[ CAS No. 321596-55-8 ] {[proInfo.proName]}

Name: 321596-55-8|Methyl 4,6-dibromo-3-hydroxypicolinate|97%
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Quality Control of [ 321596-55-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 321596-55-8 ]

Product Details of [ 321596-55-8 ]

CAS No. :	321596-55-8	MDL No. :	MFCD19440848
Formula :	C₇H₅Br₂NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WNFLHCVLPYFOGW-UHFFFAOYSA-N
M.W :	310.93	Pubchem ID :	22175130
Synonyms :

Calculated chemistry of [ 321596-55-8 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	52.94
TPSA :	59.42 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) :	-6.1 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.99
Log Po/w (XLOGP3) :	2.95
Log Po/w (WLOGP) :	2.1
Log Po/w (MLOGP) :	1.23
Log Po/w (SILICOS-IT) :	2.12
Consensus Log Po/w :	2.08

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.84
Solubility :	0.0454 mg/ml ; 0.000146 mol/l
Class :	Soluble
Log S (Ali) :	-3.86
Solubility :	0.0429 mg/ml ; 0.000138 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.21
Solubility :	0.19 mg/ml ; 0.00061 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.17

Safety of [ 321596-55-8 ]

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 [ 321596-55-8 ]

* 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 [ 321596-55-8 ]
Downstream synthetic route of [ 321596-55-8 ]

[ 321596-55-8 ] Synthesis Path-Upstream 1~6

1
[ 62733-99-7 ]
[ 321596-55-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With bromine In water at 20℃; for 20 h;	At room temperature, Br₂ (2.7 mL, 3 equiv) was added to a suspension of methyl ester 8 (2.7 g, 6.5 mmol) in water (200 mL). The mixture was stirred for 20 h at room temperature. The solution was extracted with dichloromethane, and the organic layer was washed with an aqueous solution of sodium thiosulfate, with brine, dried over MgSO₄, and concentrated under reduced pressure to give desired compound 9 (4.0 g, 76percent) as a white powder. ¹H NMR (300 MHz, CDCl₃) δ (ppm) 4.06 (s, 3H), 7.86 (s, 1H), 11.35 (br s, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 53.9, 124.7, 129.9, 130.2, 136.9, 156.0, 168.8. MS (ESI^-) m/z: 312 (40), 310 (100), 308 (45).

Reference： [1] Tetrahedron, 2011, vol. 67, # 45, p. 8757 - 8762
[2] Patent: US6355660, 2002, B1,
[3] Patent: EP1516874, 2015, B1,
[4] Patent: WO2018/5662, 2018, A1, . Location in patent: Paragraph 0291
[5] Patent: WO2018/102634, 2018, A1, . Location in patent: Page/Page column 83

2
[ 113452-72-5 ]
[ 321596-55-8 ]

Yield	Reaction Conditions	Operation in experiment
43.2%	Stage #1: at 20℃; for 1 h; Stage #2: With bromine; sodium acetate In methanol; diethyl ether; water at 0 - 20℃; for 0.5 h;	To magnetically stirred 33 wt percent hydrogen bromide (10.00 ml, 55.2 mmol) in acetic acid was added methyl 2-(((benzyloxy)carbonyl)amino)-2-(furan-2-yl)acetate (2.89 g, 10 mmol). After stirring at room temperature for 1 hr, 150 mL of anhydrous ether was added to give 2.34 g of a grey solid. To a magnetically stirred solution of this grey solid and sodium acetate (3.53 g, 43.0 mmol) in 100 mL of water at 0° C. was added dropwise of a solution of bromine (2.215 ml, 43.0 mmol) in 20 mL of MeOH. over 30 min. After stirring at room temperature, the reaction mixture was filtered through a fritted glass funnel. The off-white solid was dissolved in 75 mL of CH₂Cl₂, washed with 5 ml of a saturated aqueous solution of Na₂S₂O₃and 5 ml, of a saturated aqueous solution of NaCl, and dried (MgSO₄). Solvent removal gave methyl 4,6-dibromo-3-hydroxypicolinate (1.43 g, 4.32 mmol, 43.2percent yield) as an off-white solid; Mp 179-180° C. (recrystallized from heptane). H NMR (400 MHz, Chloroform-d) δ 11.36 (d, J=0.4 Hz, 1H), 7.86 (m, 1H), 4.07 (s, 3H).

Reference： [1] Patent: US2016/9647, 2016, A1, . Location in patent: Paragraph 0047-0048

3
[ 874-24-8 ]
[ 321596-55-8 ]

Reference： [1] Patent: US6355660, 2002, B1,
[2] Patent: WO2018/5662, 2018, A1,
[3] Patent: WO2018/102634, 2018, A1,

4
[ 70946-43-9 ]
[ 321596-55-8 ]

Reference： [1] Patent: US2016/9647, 2016, A1,

5
[ 1467-70-5 ]
[ 321596-55-8 ]

Reference： [1] Patent: US2016/9647, 2016, A1,

6
[ 869556-74-1 ]
[ 321596-55-8 ]

Reference： [1] Patent: US2016/9647, 2016, A1,

[ 321596-55-8 ] Synthesis Path-Downstream 1~88

1
[ 321596-55-8 ]
[ 100-44-7 ]
[ 321596-56-9 ]

Yield	Reaction Conditions	Operation in experiment
		The benzyl ether 15 was then prepared by condensation of 14 with benzyl chloride in the presence of sodium hydride.
	In N,N-dimethyl-formamide;	b. PREPARATION OF METHYL 4,6-DIBROMO-3-BENZYLOXYPYRIDINE-2-CARBOXYLATE (15). To a stirred mixture of sodium hydride (0.6 g) in DMF (50 mL) was slowly added 14 (7.1 g). After the addition was complete, the mixture was stirred at room temperature for 15 minutes, then benzyl chloride (3.05 g) was added all at once. The mixture was then heated at 90 C. for six hours, cooled, poured into water (500 mL) and extracted with ether (2*200 mL). The ether extracts were combined, washed with 2N NaOH (50 mL), dried (MgSO4) and the solvent was evaporated to give 15 as a light yellow solid (8.3 g). Recrystallization from a small volume of methanol gave an analytical sample, m.p. 75-76 C.
	In N,N-dimethyl-formamide;	b. PREPARATION OF METHYL 4,6-DIBROMO-3-BENZYLOXYPYRIDINE-2-CARBOXYLATE (15). To a stirred mixture of sodium hydride (0.6 g) in DMF (50 mL) was slowly added 14 (7.1 g). After the addition was complete, the mixture was stirred at room temperature for 15 minutes, then benzyl chloride (3.05 g) was added all at once. The mixture was then heated at 90 C for six hours, cooled, poured into water (500 mL) and extracted with ether (2x200 mL). The ether extracts were combined, washed with 2N NaOH (50 mL), dried (MgSO4) and the solvent was evaporated to give 15 as a light yellow solid (8.3 g). Recrystallization from a small volume of methanol gave an analytical sample, m.p. 75-76 C.

Reference： [1]Patent: US6355660,2002,B1
[2]Patent: US6355660,2002,B1
[3]Patent: EP1516874,2015,B1

2
[ 874-24-8 ]
[ 321596-55-8 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine;boron trifluoride; In methanol;	Thus, 3-hydroxypicolinic acid (12) was converted to the methyl ester 13 in refluxing methanol using boron trifluoride as catalyst. 13 was then brominated using bromine in aqueous base to give the dibromide 14.

Reference： [1]Patent: US6355660,2002,B1
[2]Patent: WO2018/5662,2018,A1
[3]Patent: WO2018/102634,2018,A1
[4]Patent: WO2019/209667,2019,A1
[5]Patent: WO2019/236396,2019,A1
[6]Patent: EP3590924,2020,A1

3
[ 62733-99-7 ]
[ 321596-55-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With bromine; In water; at 30℃;	To a solution of compound 601-B (30 g, 196 mmol) in H2O (1500 mL) was added Br2 (94 g, 590 mmol) slowly.The mixture was stirred at 30 C for overnight. Then the mixture was extracted with DCM (500 mL2), washed with brine(500 mL), dried, filtered and concentrated to afford 601-C (methyl 4,6-dibromo-3-hydroxypicolinate, 49 g, yield: 81%)as a white solid.1H NMR (300 MHz, CDCl3) delta 11.35 (s, 1H), 7.87 (s, 1H), 4.07 (s, 3H).
76%	With bromine; In water; at 20℃; for 20h;	At room temperature, Br2 (2.7 mL, 3 equiv) was added to a suspension of methyl ester 8 (2.7 g, 6.5 mmol) in water (200 mL). The mixture was stirred for 20 h at room temperature. The solution was extracted with dichloromethane, and the organic layer was washed with an aqueous solution of sodium thiosulfate, with brine, dried over MgSO4, and concentrated under reduced pressure to give desired compound 9 (4.0 g, 76%) as a white powder. 1H NMR (300 MHz, CDCl3) delta (ppm) 4.06 (s, 3H), 7.86 (s, 1H), 11.35 (br s, 1H). 13C NMR (75 MHz, CDCl3) delta 53.9, 124.7, 129.9, 130.2, 136.9, 156.0, 168.8. MS (ESI-) m/z: 312 (40), 310 (100), 308 (45).
	With bromine; sodium carbonate; In water;	a. PREPARATION OF METHYL 4,6-DIBROMO-3-HYDROXYPYRIDINE-2-CARBOXYLATE (14). To a 2 L, 3-necked flask equipped with a dropping funnel and a mechanical stirrer, was added water (800 mL) and methyl 3-hydroxypyridine-2-carboxylate (15.3 g). To this stirred solution was slowly added bromine (32 g). As the reaction progressed, a solid separated from solution and the reaction mixture became difficult to stir. After the addition was complete, the mixture was vigorously stirred until the bromine color disappeared. 1H-NMR (CDCl3) of a small sample of the crude product showed that it was about a 3:1 mixture of mono to dibrominated product. Sodium carbonate (31.8 g) was carefully added to the reaction mixture and then additional bromine (12 g) was added dropwise. After the bromine color had disappeared, the reaction mixture was adjusted to approximately pH 5 with conc. HCl, and the resulting mixture was extracted with CH2Cl2 (3*150 mL). The organic extracts were combined, dried (MgSO4) and concentrated to give an orange solid (14 g). This material could be recrystallized from methylcyclohexane (after charcoal treatment) to give 14 as a white solid, m.p. 181-183 C.

	With bromine; sodium carbonate; In water;	a. PREPARATION OF METHYL 4,6-DIBROMO-3-HYDROXYPYRIDINE-2-CARBOXYLATE (14). To a 2 L, 3-necked flask equipped with a dropping funnel and a mechanical stirrer, was added water (800 mL) and methyl 3-hydroxypyridine-2-carboxylate (15.3 g). To this stirred solution was slowly added bromine (32 g). As the reaction progressed, a solid separated from solution and the reaction mixture became difficult to stir. After the addition was complete, the mixture was vigorously stirred until the bromine color disappeared. 1H-NMR (CDCl3) of a small sample of the crude product showed that it was about a 3:1 mixture of mono to dibrominated product. Sodium carbonate (31.8 g) was carefully added to the reaction mixture and then additional bromine (12 g) was added dropwise. After the bromine color had disappeared, the reaction mixture was adjusted to approximately pH 5 with conc. HCl, and the resulting mixture was extracted with CH2Cl2 (3x150 mL). The organic extracts were combined, dried (MgSO4) and concentrated to give an orange solid (14 g). This material could be recrystallized from methylcyclohexane (after charcoal treatment) to give 14 as a white solid, m.p. 181-183 C.
	With bromine; In water; at 10 - 20℃;	To a solution of compound 20B (114 g, 0.745 mol, 1.0 eq) in water (8 L) at 10C was added bromine (114.6 mL, 2.235 mol, 3.0 eq). The reaction mixture was stirred at rt overnight. The reaction mixture was extracted with DCM (2 x 8 L). The organic phase was separated, and dried over sodium sulfate, and concentrated to give crude compound 20C (186 g, 81%) as a slightly yellow solid. JH NMR (400 MHz, CDC13) delta 11.35 (s, 1H), 7.56 (s, 1H), 4.06 (s, 3H).
	With bromine; In water; at 15℃; for 5h;	To a mixture of in compound Int-20a (50 g, 327 mmol) in H20 (5.0 L) stirred at 15C, was add bromine (157 g, 979 mmol). The mixture was stirred at 15C for 5 hours. The resulting mixture was filtered,the filter cake was washed with water and driedunder vacuum to give compound Int-20b. The crude material was used in the next reaction without further purification. 1H NMR (400 MHz, CDC13) delta 11.37 (s, 1H), 7.87 (s, 1H), 4.07 (s, 3H).
	With bromine; In water; at 15℃; for 5h;	To a mixture of compound Int-la (50 g, 327 mmol) in water (5.0 L) stirred at l5C, was added bromine (157 g, 979 mmol). The mixture was stirred at l5C for 5 hours. The resulting mixture was filtered, and the filter cake was washed with water and dried under vacuum to give compound Int-lb. The crude material was used in the next reaction without further purification. NMR (400 MHz, CDCb) d 11.37 (s, 1H), 7.87 (s, 1H), 4.07 (s, 3H).
	With bromine; In water; at 15℃; for 5h;	To a mixture of compound int-1 a (50 g, 327 mmol) in water (5.0 L) stirred at l5C, bromine (157 g, 979 mmol) was added. The mixture was stirred at l5C for 5 hours. The resulting mixture was filtered, and the filter cake was washed with water and dried under vacuum to give compound int-lb. The crude material was used in the next reaction without further purification. NMR (400 MHz, CDCb) d 11.37 (s, 1H); 7.87 (s, 1H); 4.07 (s, 3H).

Reference： [1]Patent: EP3590924,2020,A1 .Location in patent: Paragraph 0185; 0187
[2]Tetrahedron,2011,vol. 67,p. 8757 - 8762
[3]Patent: US6355660,2002,B1
[4]Patent: EP1516874,2015,B1
[5]Patent: WO2018/5662,2018,A1 .Location in patent: Paragraph 0291
[6]Patent: WO2018/102634,2018,A1 .Location in patent: Page/Page column 83
[7]Patent: WO2019/209667,2019,A1 .Location in patent: Page/Page column 20
[8]Patent: WO2019/236396,2019,A1 .Location in patent: Page/Page column 22

4
[ 321596-55-8 ]
[ 350602-03-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; dimethyl sulfate; In ethyl acetate; acetone;	A. Methyl 4,6-Dibromo-3-methoxypyridine-2-carboxylate To <strong>[321596-55-8]methyl 4,6-dibromo-3-hydroxypyridine-2-carboxylate</strong> 3.98 g (3.98 g, 12.81 mmol) in 40 mL of acetone was added K2CO3 (2.0 g, 14.47 mmol) and dimethyl sulfate (1.20 mL, 12.37 mmol). The reaction mixture was refluxed overnight and concentrated to dryness. The residue was dissolved in ethyl acetate and saturated sodium bicarbonate. The phases were separated and the aqueous phase was extracted with ethyl acetate (3*100 mL). The combined extracts were dried (MgSO4) and concentrated to dryness. The residue was purified by chromatography (silica gel). Elution with 15% ethyl acetate/hexane gave 0.980 g, of a white solid. 1H NMR(CDCl3): delta 3.95 (s, 3H); 3.90 (s, 3H); 7.80 (s, 1H).

Reference： [1]Patent: US6297197,2001,B1

5
[ 321596-55-8 ]
[ 1235142-25-2 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 8757 - 8762

6
[ 321596-55-8 ]
[ 1342906-73-3 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 8757 - 8762
[2]Tetrahedron,2011,vol. 67,p. 8757 - 8762
[3]Patent: WO2018/5662,2018,A1
[4]Patent: EP3590924,2020,A1

7
[ 321596-55-8 ]
[ 1342906-77-7 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 8757 - 8762
[2]Tetrahedron,2011,vol. 67,p. 8757 - 8762

8
[ 321596-55-8 ]
[ 1342906-80-2 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 8757 - 8762
[2]Tetrahedron,2011,vol. 67,p. 8757 - 8762

9
[ 321596-55-8 ]
[ 1342906-72-2 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 8757 - 8762

10
[ 321596-55-8 ]
[ 100-39-0 ]
[ 321596-56-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In acetone; for 18h;Reflux;	Benzyl bromide (1.2 mL, 3 equiv) was slowly added to a mixture of 9 (1.0 g, 3.2 mmol) and K2CO3 (2.0 g, 4.5 equiv) in acetone (40 mL). The reaction mixture was refluxed for 18 h. The resulting mixture was filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (cyclohexane/EtOAc 9/1, v/v) gave 5 (1.2 g, 90%) as a white solid. Mp 74 C. 1H NMR (300 MHz, CDCl3) delta (ppm) 3.92 (s, 3H), 5.13 (s, 2H), 7.35-7.44 (m, 3H), 7.49-7.53 (m, 2H), 7.88 (s, 1H). 13C NMR (75 MHz, CDCl3) delta 53.3, 77.0, 128.6, 128.7, 128.8, 131.9, 134.9, 135.4, 135.5, 145.3, 151.9, 163.3. MS (ESI+) m/z (%): 404 (65), 402 (100), 400 (60). Anal. Calcd for C14H11Br2NO3: C, 41.93; H, 2.76; N, 3.49. Found: C, 41.95; H, 2.81; N, 3.21.
68%	With potassium carbonate; In acetonitrile; under 760.051 Torr;Reflux;	A solution of compound 601-C (49 g, 157 mmol), BnBr (80.5 g, 472 mmol) and K2CO3 (98 g, 710 mmol) inCH3CN (1 L) was heated to reflux for overnight. The mixture was cooled to 25 C. The solid was removed by filtrationand the filtrate was evaporated to give the residue which was purified by triturated with PE: EtOAc = 10:1 (100 mL) at30 C for 1 hour to give 601-D (methyl 3-(benzyloxy)-4,6-dibromopicolinate, 43 g, yield: 68%) as yellow solid.1H NMR (300 MHz, CDCl3): delta 7.89 (s, 1H), 7.39-7.54 (m, 5H), 5.15 (s, 2H), 3.94 (s, 3H).
199 g	With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	To a solution of compound 20C (186 g, 0.631 mol, 1.0 eq) and cesium carbonate (514.3 g, 1.578 mol, 2.5 eq) in DMF (2 L) at 0 C was added benzyl bromide (89.1 mL, 0.757 mol, 1.2 eq). The reaction mixture was stirred at rt for 2 h. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica (PE/EA = 20: 1) to give compound 20D (199 g, 83%) as a white solid. JH NMR (400 MHz, CDC13) delta 7.88 (s, 1H), 7.52 - 7.50 (d, / = 6.1 Hz, 2H), 7.43 -7.37 (d, / = 7.2 Hz, 3H), 5.13 (s, 2H), 3.92 (s, 3H).

Reference： [1]Tetrahedron,2011,vol. 67,p. 8757 - 8762
[2]Patent: EP3590924,2020,A1 .Location in patent: Paragraph 0103; 0185; 0188
[3]Patent: WO2018/5662,2018,A1 .Location in patent: Paragraph 0292

11
[ 321596-55-8 ]
[ 321596-54-7 ]

Reference： [1]Patent: EP1516874,2015,B1

12
[ 321596-55-8 ]
[ 321596-57-0 ]

Reference： [1]Patent: EP1516874,2015,B1

13
methyl 2-amino-2-(furan-2-yl)acetate hydrobromide [ No CAS ]
[ 321596-55-8 ]

Yield	Reaction Conditions	Operation in experiment
51.6%	With bromine; sodium acetate; In methanol; water; at 0 - 20℃; for 24.5h;	To a magnetically stirred solution of methyl 2-amino-2-(furan-2-yl)acetate hydrobromide (0.84 g, 3.56 mmol) and sodium acetate (1.255 g, 15.30 mmol) in 40 mL of water at 0 C. was added dropwise a solution of bromine (0.788 ml, 15.30 mmol) in 10 mL of MeOH over 30 min, After warming to room temperature for 24 hr, the reaction mixture was filtered through a fritted glass funnel and the white solid was washed with water. Solvent removal gave methyl 4,6-dibromo-3-hydroxypicolinate (577 mg, 1.837 mmol, 51.6% yield) as a white solid; Mp 180-181 C. (recrystallized from heptane). 1H NMR (600 MHz, Chloroform-d) delta 11.35 (s, 1H), 7.86 (s, 1H), 4.07 (s, 3H); 13C NMR (151 MHz, Chloroform-d) delta 168.74, 156.02, 136.85, 130.14, 129.92, 124.67, 53.84. HRMS-ESI (m/z) calc'd for [C7H5Br2NO3]+, 308.8636. found, 308.8638.

Reference： [1]Patent: US2016/9647,2016,A1 .Location in patent: Paragraph 0045-0046

14
[ 113452-72-5 ]
[ 321596-55-8 ]

Yield	Reaction Conditions	Operation in experiment
43.2%		To magnetically stirred 33 wt % hydrogen bromide (10.00 ml, 55.2 mmol) in acetic acid was added methyl 2-(((benzyloxy)carbonyl)amino)-2-(furan-2-yl)acetate (2.89 g, 10 mmol). After stirring at room temperature for 1 hr, 150 mL of anhydrous ether was added to give 2.34 g of a grey solid. To a magnetically stirred solution of this grey solid and sodium acetate (3.53 g, 43.0 mmol) in 100 mL of water at 0 C. was added dropwise of a solution of bromine (2.215 ml, 43.0 mmol) in 20 mL of MeOH. over 30 min. After stirring at room temperature, the reaction mixture was filtered through a fritted glass funnel. The off-white solid was dissolved in 75 mL of CH2Cl2, washed with 5 ml of a saturated aqueous solution of Na2S2O3 and 5 ml, of a saturated aqueous solution of NaCl, and dried (MgSO4). Solvent removal gave methyl 4,6-dibromo-3-hydroxypicolinate (1.43 g, 4.32 mmol, 43.2% yield) as an off-white solid; Mp 179-180 C. (recrystallized from heptane). H NMR (400 MHz, Chloroform-d) delta 11.36 (d, J=0.4 Hz, 1H), 7.86 (m, 1H), 4.07 (s, 3H).

Reference： [1]Patent: US2016/9647,2016,A1 .Location in patent: Paragraph 0047-0048

15
[ 70946-43-9 ]
[ 321596-55-8 ]

Reference： [1]Patent: US2016/9647,2016,A1

16
[ 1467-70-5 ]
[ 321596-55-8 ]

Reference： [1]Patent: US2016/9647,2016,A1

17
2-(furan-2-yl)-2-(methoxyimino)acetic acid [ No CAS ]
[ 321596-55-8 ]

Reference： [1]Patent: US2016/9647,2016,A1

18
[ 869556-74-1 ]
[ 321596-55-8 ]

Reference： [1]Patent: US2016/9647,2016,A1

19
[ 321596-55-8 ]
C₁₇H₁₅NO₅ [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

20
[ 321596-55-8 ]
C₁₇H₁₅Br₂NO₅ [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

21
[ 321596-55-8 ]
C₁₆H₁₄BrNO₃ [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

22
[ 321596-55-8 ]
C₂₂H₂₆BNO₅ [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

23
[ 321596-55-8 ]
C₂₆H₃₀BNO₅ [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

24
[ 321596-55-8 ]
C₂₇H₃₂BNO₅ [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

25
[ 321596-55-8 ]
C₂₇H₃₂BNO₅ [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

26
[ 321596-55-8 ]
C₉H₈BNO₄ [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

27
[ 321596-55-8 ]
disodium (1aS,7bR)-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[6,7]oxaborinino[2,3-c]pyridine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

28
[ 321596-55-8 ]
C₉H₈BNO₄ [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

29
[ 321596-55-8 ]
disodium (1aR,7bS)-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[6,7]oxaborinino[2,3-c]pyridine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/5662,2018,A1

30
[ 321596-55-8 ]
C₇H₄Br₂NO₃^(1-)*Li⁽¹⁺⁾ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1
[2]Patent: WO2019/209667,2019,A1
[3]Patent: WO2019/236396,2019,A1

31
[ 321596-55-8 ]
C₁₅H₁₄BrNO₅ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1
[2]Patent: WO2019/209667,2019,A1
[3]Patent: WO2019/236396,2019,A1

32
[ 321596-55-8 ]
C₁₆H₁₆BrNO₅ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1
[2]Patent: WO2019/209667,2019,A1
[3]Patent: WO2019/236396,2019,A1

33
[ 321596-55-8 ]
C₁₈H₁₅F₃N₄O₄ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1

34
[ 321596-55-8 ]
C₁₉H₂₁NO₅ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1

35
[ 321596-55-8 ]
C₁₈H₂₁NO₆ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1

36
[ 321596-55-8 ]
C₁₈H₂₂N₂O₅ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1

37
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C₁₉H₂₄N₂O₇S [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1

38
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C₁₁H₁₆N₂O₆S [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1

39
[ 321596-55-8 ]
C₁₀H₁₃N₃O₃ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1

40
[ 321596-55-8 ]
C₁₁H₁₃N₃O₃ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1

41
[ 321596-55-8 ]
C₁₁H₁₂IN₃O₃ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1

42
[ 321596-55-8 ]
C₁₉H₁₇F₃N₄O₄ [ No CAS ]

Reference： [1]Patent: WO2018/102634,2018,A1

43
[ 321596-55-8 ]
[ 74-88-4 ]
[ 350602-03-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetone; at 15 - 60℃; for 2h;	To a solution of compound Int-20b (200 g, 643 mmol) in acetone (4.0 L) stirred at (0677) 15C, was added Cs2C03 (377 g, 1.160 mol) followed by dropwise addition of iodomethane (274 g, 1930 mmol). The reaction was heated at 60C for 2 hours. After it was cooled to room temperature, the reaction mixture was filtered. The filter cake was washed with acetone, and purified by silica gel chromatography eluting with petroleum ether: EtOAc=25: 1-10: 1 to give compound Int-20c. 1H NMR (400 MHz, CDC13) delta 7.85 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H).
	With caesium carbonate; In acetone; at 60℃; for 2h;	To a solution of compound Int-lb (200 g, 643 mmol) in acetone (4.0 L) stirred at l5C, was added CS2CO3 (377 g, 1.160 mol) followed by dropwise addition of iodomethane (274 g, 1930 mmol). The reaction was heated at 60C for 2 hours. After it was cooled to room temperature, the reaction mixture was filtered. The filter cake was washed with acetone, and purified by silica gel chromatography eluting with petroleum ether: EtOAc = 25:1-10: 1 to give compound Int-lc. NMR (400 MHz, CDCb) d 7.85 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H)
	With caesium carbonate; In acetone; at 15 - 60℃; for 2h;	To a solution of compound int-lb (200 g, 643 mmol) in acetone (4.0 L) stirred at l5C, was added CS2CO3 (377 g, 1.160 mol) followed by dropwise addition of iodomethane (274 g, 1930 mmol). The reaction was heated at 60C for 2 hours. After it was cooled to room temperature, the reaction mixture was filtered. The filter cake was washed with acetone, and the filtrate was concentrated under vacuum. The residue was purified by silica gelchromatography eluting with petroleum ether / EtOAc = 25: 1-10: 1 to give compound int-lc. NMR (400 MHz, CDCb) d 7.85 (s, 1H); 3.99 (s, 3H); 3.98 (s, 3H).

Reference： [1]Patent: WO2018/102634,2018,A1 .Location in patent: Page/Page column 83
[2]Patent: WO2019/209667,2019,A1 .Location in patent: Page/Page column 20-21
[3]Patent: WO2019/236396,2019,A1 .Location in patent: Page/Page column 22-23

44
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C₂₀H₂₃NO₇ [ No CAS ]