[ CAS No. 1480-64-4 ] {[proInfo.proName]}

Name: 1480-64-4|3-Chloro-2-fluoropyridine|98%
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Quality Control of [ 1480-64-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1480-64-4 ]

Product Details of [ 1480-64-4 ]

CAS No. :	1480-64-4	MDL No. :	MFCD04114144
Formula :	C₅H₃ClFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IHGMHTQDGNVKTA-UHFFFAOYSA-N
M.W :	131.54	Pubchem ID :	2762818
Synonyms :

Calculated chemistry of [ 1480-64-4 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	29.21
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) :	-5.98 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.58
Log Po/w (XLOGP3) :	1.58
Log Po/w (WLOGP) :	2.29
Log Po/w (MLOGP) :	1.51
Log Po/w (SILICOS-IT) :	2.51
Consensus Log Po/w :	1.89

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.21
Solubility :	0.819 mg/ml ; 0.00622 mol/l
Class :	Soluble
Log S (Ali) :	-1.46
Solubility :	4.55 mg/ml ; 0.0346 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.88
Solubility :	0.172 mg/ml ; 0.00131 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.57

Safety of [ 1480-64-4 ]

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 [ 1480-64-4 ]

* 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 [ 1480-64-4 ]
Downstream synthetic route of [ 1480-64-4 ]

[ 1480-64-4 ] Synthesis Path-Upstream 1~6

1
[ 2402-77-9 ]
[ 1480-64-4 ]

Yield	Reaction Conditions	Operation in experiment
71.9%	With cesium fluoride In dimethyl sulfoxide at 110℃; for 20 h;	General procedure: To a solution of 2,3-dichloropyridine(1.00 g, 6.76 mmol) in DMSO (33.8 ml) was added CsF (2.053 g, 13.51mmol) at room temperature. The mixture was stirred at 110 °C under air for 20h. The mixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with water and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with EtOAc in hexane) togive 3-chloro-2-fluoropyridine (0.639 g, 4.86 mmol, 71.9 percent) as colorlessoil. Thecompound 3B'-8B' were prepared in amanner similar to that described for 2B'.

Reference： [1] Tetrahedron Letters, 2015, vol. 56, # 44, p. 6043 - 6046
[2] Angewandte Chemie - International Edition, 2006, vol. 45, # 17, p. 2720 - 2725
[3] Patent: EP1595867, 2005, A1, . Location in patent: Page/Page column 33-34
[4] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
[5] Patent: EP1726590, 2006, A1, . Location in patent: Page/Page column 56

2
[ 372-48-5 ]
[ 1480-64-4 ]

Reference： [1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910

3
[ 54231-32-2 ]
[ 1480-64-4 ]

Reference： [1] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12137 - 12145

4
[ 626-60-8 ]
[ 1480-64-4 ]

Reference： [1] Science, 2013, vol. 342, # 6161, p. 956 - 960

5
[ 1480-64-4 ]
[ 34941-90-7 ]

Reference： [1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910

6
[ 1480-64-4 ]
[ 851179-01-6 ]

Reference： [1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910

[ 1480-64-4 ] Synthesis Path-Downstream 1~88

Yield	Reaction Conditions	Operation in experiment
81%	With Hexafluorobenzene; tetra-n-butylammonium cyanide; In dimethylsulfoxide-d6; at 20℃; for 24h;	General procedure: In Situ TBAF* with DS-2 [0087] It was found that pre-formation of TBAF* is not necessary to facilitate fluorination at room temperature. Weighing the substrate and TBACN into the reaction vessel followed by DMSO and the appropriate amount of C6F6 furnishes the desired product in excellent yield (Table 1). [TABLE-US-00001] TABLE 1 Fluorination of DS-2 with in situ generated anhydrous TBAF* Entry TBAF* Equiv Yield 1 2.0 >99% 2 2.0 >99% 3 4.0 >99% 4 4.0 >99% In addition to the model substrate DS-2, other chloropicolinates, as well as simple chloropyridines, underwent fluorination with the disclosed methods. 5-Chloropicolinates went to full conversion as demonstrated in Scheme 2 (top row). 5-Fluoropicolinic acid, however, was only formed in small quantities presumably due to deprotonation by fluoride thereby inactivating the substrate to nucleophilic aromatic substitution. Simpler chloropyridines were less effective as substrates for this method in accordance to the reactivity observed by DiMagno et al. 4,5-Dichloro-6-arylpicolinates (Scheme 2, bottom row) demonstrated fluorination first at the more activated 4-position followed by fluorination of the less activated 5-position, although the total yield was diminished due to the production of the undesired bis-cyanopicolinate product. [0091]
94%Spectr.	With tetramethylammonium fluoride; In N,N-dimethyl-formamide; at 20℃; for 24h;	General procedure: General Procedure E: General Experimental Details for NMR Yields Reported in Figure 3. In a drybox, anhydrous NMe4F (18.6 mg, 0.2 jumol, 2 equiv) and the appropriate aryi chloride or nitroarene substrate (0.1 nimol, 1 equiv) were weighed into a 4 mL vial equipped with a micro stirbar. DMF (0.5 mL) was added, and the viai was removed from the drybox and stirred at room temperature unless otherwise noted for 24 hours. The reaction was cooled to room temperature and an internal standard (1, 3, 5-trifluorobenzene, 100 iL of a 0.5 M solution in toluene) was added. An aliquot was removed for analysis by 59F NMR spectroscopy and GCMS.

2
[ 1480-64-4 ]
3-chloro-2-fluoro-4-iodopyridine [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 7873 - 7877

3
[ 1480-64-4 ]
3,3'-dichloro-2,2'-difluoro-[4,4']bipyridinyl [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 7873 - 7877

4
[ 1480-64-4 ]
[ 851179-03-8 ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 1903 - 1910

5
[ 372-48-5 ]
[ 1480-64-4 ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 1903 - 1910

6
[ 2402-77-9 ]
[ 1480-64-4 ]

Yield	Reaction Conditions	Operation in experiment
71.9%	With cesium fluoride; In dimethyl sulfoxide; at 110℃; for 20h;	General procedure: To a solution of 2,3-dichloropyridine(1.00 g, 6.76 mmol) in DMSO (33.8 ml) was added CsF (2.053 g, 13.51mmol) at room temperature. The mixture was stirred at 110 C under air for 20h. The mixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with water and brine, dried overNa2SO4 and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with EtOAc in hexane) togive 3-chloro-2-fluoropyridine (0.639 g, 4.86 mmol, 71.9 %) as colorlessoil. Thecompound 3B'-8B' were prepared in amanner similar to that described for 2B'.
	With cesium fluoride; In 1-methyl-pyrrolidin-2-one; at 150℃; for 23h;	2,3-Dichloropyridine (107.3 g) and cesium fluoride (268.2 g) were suspended in N-methyl-2-pyrrolidinone (270 ml) and stirred at 150C for 23 hours. After cooling off, the reaction mixture was poured into water, filtered through Celite, and the filtrate was extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and condensed under reduced pressure. The resulting oily residue was distilled to provide 3-chloro-2-fluoropyridine (76.14 g) as a colorless oily substance. Boiling point: 91 - 95C (15 mmHg)
	With cesium fluoride; In 1-methyl-pyrrolidin-2-one; at 180℃; for 23h;	107.3 g of 2,3-dichloropyridine was dissolved in 270 mL of N-methylpiperidone, and 268.25 g of cesium fluoride was added thereto, and stirred in a nitrogen atmosphere at 180C for 23 hours. One L of water was added to the solution, and filtered through Celite, and the filtrate was extracted twice with diethyl ether. The organic layers were combined, washed with saturated saline water, and dried with sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified through distillation (91 to 95C/15 mmHg) to obtain 76.14 g of the entitled compound as a colorless liquid.

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 6043 - 6046
[2]Angewandte Chemie - International Edition,2006,vol. 45,p. 2720 - 2725
[3]Patent: EP1595867,2005,A1 .Location in patent: Page/Page column 33-34
[4]Organic Letters,2015,vol. 17,p. 1866 - 1869
[5]Patent: EP1726590,2006,A1 .Location in patent: Page/Page column 56

7
[ 1480-64-4 ]
[ 851179-01-6 ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 1903 - 1910

8
[ 1480-64-4 ]
[ 34941-90-7 ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 1903 - 1910

9
[ 1480-64-4 ]
[ 124-38-9 ]
[ 741683-19-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of diisopropylamine (97 ml) in THF (1200 ml), n butyl lithium (2.66M-hexane solution, 239 ml) was added at -78C. The reaction liquid was stirred for 30 minutes at said temperature, and into which a solution of the above compound (76.14 g) in THF (300 ml) was added dropwise, followed by an hour's stirring. Dry ice was added to the reaction liquid, and after the temperature of the system was raised to the ambient level, the reaction mixture was poured into water and condensed under reduced pressure. The residue was extracted with ether. Hydrochloric acid was added to the aqueous phase to adjust the latter's pH to 2, followed by extraction with ethyl acetate. The organic layer was combined with the extract and washed with saturated brine, dried over anhydrous magnesium sulfate and condensed under reduced pressure. The residue was recrystallized from ether-hexane to provide 3-chloro-2-fluoroisonicotinic acid (55.9 g).
		In a nitrogen atmosphere, 97 mL of diisopropylamine was dissolved in 1.2 L of tetrahydrofuran, and at -70C, 239 mL of 2.66 M n-butyllithium-hexane solution was dropwise added thereto. The solution was stirred for 30 minutes, and then tetrahydrofuran (300 mL) solution of 76.14 g of the compound obtained in the above 1 was dropwise added thereto at -70C. This was stirred for 1 hour, and dry ice was added to the reaction solution, heated up to room temperature, and 1 L of water and diethyl ether were added thereto. Its pH was controlled to 10 with aqueous 4 M sodium hydroxide solution added to it. Then, its pH was controlled to 1 to 2 with concentrated hydrochloric acid added to it, and this was extracted three times with diethyl ether. The organic layers were combined, washed with saturated saline water, and dried with sodium sulfate. The solvent was evaporated off under reduced pressure, the residue was crystallized from ether-hexane to obtain 55.9 g of the entitled compound as a pale yellow solid.

Reference： [1]Patent: EP1595867,2005,A1 .Location in patent: Page/Page column 34
[2]Patent: EP1726590,2006,A1 .Location in patent: Page/Page column 56-57

10
[ 1480-64-4 ]
[ 46001-09-6 ]
[ 1284218-65-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7137 - 7141

11
[ 1480-64-4 ]
[ 179692-09-2 ]
[ 1307249-67-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;	PREPARATION 51Ethyl 1-(3-Chloro-2-pyridyl)-4-formyl-pyrazole-3-carboxylate; To a solution of ethyl 4-formyl-pyrazole-3-carboxylate (1.70 g, 10.1 mmol) and <strong>[1480-64-4]3-chloro-2-fluoropyridine</strong> (1.99 g, 15.1 mmol) in dimethylformamide (20 mL) is added potassium carbonate (2.80 g, 20.2 mmol) and the mixture is stirred at 100 C. for 16 hours. After completion, the reaction mixture is partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer is extracted with ethyl acetate (3×25 mL) and the combined organic extracts are dried over sodium sulfate, concentrated in vacuo and purified by column chromatography over silica gel eluting with hexane/ethyl acetate (50:50) to yield 1.5 g (54%) of the title compound. MS (m/z): 280 (M+1).

Reference： [1]Patent: US2011/118251,2011,A1 .Location in patent: Page/Page column 21

12
[ 1480-64-4 ]
[ 112758-40-4 ]
[ 1307249-51-9 ]

Yield	Reaction Conditions	Operation in experiment
52%		PREPARATION 461-(3-Chloro-2-pyridyl)-3-methyl-pyrazole-4-carbaldehyde; To a solution of 3-methyl-pyrazole-4-carbaldehyde (0.5 g, 4.5 mmol) in dry dimethylformamide (15 mL) is added potassium carbonate (2.5 g, 18 mmol,) at room temperature. The reaction mixture is stirred at 40 C. for 30 min and then 1-fluoro-2-chloropyridine (0.77 g, 6 mmol,) is added. The reaction mixture is heated at 70 C. for 16 h. After completion, the reaction mixture is cooled to room temperature, diluted with water and then extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduce pressure. The crude mixture is purified by chromatography on silica gel eluting with hexane/ethyl acetate (75:25, 65:35) to yield 0.525 g (52%) of the title compound. MS (m/z): 222 (M+1).

Reference： [1]Patent: US2011/118251,2011,A1 .Location in patent: Page/Page column 20

13
[ 1480-64-4 ]
[ 112758-40-4 ]
[ 1307248-12-9 ]

Reference： [1]Patent: US2011/118251,2011,A1

14
[ 1480-64-4 ]
2-(azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole dihydrochloride [ No CAS ]
[ 1350354-99-2 ]

Yield	Reaction Conditions	Operation in experiment
10%	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 100 - 130℃; for 3h;	STEP 4. 2-(l-(3-CHLOROPYRIDTN-2-YL)AZETIDrN-3-YL)-5-METHYL-lH- BENZO[ ]IMIDAZOLE; [00177] To a mixture of cesium carbonate (435 mg, 1.34 mmol) and 2-(azetidin-3-yl)-5- methyl-lH-benzo[i/] imidazole dihydrochloride (0.100 g, 0.384 mmol) was added NMP (1 mL) and <strong>[1480-64-4]3-chloro-2-fluoropyridine</strong> (0.105 g, 0.798 mmol). The reaction mixture was degassed and heated to 100 C for lh, then heated to 130 C for 2h. The reaction was diluted with EtOAc. The organic phase was washed with water (2 x), brine (1 x), dried over MgS04, filtered, and concentrated. Purification by flash column chromatography on silica gel (30% to 90% EtOAc in hexanes) followed by purification by reverse phase HPLC (10% to 50% water/MeCN followed by neutralization of the TFA salt with saturated NaHCOs) gave 2-(l-(3-chloropyridin-2- yl)azetidin-3-yl)-5-methyl-lH-benzo[i/]imidazole (0.011 g, 0.037 mmol, 10% yield) as a dark yellow foam.

Reference： [1]Patent: WO2011/143129,2011,A1 .Location in patent: Page/Page column 48-49

15
[ 1480-64-4 ]
[ 22739-76-0 ]
[ 1355067-13-8 ]

Yield	Reaction Conditions	Operation in experiment
53%		A solution of d8-isopropyl alcohol (4.71 mL, 61.5 mmol) in anhydrous THF (10 mL) was added slowly over 1 min to a suspension of NaH (60% in mineral oil) (2.46 g, 61.5 mmol) in anhydrous THF (50 mL). After 10 mins a solution of <strong>[1480-64-4]2-fluoro-3-chloropyridine</strong> (5.05 g, 38.4 mmol) in THF (10 mL) was added over 5 mins at 5 C. (ice bath). The reaction was then warmed to room temperature stirred for 18 hours. The reaction was diluted with THF (20 mL), cooled to 5 C. (ice bath) and quenched with water (50 mL). The mixture was extracted with EtOAc (50 mL). Brine was added to aid the separation. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a crude oil which was purified by silica gel chromatography eluting with 0 to 30% EtOAc in heptane to yield the title compound as a colourless oil (5.37 g, 53% yield):1H NMR (400 MHz, CDCl3): delta 6.78-6.81 (m, 1H), 7.60-7.62 (m, 1H), 8.03-8.04 (m, 1H).LCMS Rt=1.41 minutes. Molecular ion not observed.
53%	With sodium hydride; In tetrahydrofuran; mineral oil; at 5 - 20℃; for 18h;	A solution of d8-isopropyl alcohol (4.71 mL, 61 .5 mmol) in anhydrous THF (10 mL) was added slowly over 1 min to a suspension of NaH (60% in mineral oil) (2.46 g, 61 .5 mmol) in anhydrous THF (50 mL). After 10 minutes a solution of 2-fluoro-3- chloropyridine (5.05 g, 38.4 mmol) in THF (10 mL) was added over 5 minutes at 5 C (ice bath). The reaction was then warmed to room temperature and stirred for 18 hours. The reaction was diluted with THF (20 mL), cooled to 5 C (ice bath) and quenched with water (50 mL). The mixture was extracted with EtOAc (50 mL) and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a crude oil which was purified by silica gel column chromatography eluting with 0 to 30% EtOAc in heptane to yield the title compound as a colourless oil (5.37 g, 53%). 1H NMR (400 MHz, CDCI3): delta ppm 6.78-6.81 (m, 1 H), 7.60-7.62 (m, 1 H), 8.03-8.04 (m, 1 H). LCMS Rt = 1 .41 minutes MS m/z no mass ion observed
		Preparation 473-Chloro-2-d7-isopropoxypyhdineA solution of d -isopropyl alcohol (4.71 mL, 61 .5 mmol) in anhydrous THF (10 mL) was added over 1 minute to a suspension of NaH (60% in mineral oil) (2.46 g, 61 .5 mmol) in anhydrous THF (50 mL). After 10 minutes, a solution of <strong>[1480-64-4]2-fluoro-3-chloropyridine</strong> (5.05 g, 38.4 mmol) in THF (10 mL) was added over 5 minutes at 5 C (ice bath). The reaction was then warmed to room temperature stirred for 18 hours. The reaction was diluted with THF (20 mL), cooled to 5 C (ice bath) and quenched with water (50 mL). The mixture was extracted with EtOAc (50 mL). Brine was added to aid the separation. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a crude oil which was purified by silica gel chromatography eluting with 0 to 30% EtOAc in heptane to yield the title compound as a colourless oil (5.37 g).1H NMR (400 MHz, CDCI3): delta 6.78-6.81 (m, 1 H), 7.60-7.62 (m, 1 H), 8.03-8.04 (m, 1 H). LCMS Rt = 1 .41 minutes. Molecular ion not observed.

Reference： [1]Patent: US2012/10183,2012,A1 .Location in patent: Page/Page column 56
[2]Patent: WO2013/102826,2013,A1 .Location in patent: Page/Page column 80; 81
[3]Patent: WO2012/7869,2012,A2 .Location in patent: Page/Page column 91-92

16
[ 1480-64-4 ]
[ 1242328-96-6 ]
[ 1242328-97-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With caesium carbonate;copper(l) iodide; 1,10-Phenanthroline; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere;	(1f) Methyl 3-({6-[(3-chloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoate A solution of methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10 mmol), <strong>[1480-64-4]3-chloro-2-fluoropyridine</strong> (1.45 g, 11 mmol), copper iodide (0.19 g, 1.0 mmol), 1,10-phenanthroline (0.18 g, 1.0 mmol) and cesium carbonate (9.77 g, 30 mmol) in DMF (50 mL) was stirred in a nitrogen atmosphere at 80C for two hours. After leaving to cool, a saturated ammonium chloride aqueous solution (200 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (200 mL). Then, the organic layer was washed with water (200 mL) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (methylene chloride/methanol, 95:5) to obtain the title compound (2.46 g, 58%) as a white solid. 1H-NMR (400 MHz, CDCl3): delta ppm: 3.87 (3H, s), 3.93 (3H, s), 5.42 (2H, s), 6.98 (1H, dd, J = 4.7, 7.4 Hz), 7.10 (1H, dd, J = 2.4, 9.0 Hz), 7.22 (1H, d, J = 2.0 Hz), 7.30 (1H, dd, J = 1. 0, 8.6 Hz), 7.38 (1H, t, J = 7.8 Hz), 7.70 (1H, d, J = 7.4 Hz), 7.72-7.73 (1H, m), 7.79 (1H, dd, J = 1.6, 7.4 Hz), 7.80 (1H, d, J = 8.6 Hz), 8.02 (1H, dd, J = 1.6, 4.7 Hz).

Reference： [1]Patent: EP2404918,2012,A1 .Location in patent: Page/Page column 20-21

17
[ 1480-64-4 ]
[ 1242328-73-9 ]

Reference： [1]Patent: EP2404918,2012,A1

18
[ 1480-64-4 ]
[ 1242329-00-5 ]

Reference： [1]Patent: EP2404918,2012,A1

19
[ 1480-64-4 ]
[ 1355067-68-3 ]

Reference： [1]Patent: WO2013/102826,2013,A1

20
[ 1480-64-4 ]
[ 1355068-09-5 ]

Reference： [1]Patent: WO2013/102826,2013,A1

21
[ 1480-64-4 ]
[ 1355069-15-6 ]

Reference： [1]Patent: WO2013/102826,2013,A1

22
[ 1480-64-4 ]
[ 1446444-10-5 ]

Reference： [1]Patent: WO2013/102826,2013,A1

23
[ 1480-64-4 ]
[ 1242328-95-5 ]
[ 1242328-97-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere;	A solution of methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate (3.12 g, 10 mmol), <strong>[1480-64-4]3-chloro-2-fluoropyridine</strong> (1.45 g, 11 mmol), copper iodide (0.19 g, 1.0 mmol), 1,10-phenanthroline (0.18 g, 1.0 mmol) and cesium carbonate (9.77 g, 30 mmol) in DMF (50 mL) was stirred in a nitrogen atmosphere at 80C for two hours. After leaving to cool, a saturated ammonium chloride aqueous solution (200 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (200 mL). Then, the organic layer was washed with water (200 mL) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (methylene chloride/methanol, 95:5) to obtain the title compound (2.46 g, 58%) as a white solid. 1H-NMR (400 MHz, CDCl3) : delta ppm: 3.87 (3H, s), 3.93 (3H, s), 5.42 (2H, s), 6.98 (1H, dd, J = 4.7, 7.4 Hz), 7.10 (1H, dd, J = 2.4, 9.0 Hz), 7.22 (1H, d, J = 2.0 Hz), 7.30 (1H, dd, J = 1.0, 8.6 Hz), 7.38 (1H, t, J = 7.8 Hz), 7.70 (1H, d, J = 7.4 Hz), 7.72-7.73 (1H, m), 7.79 (1H, dd, J = 1.6, 7.4 Hz), 7.80 (1H, d, J = 8.6 Hz), 8.02 (1H, dd, J = 1.6, 4.7 Hz).
58%	With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere;	General procedure: A solution of 13 (3.12g, 10.0mmol), 2-fluoro or 2-bromo substituted pyridine (11.0mmol), CuI (0.19g, 1.00mmol), 1,10-phenanthroline (0.18g, 1.00mmol) and Cs2CO3 (9.77g, 30mmol) in DMF (50mL) was stirred under N2 at 80C for 2h. Aqueous NH4Cl solution (10%) was added to the cooled reaction mixture, and the mixture was extracted with EtOAc several times. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After concentration under reduced pressure, the residue was purified by silica gel chromatography to obtain 14.

Reference： [1]Patent: EP2615081,2013,A1 .Location in patent: Paragraph 0154
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5099 - 5117

24
[ 1480-64-4 ]
[ 1624603-99-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 97 (4S,6S)-4-(5-((3-chloropyridin-2-yl)oxy)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine The title compound was synthesized using steps and procedures analogous to those described in Method M (Example 92) above, but using <strong>[1480-64-4]3-chloro-2-fluoropyridine</strong> (Matrix) in step 5. MS m/z=422 [M]+. Calculated for C17H13ClF5N3O2: 421.75. 1H NMR (300 MHz, CHLOROFORM-d) ppm 2.19 (t, J=13.15 Hz, 1H) 2.69 (d, J=13.74 Hz, 1H) 4.18 (d, J=8.92 Hz, 3H) 4.34-4.58 (m, 1H) 4.61-4.86 (m, 1H) 6.98 (dd, J=7.38, 4.90 Hz, 1H) 7.12 (d, J=8.62 Hz, 2H) 7.30 (d, J=7.31 Hz, 2H) 7.76 (d, J=7.60 Hz, 1H) 8.00 (d, J=4.82 Hz, 1H).

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column

25
[ 626-60-8 ]
[ 1480-64-4 ]

Reference： [1]Science,2013,vol. 342,p. 956 - 960

26
[ 1480-64-4 ]
[ 105-53-3 ]
[ 940933-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In dimethyl sulfoxide; at 20 - 100℃;	Intermediate 33A: Diethyl 2-(3-chloropyridin-2-yl)malonate A mixture of <strong>[1480-64-4]3-chloro-2-fluoropyridine</strong> (5.00 g, 38.0 mmol), diethyl malonate (14.6 g, 91 mmol) and Cs2CO3 (29.7 g, 91 mmol) in DMSO (42 mL) was heated at 100 C. for 7 h. After stirring overnight at room temperature, the mixture was diluted with EtOAc, washed twice with water, then with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated to give crude diethyl 2-(3-chloropyridin-2-yl) malonate as a colorless oil, used without further purification. Mass spectrum m/z 272 (M+H)+.
	With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 7h;	A mixture of <strong>[1480-64-4]3-chloro-2-fluoropyridine</strong> (5.00 g, 38.0 mmol), diethyl malonate (14.61 g, 91 mmol) and Cs2C03 (29.7 g, 91 mmol) in DMSO (42 mL) was heated at 100 C for 7 h. After stirring overnight at room temperature, the mixture was diluted with EtOAc and washed twice with water, then with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated to give crude diethyl 2-(3-chloropyridin-2-yl)malonate as a colorless oil, used without further purification. Mass spectrum m/z 272 (M+H)+.

Reference： [1]Patent: US2014/378475,2014,A1 .Location in patent: Paragraph 0491; 0492
[2]Patent: WO2014/210087,2014,A1 .Location in patent: Page/Page column 67

27
[ 1480-64-4 ]
[ 940933-23-3 ]

Reference： [1]Patent: US2014/378475,2014,A1
[2]Patent: WO2014/210087,2014,A1

28
[ 1480-64-4 ]
sodium 2-(3-chloropyridin-2-yl)acetate [ No CAS ]

Reference： [1]Patent: US2014/378475,2014,A1
[2]Patent: WO2014/210087,2014,A1

29
[ 1480-64-4 ]
N-(3-bromo-2-methylphenyl)-2-(3-chloropyridin-2-yl)acetamide [ No CAS ]

Reference： [1]Patent: US2014/378475,2014,A1
[2]Patent: WO2014/210087,2014,A1

30
[ 1480-64-4 ]
2-(3-chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: US2014/378475,2014,A1
[2]Patent: WO2014/210087,2014,A1

31
[ 1480-64-4 ]
[ 100-46-9 ]
[ 1042512-03-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With caesium carbonate; In dimethyl sulfoxide; at 105℃; for 7h;	<strong>[1480-64-4]3-Chloro-2-fluoropyridine</strong> (5.00 g, 37.25 mmol, 1 eq.) and benzylamine (5.75 mL, 52.15 mmol, 1.4 eq.) were addedto cesium carbonate (18.21 g, 55.88 mmol, 1.5 eq.) in dimethyl sulfoxide (25 mL) and the reaction mixture wasstirred at 105 C for 7 h. After cooling to 25 C water (25 mL) was added dropwise using an ice bath to maintain thetemperature below 30C. The reaction mixture was transferred to a separation funnel. Then water (15 mL) andethyl acetate (40 mL) were added and the phases were separated. The aqueous phase was extracted with ethylacetate (2 x 50 mL). The combined organic phases were washed with water (4 x 50 mL) and brine (50 mL). Dryingover magnesium sulfate, removal of the solvent and purification by flash chromatography (2 to 3% ethyl acetate inheptanes) gave the N-benzyl-3-chloropyridin-2-amine as a white solid (6.56 g, 81%). Rf = 0.25 (5% ethyl acetate inheptanes).1H NMR (400 MHz, CDCl3): = 1H NMR (400 MHz, CDCl3): = 4.71 (d, J = 5.5 Hz, 2 H), 5.28 (br. s, 1 H), 6.57 (dd, J =7.8, 5.0 Hz, 1 H), 7.27 - 7.32 (m, 1 H), 7.33 - 7.42 (m, 4 H), 7.46 -7.51 (obs. m, 1 H), 8.07 (dd, J = 4.9, 1.6 Hz, 1 H).13C NMR (101 MHz, CDCl3): = 45.5, 113.1, 115.4, 127.3, 127.7, 128.6, 136.1, 139.3, 146.0, 153.9.LC/MS (m/z): [M + H]+ calculated for C12H12ClN2+, 219.1 ; found, 218.7
81%	With caesium carbonate; dimethyl sulfoxide; at 105℃; for 7h;	<strong>[1480-64-4]3-Chloro-2-fluoropyridine</strong> (5.00 g, 37.25 mmol, 1 eq.) and benzylamine (5.75 mL, 52.15 mmol, 1.4 eq.) were addedto cesium carbonate (18.21 g, 55.88 mmol, 1.5 eq.) in dimethyl sulfoxide (25 mL) and the reaction mixture wasstirred at 105 C for 7 h. After cooling to 25 C water (25 mL) was added dropwise using an ice bath to maintain thetemperature below 30C. The reaction mixture was transferred to a separation funnel. Then water (15 mL) andethyl acetate (40 mL) were added and the phases were separated. The aqueous phase was extracted with ethylacetate (2 x 50 mL). The combined organic phases were washed with water (4 x 50 mL) and brine (50 mL). Dryingover magnesium sulfate, removal of the solvent and purification by flash chromatography (2 to 3% ethyl acetate inheptanes) gave the N-benzyl-3-chloropyridin-2-amine as a white solid (6.56 g, 81%). Rf = 0.25 (5% ethyl acetate inheptanes).1H NMR (400 MHz, CDCl3): = 1H NMR (400 MHz, CDCl3): = 4.71 (d, J = 5.5 Hz, 2 H), 5.28 (br. s, 1 H), 6.57 (dd, J =7.8, 5.0 Hz, 1 H), 7.27 - 7.32 (m, 1 H), 7.33 - 7.42 (m, 4 H), 7.46 -7.51 (obs. m, 1 H), 8.07 (dd, J = 4.9, 1.6 Hz, 1 H).13C NMR (101 MHz, CDCl3): = 45.5, 113.1, 115.4, 127.3, 127.7, 128.6, 136.1, 139.3, 146.0, 153.9.LC/MS (m/z): [M + H]+ calculated for C12H12ClN2+, 219.1 ; found, 218.7

Reference： [1]Synlett,2014,vol. 25
[2]Synlett,2015,vol. 26,p. 197 - 200

32
[ 1480-64-4 ]
5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [ No CAS ]

Reference： [1]Patent: US2014/378475,2014,A1
[2]Patent: WO2014/210087,2014,A1

33
[ 1480-64-4 ]
5-chloro-2-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [ No CAS ]
5-chloro-2-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [ No CAS ]

Reference： [1]Patent: US2014/378475,2014,A1

34
[ 1480-64-4 ]
4-(R)-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [ No CAS ]

Reference： [1]Patent: US2014/378475,2014,A1

35
[ 1480-64-4 ]
3-chloro-4-(R)-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [ No CAS ]

Reference： [1]Patent: US2014/378475,2014,A1

36
[ 1480-64-4 ]
4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2014/210087,2014,A1

37
[ 1480-64-4 ]
4-(3-(R)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [ No CAS ]
4-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2014/210087,2014,A1

38
[ 1480-64-4 ]
4-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2014/210087,2014,A1

39
[ 1480-64-4 ]
4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-pivalamido-9H-carbazole-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2014/210087,2014,A1

40
[ 1480-64-4 ]
4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(methoxymethyl)-9H-carbazole-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2014/210087,2014,A1

41
[ 1480-64-4 ]
5-chloro-2-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [ No CAS ]

Reference： [1]Patent: WO2014/210087,2014,A1

42
[ 1480-64-4 ]
5-chloro-2-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [ No CAS ]

Reference： [1]Patent: WO2014/210087,2014,A1

43
[ 1480-64-4 ]
[ 77573-43-4 ]
3-O-(3-chloro-2-pyridyl)ingenol-5,20-acetonide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 5h;	General procedure: Ingenol-5,20-acetonide (0.13 mmol) dissolved in DMF (0.3 ml) was added a heteroaryl halide (0.65 mmol) and caesium carbonate (0.26 mmol). The mixture was stirred at 60 C. for 1 hour. After cooling to r.t. the mixture was partitioned between diethylether (2 ml) and saturated aq. sodium hydrogencarbonate (0.5 ml). The ether phase was isolated, dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography (heptane?heptane/ethyl acetate 7:3), giving the title compound as a white solid. Compound 215 was prepared according to Procedure a, but using 1.2 eq. of caesium carbonate at 40 C. for 5h.Starting material: 3-Chioro-2-fluoro-pyridine. ?H NMR (300 MHz, CDC13) oe 7.99 (dd, 1H), 7.66(dd, 1H), 6.89 (dd, 1H), 6.10-6.09 (m, 1H), 5.84 (s, 1H),5.78-5.75 (m, 1H), 4.48 (s, 1H), 4.20-4.13 (m, 3H), 4.03-4.02(m, 1H), 2.78-2.73 (m, 1H), 2.31-2.22 (m, 1H), 1.87 (d, 3H),1.83-1.74 (m, 1H), 1.42 (s, 3H), 1.39 (s, 3H), 1.10 (s, 3H),1.04 (s, 3H), 1.03 (d, 3H), 0.96-0.89 (m, 1H), 0.75-0.67 (m,1H).

Reference： [1]Patent: US2015/175622,2015,A1 .Location in patent: Paragraph 0385; 0433; 0434; 0435

44
[ 54231-32-2 ]
[ 1480-64-4 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 12137 - 12145

45
[ 1480-64-4 ]
N-(3-chloro-4-fluorophenyl)piperidine-4-carboxamide [ No CAS ]
N-(3-chloro-4-fluorophenyl)-1-(3-chloropyridin-2-yl)piperidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 160℃;Microwave irradiation; Inert atmosphere;	General procedure: To a solution of N-(3-chloro-4-fluorophenyl)piperidine-4-carboxamide (50 mg, 0.171 mmol) and2-halopyridine/pyrazine (0.171 mmol) in NMP (0.5 ml) was added DIPEA (0.077 ml, 0.443 mmol).The reaction mixture was heated for 10-50 minutes at 160C in a microwave oven.NMP (0.5 ml) and methanol (0.5ml) were added and the crude product was directly purified bypreparative HPLC (C18, acetonitrile/water gradient).