WO2013/91096,2013,A1

14
[ 845305-87-5 ]
[ 917-54-4 ]
[ 214701-49-2 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at -78℃; for 1h;	Amide 67a1 (919.0 g, 40.8 mmol) is dissolved in THF (100 mL) and cooled to -78C. The mixture is treated with MeLi (31.6 mL, 44.9 mmol) and stirred at this temperature for 1 h. The reaction is quenched with saturated NH CI and the solvent is evaporated. The residue is basified with saturated NaHC03 and extracted with EtOAc (2x). The combined organic layers are dried (MgS04), filtered and concentrated. The residue is purified by flash chromatography to obtain 67a2.

Reference： [1]Patent: WO2013/91096,2013,A1 .Location in patent: Page/Page column 78-79

15
[ 29682-15-3 ]
[ 74-89-5 ]
[ 845305-87-5 ]