[ CAS No. 213771-32-5 ] {[proInfo.proName]}

Name: 213771-32-5|Methyl 5-bromo-3-methylpicolinate|98%
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SKU: A393639
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Quality Control of [ 213771-32-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 213771-32-5 ]

SDS Specification

Alternatived Products of [ 213771-32-5 ]

Product Details of [ 213771-32-5 ]

CAS No. :	213771-32-5	MDL No. :	MFCD07375126
Formula :	C₈H₈BrNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KZPOANNAYCXMSH-UHFFFAOYSA-N
M.W :	230.06	Pubchem ID :	45789787
Synonyms :

Calculated chemistry of [ 213771-32-5 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	48.18
TPSA :	39.19 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) :	-6.22 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.15
Log Po/w (XLOGP3) :	2.09
Log Po/w (WLOGP) :	1.94
Log Po/w (MLOGP) :	1.4
Log Po/w (SILICOS-IT) :	2.33
Consensus Log Po/w :	1.98

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.82
Solubility :	0.347 mg/ml ; 0.00151 mol/l
Class :	Soluble
Log S (Ali) :	-2.54
Solubility :	0.659 mg/ml ; 0.00286 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.35
Solubility :	0.103 mg/ml ; 0.000449 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.84

Safety of [ 213771-32-5 ]

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

Application In Synthesis of [ 213771-32-5 ]

* 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 [ 213771-32-5 ]
Downstream synthetic route of [ 213771-32-5 ]

[ 213771-32-5 ] Synthesis Path-Upstream 1~9

1
[ 213771-32-5 ]
[ 794592-14-6 ]

Reference： [1] Patent: US2014/107109, 2014, A1,
[2] Patent: WO2016/22724, 2016, A1,

2
[ 886365-43-1 ]
[ 74-88-4 ]
[ 213771-32-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.666667 h;	Step C methyl 5-bromo-3-methylpyridine-2-carboxylate To a solution 5-bromo-3-methylpyridine-2-carboxylic acid (2.6 g, 12 mmol) in N,N-dimethylformamide (20.0 mL) was added potassium carbonate (4.99 g, 36.1 mmol) and methyl iodide (1.50 mL, 24.1 mmol) and the reaction was stirred 80° C. for 40 min. The reaction mixture was partitioned with EtOAc and water. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2.3 g (83percent yield) of the desired product as a yellow solid.
82%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.666667 h;	Example 11.1: methyl S-bromo-S-metliylpyridine-Z-carboxylateO; To a solution of 5-bromo-3-methylpyridine-2-carboxylic acid (450 mg, 2.08 mmol) in dimethylformamide (2 mL) was added potassium carbonate (862 mg, 6.24 mmol) and iodomethane (739 mg, 5.21 mmol) and the reaction was stirred at 80 ⁰C for 40 min. The reaction mixture was partitioned with ethyl acetate and water and the organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated to afford the product as a yellow solid (380 mg, 82percent). ¹H NMR (300 MHz, CDCl₃): δ 8.91 (s, IH), 7.86 (s, IH), 3.98 (s, 3H), 2.60 (s, 3H).

Reference： [1] Patent: US2013/96144, 2013, A1, . Location in patent: Paragraph 0392; 0393
[2] Patent: WO2008/100715, 2008, A1, . Location in patent: Page/Page column 34

3
[ 67-56-1 ]
[ 3430-18-0 ]
[ 201230-82-2 ]
[ 213771-32-5 ]

Reference： [1] Patent: EP977739, 2003, B1, . Location in patent: Page/Page column 9-10

4
[ 886365-43-1 ]
[ 213771-32-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride In methanol for 6 h; Reflux	To a mixture of 5-bromo-3-methylpicolinic acid (600 mg, 2.8 mmol) in MeOH (10 mL) was added 50C12 (397 mg, 3.3 mmol). The mixture was stirred at reflux temperature for 6 hours. LCMS showed the reaction was complete. The reaction mixture was evaporated in vacuo to afford methyl 5-bromo-3-methylpicolinate (640 mg, 99percent yield), m/z = 229.76(M+H), as an off-white solid.

Reference： [1] Patent: WO2016/127074, 2016, A1, . Location in patent: Page/Page column 31; 32

5
[ 67-56-1 ]
[ 886365-43-1 ]
[ 213771-32-5 ]

Reference： [1] Patent: WO2011/154677, 2011, A1, . Location in patent: Page/Page column 91-92
[2] Patent: US2016/176882, 2016, A1, . Location in patent: Paragraph 0466; 0467
[3] Patent: WO2017/221100, 2017, A1, . Location in patent: Paragraph 00245

6
[ 67-56-1 ]
[ 156072-86-5 ]
[ 213771-32-5 ]

Reference： [1] Patent: US2006/199817, 2006, A1, . Location in patent: Page/Page column 27

7
[ 3430-18-0 ]
[ 213771-32-5 ]

Reference： [1] Patent: US2013/96144, 2013, A1,
[2] Patent: WO2008/100715, 2008, A1,

8
[ 156072-86-5 ]
[ 213771-32-5 ]

Reference： [1] Patent: US2013/96144, 2013, A1,
[2] Patent: WO2008/100715, 2008, A1,

9
[ 213771-32-5 ]
[ 1346809-61-7 ]

Reference： [1] Patent: WO2011/154677, 2011, A1,

[ 213771-32-5 ] Synthesis Path-Downstream 1~78

1
[ 67-56-1 ]
[ 3430-18-0 ]
[ 201230-82-2 ]
[ 213771-32-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In toluene; acetonitrile; at 80℃; under 4137.29 Torr; for 16h;	To a 400 mL autoclave was charged 1.6 g (6.06 mmol) of 2,5-dibromo-3-methylpyridine, 0.45 g (0.64 mmol) of (PPh3)2PdCl2, 30 mL of toluene/CH3CN (1:1), 0.33 mL (95 mmol) of Et3N and 4 eq. of CH3OH. The autoclave was sealed, evacuated, flushed with nitrogen three times and charged with carbon monoxide to 80 psi. The autoclave was heated to 80C for 16 hrs, cooled to r.t. and the excess carbon monoxide was evacuated under vacuum. The conversion was about 55% as determined by NMR. The contents of the autoclave were transferred into a flask for concentration. The residue was then purified on a silica gel column, eluting with hexane:EtOAc to give the ester as a white solid. M.p. 61-62C. 1H NMR (CDCl3): delta 8.58 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 3.96 (s, 3H), 2.58 (s, 3H). 13C NMR (CDCl3): delta 165.82, 147.94, 145.17, 142.20, 137.63, 123.56, 52,74, 19.96. IR: 1715 cm-1.

Reference： [1]Patent: EP977739,2003,B1 .Location in patent: Page/Page column 9-10

2
[ 213771-32-5 ]
methyl 5-bromo-3-(dibromomethyl)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;	Step 1: Methyl 5-bromo-3-(dibromomethyl)picolinate A vial was charged with <strong>[213771-32-5]methyl <strong>[213771-32-5]5-bromo-3-methylpicolinate</strong></strong> (2.03 g, 8.82 mmol), carbon tetrachloride (22.06 ml), benzoyl peroxide (0.107 g, 0.441 mmol) and NBS (3.14 g, 17.65 mmol). The mixture was heated at 80 C. for 2 h. Another equivalent of NBS and 50 mg benzoyl peroxide were added, and heating was continued for 16 h. Upon cooling to RT the mixture was filtered through Celite and washed with DCM. The filtrate was concentrated, and the crude material was purified by silica gel, 10-50% EtOAc/heptane to provide the title compound as a yellow oil (3.28 g, 8.46 mmol, 96% yield).
96%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 18h;	A vial was charged with <strong>[213771-32-5]methyl <strong>[213771-32-5]5-bromo-3-methylpicolinate</strong></strong> (2.03 g, 8.82 mmol), carbon tetrachloride (22 mL), benzoyl peroxide (0.107 g, 0.441 mmol) and NBS (3.14 g, 17.65 mmol). The mixture was heated at 80 C for 2 h. Another equivalent of NBS and 50 mg benzoyl peroxide were added, and heating was continued for 16 h. Upon cooling to RT the mixture was filtered through Celite filter aid and washed with DCM. The filtrate was concentrated, and the crude material was purified by silica gel chromatography (10-50% EtOAc/heptane) to provide methyl 5- bromo-3-(dibromomethyl)picolinate as a yellow oil (260A, 3.28 g, 8.46 mmol, 96% yield).
79%	With N-Bromosuccinimide; Perbenzoic acid; at 80℃; for 16h;Inert atmosphere;	To a solution of N-bromosuccinimide (20.89 g, 117.4 mmol) and benzoylperoxide (2.84 g, 11.74 mmol) in carbon tetrachloride (150 mL) was added <strong>[213771-32-5]methyl 5-bromo-3-methyl-pyridine-2-carboxylate</strong> (9.0 g, 39 mmol). The mixture was stirred at 80 C for 16 h under nitrogen. The solution was then concentrated and the residue was purified by flash chromatography (5%-10%-20% ethyl acetate in petroleum ether) to afford methyl 5-bromo-3-(dibromomethyl)pyridine-2-carboxylate as a yellow oil (12 g, 79% yield); LCMS (ESI) [M+H]+=385.8.

With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 77℃; for 6h;

To a solution of <strong>[213771-32-5]methyl <strong>[213771-32-5]5-bromo-3-methylpicolinate</strong></strong> (1.785 g, 7.76 mmol) in 30 mL of CCl4 was added N-bromosuccinimide (4.23 g, 23.8 mmol) and benzoyl peroxide (0.199 g, 0.822 mmol). The reaction was heated at 77 C. for 6 h. The reaction mixture was cooled to RT, filtered through a pad of Celite and washed with CCl4. The filtrate was evaporated in vacuo to give a yellow oil. The oil was dissolved in 40 mL MeOH and anhydrous hydrazine (3.00 ml, 95.6 mmol) was added dropwise at 25 C. Upon complete addition the reaction mixture was heated at 78 C. overnight. The reaction mixture was cooled to RT and the solid was filtered, washed with MeOH and CHCl3 and dried by suction. The filtrate was evaporated onto silica gel and purified flash chromatography eluting with 2M NH3 in MeOH:CHCl3 (0:1?3:47) to give the title compound as a light-yellow amorphous solid. MS m/z: 225.9, 227.9 [M+1].

Reference： [1]Patent: US2014/107109,2014,A1 .Location in patent: Page/Page column
[2]Patent: WO2016/22724,2016,A1 .Location in patent: Page/Page column 265
[3]Patent: US2018/282328,2018,A1 .Location in patent: Paragraph 2254; 2255
[4]Patent: US2006/199817,2006,A1 .Location in patent: Page/Page column 27

3
[ 67-56-1 ]
[ 156072-86-5 ]
[ 213771-32-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; at 25 - 64℃;	To a solution of 5-bromo-3-methylpicolinonitrile (2.55 g, 12.9 mmol) in 100 mL of MeOH was bubbled gaseous HCl at 25 C. After 1 h the bubbling was ceased and the reaction was heated at about 64 C. overnight. The reaction was cooled to RT and gaseous HCl was bubbled into the reaction for another 1 h and the mixture was reheated at 64 C. The reaction was monitored by LCMS and when complete, the solvent was removed in vacuo and the residue was dissolved in H2O. The solution was basified with saturated NaHCO3 and extracted with EtOAc (4×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography eluting with EtOAc:hexane (0:1?1:9) to give the title compound as a white amorphous solid. MS m/z: 230.0 [M+1].

Reference： [1]Patent: US2006/199817,2006,A1 .Location in patent: Page/Page column 27

4
[ 886365-43-1 ]
[ 74-88-4 ]
[ 213771-32-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.666667h;	Step C methyl 5-bromo-3-methylpyridine-2-carboxylate To a solution 5-bromo-3-methylpyridine-2-carboxylic acid (2.6 g, 12 mmol) in N,N-dimethylformamide (20.0 mL) was added potassium carbonate (4.99 g, 36.1 mmol) and methyl iodide (1.50 mL, 24.1 mmol) and the reaction was stirred 80 C. for 40 min. The reaction mixture was partitioned with EtOAc and water. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2.3 g (83% yield) of the desired product as a yellow solid.
82%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.666667h;	Example 11.1: methyl S-bromo-S-metliylpyridine-Z-carboxylateO; To a solution of 5-bromo-3-methylpyridine-2-carboxylic acid (450 mg, 2.08 mmol) in dimethylformamide (2 mL) was added potassium carbonate (862 mg, 6.24 mmol) and iodomethane (739 mg, 5.21 mmol) and the reaction was stirred at 80 0C for 40 min. The reaction mixture was partitioned with ethyl acetate and water and the organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated to afford the product as a yellow solid (380 mg, 82%). 1H NMR (300 MHz, CDCl3): delta 8.91 (s, IH), 7.86 (s, IH), 3.98 (s, 3H), 2.60 (s, 3H).

Reference： [1]Patent: US2013/96144,2013,A1 .Location in patent: Paragraph 0392; 0393
[2]Patent: WO2008/100715,2008,A1 .Location in patent: Page/Page column 34

5
[ 213771-32-5 ]
[ 1048678-21-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 20h;	<strong>[213771-32-5]methyl <strong>[213771-32-5]5-bromo-3-methylpicolinate</strong></strong> (600 mg, 2.61 mmol, Eq: 1), N-bromosuccinimide (663 mg, 3.65 mmol, Eq: 1.4) and benzoyl peroxide (25.3 mg, 78.2 muiotaetaomicron, Eq: 0.03) were combined with carbon tetrachloride (7.5 ml). The reaction mixture was heated to 80 C and stirred for 20 h. The reaction was cooled to 23 C, diluted with 30 ml of ethyl acetate, washed with water and sodium thiosulfate. The organic layers were dried over sodium sulfate and concentrated in vacuo to give the desired compound as a white solid (800 mg, 99 %). MS (m/z) = 310.0 [M + H]+.
66%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 90℃; for 18h;	A mixture of <strong>[213771-32-5]methyl <strong>[213771-32-5]5-bromo-3-methylpicolinate</strong></strong> (450 mg, 2.0 mmol), NBS (350 mg, 2.0 mmol) and AIBN (32 mg, 0.20 mmol) in carbon tetrachloride (10 mL) was stirred at 90 C. After 18 h, the reaction was cooled to rt, filtered, and the solid was washed with carbon tetrachloride. The combined organic layers were washed with sat. NaHCO3 (aq.), brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (40 g silica gel cartridge, A=Hex, B=EtOAc; 15 min grad.; 0% B to 60% B; flow rate=40 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (400 mg, 1.3 mmol, 66% yield) as an off-white foam. MS (ESI) 307.8 (M+H).
50%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 5h;	Example 12.1: methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate; To a solution of methyl 5-biomo-3-methylpyridine-2-carboxylate (410 mg, 1.81 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (338 mg, 1.90 mmol) and 2',2-azobisisobutyronitrie (6.0 mg, 0.036 mmol) and the reaction mixture was stirred at 80 0C for 5 h. The reaction mixture was filtered and the filtrate was concentrated to afford the product as a yellow gum (600 mg, 50%). 1H NMR (300 MHz, CDCl3): delta 8.70 (s, IH), 8.07 (s, IH), 4.90 (s, 2H), 3.99 (s, 3H).

49%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 5h;	Step D methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate To a solution of <strong>[213771-32-5]methyl 5-bromo-3-methylpyridine-2-carboxylate</strong> (1.01 g, 4.39 mmol) in carbon tetrachloride (30.0 mL) was added N-bromosuccinimide (8.60E2 mg, 4.83 mmol) and 2,2'-azo-bis-isobutyronitrile (14.4 mg, 0.0877 mmol). The reaction mixture was stirred at 80 C. for 5 h. The reaction mixture was filtered and the filtrate was concentrated to afford 0.66 g (49% yield) of the desired product.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In dichloromethane; for 3.5h;Irradiation with halogen lamp;	Methyl <strong>[213771-32-5]5-bromo-3-methylpicolinate</strong> (800 mg) in dichloromethane (5 niL) was treated with N- bromosuccinimide (619 mg) and AIBN (14.28 mg). The mixture was stirred and irradiated with a 500W halogen lamp for 3.5 h. The reaction mixture was cooled and diluted with dichloromethane, and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (1036 mg).m/e (MultiMode+) 310 [M+Eta]+
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In dichloromethane; for 3.5h;Heating; Irradiation;	(ii) Methyl 5-bromo-3-(bromomethyl)picolinateMethyl <strong>[213771-32-5]5-bromo-3-methylpicolinate</strong> (Example 13, step (i), 800 mg) in dichloromethane (20 mL) was treated with N-bromosuccinide (619 mg) and AIBN (57 mg). The mixture was stirred and irradiated with a 500W halogen lamp for 3.5 h. The reaction mixture was allowed to cool to room temperature and diluted with dichloromethane, and washed with water. The organic was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (1.03 g). m/e (APCI+) 312 [M+H]
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 50℃; for 5h;	Step 1 To a solution of <strong>[213771-32-5]5-bromo-3-methyl-pyridine-2-carboxylic acid methyl ester</strong> (200 mg, 0.87 mmol, 1 eq) in tetrachloromethane (10 mL) were added N-bromosuccinimide (162 mg, 0.91 mmol, 1.05 eq) and 2,2'-azobis(2-methylpropionitrile) (3 mg, 0.017 mmol, 0.02 eq). The mixture was stirred at 50 C. during 5 h. The solvent was then evaporated and the crude residue was purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 80/20). 5-Bromo-3-bromomethyl-pyridine-2-carboxylic acid methyl ester was isolated as a white powder as a 6/4 mixture with the starting material (160 mg, 39% yield). The mixture was used in the next step.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 50℃; for 5h;	Step 1 To a solution of <strong>[213771-32-5]5-bromo-3-methyl-pyridine-2-carboxylic acid methyl ester</strong> (200 mg, 0.87 mmol, 1 eq) in tetrachloromethane (10 mL) were added N-bromosuccinimide (162 mg, 0.91 mmol, 1.05 eq) and 2,2'-azobis(2-methylpropionitrile) (3 mg, 0.017 mmol, 0.02 eq). The mixture was stirred at 50 C. during 5 h. The solvent was then evaporated and the crude residue was purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 80/20). 5-Bromo-3-bromomethyl-pyridine-2-carboxylic acid methyl ester was isolated as a white powder as a 6/4 mixture with the starting material (160 mg, 39% yield). The mixture was used in the next step.
1 g	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In dichloromethane;Irradiation;	Methyl 5-bromo-3-methylpyridine-2-carboxylate (800 mg, 3.5 mmol)(Combi-Blocks Cat. No. SS-3016) in methylene chloride (15 mL) was treated with N-bromosuccinimide (620 mg, 3.5 mmol) and AIBN [2,2'-azobis(isobutyronitrile)] (14 mg, 0.087 mmol). The mixture was stirred and irradiated with a 250W tungsten halogen lamp overnight. LCMS showed most starting material was consumed. The mixture was concentration under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (1.0 g). LCMS (M+H)+=309.9.

Reference： [1]Patent: WO2017/76852,2017,A1 .Location in patent: Page/Page column 50
[2]Patent: US2019/127358,2019,A1 .Location in patent: Paragraph 1154-1155
[3]Patent: WO2008/100715,2008,A1 .Location in patent: Page/Page column 34
[4]Patent: US2013/96144,2013,A1 .Location in patent: Paragraph 0394; 0395
[5]Patent: WO2010/128324,2010,A1 .Location in patent: Page/Page column 123
[6]Patent: WO2011/154677,2011,A1 .Location in patent: Page/Page column 92
[7]Patent: US2013/102601,2013,A1 .Location in patent: Paragraph 0347
[8]Patent: US2013/102600,2013,A1 .Location in patent: Paragraph 0333; 0334
[9]Patent: US2014/171405,2014,A1 .Location in patent: Paragraph 0391

6
[ 213771-32-5 ]
[ 1423-26-3 ]
[ 1202250-75-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 20 - 50℃;Inert atmosphere;	Intermediate 13-Methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acidA) 3-Methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester; To a degassed solution of 8.35 g (36.3 mmol) of <strong>[213771-32-5]5-bromo-3-methyl-pyridine-2-carboxylic acid methyl ester</strong> [Wu, G. G.; Wong, Y.-S.; Poirier, M. Organic Letters (1999), 1(5), 745-747] in 180 ml of dioxane were added 13.79 g (72.6 mmol) of 3-(trifluoromethyl)phenyl boronic acid and 11.54 g (108.9 mmol) of sodium carbonate (dissolved in 55 ml of H2O). While stirring, 1.33 g (1.89 mmol) of (1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) was added and the reaction mixture was stirred at RT for 4 hours, then heated up to 50 C. After 90 min, it was cooled down to RT, poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 9:1 to 1:1) to give 9.35 g (87%) of the title compound as light yellow solid. MS: 296.1 (MH+).

Reference： [1]Patent: US2009/318467,2009,A1 .Location in patent: Page/Page column 22

7
[ 213771-32-5 ]
[ 591227-12-2 ]
[ 1335299-16-5 ]

Yield	Reaction Conditions	Operation in experiment
54%		Example 23 5-Bromo-3-methyl-pyridine-2-carboxylic acid (2-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-amide To an argon purged solution of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (example 1, step 1, 80 mg, 0.381 mmol) in dioxane (5 ml) was added trimethyl aluminum solution (0.571 ml, 1.14 mmol, 3 eq). The resulting solution was stirred for 1 hour at RT. Then <strong>[213771-32-5]methyl <strong>[213771-32-5]5-bromo-3-methylpicolinate</strong></strong> (88 mg, 0.381 mmol) was added and the mixture was heated to reflux and stirred for 18 hours. The title compound (84 mg, 54%) was isolated from the crude product by flash chromatography on a 20 g SiO2 column using dichloromethane/methanol 0-10% as eluent. MS (m/e)=408.2 [M+H+].
		To an argon purged solution of 2-phenylimidazo[l,2-a]pyrimidin-7-amine (example 1, step 1, 80 mg, 0.381 mmol) in dioxane (5 ml) was added trimethyl aluminum solution (0.571 ml, 1.14 mmol, 3 eq). The resulting solution was stirred for 1 hour at RT. Then methyl 5-bromo-3- methylpicolinate (88 mg, 0.381 mmol) was added and the mixture was heated to reflux and stirred for 18 hours. The title compound (84 mg, 54%) was isolated from the crude product by flash chromatography on a 20 g Si02 column using dichloromethane / methanol 0-10 % as eluent.MS (m/e) = 408.2 [M+H+].

Reference： [1]Patent: US2011/237564,2011,A1 .Location in patent: Page/Page column 23
[2]Patent: WO2011/117264,2011,A1 .Location in patent: Page/Page column 65-66

8
[ 213771-32-5 ]
[ 1254319-55-5 ]

Reference： [1]Patent: WO2011/154677,2011,A1

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[ 213771-32-5 ]
[ 1254318-86-9 ]

Reference： [1]Patent: WO2011/154677,2011,A1

10
[ 213771-32-5 ]
[ 1352152-93-2 ]

Reference： [1]Patent: WO2011/154677,2011,A1

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[ 213771-32-5 ]
[ 1352152-94-3 ]

Reference： [1]Patent: WO2011/154677,2011,A1

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[ 213771-32-5 ]
[ 1352152-95-4 ]

Reference： [1]Patent: WO2011/154677,2011,A1

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[ 213771-32-5 ]
[ 1352152-92-1 ]

Reference： [1]Patent: WO2011/154677,2011,A1

14
[ 213771-32-5 ]
[ 1352152-15-8 ]

Reference： [1]Patent: WO2011/154677,2011,A1

15
[ 213771-32-5 ]
[ 1352152-16-9 ]

Reference： [1]Patent: WO2011/154677,2011,A1

16
[ 213771-32-5 ]
[ 1346809-61-7 ]

Reference： [1]Patent: WO2011/154677,2011,A1

17
[ 213771-32-5 ]
[ 1352152-27-2 ]

Reference： [1]Patent: WO2011/154677,2011,A1

18
[ 213771-32-5 ]
[ 1352152-28-3 ]

Reference： [1]Patent: WO2011/154677,2011,A1

19
[ 213771-32-5 ]
[ 1352152-26-1 ]

Reference： [1]Patent: WO2011/154677,2011,A1

20
[ 67-56-1 ]
[ 886365-43-1 ]
[ 213771-32-5 ]

Yield	Reaction Conditions	Operation in experiment
		(i) Methyl 5-bromo-3-methylpicolinateSulfuric acid (0.025 mL) was added to 5-bromo-3-methylpicolinic acid (1 g) in methanol (20 mL) at 20C under an atmosphere of nitrogen. The resulting solution was stirred at reflux for 19 h. The reaction mixture was allowed to cool to room temperature and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The combined organic phases was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (1.019 g).1H NMR (500 MHz, DMSO) delta 8.62 (s, 1H), 8.16 (s, 1H), 3.86 (s, 3H), 2.46 (s, 3H). m/e (APCI+) 232 [M+H]+
	With thionyl chloride; at 20 - 90℃; for 4h;	Methyl 5-bromo-3-methylpicolinate (B35.1) (0467) To a solution of 5-bromo-3-methylpicolinic acid (500 mg, 2.31 mmol) in MeOH (10 mL) was added SOCl2 (275 mg, 23.1 mmol) at rt. Then the reaction mixture was stirred at 90 C. for 4 h. The solvent was removed to give the title compound (500 mg, 94%) as a off white solid. The crude product was used in the next step without further purification. LC-MS: [M+H]+=232.0.
	With thionyl chloride; at 90℃; for 4h;	To a solution of 5-bromo-3- methylpicolinic acid (500 mg, 2.31 mmol) in MeOH (10 mL) was added SOd2 (275 mg, 23.1 mmol) at rt. Then the reaction mixture was stirred at 90 C for 4 h. The solvent was removed to give the title compound (500 mg, 94%) as a off white solid. The crude product was used in the next step without further purification. LC-MS: [M+H] = 232.0.

Reference： [1]Patent: WO2011/154677,2011,A1 .Location in patent: Page/Page column 91-92
[2]Patent: US2016/176882,2016,A1 .Location in patent: Paragraph 0466; 0467
[3]Patent: WO2017/221100,2017,A1 .Location in patent: Paragraph 00245

21
[ 3430-18-0 ]
[ 213771-32-5 ]

Reference： [1]Patent: US2013/96144,2013,A1
[2]Patent: WO2008/100715,2008,A1

22
[ 156072-86-5 ]
[ 213771-32-5 ]

Reference： [1]Patent: US2013/96144,2013,A1
[2]Patent: WO2008/100715,2008,A1

23
[ 213771-32-5 ]
[ 1430058-57-3 ]

Reference： [1]Patent: US2013/96144,2013,A1

24
[ 213771-32-5 ]
[ 1430058-59-5 ]

Reference： [1]Patent: US2013/96144,2013,A1

25
[ 213771-32-5 ]
[ 1430057-33-2 ]

Reference： [1]Patent: US2013/96144,2013,A1

26
[ 213771-32-5 ]
[ 1431470-26-6 ]

Reference： [1]Patent: US2013/102600,2013,A1
[2]Patent: US2013/102601,2013,A1

27
[ 213771-32-5 ]
[ 1431470-27-7 ]

Reference： [1]Patent: US2013/102600,2013,A1
[2]Patent: US2013/102601,2013,A1

28
[ 213771-32-5 ]
[ 1431468-79-9 ]

Reference： [1]Patent: US2013/102600,2013,A1
[2]Patent: US2013/102601,2013,A1

29
[ 213771-32-5 ]
[ 1431470-28-8 ]

Reference： [1]Patent: US2013/102600,2013,A1
[2]Patent: US2013/102601,2013,A1

30
[ 213771-32-5 ]
[ 1430057-34-3 ]

Reference： [1]Patent: US2013/96144,2013,A1

31
[ 213771-32-5 ]
[ 1430058-61-9 ]

Reference： [1]Patent: US2013/96144,2013,A1

32
[ 213771-32-5 ]
[ 1430058-63-1 ]

Reference： [1]Patent: US2013/96144,2013,A1

33
[ 213771-32-5 ]
[ 909186-02-3 ]

Reference： [1]Patent: US2014/107109,2014,A1
[2]Patent: WO2016/22724,2016,A1
[3]Patent: US2018/282328,2018,A1

34
[ 213771-32-5 ]
[ 794592-14-6 ]

Reference： [1]Patent: US2014/107109,2014,A1
[2]Patent: WO2016/22724,2016,A1

35
[ 213771-32-5 ]
[ 1600511-18-9 ]

Reference： [1]Patent: US2014/107109,2014,A1

36
[ 213771-32-5 ]
[ 1600508-22-2 ]

Reference： [1]Patent: US2014/107109,2014,A1

37
[ 213771-32-5 ]
[ 1614234-03-5 ]

Reference： [1]Patent: US2014/171405,2014,A1

38
[ 213771-32-5 ]
[ 1614234-04-6 ]

Reference： [1]Patent: US2014/171405,2014,A1

39
[ 886365-43-1 ]
[ 213771-32-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; In methanol; for 6h;Reflux;	To a mixture of 5-bromo-3-methylpicolinic acid (600 mg, 2.8 mmol) in MeOH (10 mL) was added 50C12 (397 mg, 3.3 mmol). The mixture was stirred at reflux temperature for 6 hours. LCMS showed the reaction was complete. The reaction mixture was evaporated in vacuo to afford methyl 5-bromo-3-methylpicolinate (640 mg, 99% yield), m/z = 229.76(M+H), as an off-white solid.

Reference： [1]Patent: WO2016/127074,2016,A1 .Location in patent: Page/Page column 31; 32

40
[ 213771-32-5 ]
[ 245765-71-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; In methanol; at 90℃; for 2h;	(5-Bromo-3-methylpyridin-2-yl)methanol (B35.2) (0468) To a solution of B35.1 (500 mg, 2.17 mmol) in MeOH (15 mL) was added NaBH4 (826 mg, 21.7 mmol) at rt. Then the reaction mixture was stirred at 90 C. for 2 h. The solvent was removed. The residue was dissolved in EtOAc (20 mL) and washed with water (15 mL). The organic phase was concentrated to give the title compound (300 mg, 68%) as a pale yellow oil. The crude product was used in the next step without further purification. LC-MS: [M+H]+=204.2.
	With methanol; sodium tetrahydroborate; at 90℃; for 2h;	To a solution of B35.1 (500 mg, 2.17 mmol) in MeOH (15 mL) was added NaBH4 (826 mg, 21.7 mmol) at rt. Then the reaction mixture was stirred at 90 C for 2 h. The solvent was removed. The residue was dissolved in EtOAc (20 mL) and washed with water (15 mL). The organic phase was concentrated to give the title compound (300 mg, 68%) as a pale yellow oil. The crude product was used in the next step without further purification. LC-MS: [M+H] = 204.2.

Reference： [1]Patent: US2016/176882,2016,A1 .Location in patent: Paragraph 0466; 0468
[2]Patent: WO2017/221100,2017,A1 .Location in patent: Paragraph 00246

41
[ 213771-32-5 ]
5-bromo-2-(methoxymethyl)-3-methylpyridine [ No CAS ]

Reference： [1]Patent: US2016/176882,2016,A1
[2]Patent: WO2017/221100,2017,A1

42
[ 213771-32-5 ]
3-methyl-5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinate [ No CAS ]

Reference： [1]Patent: WO2016/127074,2016,A1

43
[ 213771-32-5 ]
[ 73183-34-3 ]
(6-(methoxycarbonyl)-5-methylpyridin-3-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	A mixture of <strong>[213771-32-5]methyl <strong>[213771-32-5]5-bromo-3-methylpicolinate</strong></strong> (640 mg, 2.78 mmol),bis(pinacolato)diboron (1.06 g, 4.17 mmol), KOAc (681 mg, 6.96 mmol) and Pd(dppf)C12 (102 mg, 0.14 mmol) in 1, 4 - dioxane (8 mL) was stirred under N2 at 100 C for 4 hours. LCMS showed the reaction was fully converted to (6-(methoxycarbonyl)-5-methylpyridin-3-yl)boronic acid. The crude product was used in the next step directly without any purification. m/z = 195.80(M+H).

Reference： [1]Patent: WO2016/127074,2016,A1 .Location in patent: Page/Page column 32

44
[ 213771-32-5 ]
[ 1224604-11-8 ]

Reference： [1]Patent: WO2017/76852,2017,A1

45
[ 213771-32-5 ]
[ 1048678-22-3 ]

Reference： [1]Patent: WO2008/100715,2008,A1

46
[ 213771-32-5 ]
[ 1048678-16-5 ]

Reference： [1]Patent: WO2008/100715,2008,A1

47
[ 213771-32-5 ]
3-bromo-7-methyl-pyrido[2,3-d]pyridazin-8-one [ No CAS ]

Reference： [1]Patent: US2018/282328,2018,A1

48
[ 213771-32-5 ]
(+/-)-(trans)-N-(8-amino-6-(7-methyl-8-oxo-7,8-dihydropyrido[2,3-d]pyridazin-3-yl)-2,7-naphthyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide [ No CAS ]

Reference： [1]Patent: US2018/282328,2018,A1

49
[ 213771-32-5 ]
[ 847818-74-0 ]
methyl 3-methyl-5-(1-methyl-1H-pyrazol-5-yl)picolinate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3268 - 3285

50
[ 213771-32-5 ]
5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((3S,4S)-4-(3-fluorophenyl)piperidin-3-yl)-3-methylpicolinamide hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3268 - 3285

51
[ 213771-32-5 ]
N-((3S,4S)-4-(3-fluorophenyl)piperidin-3-yl)-3-methyl-5-(1-methyl-1H-pyrazol-5-yl)picolinamide hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3268 - 3285

52
[ 213771-32-5 ]
N-((3S,4S)-4-(4-chloro-3-(trifluoromethyl)phenyl)-piperidin-3-yl)-3-methyl-5-(1-methyl-1H-pyrazol-5-yl)picolinamide hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3268 - 3285

53
[ 213771-32-5 ]
5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-methylpicolinic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3268 - 3285

54
[ 213771-32-5 ]
3-methyl-5-(1-methyl-1H-pyrazol-5-yl)picolinic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3268 - 3285

55
[ 213771-32-5 ]
methyl 5-bromo-3-(methoxymethyl)picolinate [ No CAS ]

Reference： [1]Patent: US2019/127358,2019,A1

56
[ 213771-32-5 ]
methyl 5-hydroxy-3-methylpicolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With acetylhydroxamic acid; potassium carbonate; In dimethyl sulfoxide; at 80℃; for 5h;	To a stirred solution of <strong>[213771-32-5]methyl <strong>[213771-32-5]5-bromo-3-methylpicolinate</strong></strong> (70 mg, 0.30 mmol) in DMSO (600 mul) was added acetohydroxamic acid (69 mg, 0.91 mmol) and K2CO3 (210 mg, 1.5 mmol). The mixture was stirred at 80 C. for 5 h. The reaction mixture was cooled, concentrated and diluted with EtOAc. The organic layer was washed with H2O, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography (12 g silica gel cartridge; A=Hex, B=EtOAc; 15 min grad.; 0% B to 70% B; flow rate=12 mL/min). Fractions containing the desired product were combined, concentrated and dried in vacuo to afford the title compound (17 mg, 0.10 mmol, 33% yield) as a white solid. 1H NMR (500 MHz, Acetone) delta 9.46 (br s, 1H), 8.10 (d, J=2.5 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 3.84 (s, 3H), 2.50 (s, 3H). MS (ESI) 168.2 (M+H).

Reference： [1]Patent: US2019/127358,2019,A1 .Location in patent: Paragraph 1299-1300

57
[ 213771-32-5 ]
methyl 5-bromo-2-carboxylate-3-methylpyridine-1-oxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.4%	With dihydrogen peroxide; urea; trifluoroacetic anhydride; In dichloromethane; at 0 - 20℃;	5-Bromo-3-methylpyridinecarboxylic acid methyl ester (4.0 g, 17.4 mmol)Dissolved in 100 ml of dichloromethane.The reaction solution was cooled to 0 C, and urine peroxide (4.91 g, 52.2 mmol) was added.Trifluoroacetic anhydride (10.96 g, 52.2 mmol) was then added dropwise at 0 C.The reaction was stirred at room temperature overnight.The reaction solution was poured into ice water, and the pH was adjusted to 7 with a saturated solution of dipotassium hydrogen phosphate. The mixture was extracted twice with dichloromethane (100 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the product (4.0 g, yield 93.4%).

Reference： [1]Patent: CN110256432,2019,A .Location in patent: Paragraph 0211-0216

58
[ 213771-32-5 ]
[ 1006365-26-9 ]