[ CAS No. 884495-37-8 ] {[proInfo.proName]}

Name: 884495-37-8|2-Chloro-5-fluoropyridin-3-amine|98%
Brand: Ambeed
SKU: A138340
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Quality Control of [ 884495-37-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 884495-37-8 ]

Product Details of [ 884495-37-8 ]

CAS No. :	884495-37-8	MDL No. :	MFCD08277275
Formula :	C₅H₄ClFN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MSCZFRUXABFTJN-UHFFFAOYSA-N
M.W :	146.55	Pubchem ID :	44754868
Synonyms :

Calculated chemistry of [ 884495-37-8 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.61
TPSA :	38.91 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) :	-6.32 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.33
Log Po/w (XLOGP3) :	1.23
Log Po/w (WLOGP) :	1.88
Log Po/w (MLOGP) :	0.85
Log Po/w (SILICOS-IT) :	1.77
Consensus Log Po/w :	1.41

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.02
Solubility :	1.41 mg/ml ; 0.00962 mol/l
Class :	Soluble
Log S (Ali) :	-1.64
Solubility :	3.32 mg/ml ; 0.0227 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.54
Solubility :	0.424 mg/ml ; 0.00289 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.76

Safety of [ 884495-37-8 ]

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 [ 884495-37-8 ]

* 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 [ 884495-37-8 ]
Downstream synthetic route of [ 884495-37-8 ]

[ 884495-37-8 ] Synthesis Path-Upstream 1~8

1
[ 884495-37-8 ]
[ 21717-96-4 ]

Reference： [1] Patent: CN107827887, 2018, A,

2
[ 884495-37-8 ]
[ 136888-21-6 ]

Yield	Reaction Conditions	Operation in experiment
65 g	With ethylenediaminetetraacetic acid; dihydrogen peroxide; potassium carbonate In water; acetonitrile at 20℃; for 1 h;	In a high-pressure reactor, 85 g (0.5 mol) of 2,3-dichloro-5-fluoropyridine was added to 200 mL of ammonia water.Set the temperature to 180 °C, high pressure reaction 24h,TLC detects the reaction of the raw material completely.The solvent was evaporated to give 2-chloro-5-fluoro-3-aminopyridine 65 g;2-chloro-5-fluoro-3-aminopyridine 65 g (0.45 mol)Placed in 900 mL round bottom flask in acetonitrile,Aqueous buffer solution 450mL (0.6M K2CO3-4x10-4M EDTA disodium salt) was added successively,Acetonitrile 350mL (3mol) and 30percent H2O2 in water290mL (3mol),The reaction mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate (3 x 300 mL).Combine organic layers,Dry with anhydrous Na2SO4,Remove the solvent under vacuum to obtain the product of sufficient purity 2-chloro-5-fluoro-3-nitropyridine65g;To a solution of 2-chloro-5-fluoro-3-nitropyridine 65 g (0.35 mol) in DMSO/H2O (9:1, 3500 mL) was added L-Proline 230g (2mol),Na2CO3 210g (2mol),NaN3 230g (3.5mol),Sodium ascorbate 350g (1.75mol) andCuSO4·5H2O500g (2 mol);The mixture was stirred in an oil bath at 70 °C for 24 hours.Then pour the mixture into 10,000 mL of ice water.The solid product was filtered and crystallized to obtain 47 g of 2-amino-5-fluoro-3-nitropyridine.Suggest an editExample 1See also1
65 g	With dihydrogen peroxide In water; acetonitrile at 20℃; for 1 h;	In a high-pressure reaction vessel, 2,3-dichloro-5-fluoropyridine 85g (0.5 mol) was added to 200 mL of ammonia water, and the temperature was set at 180° C., and the reaction under high pressure was performed for 24 h. The reaction of the starting material was complete by TLC, and the solvent was swirled to obtain 2- Chloro-5-fluoro-3-aminopyridine 65g;Place 2-chloro-5-fluoro-3-aminopyridine 65 g (0.45 mol) in a 900 mL round-bottomed flask in acetonitrile, and add 450 mL of water buffer solution (0.6 M K2CO3-4×10-4 M EDTA disodium salt). 350 mL (3 mol) of acetonitrile and 290 mL (3 mol) of a 30percent H2O2 aqueous solution, and the reaction mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate (3 x 300 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solvent was removed to give a sufficiently pure product, 2-chloro-5-fluoro-3-nitropyridine, 65 g;To a solution of 65 g (0.35 mol) of 2-chloro-5-fluoro-3-nitropyridine in DMSO/H2O (mass ratio 9:1, 3500 mL) was added L-proline 230 g (2 mol), Na2CO3 210 g (2 mol), NaN3 230 g (3.5 mol), sodium ascorbate 350 g (1.75 mol) and CuSO4.5H2O 500 g (2 mol); the mixture was stirred in an oil bath at 70C for 24 hours, and then the mixture was poured into 5000 mL of ice water to give a solid product. Filter and crystallize to obtain 47g of 2-amino-5-fluoro-3-nitropyridine; add 2-amino-5-fluoro-3-nitropyridine to the aqueous solution of sulfuric acid, add a certain amount of chloroacetic acid, and heat to 120°C. After TLC monitored the reaction of the raw materials, the reaction mixture was extracted with methylene chloride. The pH of the organic phase was adjusted to 7-8 with a saturated sodium carbonate solution, and the organic phase was concentrated to obtain 2-amino-5-fluoro-pyridine.

Reference： [1] Patent: CN107903266, 2018, A, . Location in patent: Paragraph 0026; 0027
[2] Patent: CN107827887, 2018, A, . Location in patent: Paragraph 0027; 0028

3
[ 884495-37-8 ]
[ 212268-13-8 ]

Reference： [1] Patent: US2013/184240, 2013, A1,

4
[ 884495-37-8 ]
[ 212268-12-7 ]

Reference： [1] Patent: CN107903266, 2018, A,
[2] Patent: CN107827887, 2018, A,

5
[ 75302-64-6 ]
[ 884495-37-8 ]

Reference： [1] Patent: EP2022793, 2009, A1, . Location in patent: Page/Page column 94
[2] Patent: EP2221309, 2010, A1, . Location in patent: Page/Page column 15
[3] Patent: EP2022793, 2009, A1, . Location in patent: Page/Page column 94

6
[ 1394899-03-6 ]
[ 884495-37-8 ]

Reference： [1] Patent: US2013/225552, 2013, A1, . Location in patent: Paragraph 0573

7
[ 136888-21-6 ]
[ 884495-37-8 ]

Reference： [1] Patent: EP2394987, 2011, A1, . Location in patent: Page/Page column 10

8
[ 38186-88-8 ]
[ 884495-37-8 ]

Reference： [1] Patent: US2013/225552, 2013, A1,

[ 884495-37-8 ] Synthesis Path-Downstream 1~88

1
[ 884495-37-8 ]
[ 920-46-7 ]
[ 959617-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 0 - 20℃; for 0.5h;	To a solution of 1.2 g of <strong>[884495-37-8]2-chloro-5-fluoropyridin-3-amine</strong> in 5 mL of pyridine, 0.86 mL of 2-methylacryloyl chloride was added under cooling with ice, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate = 100:0 to 50:50 to obtain 1.1 g of N-(2-chloro-5-fluoropyridin-3-yl)-2-methylacrylamide as a colorless oily substance. 1H-NMR (CDCl3) delta: 2.11 (3H, dd, J = 1.5, 1.0 Hz), 5.60-5.63 (1H, m), 5.93-5.96 (1H, m), 7.99-8.02 (1H, m), 8.15 (1H, s), 8.72 (1H, dd, J = 9.9, 2.8 Hz)

Reference： [1]Patent: EP2022793,2009,A1 .Location in patent: Page/Page column 94-95

2
[ 141-32-2 ]
[ 884495-37-8 ]
[ 959616-86-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; triphenylphosphine;palladium diacetate; In acetic acid butyl ester; at 30℃;Reflux; Inert atmosphere;	Example 3 A mixed solution of 150 mL of butyl acetate and 73 mL of butyl acrylate was refluxed with heating for 45 minutes under a nitrogen atmosphere. The reaction mixture was cooled to 30C, 50.0 g of 2-chloro-5-fluoropyridine-3-amine, 3.8 g of palladium (II) acetate, 44.8 g of triphenylphosphine and 36.6 g of sodium carbonate were added thereto, and the mixture was refluxed for 13 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 150 mL of water and 700 mL of butyl acetate were added thereto, and the mixture was stirred for 1 hour. Insoluble matter was filtered out, and the filter residue was washed using 50 mL of butyl acetate. The filtrate and the wash liquid were combined, the organic layer was separated, and 800 mL of the solvent was evaporated under reduced pressure. To the obtained residue, 300 mL of cyclohexane and 30 mL of toluene were added dropwise, the mixture was cooled to 5C, and the solid product was obtained by filtration and washed using a mixed solution of toluene-cyclohexane (1:2) and toluene to give 57.8 g of butyl (2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate as a yellow solid. 1H-NMR(CDCl3)delta value: 0.96(3H,t,J=7.3Hz),1.38-1.48(2H,m),1.64-1.72(2H,m),4.10(2H,brs),4.21(2H,t,J=6.6Hz),6.72(1H,dd,J=9.8,2.3Hz),6.86(1H,d,J=15.1Hz),7.7 1(1H,d,J=15.1Hz),7.94(1H,d,J=2.3Hz)
		To a solution of 150 g of <strong>[884495-37-8]2-chloro-5-fluoropyridin-3-amine</strong> in 600 mL of N,N-dimethylformamide, 190 mL of butyl acrylate and 287 mL of triethylamine were added under a nitrogen flow, and the mixture was stirred at 110C for 2 hours. The reaction mixture was cooled to 58C, thereto were added 13.1 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred at 110 to 120C for 40 minutes. The reaction mixture was cooled to 57C, 13.1 g of bis(tri-tert-butylphosphine)palladium(0) was added thereto, and the mixture was stirred at 110 to 120C for 3 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The insoluble substance was filtered off, the organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Cyclohexane and ethyl acetate were added to the resultant residue, and the solid was filtered off to obtain 200 g of butyl (2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate as a light brown solid. 1H-NMR (CDCl3) delta: 0.95 (3H, t, J = 7.3 Hz), 1.38-1.48 (2H, m), 1.64-1.72 (2H, m), 4.13 (2H, s), 4.21 (2H, t, J = 6.7 Hz), 6.71 (1H, dd, J = 9.8, 2.3 Hz), 6.86 (1H, d, J = 15.3 Hz), 7.72 (1H, d, J = 15.3 Hz), 7.94 (1H, d, J = 2.3 Hz)

Reference： [1]Patent: EP2221309,2010,A1 .Location in patent: Page/Page column 16
[2]Patent: EP2022793,2009,A1 .Location in patent: Page/Page column 80

3
[ 75302-64-6 ]
[ 884495-37-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hypochlorite; sodium hydroxide; In water; at 20 - 45℃;	Example 1 To a solution of 0.11 kg of sodium hydroxide in 1000 mL of water, 1.4 kg of a 12% sodium hypochlorite aqueous solution and 0.40 kg of 2-chloro-5-fluoronicotinamide were added, and the mixture was stirred for 2 hours and 30 minutes at room temperature. The reaction mixture was heated to 45C and stirred for 4 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 6 mol/L hydrochloric acid were added thereto. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, anhydrous magnesium sulfate and activated carbon were added thereto, and the mixture was stirred for 30 minutes at room temperature. Insoluble matter was filtered out and the solvent was evaporated under reduced pressure to give 0.29 kg of 2-chloro-5-fluoropyridin-3-amine as a brown solid. 1H-NMR(CDCl3)delta value: 4.22(2H,s),6.79(1H,dd,J=9.3,2.7Hz),7.67(1H,d,J=2.7Hz)
	With sodium hydroxide; sodium hypochlorite; In water; at 20 - 45℃; for 6.5h;	To a solution of 0.11 kg of sodium hydroxide in 1000 mL of water, 1.4 kg of a 12% aqueous sodium hypochlorite solution and 0.40 kg of 2-chloro-5-fluoronicotinamide were added, and the mixture was stirred at room temperature for 2 hours 30 minutes. The reaction mixture was heated to 45C and stirred for 4 hours. The reaction mixture was cooled to room temperature, and thereto were added ethyl acetate and a 6 mol/L aqueous hydrochloric acid solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, anhydrous magnesium sulfate and active carbon were added thereto, and the mixture was stirred at room temperature for 30 minutes. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 0.29 kg of 2-chloro-5-fluoropyridin-3-amine as a brown solid. 1H-NMR (CDCl3) delta: 4.22 (2H, s), 6.79 (1H, dd, J = 9.3, 2.7 Hz), 7.67 (1H, d, J = 2.7 Hz)

Reference： [1]Patent: EP2221309,2010,A1 .Location in patent: Page/Page column 15
[2]Patent: EP2022793,2009,A1 .Location in patent: Page/Page column 94

4
[ 884495-37-8 ]
[ 375853-82-0 ]
[ 1196698-25-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; for 1h;Reflux;	A degassed solution of <strong>[884495-37-8]2-chloro-5-fluoro-3-amino-pyridine</strong> (3.5 g), 4- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2/f-pyridine-l-carboxylic acid tert-butyl ester (8.89 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)palladium(II) chloride (0.84 g) in dioxane (157 ml) was treated with a degassed solution of sodium carbonate (7.6 g) in water (72 ml). The reaction mixture was stirred at reflux for 1 hour, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane / ethyl acetate 8:2) afforded 3-amino-5-fluoro-3',6'-dihydro-2'H-[2,4']bipyridinyl-r-carboxylic acid tert-hutyl ester (4.6 g) as a solid. MS (ES+) 294 (MEta+), 238 (M-isoprene); IH NMR (400 MHz, CDCl3) 1.48 (s, 9H), 2.53 (m, 2H), 3.64 (t, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 5.99 (m, IH), 6.70 (dd, IH), 7.85 (d, IH).
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; for 1h;Reflux;	Step A: A degassed solution of <strong>[884495-37-8]2-chloro-5-fluoro-3-amino-pyridine</strong> (3.5 g), 4- (4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2//-pyridine-l -carboxylic acid tert-butyl ester (8.89 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)palladium(II) chloride (0.84 g) in dioxane (157 ml) was treated with a degassed solution of sodium carbonate (7.6 g) in water (72 ml). The reaction mixture was stirred at reflux for 1 hour, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was diluted with ethyl acetate, washed with water then brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane / ethyl acetate 8:2) afforded 3-amino-5-fluoro-31,6'-dihydro-2'//-[2,4']bipyridinyl-lt- carboxylic acid tert-butyl ester (4.6 g) as a solid. MS (ES+) 294 (MH+), 238 (M-isoprene); IH NMR (400 MHz, CDCl3) 1.48 (s, 9H), 2.53 (m, 2H), 3.64 (t, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 5.99 (m, IH), 6.70 (dd, IH), 7.85 (d, IH).

Reference： [1]Patent: WO2010/9968,2010,A1 .Location in patent: Page/Page column 33-34
[2]Patent: WO2009/138219,2009,A2 .Location in patent: Page/Page column 23

5
[ 141-32-2 ]
[ 884495-37-8 ]
[ 1159266-52-0 ]

Yield	Reaction Conditions	Operation in experiment
	With formic acid; N-ethyl-N,N-diisopropylamine; johnphos;(bis(tricyclohexyl)phosphine)palladium(II) dichloride; at 20 - 100℃;Reflux;	Example 2 To a suspension of 25.0 g of <strong>[884495-37-8]2-chloro-5-fluoropyridin-3-amine</strong>, 3.8 g of bis(tricyclohexyl phosphine)palladium (II) chloride and 1.5 g of 2-(di-tert-butylphosphino)biphenyl in 75 mL of butyl acrylate, 44.1 g of diisopropylethylamine was added,, 15.7 g of formic acid was added dropwise thereto at room temperature, and the mixture was refluxed for 3 hours. To the reaction mixture, 32.1 g of diisopropylethylamine and 11.5 g of formic acid were added at 100C, and the mixture was refluxed for 5 hours. The reaction mixture was cooled to 80C, 50 mL of toluene and 75 mL of water were added thereto and the resultant mixture was cooled to room temperature. The solid product was obtained by filtration, and washed using in the order of toluene and water to give 18.0 g of 7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a white solid. 1H-NMR(DMSO-d6)delta value: 2.60(2H,t,J=7.7Hz),3.00(2H,t,J=7.7Hz),7.03(1H,dd,J=9.8,2.7Hz),8.07(1H,d,J=2.7Hz),10.3(1H,br s)

Reference： [1]Patent: EP2221309,2010,A1 .Location in patent: Page/Page column 16

6
[ 141-32-2 ]
[ 884495-37-8 ]
[ 1159266-53-1 ]

Reference： [1]Organic Letters,2010,vol. 12,p. 3422 - 3425

7
[ 884495-37-8 ]
2,3-dichloro-5-fluoropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite;copper(l) chloride; In water; at 5 - 20℃; for 2.16667h;	Preparation Example 15 A mixture of sodium nitrite (1.5 g) and water (4 mL) was added dropwise to a mixture of <strong>[884495-37-8]2-chloro-5-fluoropyridin-3-amine</strong> (2 g) and concentrated hydrochloric acid (30 mL) at below 5C, followed by stirring at the same temperature for 10 minutes. A mixture of copper (I) chloride (1.35 g) and concentrated hydrochloric acid (10 mL) was further added at the same temperature to the reaction mixture, followed by stirring at room temperature for 2 hours. The reaction mixture was neutralized and diluted with ethyl acetate and the insoluble matter was separated by filtration. The filtrate was subjected to liquid separation and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 2,3-dichloro-5-fluoropyridine (1.0 g).

Reference： [1]Patent: EP2394987,2011,A1 .Location in patent: Page/Page column 11

8
[ 884495-37-8 ]
[ 212268-13-8 ]

Reference： [1]Patent: US2013/184240,2013,A1

9
[ 884495-37-8 ]
[ 1364719-75-4 ]

Reference： [1]Patent: US2013/184240,2013,A1

10
[ 884495-37-8 ]
[ 100-46-9 ]
[ 1364719-53-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 7h;Reflux;	Example 13 To a solution of <strong>[884495-37-8]2-chloro-5-fluoro-3-nitropyridine</strong> 36 (1.378 g, 7.81 mmol) in THF (10 ml) were successively added DIPEA (4.09 ml, 23.42 mmol) and benzylamine (1.71 ml, 15.61 mmol), and the reaction mixture was stirred under heating to reflux for 7 hours. The reaction mixture was allowed to cool to room temperature, and 20 ml of distilled water was added thereto, followed by extraction three times with 20 ml of ethyl acetate and drying over sodium sulfate. The solvent was removed under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane/EtOAc=10:1) to obtain Compound 37 as a mixture with benzylamine.Compound 37; 1H-NMR (DMSO-d6) delta: 4.78 (d, J=6.08 Hz, 2H), 7.20-7.35 (m, 5H), 8.41 (dd, J=8.36, 2.79 Hz, 1H), 8.58 (d, J=2.79 Hz, 1H), 8.90 (t, J=6.08 Hz, 1H).

Reference： [1]Patent: US2013/184240,2013,A1 .Location in patent: Paragraph 0710; 0711; 0713

11
[ 884495-37-8 ]
[ 100-46-9 ]
[ 1364719-61-8 ]

Reference： [1]Patent: US2013/184240,2013,A1

12
[ 38186-88-8 ]
[ 884495-37-8 ]

Reference： [1]Patent: US2013/225552,2013,A1

13
[ 1394899-03-6 ]
[ 884495-37-8 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In dichloromethane; at 45℃; for 1h;	Tert-butyl (2-chloro-5-fluoropyridin-3-yl)carbamate (Intermediate 36) (0.500 g, 2.027 mmol) was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (0.5 mL). The mixture was stirred at 45 C. for 1 hour then cooled to room temperature. The solution was evaporated to dryness under reduced pressure and the crude amine partitioned between 50% saturated sodium bicarbonate (80 mL) and ethyl acetate (60 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The solid amine intermediate was combined with anhydrous cupric acetate (0.375 g, 2.065 mmol), sodium carbonate (1.00 g, 9.43 mmol), 2,2?-bipyridyl (0.325 g, 2.081 mmol) and cyclopropylboronic acid (0.305 g, 3.55 mmol). 1,2-Dichloroethane (5 mL) was added and the mixture heated at 70 C. in air. After 2 hours, the mixture was cooled and diluted with ethyl acetate (300 mL). It was washed with a mixture of saturated ammonium chloride (50 mL), water (100 mL), and ammonium hydroxide (20 mL) before drying with magnesium sulfate and evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave 2-chloro-N-cyclopropyl-5-fluoropyridin-3-amine (0.270 g, 1.447 mmol, 71.4% yield).

Reference： [1]Patent: US2013/225552,2013,A1 .Location in patent: Paragraph 0573

14
[ 884495-37-8 ]
[ 1452561-11-3 ]

Reference： [1]Patent: US2013/225552,2013,A1

15
[ 884495-37-8 ]
[ 1452552-40-7 ]

Reference： [1]Patent: US2013/225552,2013,A1

16
[ 884495-37-8 ]
[ 411235-57-9 ]
[ 1452560-54-1 ]