[ CAS No. 847729-27-5 ] {[proInfo.proName]}

Name: 847729-27-5|Methyl 2-chloro-5-fluoronicotinate|97%
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SKU: A144221
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Quality Control of [ 847729-27-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 847729-27-5 ]

Product Details of [ 847729-27-5 ]

CAS No. :	847729-27-5	MDL No. :	MFCD09763661
Formula :	C₇H₅ClFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VYUNQTNDEVFXPO-UHFFFAOYSA-N
M.W :	189.57	Pubchem ID :	24229209
Synonyms :

Calculated chemistry of [ 847729-27-5 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.48
TPSA :	39.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.2 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.92
Log Po/w (XLOGP3) :	1.77
Log Po/w (WLOGP) :	2.08
Log Po/w (MLOGP) :	1.36
Log Po/w (SILICOS-IT) :	2.27
Consensus Log Po/w :	1.88

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.37
Solubility :	0.812 mg/ml ; 0.00428 mol/l
Class :	Soluble
Log S (Ali) :	-2.21
Solubility :	1.17 mg/ml ; 0.00615 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.0
Solubility :	0.19 mg/ml ; 0.001 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.8

Safety of [ 847729-27-5 ]

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 [ 847729-27-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 847729-27-5 ]
Downstream synthetic route of [ 847729-27-5 ]

[ 847729-27-5 ] Synthesis Path-Upstream 1~3

1
[ 38186-88-8 ]
[ 74-88-4 ]
[ 847729-27-5 ]

Reference： [1] Patent: WO2008/76425, 2008, A1, . Location in patent: Page/Page column 82

2
[ 38186-88-8 ]
[ 18107-18-1 ]
[ 847729-27-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	at 0℃; for 1 h;	EXAMPLE 58 4- ( (F 5-FLUORO-2- (4-FLUOROBENZYL) PYRIDIN-3- YL1CARBONYL} AMINO) METHYL1BENZOIC ACID STEP 1. Methyl 5-FLUORO-2- (4-FLUOROBENZYL) nicotinate; 2-Chloro-5-fluoronicotinic acid (1.00 g, 5.70 mmol) was treated with 2 M solution of (Trimethylsilyl) DIAZOMETHANE in hexane (5.70 mL, 11.4 mmol), methanol (4 mL), and dichloromethane (14 mL) at 0 °C for 1 h. The mixture was quenched with acetic acid and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 0.78 g (72percent) of the title compounds as colorless oil : IH-NMR (CDC13) 6 8.41 (1H, d, J = 3. 1 HZ), 7.93 (1H, dd, J = 7. 6,3. 1 HZ), 3.98 (3H, s).
72%	at 0℃; for 1 h;	2-Chloro-5-fluoronicotinic acid (EP 634413, 1.00 g, 5.70 mmol) was treated with 2 M solution of (Trimethylsilyl)diazomethane in hexane (5.70 mL, 11.4 mmol), methanol (4 mL), and dichloromethane (14 mL) at 0 °C for 1 h. The mixture was quenched with acetic acid and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 0.78 g (72percent) of the title compounds as colorless oil: ¹H-NM R (CDCl3) No. 8.41 (1 H, d, J=3.1 Hz), 7.93 (1 H, dd, J=7.6, 3.1 Hz), 3.98 (3H, s).

Reference： [1] Patent: WO2005/21508, 2005, A1, . Location in patent: Page/Page column 97
[2] Patent: WO2005/102389, 2005, A2, . Location in patent: Page/Page column 142-143

3
[ 67-56-1 ]
[ 38186-88-8 ]
[ 847729-27-5 ]

Yield	Reaction Conditions	Operation in experiment
25%	for 30 h; Heating / reflux	To' a solution of 2-chloro-5-fluoronicotinic acid (5.2 g, 30 mmol) in methanol (20 ml) was added conc. sulfuric acid (0.5 ml) and the reaction mixture was stirred at reflux for 30 hours. The reaction mixture was cooled to 0 °C and 0.5 N sodium hydroxide solution was added to the mixture. The whole was extracted with diethylether. The organic phase was washed with brine, dried (sodium sulfate), and concentrated to afford 3.2 g (25percent) of the title compound: ¹H-NMR (CDCl3) 8 8.41 (1 H, d, J = 3.0 Hz), 7.93 (1 H, dd, J = 3.0,7.6 Hz), 3.98 (3H, s).

Reference： [1] Patent: WO2005/102389, 2005, A2, . Location in patent: Page/Page column 200
[2] Patent: WO2005/105732, 2005, A1, . Location in patent: Page/Page column 53

[ 847729-27-5 ] Synthesis Path-Downstream 1~25

1
[ 847729-27-5 ]
[ 3731-51-9 ]
5-fluoro-2-[(pyridin-2-ylmethyl)-amino]-nicotinic acid methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1191 - 1196

2
[ 847729-27-5 ]
[ 13061-96-6 ]
methyl 5-fluoro-2-(4-fluorobenzyl)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; for 20h;Product distribution / selectivity;	A mixture of <strong>[847729-27-5]methyl 2-chloro-5-fluoronicotinate</strong> (step 1,1.5 g, 7.91 mmol), tetrakis (triphenylphoshine)palladium (914 mg, 0.79 mmol), methyboronic acid (521 mg, 8.70 mmol) and potassium carbonate (3.28 g, 23.7 mmol) in 1,4- dioxane (20 ml) was heated at 110 C for 20 h under nitrogen atmosphere. The reaction mixture was filtered through a pad of celite (Celite(trademark) (diatomaceous earth) ) and the filtrate was concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20/(at) to 4/1 ) to afford 936 mg (64%) of the title compound: ¹H-NMR (CDCl3) 8 8.49 (1H, d, J = 3.0 Hz), 7.93 (1H, dd, J = 3.0, 8.7 Hz), 3.94

Reference： [1]Patent: WO2005/102389,2005,A2 .Location in patent: Page/Page column 200

3
[ 847729-27-5 ]
5-fluoro-2-[(pyridin-2-ylmethyl)-amino]-nicotinic acid hydrazide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1191 - 1196

4
[ 847729-27-5 ]
(2,3-dihydrobenzo[1,4]dioxin-6-yl)-{5-[5-fluoro-2-(pyridin-2-ylmethoxy)-pyridin-3-yl]-[1,3,4]oxadiazol-2-yl}amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1191 - 1196

5
[ 847729-27-5 ]
C₂₁H₁₉FN₆O₃S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1191 - 1196

6
[ 38186-88-8 ]
[ 18107-18-1 ]
[ 847729-27-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	In methanol; hexane; dichloromethane; at 0℃; for 1h;	EXAMPLE 58 4- ( (F 5-FLUORO-2- (4-FLUOROBENZYL) PYRIDIN-3- YL1CARBONYL} AMINO) METHYL1BENZOIC ACID STEP 1. Methyl 5-FLUORO-2- (4-FLUOROBENZYL) nicotinate; 2-Chloro-5-fluoronicotinic acid (1.00 g, 5.70 mmol) was treated with 2 M solution of (Trimethylsilyl) DIAZOMETHANE in hexane (5.70 mL, 11.4 mmol), methanol (4 mL), and dichloromethane (14 mL) at 0 C for 1 h. The mixture was quenched with acetic acid and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 0.78 g (72%) of the title compounds as colorless oil : IH-NMR (CDC13) 6 8.41 (1H, d, J = 3. 1 HZ), 7.93 (1H, dd, J = 7. 6,3. 1 HZ), 3.98 (3H, s).
72%	In methanol; hexane; dichloromethane; at 0℃; for 1h;Product distribution / selectivity;	2-Chloro-5-fluoronicotinic acid (EP 634413, 1.00 g, 5.70 mmol) was treated with 2 M solution of (Trimethylsilyl)diazomethane in hexane (5.70 mL, 11.4 mmol), methanol (4 mL), and dichloromethane (14 mL) at 0 C for 1 h. The mixture was quenched with acetic acid and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 0.78 g (72%) of the title compounds as colorless oil: ¹H-NM R (CDCl3) No. 8.41 (1 H, d, J=3.1 Hz), 7.93 (1 H, dd, J=7.6, 3.1 Hz), 3.98 (3H, s).

Reference： [1]Patent: WO2005/21508,2005,A1 .Location in patent: Page/Page column 97
[2]Patent: WO2005/102389,2005,A2 .Location in patent: Page/Page column 142-143

7
[ 847729-27-5 ]
[ 312693-07-5 ]
methyl 5-fluoro-2-(4-fluorobenzyl)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		STEP 2. Methyl 5-fluoro-2- (4-fluorobenzvl) nicotinate; To a stirred solution of <strong>[847729-27-5]methyl 2-chloro-5-fluoronicotinate</strong> (step 1, 350 mg, 1.85 mmol) and dichlorobis [triphenylphosphine] nickel (1I) (362 mg, 0.55 mmol) in tetrahydrofuran (15 mL) was added a 0.5 M solution of 4-fluorobenzylzinc chloride in tetrahydrofuran (5.54 mL, 2.77 mmol) at 0 C under nitrogen. The resulting mixture was warmed to room temperature and stirred for 16 h. The mixture was poured into saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (100 ML). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 439 mg (90%) of the title compounds as colorless oil: H-NMR (CDC13) 6 8.56 (1H, d, J = 2.8 Hz), 7.91 (1H, dd, J = 8.6, 2.9 Hz), 7.26-7. 19 (2H, m), 6.98-6. 92 (2H, M), 4.52 (2H, s), 3.89 (3H, s); MS (ESI) m/z 264 (M + H) +.
90%	bis(triphenylphosphine)nickel(II) chloride; In tetrahydrofuran; at 0 - 20℃; for 16h;Product distribution / selectivity;	To a stirred solution of <strong>[847729-27-5]methyl 2-chloro-5-fluoronicotinate</strong> (step 1,350 mg, 1.85 mmol) and dichlorobis [triphenylphosphine]nickel (362 mg, 0.55 mmol) in tetrahydrofuran (15 mL) was added a 0.5 M solution of 4-fluorobenzylzinc chloride in tetrahydrofuran (5.54 mL, 2.77 mmol) at 0 C under nitrogen. The resulting mixture was warmed to room temperature and stirred for 16 h. The mixture was poured into saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 439 mg (90%) of the title compounds as colorless oil: ¹H- NMR (CDC13) No. 8.56 (1H, d, J=2.8 Hz), 7.91 (1H, dd, J=8.6,2.9 Hz), 7.26-7.19 (2H, m), 6.98-6.92 (2H, m), 4.52 (2H, s), 3.89 (3H, s) ; MS (ESI) m/z 264 (M + H

Reference： [1]Patent: WO2005/21508,2005,A1 .Location in patent: Page/Page column 97-98
[2]Patent: WO2005/102389,2005,A2 .Location in patent: Page/Page column 143

8
[ 67-56-1 ]
[ 38186-88-8 ]
[ 847729-27-5 ]

Yield	Reaction Conditions	Operation in experiment
25%	With sulfuric acid; for 30h;Heating / reflux;Product distribution / selectivity;	To' a solution of 2-chloro-5-fluoronicotinic acid (5.2 g, 30 mmol) in methanol (20 ml) was added conc. sulfuric acid (0.5 ml) and the reaction mixture was stirred at reflux for 30 hours. The reaction mixture was cooled to 0 C and 0.5 N sodium hydroxide solution was added to the mixture. The whole was extracted with diethylether. The organic phase was washed with brine, dried (sodium sulfate), and concentrated to afford 3.2 g (25%) of the title compound: ¹H-NMR (CDCl3) 8 8.41 (1 H, d, J = 3.0 Hz), 7.93 (1 H, dd, J = 3.0,7.6 Hz), 3.98 (3H, s).
		STEP 1. Methyl 2-chloro-5-fluoronicotinate; To a solution of 2-chloro-5-fluoronicotinic acid (5.2 g, 30 mmol) in methanol (20 ml) was added conc. sulfuric acid (0.5 ml) and the reaction mixture was stirred at reflux for 30 hours. The reaction mixture was cooled to 0 C and 0.5 N sodium hydroxide solution was added to the mixture. The whole was extracted with diethylether. The organic phase was washed with brine, dried (sodium sulfate), and concentrated to afford 3.2 g (25%) of the title compound: 'H-NMR (CDCls) 8 8.41 (1 H, d, J = 3.0 Hz), 7.93 (1 H, dd, J = 3.0, 7.6 Hz), 3.98 (3H, s).

Reference： [1]Patent: WO2005/102389,2005,A2 .Location in patent: Page/Page column 200
[2]Patent: WO2005/105732,2005,A1 .Location in patent: Page/Page column 53

9
[ 847729-27-5 ]
[ 13061-96-6 ]
[ 868636-57-1 ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; for 20h;	STEP 2. Methyl 5-fluoro-2-methvlnicotinate; A mixture of <strong>[847729-27-5]methyl 2-chloro-5-fluoronicotinate</strong> (step 1, 1.5 g, 7.91 mmol), tetrakis (triphenylphoshine)palladium (914 mg, 0.79 mmol), methyboronic acid (521 mg, 8.70 mmol) and potassium carbonate (3.28 g, 23.7 mmol) in 1,4-dioxane (20 ml) was heated at 110 C for 20 h under nitrogen atmosphere. The reaction mixture was filtered through a pad of celite (Celite(trademark) (diatomaceous earth) ) and the filtrate was concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20/1 to 4/1) to afford 936 mg (64%) of the title compound: ¹H-NMR (CDCl3) No. 8.49 (1 H, d, J = 3.0 Hz), 7.93 (1 H, dd, J = 3.0, 8.7 Hz), 3.94 (3H, s), 2.81 (3H, s).

Reference： [1]Patent: WO2005/105732,2005,A1 .Location in patent: Page/Page column 53-54

10
[ 38186-88-8 ]
[ 74-88-4 ]
[ 847729-27-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone; at 20 - 35℃; for 18h;	Example 77; [0228] (a) Methyl 2-chloro-5-fluoronicotinate. To a mixture of 2- chloro-5-fluoronicotinic acid (6.66 g, 37.9 mmol) and K2CO3 (15.7 g, 1 14 mmol) in acetone (125 mL) was added iodomethane (2.60 mL, 41.7 mmol) dropwise with stirring at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 35C for 18 hours and was filtered over a plug of Celite. The filtrate was evaporated under reduced pressure to give the title compound. MS (ESI, pos. ion) m/z: 190 (M+l).

Reference： [1]Patent: WO2008/76425,2008,A1 .Location in patent: Page/Page column 82

11
[ 847729-27-5 ]
[ 74-89-5 ]
[ 169806-37-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In tetrahydrofuran; at 20℃; for 63.25h;	(b) Methyl 5-fluoro-2-(methylamino)nicotinate. A mixture of <strong>[847729-27-5]methyl 2-chloro-5-fluoronicotinate</strong> (3.82 g, 20 mmol) and K2CO3 (5.6 g, 40 mmol) in THF (25 mL) was stirred under nitrogen for 15 minutes. To the mixture was added a 2 M solution of methylamine in THF (10 mL, 20 mmol), and stirring was continued for 63 hours. The reaction mixture was filtered over Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (DCM) to give the title compound as an orange oil. MS (ESI, pos. ion) m/z: 185 (M+l).

Reference： [1]Patent: WO2008/76425,2008,A1 .Location in patent: Page/Page column 83

Yield	Reaction Conditions	Operation in experiment
1.8 g	With methanol; In diethyl ether; at -20℃; for 1h;	General procedure: A solution of 2-chloro-5-(trifluoromethyl)nicotinic acid (500 mg, 2.21 mmole, available from Apollo PC9219) in a mixture diethyl ether/methanol (5 ml)/(15 ml) was cooled to -20 C. then trimethylsilyldiazomethane (2M solution in diethyl ether) (2.15 ml, 4.43 mmol) was added dropwise. The reaction mixture was stirred at -20 C. for 1 h then allowed to warm to room temperature. After solvent evaporation, the obtained residue was loaded on SPE-Si cartridge (10g) eluting with a mixture cyclohexane/dichloromethane from 80/20 to 60/40. Collected fractions, after solvent evaporation, afforded the title compound (D66) (300 mg)

13
[ 847729-27-5 ]
[ 1380753-04-7 ]
[ 1380753-55-8 ]

Yield	Reaction Conditions	Operation in experiment
		Description 90: methyl 5-fluoro-2-(3-((4-fluoro-2- methylphenyl)amino)azetidin-1-yl)nicotinate (D90)A mixture of <strong>[847729-27-5]methyl 2-chloro-5-fluoronicotinate</strong> (D69) (199.85 mg, 1 .054 mmol) and potassium carbonate (291 mg, 2.108 mmol) in tetrahydrofuran (2ml) was stirred under N2 nitrogen 15 min at room temperature. N-(4-fluoro-2- methylphenyl)azetidin-3-amine (D55) (190 mg, 1 .054 mmol) was added and the resulting mixture was stirred 1 day at room temperature. The residue obtained after solvent evaporation was purified by Biotage SNAP-Si column eluting with a mixture cyclohexane/ethyl acetate from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D90)(155 mg)MS: (ES/+) m/z: 334.6 [MH+] C17H17F2N302 requires 333.331 H NMR (400MHz ,CHLOROFORM-d) delta = 8.24 (d, J = 2.9 Hz, 1 H), 7.80 (dd, J = 2.9, 8.3 Hz, 1 H), 6.91 - 6.75 (m, 2 H), 6.32 (dd, J = 4.9, 8.3 Hz, 1 H), 4.50 (dd, J = 7.3, 9.3 Hz, 2 H), 4.40 - 4.27 (m, 1 H), 3.97 - 3.81 (m, 5 H), 3.72 (d, J = 6.4 Hz, 1 H), 2.18 (s, 3 H)
155 mg	With potassium carbonate; In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere;	A mixture of <strong>[847729-27-5]methyl 2-chloro-5-fluoronicotinate</strong> (D69) (199.85 mg, 1.054 mmol) and potassium carbonate (291 mg, 2.108 mmol) in tetrahydrofuran (2 ml) was stirred under N2 nitrogen 15 min at room temperature. N-(4-fluoro-2-methylphenyl)azetidin-3-amine (D55) (190 mg, 1.054 mmol) was added and the resulting mixture was stirred 1 day at room temperature. The residue obtained after solvent evaporation was purified by Biotage SNAP-Si column eluting with a mixture cyclohexane/ethyl acetate from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D90)(155 mg)

Reference： [1]Patent: WO2012/76063,2012,A1 .Location in patent: Page/Page column 80
[2]Patent: US2013/261100,2013,A1 .Location in patent: Paragraph 0591-0592

14
[ 847729-27-5 ]
[ 868636-58-2 ]

Reference： [1]Patent: WO2005/102389,2005,A2
[2]Patent: WO2005/102389,2005,A2

15
[ 847729-27-5 ]
[ 169806-26-2 ]

Reference： [1]Patent: WO2008/76425,2008,A1

16
[ 847729-27-5 ]
[ 1034131-47-9 ]

Reference： [1]Patent: WO2008/76425,2008,A1

17
[ 847729-27-5 ]
2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-fluorothieno[2,3-b]pyridine-3-carboxamide [ No CAS ]