[ CAS No. 1052714-46-1 ] {[proInfo.proName]}

Name: 1052714-46-1|6-Bromo-5-fluoropicolinic acid|98%
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SKU: A265037
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Quality Control of [ 1052714-46-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1052714-46-1 ]

Product Details of [ 1052714-46-1 ]

CAS No. :	1052714-46-1	MDL No. :	MFCD13185797
Formula :	C₆H₃BrFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UVDJYBXHNFJTME-UHFFFAOYSA-N
M.W :	220.00	Pubchem ID :	53401194
Synonyms :

Calculated chemistry of [ 1052714-46-1 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	38.85
TPSA :	50.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.34 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.14
Log Po/w (XLOGP3) :	1.84
Log Po/w (WLOGP) :	2.1
Log Po/w (MLOGP) :	0.09
Log Po/w (SILICOS-IT) :	1.86
Consensus Log Po/w :	1.41

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.7
Solubility :	0.438 mg/ml ; 0.00199 mol/l
Class :	Soluble
Log S (Ali) :	-2.51
Solubility :	0.673 mg/ml ; 0.00306 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.54
Solubility :	0.639 mg/ml ; 0.0029 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.91

Safety of [ 1052714-46-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1052714-46-1 ]

* 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 [ 1052714-46-1 ]
Downstream synthetic route of [ 1052714-46-1 ]

[ 1052714-46-1 ] Synthesis Path-Upstream 1~3

1
[ 67-56-1 ]
[ 1052714-46-1 ]
[ 1210419-26-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 20℃; for 2 h;	Synthesis of methyl 6-bromo-5-fluoropicolinate To a solution of 6-bromo-5-fluoropicolinic acid (1.0 equiv.) in methanol (0.2 M) was added H₂SO₄ (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHCO₃. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99percent). LC/MS=233.9/235.9 (M+H), Rt=0.69 min.
99%	Stage #1: at 20℃; for 2 h; Stage #2: With sodium hydrogencarbonate In water	Synthesis of methyl 6-bromo-5-fluoropicolinate[00151] To a solution of 6-bromo-5-fluoropicolinic acid (1.0 equiv.) in methanol (0.2 M) was added H₂S0₄ (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHC0₃. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99percent). LCMS (m/z): 233.9/235.9 (MH⁺), R, = 0.69 min.
99%	Stage #1: at 20℃; for 2 h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	To a solution of 6-bromo-5-fluoropicolinic acid (1.0 equiv.) in methanol (0.2 M) was added H₂SO₄(4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHCO₃. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99percent). LC/MS=233.9/235.9 (M+H), Rt=0.69 min.

99%	at 20℃; for 2 h;	To a solution of 6-bromo-5-fluoropicolinic acid (1.0 equiv.) in methanol (0.2 M) was added H₂SO₄(4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHCO₃. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99percent). LC/MS=233.9/235.9 (M+H), Rt=0.69 min.
99%	at 20℃; for 2 h;	Synthesis of methyl 6-bromo-5-fluoropicolinate To a solution of 6-bromo-5-fluoropicolinic acid (1.0 equiv.) in methanol (0.2 M) was added H₂SO₄ (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHC0₃. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fiuoropicolinate as a white solid (>99percent). LC/MS = 233.9/235.9 (M+H), Rt = 0.69 min.
99%	at 20℃; for 2 h;	Synthesis of methyl 6-bromo-5-fluoropicolinate To a solution of 6-bromo-5-fluoropicolinic acid (1.0 equiv.) in methanol (0.2 M) was added H₂SO₄ (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHC0₃. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99percent). LC/MS = 233.9/235.9 (M+H), Rt = 0.69 min.

Reference： [1] Patent: US2010/56576, 2010, A1, . Location in patent: Page/Page column 48
[2] Patent: WO2012/4217, 2012, A1, . Location in patent: Page/Page column 65-66
[3] Patent: US2012/225062, 2012, A1, . Location in patent: Page/Page column 26; 27
[4] Patent: US2012/225061, 2012, A1, . Location in patent: Page/Page column 22
[5] Patent: WO2013/175388, 2013, A1, . Location in patent: Page/Page column 44
[6] Patent: WO2014/33631, 2014, A1, . Location in patent: Page/Page column 42

2
[ 1052714-46-1 ]
[ 1210419-26-3 ]

Reference： [1] Patent: US2012/225061, 2012, A1,
[2] Patent: US2012/225062, 2012, A1,

3
[ 374633-36-0 ]
[ 1052714-46-1 ]

Yield	Reaction Conditions	Operation in experiment
17%	Stage #1: With potassium permanganate In water at 100℃; for 53 h; Stage #2: With hydrogenchloride In water	Synthesis of 6-bromo-5-fluoropicolinic acid To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H₂O (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100° C. for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4 cm*2 inches) and rinsed with H₂O (150 mL). The combined aqueous was acidified with 1N HCl to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl_(sat.), dried over MgSO₄, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17percent) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt=2.05 min.
17%	Stage #1: With potassium permanganate In water at 100℃; for 53 h; Stage #2: With hydrogenchloride In water	Synthesis of 6-bromo-5-fluoropicolinic acid[00144] To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H₂0 (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100 °C for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4cm x 2 inches) and rinsed with H₂0 (150 mL). The combined aqueous was acidified with IN HC1 to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl_(sat), dried over MgS04, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17percent) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt = 2.05 min.
17%	Stage #1: With pyridine; potassium permanganate In water at 85℃; for 48 h; Stage #2: With hydrogenchloride In water	Step A: Preparation of 6-bromo-5-fluoropicolinic acid: 2-Bromo-3-fluoro-6- methylpyridine (3.60 g, 18.9 mmol) was dissolved in 10 mL of pyridine in pressure tube. To this was added 50 mL of water, and the mixture was warmed to 85 °C. Potassium permanganate (5.99 g, 37.9 mmol) was added, the tube was capped, and the mixture was stirred at 85 °C for 48 hours. The mixture was filtered through GF/F filter paper, and the filtrate was concentrated to about half volume under reduced pressure. The remaining material was acidified to pH 4 with 1M aqueous HC1 and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give 0.70 g of the title compound (17percent).

17%	With potassium permanganate In water	Synthesis of 6-bromo-5-fluoropicolinic acid To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H₂O (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100° C. for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4 cm*2 inches) and rinsed with H₂O (150 mL). The combined aqueous was acidified with 1N HCl to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat.), dried over MgSO₄, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17percent) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt=2.05 min.
17%	Stage #1: With potassium permanganate In water at 100℃; for 53 h; Stage #2: With hydrogenchloride In water	To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H₂O (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100° C. for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4 cm.x.2 inches) and rinsed with H₂O (150 mL). The combined aqueous was acidified with 1N HCl to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat.), dried over MgSO₄, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17percent) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt=2.05 min.
17%	With potassium permanganate In water at 100℃; for 53 h;	To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H₂O (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100° C. for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4 cm.x.2 inches) and rinsed with H₂O (150 mL). The combined aqueous was acidified with 1N HCl to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat.), dried over MgSO₄, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17percent) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt=2.05 min.
17%	With potassium permanganate In water at 100℃; for 53 h;	Synthesis of 6-bromo-5-fluoropicolinic acid To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H₂0 (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100 °C for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4cm x 2 inches) and rinsed with H₂0 (150 mL). The combined aqueous was acidified with IN HC1 to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat), dried over MgSC^, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17percent) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt = 2.05 min.
17%	With potassium permanganate In water at 100℃; for 53 h;	Synthesis of 6-bromo-5-fluoropicolinic acid To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H₂0 (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100 °C for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4cm x 2 inches) and rinsed with H₂0 (150 mL). The combined aqueous was acidified with IN HC1 to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl_(sat.₎, dried over MgS0₄, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17percent) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt = 2.05 min.
13%	With potassium permanganate In water at 90℃; for 3 h;	Potassium permanganate (2.50 g, 15.8 mmol) was added portionwise to asuspension of 2-bromo-3-fluoro-6-methylpyridine (1 g, 5.26 mmol) in water (22 ml) at 90 00The reaction was stirred for 3 hours and then filtered through Celite® while hot, washing with hot water. The filtrate was acidified to pH 1 via addition of 6 N HCI. The resultant precipitate was collected by filtration to give the title compound (0.15 g, 13 percent yield). MS (mlz) 219.9 (M+H).

Reference： [1] Patent: US2010/56576, 2010, A1, . Location in patent: Page/Page column 46
[2] Patent: WO2012/4217, 2012, A1, . Location in patent: Page/Page column 62-63
[3] Patent: WO2012/82689, 2012, A1, . Location in patent: Page/Page column 91-92
[4] Patent: US2012/225061, 2012, A1,
[5] Patent: US2012/225062, 2012, A1,
[6] Patent: US2012/225062, 2012, A1, . Location in patent: Page/Page column 26
[7] Patent: US2012/225061, 2012, A1, . Location in patent: Page/Page column 22
[8] Patent: WO2013/175388, 2013, A1, . Location in patent: Page/Page column 43-44
[9] Patent: WO2014/33631, 2014, A1, . Location in patent: Page/Page column 41
[10] Patent: WO2017/6295, 2017, A1, . Location in patent: Page/Page column 97; 98

[ 1052714-46-1 ] Synthesis Path-Downstream 1~88

1
[ 1052714-46-1 ]
[ 168267-41-2 ]
[ 1210418-85-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 0.5h;Microwave irradiation;	Synthesis of 6-(3,4-difluorophenyl)-5-fluoropicolinic acid To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in DME and 2M Na2C03 (3: 1, 0.25 M) was added 3,4-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) in a microwave vial. The vial was heated in the microwave at 120 C for 30 minutes. The mixture was diluted with ethyl acetate and IN NaOH was added. The organic phase was separated and extracted three more times with IN NaOH and once with 6N NaOH. The combined aqueous phases were filtered and acidified to pH 1 by the addition of concentrated HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 6- (3,4-difluorophenyl)-5-fiuoropicolinic acid in 70% yield. LC/MS = 254.1 (M+H), Rt = 0.81 min.

Reference： [1]Patent: WO2014/33631,2014,A1 .Location in patent: Page/Page column 79

2
[ 1052714-46-1 ]
[ 121219-16-7 ]
[ 1210418-75-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;microwave irradiation;	Synthesis of 6-(2,3-difluorophenyl)-5-fluoropicolinic acid To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in DME and 2M Na2CO3 (3:1, 0.25 M) was added 2,3-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) in a microwave vial. The vial was heated in the microwave at 120 C. for 30 minutes. The mixture was diluted with ethyl acetate and 1N NaOH was added. The organic phase was separated and extracted three more times with 1N NaOH and once with 6N NaOH. The combined aqueous phases were filtered and acidified to pH I by the addition of concentrated HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 6-(2,3-difluorophenyl)-5-fluoropicolinic acid in 78%. LC/MS=254.1 (M+H), Rt=0.75 min.
78%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 0.5h;Microwave irradiation;	Synthesis of 6-(2,3-difluorophenyl)-5-fluoropicolinic acid To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in DME and 2M Na2C03 (3: 1, 0.25 M) was added 2,3-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) in a microwave vial. The vial was heated in the microwave at 120 C for 30 minutes. The mixture was diluted with ethyl acetate and IN NaOH was added. The organic phase was separated and extracted three more times with IN NaOH and once with 6N NaOH. The combined aqueous phases were filtered and acidified to pH 1 by the addition of concentrated HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 6- (2,3-difluorophenyl)-5-fiuoropicolinic acid in 78%. LC/MS = 254.1 (M+H), Rt = 0.75 min.

Reference： [1]Patent: US2010/56576,2010,A1 .Location in patent: Page/Page column 40
[2]Patent: WO2014/33631,2014,A1 .Location in patent: Page/Page column 77

3
[ 1052714-46-1 ]
[ 1993-03-9 ]
[ 1210418-84-0 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

4
[ 1052714-46-1 ]
[ 144025-03-6 ]
[ 1210418-87-3 ]

Yield	Reaction Conditions	Operation in experiment
79%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 0.5h;Microwave irradiation;	Synthesis of 6-(2,4-difluorophenvD-5-fluoropicolinic acid To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in DME and 2M Na2C03 (3: 1, 0.25 M) was added 2,4-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) in a microwave vial. The vial was heated in the microwave at 120 C for 30 minutes. The mixture was diluted with ethyl acetate and IN NaOH was added. The organic phase was separated and extracted three more times with IN NaOH and once with 6N NaOH. The combined aqueous phases were filtered and acidified to pH 1 by the addition of concentrated HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 6- (2,4-difluorophenyl)-5-fiuoropicolinic acid in 79% yield. LC/MS = 254.1 (M+H), Rt = 0.75 min.

Reference： [1]Patent: WO2014/33631,2014,A1 .Location in patent: Page/Page column 78

5
[ 1052714-46-1 ]
2,5-difurorboronic acid [ No CAS ]
[ 1210418-86-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 0.5h;Microwave irradiation;	Synthesis of 6-(2,5-difluorophenyl)-5-fluoropicolinic acid To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in DME and 2M Na2C03 (3: 1, 0.25 M) was added 2,5-difluorophenylboronic acid acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) in a microwave vial. The vial was heated in the microwave at 120 C for 30 minutes. The mixture was diluted with ethyl acetate and IN NaOH was added. The organic phase was separated and extracted three more times with IN NaOH and once with 6N NaOH. The combined aqueous phases were filtered and acidified to pH 1 by the addition of concentrated HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give (2,5-difluorophenyl)-5-fiuoropicolinic acid in 80% yield. LC/MS = 254.1 (M+H), Rt 0.74 min.

Reference： [1]Patent: WO2014/33631,2014,A1 .Location in patent: Page/Page column 78-79

6
[ 374633-36-0 ]
[ 1052714-46-1 ]

Yield	Reaction Conditions	Operation in experiment
17%		Synthesis of 6-bromo-5-fluoropicolinic acid To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H2O (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100 C. for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4 cm*2 inches) and rinsed with H2O (150 mL). The combined aqueous was acidified with 1N HCl to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat.), dried over MgSO4, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17%) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt=2.05 min.
17%		Synthesis of 6-bromo-5-fluoropicolinic acid[00144] To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H20 (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100 C for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4cm x 2 inches) and rinsed with H20 (150 mL). The combined aqueous was acidified with IN HC1 to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat), dried over MgS04, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17%) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt = 2.05 min.
17%		Step A: Preparation of 6-bromo-5-fluoropicolinic acid: 2-Bromo-3-fluoro-6- methylpyridine (3.60 g, 18.9 mmol) was dissolved in 10 mL of pyridine in pressure tube. To this was added 50 mL of water, and the mixture was warmed to 85 C. Potassium permanganate (5.99 g, 37.9 mmol) was added, the tube was capped, and the mixture was stirred at 85 C for 48 hours. The mixture was filtered through GF/F filter paper, and the filtrate was concentrated to about half volume under reduced pressure. The remaining material was acidified to pH 4 with 1M aqueous HC1 and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give 0.70 g of the title compound (17%).

17%	With potassium permanganate; In water;	Synthesis of 6-bromo-5-fluoropicolinic acid To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H2O (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100 C. for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4 cm*2 inches) and rinsed with H2O (150 mL). The combined aqueous was acidified with 1N HCl to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat.), dried over MgSO4, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17%) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt=2.05 min.
17%		To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H2O (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100 C. for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4 cm×2 inches) and rinsed with H2O (150 mL). The combined aqueous was acidified with 1N HCl to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat.), dried over MgSO4, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17%) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt=2.05 min.
17%	With potassium permanganate; In water; at 100℃; for 53h;	To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H2O (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100 C. for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4 cm×2 inches) and rinsed with H2O (150 mL). The combined aqueous was acidified with 1N HCl to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat.), dried over MgSO4, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17%) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt=2.05 min.
17%	With potassium permanganate; In water; at 100℃; for 53h;	Synthesis of 6-bromo-5-fluoropicolinic acid To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H20 (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100 C for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4cm x 2 inches) and rinsed with H20 (150 mL). The combined aqueous was acidified with IN HC1 to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat), dried over MgSC^, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17%) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt = 2.05 min.
17%	With potassium permanganate; In water; at 100℃; for 53h;	Synthesis of 6-bromo-5-fluoropicolinic acid To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H20 (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100 C for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4cm x 2 inches) and rinsed with H20 (150 mL). The combined aqueous was acidified with IN HC1 to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat.), dried over MgS04, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17%) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt = 2.05 min.
13%	With potassium permanganate; In water; at 90℃; for 3h;	Potassium permanganate (2.50 g, 15.8 mmol) was added portionwise to asuspension of 2-bromo-3-fluoro-6-methylpyridine (1 g, 5.26 mmol) in water (22 ml) at 90 00The reaction was stirred for 3 hours and then filtered through Celite while hot, washing with hot water. The filtrate was acidified to pH 1 via addition of 6 N HCI. The resultant precipitate was collected by filtration to give the title compound (0.15 g, 13 % yield). MS (mlz) 219.9 (M+H).

Reference： [1]Patent: US2010/56576,2010,A1 .Location in patent: Page/Page column 46
[2]Patent: WO2012/4217,2012,A1 .Location in patent: Page/Page column 62-63
[3]Patent: WO2012/82689,2012,A1 .Location in patent: Page/Page column 91-92
[4]Patent: US2012/225061,2012,A1
[5]Patent: US2012/225062,2012,A1 .Location in patent: Page/Page column 26
[6]Patent: US2012/225061,2012,A1 .Location in patent: Page/Page column 22
[7]Patent: WO2013/175388,2013,A1 .Location in patent: Page/Page column 43-44
[8]Patent: WO2014/33631,2014,A1 .Location in patent: Page/Page column 41
[9]Patent: WO2017/6295,2017,A1 .Location in patent: Page/Page column 97; 98

7
[ 1052714-46-1 ]
[ 1210419-26-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In methanol;	Synthesis of methyl 6-bromo-5-fluoropicolinate To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in methanol (0.2 M) was added H2SO4 (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHCO3. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99%). LC/MS=233.9/235.9 (M+H), Rt=0.69 min.

Reference： [1]Patent: US2012/225061,2012,A1

8
[ 67-56-1 ]
[ 1052714-46-1 ]
[ 1210419-26-3 ]

Yield	Reaction Conditions	Operation in experiment
> 99%	With sulfuric acid; at 20℃; for 2h;	Synthesis of methyl 6-bromo-5-fluoropicolinate To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in methanol (0.2 M) was added H2SO4 (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHCO3. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99%). LC/MS=233.9/235.9 (M+H), Rt=0.69 min.
> 99%		Synthesis of methyl 6-bromo-5-fluoropicolinate[00151] To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in methanol (0.2 M) was added H2S04 (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHC03. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99%). LCMS (m/z): 233.9/235.9 (MH+), R, = 0.69 min.
> 99%		To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in methanol (0.2 M) was added H2SO4 (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHCO3. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99%). LC/MS=233.9/235.9 (M+H), Rt=0.69 min.

> 99%	With sulfuric acid; at 20℃; for 2h;	To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in methanol (0.2 M) was added H2SO4 (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHCO3. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99%). LC/MS=233.9/235.9 (M+H), Rt=0.69 min.
> 99%	With sulfuric acid; at 20℃; for 2h;	Synthesis of methyl 6-bromo-5-fluoropicolinate To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in methanol (0.2 M) was added H2SO4 (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHC03. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fiuoropicolinate as a white solid (>99%). LC/MS = 233.9/235.9 (M+H), Rt = 0.69 min.
> 99%	With sulfuric acid; at 20℃; for 2h;	Synthesis of methyl 6-bromo-5-fluoropicolinate To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in methanol (0.2 M) was added H2SO4 (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHC03. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99%). LC/MS = 233.9/235.9 (M+H), Rt = 0.69 min.

Reference： [1]Patent: US2010/56576,2010,A1 .Location in patent: Page/Page column 48
[2]Patent: WO2012/4217,2012,A1 .Location in patent: Page/Page column 65-66
[3]Patent: US2012/225062,2012,A1 .Location in patent: Page/Page column 26; 27
[4]Patent: US2012/225061,2012,A1 .Location in patent: Page/Page column 22
[5]Patent: WO2013/175388,2013,A1 .Location in patent: Page/Page column 44
[6]Patent: WO2014/33631,2014,A1 .Location in patent: Page/Page column 42

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[ 1052714-46-1 ]
[ 1210419-29-6 ]

Reference： [1]Patent: WO2012/4217,2012,A1
[2]Patent: WO2013/175388,2013,A1
[3]Patent: WO2014/33631,2014,A1

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[ 1052714-46-1 ]
[ 1210419-31-0 ]

Reference： [1]Patent: WO2012/4217,2012,A1
[2]Patent: WO2013/175388,2013,A1
[3]Patent: WO2014/33631,2014,A1

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[ 1052714-46-1 ]
[ 1210419-27-4 ]

Reference： [1]Patent: US2012/225061,2012,A1
[2]Patent: US2012/225061,2012,A1

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[ 1052714-46-1 ]
[ 1210419-33-2 ]

Reference： [1]Patent: US2012/225061,2012,A1
[2]Patent: US2012/225061,2012,A1

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[ 1052714-46-1 ]
[ 1355011-35-6 ]

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[ 1052714-46-1 ]
[ 1355011-36-7 ]

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[ 1052714-46-1 ]
[ 1395281-19-2 ]

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[2]Patent: US2012/225061,2012,A1

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[ 1052714-46-1 ]
[ 1395281-22-7 ]

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[ 1052714-46-1 ]
[ 1395281-25-0 ]

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[2]Patent: US2012/225061,2012,A1

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[ 1052714-46-1 ]
[ 1395281-28-3 ]

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[ 1052714-46-1 ]
[ 1395281-58-9 ]

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[2]Patent: WO2014/33631,2014,A1

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[ 1052714-46-1 ]
[ 1395281-70-5 ]

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[2]Patent: WO2014/33631,2014,A1

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[ 1052714-46-1 ]
[ 1395281-73-8 ]

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[ 1052714-46-1 ]
[ 1395281-76-1 ]

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[2]Patent: WO2014/33631,2014,A1

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[ 1052714-46-1 ]
[ 1395281-79-4 ]

Reference： [1]Patent: US2012/225061,2012,A1

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[ 1052714-46-1 ]
[ 1395281-82-9 ]

Reference： [1]Patent: US2012/225061,2012,A1
[2]Patent: WO2014/33631,2014,A1

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[ 1052714-46-1 ]
[ 1395281-85-2 ]

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[ 1052714-46-1 ]
[ 1395281-91-0 ]

Reference： [1]Patent: US2012/225061,2012,A1
[2]Patent: WO2014/33631,2014,A1

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[ 1052714-46-1 ]
[ 1395281-94-3 ]

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[ 1052714-46-1 ]
[ 1395281-97-6 ]

Reference： [1]Patent: US2012/225061,2012,A1
[2]Patent: WO2014/33631,2014,A1

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[ 1052714-46-1 ]
[ 1395282-00-4 ]

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[ 1052714-46-1 ]
[ 1395282-09-3 ]

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[2]Patent: WO2014/33631,2014,A1

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[ 1052714-46-1 ]
[ 1395282-12-8 ]

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[ 1052714-46-1 ]
[ 1395282-55-9 ]

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[2]Patent: WO2014/33631,2014,A1

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[ 1052714-46-1 ]
[ 1395282-58-2 ]

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[ 1052714-46-1 ]
[ 1395282-67-3 ]

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[ 1052714-46-1 ]
[ 1395283-25-6 ]

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[ 1052714-46-1 ]
[ 1395283-28-9 ]

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[ 1052714-46-1 ]
[ 1395283-38-1 ]

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[ 1052714-46-1 ]
[ 1395283-41-6 ]

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[ 1052714-46-1 ]
[ 1395283-51-8 ]

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[ 1052714-46-1 ]
[ 1395283-54-1 ]

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[ 1052714-46-1 ]
[ 1395283-68-7 ]

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[ 1052714-46-1 ]
[ 1395283-71-2 ]

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[ 1395283-79-0 ]

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[ 1052714-46-1 ]
[ 1395283-82-5 ]

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[ 1052714-46-1 ]
[ 1395283-91-6 ]

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[ 1052714-46-1 ]
[ 1395283-94-9 ]

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[ 1052714-46-1 ]
[ 1395284-06-6 ]

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[ 1052714-46-1 ]
[ 1395284-09-9 ]

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[ 1052714-46-1 ]
[ 1395986-06-7 ]

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[ 1052714-46-1 ]
[ 1395986-13-6 ]

Reference： [1]Patent: US2012/225062,2012,A1

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[ 1052714-46-1 ]
[ 1257294-51-1 ]

Reference： [1]Patent: US2013/178478,2013,A1
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2683 - 2691
[3]Patent: WO2019/241131,2019,A1

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[ 1052714-46-1 ]
[ 1446793-51-6 ]

Reference： [1]Patent: US2013/178478,2013,A1
[2]Patent: WO2014/60371,2014,A1

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[ 1052714-46-1 ]
[ 1446793-53-8 ]

Reference： [1]Patent: US2013/178478,2013,A1
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2683 - 2691
[3]Patent: WO2014/60371,2014,A1

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[ 1052714-46-1 ]
[ 1446793-55-0 ]

Reference： [1]Patent: US2013/178478,2013,A1
[2]Patent: WO2014/60371,2014,A1

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[ 1052714-46-1 ]
[ 1446793-57-2 ]

Reference： [1]Patent: US2013/178478,2013,A1
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2683 - 2691
[3]Patent: WO2014/60371,2014,A1

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[ 1052714-46-1 ]
[ 1446793-59-4 ]

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[ 1052714-46-1 ]
[ 1446791-15-6 ]

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[ 1052714-46-1 ]
[ 75-65-0 ]
[ 1446793-48-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With diphenyl phosphoryl azide; triethylamine; In tert-butyl alcohol; at 25 - 70℃; for 2.33333h;	Into a 250 mL round-bottom flask, was placed 6-bromo-5-fluoropyridine-2- carboxylic acid (6.3 g, 28.6 mmol, 1 eq), t-BuOH (50 mL), TEA (4 mL, 28.8 mmol, 1 eq), DPPA (6.2 mL, 23 mmol, 0.79 eq). The resulting solution was stirred for 20 min at 25C then refluxed for 2 h at 70C in an oil bath. The resulting solution was diluted with water, extracted with 3x350 mL of ethyl acetate, and concentrated. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether. This resulted in 8.67 g (99%) of tert-butyl N-(6-bromo-5- fluoropyridin-2-yl)carbamate as yellow oil. LCMS: m/z = 291.1 [M+H]+.
60.5%	With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine; at 100℃; for 12h;Inert atmosphere;	6-Bromo-5-fluoropicolinic acid (2000 mg, 9.09 mmol) was dissolved in t-BuOH (60 mL). Then DPPA (2576.9 mg, 9.36 mmol) and DIEA (1292.5 mg, 10.00 mmol) were added. The reaction mixture was stirred at 100 C. for 12 h under N2. The solvent was concentrated. The residue was purified by flash column chromatography over silica gel (gradient eluent: EtOAc/petrol ether from 1/20 to 1/5). The product fractions were collected and the solvent was concentrated to give the desired product as a colorless gum (1.6 g, yield: 60.5%). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.50 (s, 9H), 7.21 (br s, 1H), 7.39 (dd, J=6.9, 8.9 Hz, 1H), 7.88 (dd, J=3.1, 8.8 Hz, 1H).
59%	With diphenyl phosphoryl azide; triethylamine; In tert-butyl alcohol; at 85℃; for 2h;	Step 1 (6-Bromo-5-fluoro-pyridin-2-yl)-carbamic acid tert-butyl ester To a solution of <strong>[1052714-46-1]6-bromo-5-fluoro-2-picolinic acid</strong> (2 g, 9.09 mmol) in tert-butanol (46 mL) and triethylamine (1.27 mL, 9.09 mmol, Eq: 1.00) was added DPPA (1.97 mL, 9.09 mmol). The slurry was stirred at room temperature until all solids dissolved (?15 min), after which it was heated to 85 C. for 2 h. Upon cooling the mixture was concentrated onto silica gel and chromatographed (silica, 5% to 30% EtOAc in hexanes) to give slightly impure (6-bromo-5-fluoro-pyridin-2-yl)-carbamic acid tert-butyl ester (1.55 g, 59%). 1H NMR (400 MHz, CHLOROFORM-d6) delta ppm 7.97 (d, J=8.6 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 1.53 (s, 9H).

59%

With diphenyl phosphoryl azide; triethylamine; at 20 - 85℃; for 2.25h;

Step 1 (6-Bromo-5-fluoro-pyridin-2-yl)-carbamic acid tert-butyl ester To a solution of <strong>[1052714-46-1]6-bromo-5-fluoro-2-picolinic acid</strong> (2 g, 9.09 mmol) in tert-butanol (46 mL) and triethylamine (1.27 mL, 9.09 mmol, Eq: 1.00) was added DPPA (1.97 mL, 9.09 mmol). The slurry was stirred at room temperature until all solids dissolved (-15 min), after which it was heated to 85 C for 2 h. Upon cooling, the mixture was concentrated, adsorbed onto silica gel and purified by chromatography (silica, 5% to 30 % EtOAc in hexanes) to give (6-bromo-5- fluoro-pyridin-2-yl)-carbamic acid tert-butyl ester (1.55 g, 59 %). 1H NMR (400 MHz, CHLOROFORM-^) delta ppm 7.97 (d, J=8.6 Hz, 1 H), 7.43 (d, J=8.6 Hz, 1 H), 1.53 (s, 9 H).

Reference： [1]Patent: WO2019/241131,2019,A1 .Location in patent: Paragraph 00402
[2]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 2084; 2085
[3]Patent: US2013/178478,2013,A1 .Location in patent: Paragraph 0493; 0494
[4]Journal of Medicinal Chemistry,2014,vol. 57,p. 2683 - 2691
[5]Patent: WO2014/60371,2014,A1 .Location in patent: Page/Page column 97

59
[ 1052714-46-1 ]
[ 1586044-92-9 ]
[ 1586044-96-3 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 95 tert-Butyl N-[(3R,4R,7S)-7-[4-[(6-bromo-5-fluoro-pyridine-2-carbonyl)amino]-2-methyl-pyrazol-3-yl]-3-methoxy-oxepan-4-yl]carbamate Following the procedure for Example 65, starting from tert-butyl N-[(3R,4R,7S)-3-methoxy-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate (intermediate 93) and replacing 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid with <strong>[1052714-46-1]6-bromo-5-fluoro-pyridine-2-carboxylic acid</strong> (see US2010/56576 A1) gave tert-butyl N-[(3R,4R,7S)-7-[4-[(6-bromo-5-fluoro-pyridine-2-carbonyl)amino]-2-methyl-pyrazol-3-yl]-3-methoxy-oxepan-4-yl]carbamate (contaminated with tetramethylurea) as a clear oil (169 mg, 30% over two steps). 1H NMR (400 MHz, CDCl3) delta 10.37 (s, 1H), 8.26-8.17 (m, 2H), 7.63-7.55 (m, 1H), 5.02 (br s, 1H), 4.96 (dd, J=9.0, 3.6 Hz, 1H), 4.32 (dd, J=13.2, 4.4 Hz, 1H), 4.05-3.94 (m, 2H), 3.85-3.80 (m, 1H), 3.78 (s, 3H), 3.47 (s, 3H), 2.10-1.91 (m, 3H), 1.86-1.78 (m, 1H), 1.45 (s, 9H).

Reference： [1]Patent: US2014/88117,2014,A1 .Location in patent: Page/Page column

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[ 1052714-46-1 ]
[ 1586040-63-2 ]

Reference： [1]Patent: US2014/88117,2014,A1

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[ 1052714-46-1 ]
N-(5-((2S,5R,6S)-5-amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2,5-difluorophenyl)-5-fluoropicolinamide [ No CAS ]

Reference： [1]Patent: US2014/88117,2014,A1

62
[ 1052714-46-1 ]
[ 1586040-59-6 ]

Reference： [1]Patent: US2014/88117,2014,A1

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[ 1052714-46-1 ]
[ 1586040-62-1 ]

Reference： [1]Patent: US2014/88117,2014,A1

64
[ 1052714-46-1 ]
[ 1586044-66-7 ]
[ 1586045-12-6 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 103 tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate Following the procedure for Example 65, starting from tert-butyl N-[(3S,4R,7S)-3-fluoro-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate (intermediate 80) and replacing 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid with <strong>[1052714-46-1]6-bromo-5-fluoro-pyridine-2-carboxylic acid</strong> (see US2010/56576 A1) gave tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate.

Reference： [1]Patent: US2014/88117,2014,A1 .Location in patent: Page/Page column

65
[ 1052714-46-1 ]
[ 1355011-39-0 ]

Reference： [1]Patent: WO2014/33631,2014,A1

66
[ 1052714-46-1 ]
[ 1395282-15-1 ]

Reference： [1]Patent: WO2014/33631,2014,A1

67
[ 1052714-46-1 ]
[ 1355011-30-1 ]

Reference： [1]Patent: WO2014/33631,2014,A1

68
[ 1052714-46-1 ]
[ 1355011-31-2 ]

Reference： [1]Patent: WO2014/33631,2014,A1

69
[ 1052714-46-1 ]
[ 126726-62-3 ]
[ 1446793-51-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2683 - 2691

70
[ 1052714-46-1 ]
[ 1569897-43-3 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2683 - 2691
[2]Patent: WO2014/60371,2014,A1

71
[ 1052714-46-1 ]
C₂₈H₃₁F₂N₅O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

72
[ 1052714-46-1 ]
N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-6-(2-fluorophenyl)picolinamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

73
[ 1052714-46-1 ]
N-(4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-yl)-5-fluoro-6-(2-fluorophenyl)picolinamide trifluoroacetate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

74
[ 1052714-46-1 ]
N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-6-(2-fluorophenyl)picolinamide trifluoroacetate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

75
[ 1052714-46-1 ]
[ 1242145-43-2 ]
ethyl 2-ethoxy-4-(3-fluoro-6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: WO2017/6295,2017,A1

76
[ 1052714-46-1 ]
[ 1242145-43-2 ]
6-(3-ethoxy-4-(ethoxycarbonyl) phenyl)-5-fluoropicolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 18h;Inert atmosphere;	To a solution of ethyl 2-ethoxy-4-(4,4, 5, 5-tetramethyl- 1, 3,2-dioxaborolan-2- yl)benzoate (439 mg, 1.37 mmol) and <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (302 mg, 1.37 mmol) in 1,4-dioxane (6.9 ml) was added a solution of sodium carbonate (436 mg, 4.11 mmol) in water (2 ml). The reaction was purged with nitrogen and PdCI2(dppf)-CH2CI2 adduct (112 mg, 0.14 mmol) was added and the reaction then heated at 80 00 for 18 hours. The reactionwas then cooled to room temperature and concentrated. The residue was partitioned between water and EtOAc and the aqueous phase acidified. The layers were separated, and the aqueous phase was extracted with further EtOAc (3 x 20 ml). The combined organic extracts were dried over Mg504, filtered, and concentrated to give the title compound as an orange solid (129 mg, 28 % yield). MS (mlz) 334.0 (M+H).

Reference： [1]Patent: WO2017/6295,2017,A1 .Location in patent: Page/Page column 96

77
[ 1052714-46-1 ]
(9H-fluoren-9-yl)methyl (aminomethyl)carbamate trifluoroacetic acid salt [ No CAS ]
(9H-fluoren-9-yl)methyl (aminomethyl)carbamate hydrochloride [ No CAS ]
(9H-fluoren-9-yl)methyl ((6-bromo-5-fluoropicolinamido)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;	A solution of (9H-fluoren-9-yl)methyl (am inomethyl)carbamate trifluoroacetic acid salt (0.49 g, 1.28 mmol), (9H-fluoren-9-yl)methyl (aminomethyl)carbamate hydrochloride (0.6 g, 1.97 mmol), <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (0.74 g, 3.38 mmol), HATU (1.54 g, 4.05 mmol) and DIPEA (1.77 ml, 10.1 mmol) in DMF (15.1 ml) was stirred at room temperature for2hours. Water was then added and the reaction placed in a refrigerator overnight. The reaction was then allowed to warm to room temperature and the solid was collected by filtration, washed with water and air dried to give the title compound as a grey solid (1.23 g, 77 % yield). MS (mlz) 472.1 (M+2).

Reference： [1]Patent: WO2017/6295,2017,A1 .Location in patent: Page/Page column 106

78
[ 1052714-46-1 ]
(9H-fluoren-9-yl)methyl ((5-fluoro-6-phenylpicolinamido)methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2017/6295,2017,A1

79
[ 1052714-46-1 ]
N-(aminomethyl)-5-fluoro-6-phenylpicolinamide [ No CAS ]

Reference： [1]Patent: WO2017/6295,2017,A1

80
[ 1052714-46-1 ]
(3-ethyl-8-fluoroindolizin-5-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol [ No CAS ]

Reference： [1]Patent: WO2017/194716,2017,A1

81
[ 1052714-46-1 ]
3-ethyl-8-fluoroindolizine-5-carbaldehyde [ No CAS ]

Reference： [1]Patent: WO2017/194716,2017,A1

82
[ 1052714-46-1 ]
(3-ethyl-8-fluoroindolizin-5-yl)methanol [ No CAS ]

Reference： [1]Patent: WO2017/194716,2017,A1

83
[ 1052714-46-1 ]
ethyl 5-fluoro-6-pent-1-ynyl-pyridine-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/194716,2017,A1

84
[ 1052714-46-1 ]
ethyl 3-ethyl-8-fluoroindolizine-5-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/194716,2017,A1

85
[ 1052714-46-1 ]
(3-chloro-8-fluoro-indolizin-5-yl)-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methanol [ No CAS ]

Reference： [1]Patent: WO2017/194716,2017,A1

86
[ 1052714-46-1 ]
3-chloro-8-fluoro-indolizine-5-carbaldehyde [ No CAS ]

Reference： [1]Patent: WO2017/194716,2017,A1

87
[ 1052714-46-1 ]
(3-chloro-8-fluoro-indolizin-5-yl)methanol [ No CAS ]

Reference： [1]Patent: WO2017/194716,2017,A1

88
[ 1052714-46-1 ]
ethyl 3-chloro-8-fluoro-indolizine-5-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/194716,2017,A1

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1052714-46-1 ] {[proInfo.proName]}

Quality Control of [ 1052714-46-1 ]

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Product Details of [ 1052714-46-1 ]

Calculated chemistry of [ 1052714-46-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1052714-46-1 ]

Application In Synthesis of [ 1052714-46-1 ]

[ 1052714-46-1 ] Synthesis Path-Upstream 1~3

[ 1052714-46-1 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 1052714-46-1 ]

Fluorinated Building Blocks

Bromides

Carboxylic Acids

Related Parent Nucleus of [ 1052714-46-1 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1052714-46-1 ]

Related Parent Nucleus of
[ 1052714-46-1 ]