[ CAS No. 34552-15-3 ]

Name: 34552-15-3|2-Chloro-3-fluoro-5-methylpyridine|98%
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Quality Control of [ 34552-15-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 34552-15-3 ]

Product Details of [ 34552-15-3 ]

CAS No. :	34552-15-3	MDL No. :	MFCD06658238
Formula :	C₆H₅ClFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XZJURWKNRAGMCG-UHFFFAOYSA-N
M.W :	145.56	Pubchem ID :	13541365
Synonyms :

Calculated chemistry of [ 34552-15-3 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	34.17
TPSA :	12.89 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) :	-5.57 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.92
Log Po/w (XLOGP3) :	2.28
Log Po/w (WLOGP) :	2.6
Log Po/w (MLOGP) :	1.85
Log Po/w (SILICOS-IT) :	2.88
Consensus Log Po/w :	2.31

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.67
Solubility :	0.31 mg/ml ; 0.00213 mol/l
Class :	Soluble
Log S (Ali) :	-2.19
Solubility :	0.945 mg/ml ; 0.00649 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.29
Solubility :	0.0755 mg/ml ; 0.000519 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.71

Safety of [ 34552-15-3 ]

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 [ 34552-15-3 ]

* 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 [ 34552-15-3 ]
Downstream synthetic route of [ 34552-15-3 ]

[ 34552-15-3 ] Synthesis Path-Upstream 1~3

1
[ 99268-30-1 ]
[ 34552-15-3 ]

Yield	Reaction Conditions	Operation in experiment
44%	With hydrogenchloride In dichloromethane; acetonitrile	EXAMPLE 11 Preparation of 2-chloro-3-fluoro-5-methylpyridine 2-Fluoro-4-chloro-4-formylvaleronitrile, 1.92 g, was placed in a 50 ml Carius tube with 10 ml of acetonitrile. Dry HCl gas was passed into the solution for 10 seconds. The reaction mixture was then heated at 180° C. for 20 minutes. The acetonitrile was then removed under reduced pressure, dissolved in 5 ml of methylene chloride and eluted on a silica gel column (230-400 mesh, 4 cm*20 cm). The first fraction obtained contained the desired 2-chloro-3-fluoro-5-methylpyridine. Removal of the solvent in vacuo afforded 700 mg of the product (44percent yield). 1 Hnmr (Acetone d₆); δ 2.35 (S, 3H, --CH₃); δ 7.50 (dd, 1H, pyr-44); δ 8.07 (broad S 14 pyr-64). IR NaCl neat. 1450 cm^-1, 1408 cm^-1, 1215 cm^-1, 1085 cm^-1, 880 cm^-1, 720 cm^-1, 711 cm^-1. Chemical Ionization Mass Spectrum (CM₄) MH⁺ m/e, 146 (100percent), MH⁺ +2, m/e 148 (35percent).

Reference： [1] Journal of Organic Chemistry, 1985, vol. 50, # 25, p. 5115 - 5119
[2] Patent: US4562009, 1985, A,

2
[ 34552-15-3 ]
[ 38186-86-6 ]

Yield	Reaction Conditions	Operation in experiment
49%	at 100℃; for 4 h;	To a solution of 2-chloro-3-fluoro-5-methylpyridine (512 mg, 3.S2mmol) in pyridine (2.5 mL) and water (2.5 mL) was added one portion of potassium permanganate (1.1 g, 6.9 mmol). The reaction mixture was heated to 100 °C. Two more equal portion of potassium permanganate (for a total of 3.3 g, 20.7 mmol) were added afterrespectively 1 h and 2 h of stirring at 100 °C. When needed, the solid accumulated in the condenser were washed down with water and pyridine. After another 1 h of stirring at 100 °C, the reaction mixture was cooled down to room temperature. The reaction mixture was quenched with saturated aqueous Na2S2O3 and stirred 30 minutes. The mixture was filtered, then acidified to pH 2 with HC1 5 M. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (lx), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 90percent to 70percent PE-EtOAc gradient to give the title compound as a white solid (300 mg, 49percent).

Reference： [1] Patent: WO2018/154118, 2018, A2, . Location in patent: Page/Page column 106; 107
[2] Patent: WO2010/132016, 2010, A1, . Location in patent: Page/Page column 91

3
[ 34552-15-3 ]
[ 950691-52-8 ]

Reference： [1] Patent: WO2012/75917, 2012, A1,
[2] Patent: WO2016/11930, 2016, A1,

[ 34552-15-3 ] Synthesis Path-Downstream 1~31

1
[ 99268-30-1 ]
[ 34552-15-3 ]

Yield	Reaction Conditions	Operation in experiment
44%	With hydrogenchloride; In dichloromethane; acetonitrile;	EXAMPLE 11 Preparation of 2-chloro-3-fluoro-5-methylpyridine 2-Fluoro-4-chloro-4-formylvaleronitrile, 1.92 g, was placed in a 50 ml Carius tube with 10 ml of acetonitrile. Dry HCl gas was passed into the solution for 10 seconds. The reaction mixture was then heated at 180 C. for 20 minutes. The acetonitrile was then removed under reduced pressure, dissolved in 5 ml of methylene chloride and eluted on a silica gel column (230-400 mesh, 4 cm*20 cm). The first fraction obtained contained the desired 2-chloro-3-fluoro-5-methylpyridine. Removal of the solvent in vacuo afforded 700 mg of the product (44% yield). 1 Hnmr (Acetone d6); delta 2.35 (S, 3H, --CH3); delta 7.50 (dd, 1H, pyr-44); delta 8.07 (broad S 14 pyr-64). IR NaCl neat. 1450 cm-1, 1408 cm-1, 1215 cm-1, 1085 cm-1, 880 cm-1, 720 cm-1, 711 cm-1. Chemical Ionization Mass Spectrum (CM4) MH+ m/e, 146 (100%), MH+ +2, m/e 148 (35%).

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 5115 - 5119
[2]Patent: US4562009,1985,A

3
[ 34552-15-3 ]
[ 904745-61-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-Bromosuccinimide; dibenzoyl peroxide; In acetonitrile;Reflux;	Compound A35-1 (5g, 34.3mmol) was dissolved in acetonitrile (100mL), was added NBS (18.3g, 103mmol) and benzoyl peroxide (829mg,3.43 mmol), refluxed overnight, cooled to room temperature, water (200 mL), ethyl acetate (200mL × 3). The organic phase was washed with saturated brine (300mL × 3)Washed, dried over anhydrous sodium sulfate, and sodium sulfate was filtered, spin-dry the solvent, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to give a yellow oil(7.45g, 97%).
97%	With N-Bromosuccinimide; dibenzoyl peroxide; In acetonitrile;Reflux;	To a solution of <strong>[34552-15-3]2-chloro-3-fluoro-5-methylpyridine</strong> (5 g, 34.3 mmol) and NBS (18.3 g, 103 mmol) in CH3CN (100 mL) was added BPO (829 mg, 3.43 mmol). The mixture was refluxed overnight. After cooling to room temperature, H2O (200 mL) was added and the mixture was extracted with ethyl acetate (200 mLx3).The combined organic layers were washed with brine (100 mLx3) and dried over Na2SO4. After concentration and purification by column chromatography (petroleum ether/ethylacetate = 100:1), 47 was obtained as a yellow oil (7.45 g, 97%). 1HNMR (400 MHz, CDCl3) d 8.23 (d, J = 1.2 Hz, 1H), 7.56-7.53 (m,1H), 4.45 (s, 2H).
51%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Reflux;	Synthesis Example 16 N-[1-((6-chloro-5-fluoropyridin-3-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide (Compound 227) <strong>[34552-15-3]2-chloro-3-fluoro-5-methylpyridine</strong> in an amount of 4.00 g (27.6 mmol) was dissolved in 80 mL of carbon tetrachloride, following which 7.37 g (41.4 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added and the mixture was refluxed overnight under heating. Following reaction completion, the reaction mixture was returned to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane/ethyl acetate=19:1), giving 3.06 g of 5-(bromomethyl)-2-chloro-3-fluoropyridine (yield, 51%). 1H-NMR (CDCl3, delta, ppm): 4.45 (2H, s), 7.54 (1H, dd), 8.23 (1H, s)

51%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Reflux;	4.00 g (27.6 mmol) of <strong>[34552-15-3]2-chloro-3-fluoro-5-methyl pyridine</strong> was dissolved in 80 ml of carbon tetrachloride, 7.37 g (41.4 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed overnight. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 19:1) to obtain 3.06 g (yield 51%) of 5-(bromomethyl)-2-chloro-3-fluoropyridine. [0241] 1H-NMR (CDCl3, delta, ppm): 4.45(2H, s), 7.54(1H, dd), 8.23(1H, s)
51%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Reflux;	4.00g (27.6 mmol) of <strong>[34552-15-3]2-chloro-3-fluoro-5-methyl pyridine</strong> was dissolved in 80 ml of carbon tetrachloride, 7.37g (41.4 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed overnight. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 19:1) to obtain 3.06 g (yield 51%) of 5-(bromomethyl)-2-chloro-3-fluoropyridine. [0232] 1H-NMR (CDC13, delta, ppm): 4.45(2H, s), 7.54 (1H, td), 8.23 (1H, s)
51%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Reflux;	In 80 ml of carbon tetrachloride, 4.00 g (27.6 mmol) of <strong>[34552-15-3]2-chloro-3-fluoro-5-methylpyridine</strong> was dissolved. To this solution, 7.37 g (41.4 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added, and the mixture was heated under reflux overnight. After completion of the reaction, the reaction liquid was returned to room temperature, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1). Thus, 3.06 g of 5-(bromomethyl)-2-chloro-3-fluoropyridine was obtained (Percentage Yield: 51%). 1H-NMR (CDCl3, delta, ppm): 4.45 (2H, s), 7.54 (1H, dd), 8.23 (1H, s)
48%	With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane;Heating / reflux;	A suspension of <strong>[34552-15-3]2-chloro-3-fluoro-5-methylpyridine</strong> (5.1 g, 35 mmol), N- bromosuccinimide (6.1 g, 35 mmol) and benzolyperoxide (0.16 g, 0.66 mmol) in carbon tetrachloride (100 mL) was refluxed overnight. Upon cooling down, the solid was filtered off and the filtrate was concentrated and loaded onto a silica gel column eluted with 5 percent EtOAc in hexane to give 3.77 g of the desired 2- chloro-3-fluoro-5-bromomethylpyridine as colorless oil in 48 percent yield. GC- MS calcd. for C6H4BrClFN: 224.46. Found: 224.
48%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Heating / reflux;	Example II Preparation of [(5-fluroro-6-chloropyridin-3-yl)methyl](methyl)-oxido-lambda4-sulfanylidenecyanamide (2) A suspension of <strong>[34552-15-3]2-chloro-3-fluoro-5-methylpyridine</strong> (5.1 g, 35 mmol), N-bromosuccinimide (6.1 g, 35 mmol) and benzolyperoxide (0.16 g, 0.66 mmol) in carbon tetrachloride (100 mL) was refluxed overnight. Upon cooling down, the solid was filtered off and the filtrate was concentrated and loaded onto a silica gel column eluted with 5% EtOAc in hexane to give 3.77 g of the desired 2-chloro-3-fluoro-5-bromomethylpyridine as colorless oil in 48% yield. GC-MS calcd. for C6H4BrClFN: 224.46. Found: 224.

Reference： [1]Patent: CN105254613,2016,A .Location in patent: Paragraph 0263; 0264; 0265
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5861 - 5872
[3]Patent: US2013/150414,2013,A1 .Location in patent: Paragraph 0397; 0398
[4]Patent: EP2633756,2013,A1 .Location in patent: Paragraph 0240; 0241
[5]Patent: EP2634174,2013,A2 .Location in patent: Paragraph 0231; 0232
[6]Patent: EP2749555,2014,A1 .Location in patent: Paragraph 0120
[7]Patent: WO2008/30266,2008,A2 .Location in patent: Page/Page column 25
[8]Patent: US2008/108667,2008,A1 .Location in patent: Page/Page column 8

4
2-fluoro-4-chloro-4-methyl-5,5-dimethoxypentanenitrile [ No CAS ]
[ 34552-15-3 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 5115 - 5119

5
2,4-dichloro-2-fluoro-4-methyl-5,5-dimethoxypentanenitrile [ No CAS ]
[ 34552-15-3 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 5115 - 5119

6
[ 34552-15-3 ]
[ 951652-82-7 ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-chloro-succinimide; 2,2'-azobis(isobutyronitrile); In chlorobenzene;Reflux;	X-4 6-Chloro-3-chloromethyl-5-fluoropyridine (G=Cl, A=6-chloro-5-fluoropyrid-3-yl); 1.00 g (6.87 mmol) of <strong>[34552-15-3]6-chloro-5-fluoro-3-methylpyridine</strong> (F. L. Setliff, Organic Preparations and Procedures International 1971, 3, 217-222), 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2'-azobis(2-methylpropionitrile) in 100 ml of chlorobenzene are boiled under reflux for 2 days. After about 16 hours and 32 hours, in each case a further 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2'-azobis(2-methylpropionitrile) are added. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:20) gives 0.65 g (53% of theory) of 6-chloro-3-chloromethyl-5-fluoropyridine.1H-NMR (CD3CN): delta [ppm]=4.68 (s, 2H), 7.69 (d, 1H), 8.27 (s, 1H)
53%	With N-chloro-succinimide; 2,2'-azobis(isobutyronitrile); In chlorobenzene; for 48.0h;Reflux;	1.00 g (6.87 mmol) of <strong>[34552-15-3]6-chloro-5-fluoro-3-methylpyridine</strong> (F. L. Setliff, Organic Preparations and Procedures International 1971, 3, 217-222), 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2'-azobis(2-methylpropanenitrile) in 100 ml of chlorobenzene are boiled under reflux for 2 days. After about 16 and 32 hours, in each case a further 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2'-azobis(2-methylpropanenitrile) are added. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:20) gives 0.65 g (53% of theory) of 6-chloro-3-chloromethyl-5-fluoropyridine.1H-NMR (CD3CN): delta [ppm]=4.68 (s, 2H), 7.69 (d, 1H), 8.27 (s, 1H)
53%	With N-chloro-succinimide;2,2'-azobis(isobutyronitrile); In chlorobenzene; for 48.0h;Reflux;	1.00 g (6.87 mmol) of <strong>[34552-15-3]6-chloro-5-fluoro-3-methylpyridine</strong> (F. L. Setliff, Organic Preparations and Procedures International 1971, 3, 217-222), 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2'-azobis(2-methylpropannitrile) in 100 ml of chlorobenzene are boiled under reflux for 2 days. During this reaction, after about 16 hours and 32 hours, a further 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2'-azobis(2-methylpropannitrile) are added in each case. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphite and concentrated under reduced pressure. Column chromatography of the residue on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:20) gives 0.65 g (53% of theory) of 6-chloro-3-chloromethyl-5-fluoropyridine.1H NMR (CD3CN): delta [ppm]=4.68 (s, 2H), 7.69 (d, 1H), 8.27 (s, 1H)

Reference： [1]Patent: US2009/181947,2009,A1 .Location in patent: Page/Page column 39
[2]Patent: US2009/247551,2009,A1 .Location in patent: Page/Page column 28
[3]Patent: US2010/48646,2010,A1 .Location in patent: Page/Page column 26

7
[ 34552-15-3 ]
[ 38186-86-6 ]

Yield	Reaction Conditions	Operation in experiment
49%	With pyridine; potassium permanganate; water; at 100℃; for 4.0h;	To a solution of 2-chloro-3-fluoro-5-methylpyridine (512 mg, 3.S2mmol) in pyridine (2.5 mL) and water (2.5 mL) was added one portion of potassium permanganate (1.1 g, 6.9 mmol). The reaction mixture was heated to 100 C. Two more equal portion of potassium permanganate (for a total of 3.3 g, 20.7 mmol) were added afterrespectively 1 h and 2 h of stirring at 100 C. When needed, the solid accumulated in the condenser were washed down with water and pyridine. After another 1 h of stirring at 100 C, the reaction mixture was cooled down to room temperature. The reaction mixture was quenched with saturated aqueous Na2S2O3 and stirred 30 minutes. The mixture was filtered, then acidified to pH 2 with HC1 5 M. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (lx), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 90% to 70% PE-EtOAc gradient to give the title compound as a white solid (300 mg, 49%).
	With pyridine; potassium permanganate; water; at 100℃; for 4.0h;	b) -Chloro-S-fluoronicotinic acidPotassium permanganate (1.09 g, 6.87 mmol) was added to a mixture of 2-chloro-3-fluoro- 5-methylpyridine (0.5 g, 3.43 mmol), water (2 mL) and pyridine (2 mL) and the mixture was heated at 100 0C for 1 h. Solid material stuck in the reflux condenser was washed down with pyridine. More potassium permanganate (2.17 g, 13.7 mmol) was added in portions and heating at 100 0C was continued for a total of 3 h. The reaction mixture was filtered to remove the solids and the filtrate was concentrated to give the crude title compound. MS (ESI) m/z 174 [M-I]".

Reference： [1]Patent: WO2020/1448,2020,A1 .Location in patent: Page/Page column 39; 255-256
[2]Patent: WO2018/154118,2018,A2 .Location in patent: Page/Page column 106; 107
[3]Patent: WO2010/132016,2010,A1 .Location in patent: Page/Page column 91

8
[ 34552-15-3 ]
[ 950691-52-8 ]

Reference： [1]Patent: WO2012/75917,2012,A1
[2]Patent: WO2016/11930,2016,A1

9
[ 34552-15-3 ]
[ 1369256-86-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Reflux;	D362-chloro-5-(dibromomethyl)-3-fluoropyridine A suspension of <strong>[34552-15-3]2-chloro-3-fluoro-5-methylpyridine</strong> (5.0 g, 34.3 mmol), dibenzoyl peroxide (1.109 g, 3.43 mmol) and NBS (18.34 g, 103 mmol) in CC14 (100 mL) was refluxed for overnight, then cooled to rt and washed with water and brine, dried over sodium sulfate, concentrated. Purification via ISCO system afforded the title product (8.2 g) as a brown solid. LC- MS (ESI): m/z 300 [M + H] +; 3.25 min (ret time).

Reference： [1]Patent: WO2012/75917,2012,A1 .Location in patent: Page/Page column 30-31
[2]Patent: WO2016/11930,2016,A1 .Location in patent: Page/Page column 146; 147

10
[ 34552-15-3 ]
[ 1363400-57-0 ]

Reference： [1]Patent: US2013/150414,2013,A1
[2]Patent: EP2749555,2014,A1

11
[ 34552-15-3 ]
[ 1453496-80-4 ]

Reference： [1]Patent: EP2633756,2013,A1

12
[ 34552-15-3 ]
[ 1453496-92-8 ]

Reference： [1]Patent: EP2633756,2013,A1

13
[ 540-88-5 ]
[ 34552-15-3 ]
tert-butyl 2-(3-fluoro-5-methyl-2-pyridyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With [2-(di-tert-butylphosphino)-2?,4?,6?-triisopropyl-1,1?-biphenyl][2-((2-aminoethyl)phenyl)]palladium(II) chloride; lithium hexamethyldisilazane; In toluene; at 0 - 20℃;Inert atmosphere;	[00328] Intermediate I 8a: tert-Butyl 2-(3-fluoro-5-methyl-2-pyridyl)acetate [00329] 2-Ch loro-3-fluoro-5-methylpyridine (500mg, 3 .44mmol), tert-butyl acetate (0.69mL, 5.lSmmol) and tBuxphos Pd Gi (23.59mg, 0.O3mmol) were combined, stirred and cooled to 0 Cunder a nitrogen atmosphere. LiHMDS (1 M in toluene) (10.31 mL, 10.31 mmol) was added slowly and the mixture allowed to warm to room temperature and stirred overnight. Sat. aq, NH4CI (lOmL) was added and the resulting mixture extracted with EtOAc (3 x 2OmL). The organics were combined, washed with brine (2OmL), dried over Na2504, filtered then evaporated to dryness to give a brown oil which was purified by column chromatography eluting with 0% to 50% EtOAc inheptane to give tert-butyl 2-(3-fluoro-5-methyl-2-pyridyl)acetate (440mg, 1 .9Ommol, 57% yield) as a yellow oil.1H NMR (CDCI3, 400MHz) O/ppm: 8.06 (1H, s), 7.07 (1H, d, J= 10.0Hz), 3.68 (2H, d, J= 2.4Hz),2.21 (3H, s), 1.31 (9H, s).MS Method 2: RT: 1.68 mm, mlz 226.2 [M+H]

Reference： [1]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00328; 00329

14
[ 34552-15-3 ]
2-(3-fluoro-5-methyl-2-pyridyl)acetic acid [ No CAS ]

Reference： [1]Patent: WO2016/51193,2016,A1

15
[ 34552-15-3 ]
C₆H₄ClFN₄ [ No CAS ]

Reference： [1]Patent: CN105254613,2016,A
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5861 - 5872

16
[ 34552-15-3 ]
[ 1256826-59-1 ]

Reference： [1]Patent: CN105254613,2016,A
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5861 - 5872

17
[ 34552-15-3 ]
(3-fluoro-2'-methyl-[2,4'-bipyridin]-5-yl)methanamine [ No CAS ]

Reference： [1]Patent: CN105254613,2016,A
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5861 - 5872

18
[ 34552-15-3 ]
C₁₆H₁₂ClF₂N₅ [ No CAS ]

Reference： [1]Patent: CN105254613,2016,A

19
[ 34552-15-3 ]
C₂₄H₂₁F₂N₇ [ No CAS ]

Reference： [1]Patent: CN105254613,2016,A

20
[ 100-02-7 ]
[ 34552-15-3 ]
C₁₂H₉FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1, the three 100mL flask with a nitrogen apparatus, 40 ml of DMF was added, followed by adding 2.18g (0.02mol) of p-aminophenol and 1.92g (0.02mol) of sodium tert-butoxide (that is, the STB), at room temperature, the reaction was stirred about 1h, and then added 2.901g (0.02mol) 2- chloro-3-fluoro-5-methylpyridine and 2.76g (0.02mol) K2CO3, And stirring was continued at room temperature, the progress of the reaction by TLC, After completion of the reaction, the solvent DMF was distilled off under reduced pressure, dissolved with 50ml of chloroform, and extracted with distilled water, The chloroform layer was dried over anhydrous sodium sulfate, and allowed to stand overnight, filtered concentrated to give a dark brown powder, was added anhydrous ethanol 120mL above dark brown powder, distilled water 24mL, ammonium chloride 9.6g, 6.5g after reduced iron heated to reflux, TLC detection reaction, after about 1h, the raw material point disappears, pumping It was filtered, washed with distilled water and dried to give the product, namely 4- (3-fluoro-5-methyl-2-pyridyloxy aniline

Reference： [1]Patent: CN105439945,2016,A .Location in patent: Paragraph 0076; 0078; 0153; 0155

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[ 34552-15-3 ]
2-[4-(3-fluoro-5-methyl-2-pyridyloxy)anilino]propionic acid ethyl ester [ No CAS ]

Reference： [1]Patent: CN105439945,2016,A

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[ 34552-15-3 ]
4-(3-fluoro-5-methyl-2-pyridyloxy)aniline [ No CAS ]

Reference： [1]Patent: CN105439945,2016,A

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[ 34552-15-3 ]
2-[4-(3-fluoro-5-methyl-2-pyridyloxy)anilino]acetic acid ethyl ester [ No CAS ]

Reference： [1]Patent: CN105439945,2016,A

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[ 34552-15-3 ]
N-((3-fluoro-2'-methyl-[2,4'-bipyridin]-5-yl)methyl)-9H-carbazole-2-carboxamide [ No CAS ]