136888-21-6|2-Chloro-5-fluoro-3-nitropyridine| Ambeed

Structure of 136888-21-6

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Quality Control of [ 136888-21-6 ] Purity: 98% SDS Specification

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Product Details of [ 136888-21-6 ]

CAS No. :	136888-21-6
Formula :	C₅H₂ClFN₂O₂
M.W :	176.53
SMILES Code :	ClC1=NC=C(C=C1[N+](=O)[O-])F
MDL No. :	MFCD06659490
InChI Key :	SVVZGNAZMPSGMU-UHFFFAOYSA-N
Pubchem ID :	10773626

Safety of [ 136888-21-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 136888-21-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	38.03
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	58.71 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.06
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.74
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.2
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.31
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.37
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.14

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.37
Solubility	0.756 mg/ml ; 0.00428 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.59
Solubility	0.454 mg/ml ; 0.00257 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.3
Solubility	0.887 mg/ml ; 0.00502 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.14 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	3.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.03

Application In Synthesis of [ 136888-21-6 ]

* 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.

Downstream synthetic route of [ 136888-21-6 ]

[ 136888-21-6 ] Synthesis Path-Downstream 1~35

1
[ 136888-20-5 ]
[ 136888-21-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With benzyltrimethylammonium chloride; trichlorophosphate; In acetonitrile; at 80℃; for 6h;	a) Synthesis of 2-chloro-5-fluoro-3-nitro-pyridine 5-fluoro-3-nitro-pyridin-2-ol (2 g, 12.7 mmol) and benzyltrimethyl ammonium chloride (1.17 g, 6.35 mmol) were dissolved in acetonitrile, and phosphorus oxychloride (3.5 ml, 38.1 mmol) was added thereto and stirred at 80 C. for 6 hours. The reaction mixture was cooled and poured into ice water to quench the reaction, and extracted with dichloromethane. The combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of dichloromethane:methanol=30:1. The fractions containing the product were collected and evaporated to obtain yellow liquid (1.57 g, 70%). 1H-NMR (CDCl3, 300 MHz); delta=8.56 (d, J=2.7 Hz, 1H), 8.40 (dd, J=6.5 Hz, 2.7 Hz, 1H). MS (ESI); 176.9 (M++1).
69%	With tetraethylammonium chloride; trichlorophosphate; In acetonitrile; at 90℃; for 24h;	PREPARATION 53 2-Chloro-5-fluoro-3-nitropyridine 5-Fluoro-3-nitro-pyridin-2-ol (1.00 g, 5.33 mmol) was dissolved in acetonitrile (40 mL) and tetraethylammonium chloride (2.10g, 12.65 mmol) was added. The mixture became clear, phosphorous oxytrichloride (1.94 g, 12.65 mmol) was added at room temperature and the mixture was heated at 90 ºC for 24h. The reaction mixture was evaporated to dryness; the residue was taken up with water (100 mL) and extracted with ethyl acetate (2x100 mL). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. A yellow solid (0.90 g, 69%) was isolated, pure enough to perform the next synthetic step. LRMS (m/z): 177 (M+1)+
41%	With trichlorophosphate;N,N-dimethyl-formamide; at 110℃; for 18h;	A mixture of the pyridine of preparation 55 (105 mg, 0.66 mmol), phosphorus oxychloride (1 ml) and Lambda/,Lambda/-dimethyIformamide (10 mul, catalytic) was heated at 11O0C for 18 hours. The cooled reaction mixture was then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane/acetonitrile as eluant (100:0 to 50:50 v/v) to yield the title compound (48 mg, 41%) as a solid. 1H NMR (400MHz, CDCI3): delta 8.03 (dd, 1 H), 8.55 (d, 1 H).

	With trichlorophosphate; In 1,2-dimethoxyethane; at 110℃; for 5h;	In Step B, compound zz2' (500 mg, 3.16 mmol) was dissolved in phosphorous oxychloride (1.7 mL, 18.9 mmol) and dimethoxyethane at room temperature. The reaction was heated to 110 C. for 5 hours. The excess phosphorous oxychloride was then removed by concentrating the reaction mixture in vacuo. The residue was chromatographed on silica gel, eluted with chloroform (100%) to afford 176 mg of product zz3'.
	With tetraethylammonium chloride; trichlorophosphate; In acetonitrile; at 20 - 90℃; for 24h;	5-Fluoro-3-nitro-pyridin-2-ol (1 .00 g, 5.33 mmol) was dissolved in acetonitrile (40 mL) and tetraethylammonium chloride (2.1 Og, 12.65 mmol) was added. The mixture became clear, phosphorous oxytrichloride (1 .94 g, 12.65 mmol) was added at room temperature and the mixture was heated at 90 C for 24h. The reaction mixture was evaporated to dryness; the residue was taken up with water (100 mL) and extracted with ethyl acetate (2x100 mL). The organic layer was dried with sodium sulphate, filtered and evaporated to dryness. A yellow solid (0.90 g, 69%) was isolated, pure enough to perform the next synthetic step.LRMS (m/z): 177 (M+1 )+

References: [1]Patent: US2011/28467,2011,A1 .Location in patent: Page/Page column 52.
[2]Patent: EP2518071,2012,A1 .Location in patent: Page/Page column 43.
[3]Patent: WO2006/114706,2006,A1 .Location in patent: Page/Page column 45.
[4]Journal of Heterocyclic Chemistry,1996,vol. 33,p. 287 - 293.
[5]Patent: US2004/110785,2004,A1 .Location in patent: Page 77.
[6]Patent: WO2012/146667,2012,A1 .Location in patent: Page/Page column 97-98.

2
[ 136888-21-6 ]
[ 105-53-3 ]
[ 136888-23-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In dimethylformamide [DMF]; ethyl acetate; N,N-dimethyl-formamide;	C. 6-Fluoro-4-azaoxindole In a dry flask was placed sodium hydride as a 60% suspension in oil (3.1 g, 77.5 mmol). Most of the oil was removed by washing twice with hexanes. The remaining solid sodium hydride was then suspended in dry dimethylformamide (DMF) (100 mL) and cooled to 0 C. Diethyl malonate (11.8 mL, 77.7 mmol) was then added dropwise with stirring. The mixture was stirred at 0 C. for 1 hour after which a solution of <strong>[136888-21-6]2-chloro-5-fluoro-3-nitropyridine</strong> (5.21 g, 29.5 mmol) in DMF (40 mL) was added. Stirring at room temperature was continued overnight and the reaction mixture was poured into ice/water. Following acidification to pH 3 with 6N HCl solution, the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to leave a red oil. This was subjected to flash chromatography on silica gel using 3:7 ethyl acetate/hexanes, as eluant. All fractions containing the desired product were combined and concentrated to yield an oil containing 2-bis(ethoxycarbonyl)methyl-5-fluoro-3-nitropyridine and diethyl malonate in a molar ratio of approximately 11:9 weighing 11.5 g. The yield of 2-bis(ethoxycarbonyl)methyl-5-fluoro-3-nitropyridine was calculated to be approximately 8 g (90%).
	With hydrogenchloride; In dimethylformamide [DMF]; ethyl acetate; N,N-dimethyl-formamide;	C. 6-Fluoro-4-azaoxindole In a dry flask was placed sodium hydride as a 60% suspension in oil (3.1 g, 77.5 mmol). Most of the oil was removed by washing twice with hexanes. The remaining solid sodium hydride was then suspended in dry dimethylformamide (DMF) (100 mL) and cooled to 0C. Diethyl malonate (11.8 mL, 77.7 mmol) was then added dropwise with stirring. The mixture was stirred at 0C for 1 hour after which a solution of <strong>[136888-21-6]2-chloro-5-fluoro-3-nitropyridine</strong> (5.21 g, 29.5 mmol) in DMF (40 mL) was added. Stirring at room temperature was continued overnight and the reaction mixture was poured into ice/water. Following acidification to pH 3 with 6N HCl solution, the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to leave a red oil. This was subjected to flash chromatography on silica gel using 3:7 ethyl acetate/hexanes, as eluant. All fractions containing the desired product were combined and concentrated to yield an oil containing 2-bis(ethoxycarbonyl)methyl-5-fluoro-3-nitropyridine and diethyl malonate in a molar ratio of approximately 11:9 weighing 11.5 g. The yield of 2-bis(ethoxycarbonyl)methyl-5-fluoro-3-nitropyridine was calculated to be approxiamtely 8 g (90%).
	With sodium hydride; In N,N-dimethyl-formamide; at 20℃;Cooling with ice;	Diethyl malonate (9.98 g, 62.3 mmol) was diluted in DMF (50 ml), to which was then added 60 wt%sodium hydride (2.266 g, 56.6 mmol) under ice cooling, and the resulting mixture was stirred under ice cooling and at room temperature. After that, a solution of Compound 33 (5.00 g, 28.3 mmol) dissolved in DMF (5 ml) was added to the reaction mixture under ice cooling, and the resulting mixture was stirred at room temperature. After completion of the reaction, ethyl acetate was added to the reaction mixture under ice cooling, and the resulting mixture was washed with 2 mol/L aqueous solution of hydrochloric acid and with water. The obtained organic layer was dried over magnesium sulfate, and then the solvent was removed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography. About 80% portion of the purified product was diluted in DMSO (50 ml), to which were then added water (0.5 ml) and lithium chloride (4.86 g, 115 mmol), and the resulting mixture was stirred at 110C. After completion of the reaction, a mixed solvent of ethyl acetate and hexane was added to the reaction mixture, from which insoluble materials were removed, and which was then washed with water. The obtained organic layer was dried over magnesium sulfate, and then the solvent was removed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain Compound 122 (2.98 g). Compound 122; Method B LC/MS retention time = 1.65 min. MS (ESI) m/z = 229.15(M+H)+.

References: [1]Journal of Heterocyclic Chemistry,1996,vol. 33,p. 287 - 293.
[2]Patent: US5811432,1998,A .
[3]Patent: EP436333,1991,A2 .
[4]Journal of Medicinal Chemistry,2014,vol. 57,p. 5728 - 5737.
[5]Patent: EP3187498,2017,A1 .Location in patent: Paragraph 0318; 0319.

3
[ 51173-05-8 ]
[ 136888-21-6 ]

References: [1]Journal of Heterocyclic Chemistry,1996,vol. 33,p. 287 - 293.

4
[ 136888-21-6 ]
[ 136888-22-7 ]

References: [1]Journal of Heterocyclic Chemistry,1996,vol. 33,p. 287 - 293.

5
[ 136888-21-6 ]
[ 136888-24-9 ]

References: [1]Journal of Heterocyclic Chemistry,1996,vol. 33,p. 287 - 293.

6
[ 1826-67-1 ]
[ 136888-21-6 ]
7-chloro-4-fluoro-1H-pyrrolo[2,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at -20℃; for 15h;	In Step C, compound zz3' (140 mg, 0.79 mmol) was dissolved in THF (5 mL) and cooled to -78 C. under a nitrogen atmosphere. To this solution was added dropwise a solution of vinyl magnesium bromide (1.2 mmol, 1.0 M in diethyl ether, 1.2 mL). The reaction mixture was then kept at -20 C. for 15 hours. The reaction mixture was then quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica to provide 130 mg of precursor 2d 1H NMR (500 MHz, CD3OD) delta7.78 (s, 1H), 7.60 (d, 1H, J=3.0 Hz), 6.71 (d, 1H, J=3.05 Hz). MS m/z: (M+H)+ calcd for C7H5ClFN2: 171.10; found 171.00. HPLC retention time: 1.22 minutes (column A).

References: [1]Patent: US2004/110785,2004,A1 .Location in patent: Page 77.
[2]Patent: US2004/63744,2004,A1 .Location in patent: Page/Page column 50.

7
[ 136888-21-6 ]
C₅H₂ClFN₂OS [ No CAS ]

References: [1]Patent: US2004/63744,2004,A1 .Location in patent: Page/Page column 50.

Yield	Reaction Conditions	Operation in experiment
48%		B. 2-Chloro-5-fluoro-3-nitropyridine To a mixture of phosphorus pentachloride (9.41 g, 45.2 mmol) and phosphorus oxychloride (4.2 mL, 45.1 mmol) at 60 C. was added in portions 5-fluro-2-hydroxy-3-nitropyridine (6.5 g, 41.1 mmol). The mixture was stirred in an oil bath at 100 C. under nitrogen overnight, cooled to room temperature and poured into ice/water. After addition of more water and ethyl acetate, the mixture was filtered through Celite to remove dark insoluble material. The organic phase was washed with brine, filtered again to remove more dark material, dried over MgSO4 and concentrated. The residue was subjected to flash chromatography on silica gel using chlorform as eluant. Fractions containing the title compound were combined and concentrated to provide a yellow oil (3.51 g, 48%) which solidified on standing at 5 C. overnight.
48%		B. 2-Chloro-5-fluoro-3-nitropyridine To a mixture of phosphorus pentachloride (9.41 g, 45.2 mmol) and phosphorus oxychloride (4.2 mL, 45.1 mmol) at 60C was added in portions 5-fluro-2-hydroxy-3-nitropyridine (6.5 g, 41.1 mmol). The mixture was stirred in an oil bath at 100C under nitrogen overnight, cooled to room temperature and poured into ice/water. After addition of more water and ethyl acetate, the mixture was filtered through CeliteRto remove dark insoluble material. The organic phase was washed with brine, filtered again to remove more dark material, dried over MgSO4 and concentrated. The residue was subjected to flash chromatography on silica gel using chlorform as eluant. Fractions containing the title compound were combined and concentrated to provide a yellow oil (3.51 g, 48%) which solidified on standing at 5C overnight.

9
1-[4-(4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-amine dihydrochloride [ No CAS ]
[ 136888-21-6 ]
[ 913264-51-4 ]

Yield	Reaction Conditions	Operation in experiment
80%		The amine of preparation 49 (166 mg, 0.464 mmol) was dissolved in dichloromethane (10 ml) and the solution was treated with 1 N sodium hydroxide solution (10 ml). The layers were separated, and the organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The pyridine of preparation 56 (41 mg, 0.23 mmol) was added to a solution of this amine in tetrahydrofuran (3 ml). The reaction mixture was heated at reflux for 18 hours. The cooled mixture was then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane/methanol/ammonia as eluant (99:1 :0 to 95:5:0.5 v/v/v) to yield the title compound (80 mg, 80%) as a solid.1H NMR (400MHz, CD3OD): delta 1.52-1.62 (m, 2H), 1.96-2.02 (m, 2H), 2.23 (s, 3H), 2.95 (t, 2H), 3.29- 3.33 (m, 2H), 4.28 (m, 1 H), 7.51 (d, 2H), 7.64 (d, 2H), 8.29 (dd, 1 H), 8.42 (s, 1 H); LRMS APCI+ m/z 432 [MH]+.

References: [1]Patent: WO2006/114706,2006,A1 .Location in patent: Page/Page column 46.

10
[ 96-35-5 ]
[ 136888-21-6 ]
[ 1198154-59-4 ]

Yield	Reaction Conditions	Operation in experiment
66%		b) Synthesis of (5-fluoro-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester Hydroxy-acetic acid methyl ester (0.96 g, 10.7 mmol) was dissolved in 2 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (0.42 g, 10.7 mmol) was added thereto at room temperature. After stirring for 30 minutes, <strong>[136888-21-6]2-chloro-5-fluoro-3-nitro-pyridine</strong> (1.57 g, 8.89 mmol) dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain (5-fluoro-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow liquid (1.35 g, 66%). 1H-NMR (CDCl3, 300 MHz); delta=8.25 (d, J=2.7 Hz, 1H), 8.40 (dd, J=6.9 Hz, 2.7H, 1 Hz), 5.06 (s, 2H), 3.78 (s, 3H). MS (ESI); 231.1 (M++1).

References: [1]Patent: US2011/28467,2011,A1 .Location in patent: Page/Page column 52-53.

11
[ 136888-21-6 ]
2,3-dichloro -5-fluoropyridine [ No CAS ]

References: [1]Patent: EP2394987,2011,A1 .

12
[ 136888-21-6 ]
[ 884495-37-8 ]

Yield	Reaction Conditions	Operation in experiment
	With iron; ammonium chloride; In tetrahydrofuran; ethanol; water; for 5h;Reflux;	Preparation Example 7 A mixture of <strong>[136888-21-6]2-chloro-5-fluoro-3-nitropyridine</strong> (4 g), iron powder (6.3 g), ammonium chloride (606 mg), THF (20 mL), water (20 mL) and ethanol (40 mL) was stirred under refluxing with heating for 5 hours. The reaction mixture was cooled to room temperature, the insoluble matter was separated by filtration and the filtrate was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure to obtain 2-chloro-5-fluoropyridin-3-amine (3.3 g).
11 g	With iron; acetic acid; at 80℃; for 0.5h;	Step A: 2-Chloro-5-fluoropyridin-3-amine. Fe (15.2 g, 272 mmol) was added in portions to a solution of <strong>[136888-21-6]2-chloro-5-fluoro-3-nitropyridine</strong> (12 g, 68 mmol) and HOAc (200 mL). The reaction mixture was stirred at 80 C. for 0.5 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was suspended in ethyl acetate (100 mL), the resultant suspension filtered through a pad of Celite, and the pad washed with ethyl acetate (20 mL). The filtrate was neutralized with sat. NaHCO3(200 mL) and the resultant mixture extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to give the product (11 g), which was used in the next step without further purification. MS (ESI): mass calcd. for C5H4ClFN2 146.0, found 146.8 [M+H]+.

References: [1]Patent: EP2394987,2011,A1 .Location in patent: Page/Page column 10.
[2]Patent: US2020/55874,2020,A1 .Location in patent: Paragraph 1831-1832; 1877-1888.

13
[ 6373-46-2 ]
[ 136888-21-6 ]
[ 1353678-59-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1331-ethyl-6-fluoro-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 133a) N2-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine A mixture of 4-(benzyloxy)aniline (2.26 g), <strong>[136888-21-6]2-chloro-5-fluoro-3-nitropyridine</strong> (2 g) and K2CO3 (3.13 g) in DMF (20 ml) was stirred at 120 C. for 5 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and collected by filtration. The obtained solid was dissolved in EtOH (20 ml), and Pt/C (2 g) was added. Under H2 atmosphere, the mixture was stirred for 1 h, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g).1H NMR (300 MHz, DMSO-d6) delta 5.04 (2H, s), 5.39 (2H, s), 6.69-6.80 (1H, m), 6.86-6.94 (2H, m), 7.29-7.50 (8H, m), 7.54 (1H, s).

References: [1]Patent: US2011/319394,2011,A1 .Location in patent: Page/Page column 108.

14
[ 136888-21-6 ]
[ 1353678-61-1 ]

References: [1]Patent: US2011/319394,2011,A1 .
[2]Patent: US2011/319394,2011,A1 .

15
[ 136888-21-6 ]
[ 1353678-58-6 ]

References: [1]Patent: US2011/319394,2011,A1 .
[2]Patent: US2011/319394,2011,A1 .

16
[ 136888-21-6 ]
[ 1353678-60-0 ]

References: [1]Patent: US2011/319394,2011,A1 .
[2]Patent: US2011/319394,2011,A1 .

17
[ 6373-46-2 ]
[ 136888-21-6 ]
N₂-[4-(benzyloxy)phenyl]-5-fluoropyridine-3-nitro-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 5h;	Example 132; 1-ethyl-6-fluoro-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 132a) N2-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine A mixture of 4-(benzyloxy)aniline (2.26 g), <strong>[136888-21-6]2-chloro-5-fluoro-3-nitropyridine</strong> (2 g) and K2CO3 (3.13 g) in DMF (20 mL) was stirred at 120 C. for 5 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and collected by filtration. The solid obtained above was dissolved in EtOH (20 ml), and Pt/C (2 g) was added. Under H2 atmosphere, the mixture was stirred for 1 h, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g).1H NMR (300 MHz, DMSO-d6) delta 5.04 (2H, s), 5.39 (2H, s), 6.69-6.80 (1H, m), 6.86-6.94 (2H, m), 7.29-7.50 (8H, m), 7.54 (1H, s).

References: [1]Patent: US2011/319394,2011,A1 .Location in patent: Page/Page column 107.

18
[ 136888-21-6 ]
[ 1353678-59-7 ]

References: [1]Patent: US2011/319394,2011,A1 .

19
[ 21717-96-4 ]
[ 136888-21-6 ]

References: [1]Patent: EP2471792,2012,A1 .

20
[ 212268-12-7 ]
[ 136888-21-6 ]

Yield	Reaction Conditions	Operation in experiment
		(Reference Example 2-2) 5-Fluoro-3-nitropyridine-2-amine (2.66 g) suspended in concentrated hydrochloric acid (35 ml) was cooled to -15C, and an aqueous solution (7 ml) of sodium nitrite (2.57 g) was added dropwise over 10 minutes. After stirring at -10C for 1 hour, and further stirring at room temperature for 1 hour, under ice cooling a 30% aqueous sodium hydroxide solution was added for neutralization. The insolubles were collected by filtration, washed with water, air-dried, and then redissolved in ethyl acetate, before the insolubles were filtered off. The filtrate was concentrated under reduced pressure to afford 2-chloro-5-fluoro-3-nitropyridine (1.41 g). 1H NMR (400 MHz, CDCl3) delta: 8.03 (dd, 1H, J = 6.6, 2.7 Hz), 8.55 (d, 1H, J = 2.7 Hz).

References: [1]Patent: EP2471792,2012,A1 .Location in patent: Page/Page column 39-40.

21
[ 62-53-3 ]
[ 136888-21-6 ]
[ 1404085-49-9 ]

Yield	Reaction Conditions	Operation in experiment
72%	at 100℃; for 3h;	PREPARATION 54 5-Fluoro-3-nitro-N-phenylpyridin-2-amine 2-Chloro-5-fluoro-3-nitropyridine (0.90 g, 5.10 mmol, Preparation 53) and aniline (4.7 mL, 51 mmol) were mixed and heated at 100 ºC for 3h. Once at room temperature, the reaction mixture was diluted with DCM, washed with water and the organic layer was dried from sodium sulfate, filtered and evaporated. The oily residue was recrystallized once from Ethyl acetate/Heptane which gave 737 mg of the final product as orange/red crystals. Column chromatography afforded a second batch of 120 mg. Total yield: 857 mg (72%). LRMS (m/z): 234 (M+1)+
72%	at 100℃; for 3h;	2-Chloro-5-fluoro-3-nitropyridine (0.90 g, 5.10 mmol, Preparation 53) and aniline (4.7 mL, 51 mmol) were mixed and heated at 100 C for 3h. Once at room temperature, the reaction mixture was diluted with DCM, washed with water and the organic layer was dried from sodium sulphate, filtered and evaporated. The oily residue was recrystallized once from Ethyl acetate/Heptane which gave 737 mg of the final product as orange/red crystals. Column chromatography afforded a second batch of 120 mg. Total yield: 857 mg (72%).LRMS (m/z): 234 (M+1 )+

References: [1]Patent: EP2518071,2012,A1 .Location in patent: Page/Page column 43.
[2]Patent: WO2012/146667,2012,A1 .Location in patent: Page/Page column 98.

22
[ 136888-21-6 ]
[ 1615714-24-3 ]