71902-33-5|3,5-Difluoropyridine| Ambeed

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Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
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Product Details of [ 71902-33-5 ]

CAS No. :	71902-33-5
Formula :	C₅H₃F₂N
M.W :	115.08
SMILES Code :	FC1=CN=CC(F)=C1
MDL No. :	MFCD03412222
Boiling Point :	No data available

Safety of [ 71902-33-5 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H225-H302+H312+H332-H315-H319-H335-H400
Precautionary Statements:	P210-P261-P273-P280-P305+P351+P338
Class:	3
UN#:	1993
Packing Group:	Ⅱ

Calculated chemistry of [ 71902-33-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	8
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	24.15
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	12.89 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.61
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	1.05
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.	1.33
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	2.29
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.69

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.77
Solubility	1.95 mg/ml ; 0.017 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-0.91
Solubility	14.1 mg/ml ; 0.123 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-2.53
Solubility	0.342 mg/ml ; 0.00297 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	Yes
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.	-6.26 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	2.0
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	0.0 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)	1.26

Application In Synthesis [ 71902-33-5 ]

* 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 [ 71902-33-5 ]
Downstream synthetic route of [ 71902-33-5 ]

[ 71902-33-5 ] Synthesis Path-Upstream 1~1

1
[ 2457-47-8 ]
[ 71902-33-5 ]
[ 514797-99-0 ]

References: [1] Journal of Organic Chemistry, 2014, vol. 79, # 12, p. 5827 - 5833.

[ 71902-33-5 ] Synthesis Path-Downstream 1~26

1
[ 71902-33-5 ]
[ 851178-97-7 ]

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

2
[ 627-31-6 ]
[ 71902-33-5 ]
1-(3,5-difluoropyridinio)-3-iodopropane iodide [ No CAS ]

References: [1]Journal of Fluorine Chemistry,2005,vol. 126,p. 1160 - 1165.

3
[ 71902-33-5 ]
[ 74-88-4 ]
3,5-difluoropyridine methiodide [ No CAS ]

References: [1]Journal of Fluorine Chemistry,2005,vol. 126,p. 1160 - 1165.

4
[ 16026-77-0 ]
[ 71902-33-5 ]
[ 1020172-85-3 ]

Yield	Reaction Conditions	Operation in experiment
		Example A3 In NMP (15 mL) was placed 3-amino-4-chlorophenol (1.70 g, 11.8 mmol) and potassium t-butoxide (1.40 g, 12.4 mmol) and the mixture was stirred overnight at RT. The dark solution was treated with the <strong>[71902-33-5]3,5-difluoropyridine</strong> (2.73 g, 23.7 mmol) and powdered potassium carbonate (818 mg, 5.92 mmol) and the mixture was then warmed to 80 C. and stirred for 24 h. The resulting black mixture was cooled to RT, diluted with brine (100 mL) and extracted with ethyl acetate (350 mL). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL), dried (Na2SO4), concentrated in vacuo and purified via column chromatography to yield 2-chloro-5-(5-fluoropyridin-3-yloxy)benzenamine as a thick oil which was used without further purification. 1H-NMR (DMSO-d6): delta 5.57 (br s, 2H), 6.26-6.30 (dd, 1H), 650 (s, 1H), 7.19-7.22 (m, 1H), 7.45-7.50 (m, 1H), 8.26 (s, 1H), 8.39 (s, 1H). MS (ESI) m/z: 239.0 (M+H+).
		In NMP (15 mL) was placed 3-amino-4-chlorophenol (1.70 g, 11.8 mmol) and potassium t-butoxide (1.40 g, 12.4 mmol) and the mixture was stirred overnight at RT. The dark solution was treated with the <strong>[71902-33-5]3,5-difluoropyridine</strong> (2.73 g, 23.7 mmol) and powdered potassium carbonate (818 mg, 5.92 mmol) and the mixture was then warmed to 80 C and stirred for 24 h. The resulting black mixture was cooled to RT, diluted with brine (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL), dried (Na2SC>4), concentrated in vacuo and purified via column chromatography to yield 2-chloro-5-(5-fluoropyridin-3-yloxy)benzenamine as a thick oil which was used without further purification. -NMR (DMSO-i: delta 5.57 (br s, 2H), 6.26-6.30 (dd, 1H), 6.50 (s, 1H), 7.19-7.22 (m, 1H), 7.45-7.50 (m, 1H), 8.26 (s, 1H), 8.39 (s, 1H). MS (ESI) m z: 239.0 (M+H+).

References: [1]Patent: US2008/90856,2008,A1 .Location in patent: Page/Page column 34.
[2]Patent: WO2013/36232,2013,A2 .Location in patent: Paragraph 00221.

5
[ 71902-33-5 ]
5-[4-fluoro-3-(3,5-difluoropyridin-2-yl)-phenyl]-3-(3,5-difluoropyridin-2-yl)pyridazine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2600 - 2610.

6
[ 71902-33-5 ]
5-[3-(3,5-difluoro-pyridin-2-yl)-4-fluoro-phenyl]-3-(3,5-difluoro-4-trimethylsilanyl-pyridin-2-yl)-pyridazine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2600 - 2610.

7
[ 851179-05-0 ]
[ 71902-33-5 ]

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

8
[ 2875-18-5 ]
[ 71902-33-5 ]

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

9
[ 700-16-3 ]
[ 71902-33-5 ]

References: [1]Chemistry - A European Journal,2005,vol. 11,p. 1903 - 1910.
[2]Journal of the Chemical Society. Perkin transactions I,1998,p. 1705 - 1713.

10
[ 76469-41-5 ]
[ 71902-33-5 ]

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

11
[ 71902-33-5 ]
[ 67815-54-7 ]

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

12
[ 71902-33-5 ]
3,5-difluoro-2-nitropyridine N-oxide [ No CAS ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1998,p. 1705 - 1713.

13
[ 71902-33-5 ]
3,5-difluoro-4-nitropyridine N-oxide [ No CAS ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1998,p. 1705 - 1713.

14
[ 2457-47-8 ]
[ 71902-33-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium fluoride;1,3-dimethyl-2-(N',N',N",N"-tetramethylguanidino)-4,5-dihydro-3H-imidazolium chloride; In sulfolane; at 205℃; under 2250.23 - 9300.93 Torr; for 48h;	Example 1; Preparation of 3,5-difluoropyridine; 1000 g of dichloropyridine and 1580 g of dry potassium fluoride were initially charged in 1700 ml of sulpholane in an autoclave. Subsequently, 84 g of CNC catalyst (compound (III-1)) were added, nitrogen was injected to 3 bar and the mixture was heated to 205° C. with stirring for 48 h. During the reaction, a maximum total pressure of 12.4 bar arose. Subsequently, the mixture was cooled to 10° C. and the product was distilled off at standard pressure. After redistillation, 473 g of dichloropyridine (60percent of theory) were obtained as a colourless liquid.

References: [1]Patent: US2006/9643,2006,A1 .Location in patent: Page/Page column 4-5.

15
[ 899898-46-5 ]
[ 71902-33-5 ]
5-(5-Fluoro-pyridin-3-ylamino)-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.75h;Microwave irradiation;	E) 5-Amino-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide (0.15 g, 0.605 mmol) was dissolved in 5 mL fry DMF. 3,5-Difluoropyridine (0.213 g, 1.85 mmol) and cesium carbonate (0.59 g, 1.85 mmol) were added. The reaction mixture was irradiated in the microwave at 150° C. for 45 min, diluted with 100 mL water and extracted three times with ethyl acetate (50 mL each). The organic phases were pooled, dried with sodium sulfate and evaporated. The crude product was flash-chromatographed on silica gel with heptane/ethyl acetate 100:0-->0:100 gradient to yield the title compound as an off-white solid (0.135 g, 65percent)

References: [1]Patent: US2006/160857,2006,A1 .Location in patent: Page/Page column 44.

16
[ 908831-93-6 ]
[ 71902-33-5 ]
3-(5-Fluoro-pyridin-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With caesium carbonate; In N,N-dimethyl-formamide; at 120 - 160℃; for 73h;Microwave irradiation;	EXAMPLE 7 3-(5-Fluoro-pyridin-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide In a 5 ml microwave reaction vessel were dissolved 70 mg (0.29 mmol) 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (Example 5) and 266 mg (2.31 mmol, 8.0 equiv.) of <strong>[71902-33-5]3,5-difluoropyridine</strong> in 1.5 ml of DMF. Cesium carbonate (376 mg, 1.16 mmol, 4.0 equiv.) was added and the suspension was sonicated under argon for 10 min. The mixture was heated for 72 h at 120° C. in an oil bath and then 1 h at 160° C. under microwave irradiation. The dark brown suspension was filtered over Dicalite which was washed with ethyl acetate. The filtrate was evaporated to dryness in vaccuo, and the residue dissolved in 200 ml of ethyl acetate, which was washed once with brine. After drying over magnesium sulfate and concentration in vaccuo, the residue (90 mg) was purified by flash chromatography (gradient heptane/ethyl acetate 1:1 to 0:1) to yield the title compound, light yellow solid, (23 mg, 24percent). MS (ISP): m/e=338.1 (M+H+).

References: [1]Patent: US2006/199960,2006,A1 .Location in patent: Page/Page column 18.

17
3-Amino-pyrazine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride [ No CAS ]
[ 71902-33-5 ]
3-(5-Fluoro-pyridin-3-ylamino)-pyrazine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With caesium carbonate; In N,N-dimethyl-formamide; at 180℃; for 1h;microwave irradiation;	3-Amino-pyrazine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride (120 mg, 0.47 mmol), <strong>[71902-33-5]3,5-difluoropyridine</strong> (500 mg, 4.4 mmol), cesium carbonate (610 mg, 1.89 mmol) and 1 mL N,N-dimethylformamide were mixed and stirred under microwave irradiation for 60 minutes at 180° C. The reaction mixture was extracted with sat. NaHCO3- solution and three times ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->30:70 gradient). The desired compound was obtained as a yellow solid (24 mg, 16percent), MS: m/e=314.0 (M+H+).

References: [1]Patent: US2006/199828,2006,A1 .Location in patent: Page/Page column 13.

18
[ 27489-62-9 ]
[ 71902-33-5 ]
4-trans(5-fluoro-pyridin-3-yloxy)cyclohexylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With NaH; In N,N-dimethyl-formamide; mineral oil;	Example 62A 4-trans(5-fluoro-pyridin-3-yloxy)cyclohexylamine To a stirred solution of trans-4-aminocyclohexanol (460 mg, 4 mmol) in DMF (5 mL) at 0° C. was added 60percent NaH in mineral oil (480 mg, 12 mmol). The reaction mixture was stirred at 0° C. for 1/2 hour and then <strong>[71902-33-5]3,5-difluoro-pyridine</strong> (560 mg, 4.8 mmol) was added. It was heated to 60° C. for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 211 (M+H)+.

References: [1]Patent: US2004/259843,2004,A1 .

19
[ 6290-49-9 ]
[ 71902-33-5 ]
[ 1075756-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro-trimethyl-silane; lithium diisopropyl amide; In tetrahydrofuran;	3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -720C (external -8O0C). LDA (23.9 mL, 1.1 eq.) was added drop-wise so that the internal temp did not increase more than 30C during addition. The reaction mixture turned into a deep brownish, thick phase and was stirred for 30 minutes at this temperature. TMS-Cl (43.4 mL, 43.45 mmol) was added drop-wise in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop-wise in a quicker version, and the reaction mixture was allowed to stir for 2h. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction mixture was quenched at -780C by adding 20 ml of saturated NH4Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification utilizing ISCO (0-25percent EtOAc/hexanes), gave the title compound (3 g). LCMS: 188 [M+H]+.
		Intermediate 30 l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -720C (external -8O0C). LDA (23.9 mL, 1.1 eq.) was added drop-wise at such rate that the internal temp did not increase more than 30C during addition. The reaction mixture turned into a deep brownish, thick phase and was stirred for 30 minutes at this temperature. TMS-Cl (43.4 mL, 43.45 mmol) was added via syringe in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop-wise in a quicker version, and the reaction mixture was allowed to stir for 2 hours. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction mixture was quenched at -780C by adding 20 ml of saturated NH4Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification utilizing ISCO (0-^25percent EtOAc/hexanes), gave the title product (3 g). LCMS: 188 [M+H]+.
		Intermediate 49 l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -72°C (external -800C). LDA (23.9 mL, 1.1 eq.) was added drop-wise so that the internal temp did not increase more than 3°C during addition. The reaction turned into a deep brownish, thick phase. The reaction was stirred for 30 minutes. TMS-Cl (43.4 mL, 43.45 mmol) was added drop-wise in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop- wise in a quicker version, and the reaction was allowed to stir for 2h. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction was quenched at - 78°C by adding 20 ml of saturated NH4Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification by ISCO (0-25percent EtOAc/hexanes), gave the title compound (3 g). LCMS: 188 [M+H]+.

3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -72°C (external -800C). LDA (23.9 rnL, 1.1 eq.) was added drop-wise so that the internal temperature did not increase more than 3°C during addition. The reaction mixture turned into a deep brownish, thick phase. The reaction mixture was stirred for 30 mins. TMS-Cl (43.4 mL, 43.45 mmol) was added in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop-wise in a quicker version, and the reaction mixture was allowed to stir for 2 hours. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction mixture was quenched at -78°C by adding 20 ml of saturated NH4Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification by ISCO (0- 25percent EtOAc/hexanes), gave the title product (3 g). LCMS: 188 [M+H]+.

References: [1]Patent: WO2010/20810,2010,A1 .Location in patent: Page/Page column 60.
[2]Patent: WO2010/38060,2010,A1 .Location in patent: Page/Page column 80.
[3]Patent: WO2008/132502,2008,A1 .Location in patent: Page/Page column 98.
[4]Patent: WO2009/150462,2009,A1 .Location in patent: Page/Page column 69.

20
[ 71902-33-5 ]
[ 27489-62-9 ]
4-trans(5-fluoro-pyridin-3-yloxy)cyclohexylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of trans-4-aminocyclohexanol (460 mg, 4 mmol) in DMF (5 mL) at 0 [°C] was added 60percent NaH in mineral oil (480 mg, 12 mmol). The reaction mixture was stirred at 0 [°C] for [percent 2 HOUR] and then <strong>[71902-33-5]3,5-difluoro-pyridine</strong> (560 mg, 4.8 mmol) was added. It was heated to 60 [°C] for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 211 (M+H) +.

References: [1]Patent: WO2004/26822,2004,A2 .Location in patent: Page 84.

21
[ 1942-45-6 ]
[ 71902-33-5 ]
[ 1092526-19-6 ]
C₂₁H₃₁F₂N [ No CAS ]

References: [1]Journal of the American Chemical Society,2008,vol. 130,p. 16170 - 16171.

22
[ 107-31-3 ]
[ 71902-33-5 ]
[ 870234-98-3 ]

Yield	Reaction Conditions	Operation in experiment
81%		Example 113A 3,5-Difluoroisonicotinaldehyde Under argon and at -70° C., 44 ml of 2.5 M n-butyllithium solution in n-hexane (110 mmol, 1.1 equivalent) were slowly added dropwise to 15.4 ml of diisopropylamine (110 mmol, 1.1 equivalent) in 23 ml of THF. The solution formed was warmed to 0° C. and stirred at this temperature for 30 min. The reaction mixture was then brought to -70° C. and diluted with 23 ml of THF, and 11.5 g of <strong>[71902-33-5]3,5-difluoropyridine</strong> (100 mmol, 1 equivalent) dissolved in 72 ml of THF, were added dropwise. The mixture was stirred at -70° C. for 30 min. 12.4 ml of methyl formate (200 mmol, 2 equivalent), dissolved in 23 ml of THF, were then slowly added dropwise. After 1.5 h at -70° C., the reaction solution was quickly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with in each case 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated using a rotary evaporator. This gave 11.6 g (81percent of theory) of the title compound which were directly reacted further. GC-MS (Method 14): Rt=1.82 min MS (ESpos): m/z=144.0 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=8.75 (br. s, 2H), 10.24 (br. s, 1H).
81%		Example 25A 3,5-Difluoroisonicotinaldehyde Under argon and at -70° C., 44 ml of 2.5 M n-butyllithium solution in n-hexane (110 mmol, 1.1 equivalents) were slowly added dropwise to 15.4 ml of diisopropylamine (110 mmol, 1.1 equivalents) in 23 ml of THF. The resulting solution was warmed to 0° C. and stirred at this temperature for 30 min. The reaction mixture was then cooled to -70° C. and diluted with 23 ml of THF, and 11.5 g of <strong>[71902-33-5]3,5-difluoropyridine</strong> (100 mmol, 1 equivalent), dissolved in 72 ml THF, were then added dropwise. The mixture was stirred at -70° C. for a further 30 min 12.4 ml of methyl formate (200 mmol, 2 equivalents), dissolved in 23 ml of THF, were then slowly added dropwise. After 1.5 h at -70° C., the reaction solution was slowly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with in each case 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. This gave 11.6 g (81percent of theory) of the title compound, which were directly reacted further. GC-MS (Method 14): Rt=1.82 min MS (ESpos): m/z=144.0 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=8.75 (br. s, 2H), 10.24 (br. s, 1H).
52%		Compound 13A: LDA (68 ml, 478 mmol) and THF (500 ml) were cooled to 0° C. while stirring under nitrogen and n-BuLi (192 ml, 478 mmol, 2.5 M in hexanes) was added dropwise. After 30 min, the mixture was cooled to -78° C. (dry ice/acetone bath) and <strong>[71902-33-5]3,5-difluoropyridine</strong> (50 g, 434 mmol) dissolved in 500 ml of THF was added dropwise while maintaining the temperature below -69° C. After 4 h, methyl formate (54 ml, 868 mmol) dissolved in 135 ml of THF was added dropwise (completed addition in 1.25 h). In a separate flask, 1 L sat. NaHCO3 was cooled to 0° C. while stirring. The reaction mixture was added to the NaHCO3 solution while stirring and the mixture was allowed to warm to room temperature. The organic layer was separated and the water layer was extracted with ethyl acetate (4.x., 250 mL). The combined organic extracts were washed with sat. brine, dried over Na2SO4 and concentrated to obtain a dark purple oil. Purification using flash column chromatography gave 32.5 g (52percent yield) of compound 13A.

7.85 g		PREPARATION EXAMPLE 10: N-rri -(3.5-difluoro-4-DyridvncvcloDroDyllmethyll-2- (trifluoromethyl)pyridine-3-carboxamide (Compound A126)Step 1 : <strong>[71902-33-5]3,5-difluoropyridine</strong>-4-carbaldehvdeAt 0°C A solution of LDA 2M in THF (47.792 mL, 95.58 mmol) was diluted with 50mL THF. It was cooled down to -78°C, then a solution of 3,5-Difluoropyridine (7.886 mL, 86.89 mmol) in 100mL THF was added dropwise while maintening the temperature below -70°C, (complete addition in 20 min). It gave a yellow suspension. The reaction mixture was stirred 3h at -78°C. A solution of Methyl formate (10.8 mL, 173.79 mmol) in 25mL THF was added dropwise in 15 min. The reaction mixture became a pale yellow solution. It was stirred 45 min at -75°C and then transferred via cannula to a stirred solution of 100mL sat aq NaHC03 held at about 0°C. It was extracted twice with EtOAc and the combined organic phases were washed with brine and dried with IS^SC^. The solvent was evaporated (165mbar, 30°C), 36.7 g of residue were obtained as a yellow liquid. The crude product was purified by flash chromatography (Solvent: CH2CI2). The product was isolated as a pale yellow oil (7.85 g), which crystallized upon standing.1H-NMR (CDCI3): 10.4 (s, 1 H), 8.57 (s, 2H).
	With diisopropylamine;	Example 25A 3,5-Difluoroisonicotinaldehyde Under argon and at -70° C., 44 ml of 2.5 M n-butyllithium solution in n-hexane (110 mmol, 1.1 equivalents) were slowly added dropwise to 15.4 ml of diisopropylamine (110 mmol, 1.1 equivalents) in 23 ml of THF. The resulting solution was warmed to 0° C. and stirred at this temperature for 30 min. The reaction mixture was then cooled to -70° C. and diluted with 23 ml of THF, and 11.5 g of <strong>[71902-33-5]3,5-difluoropyridine</strong> (100 mmol, 1 equivalent), dissolved in 72 ml THF, were then added dropwise. The mixture was stirred at -70° C. for a further 30 min. 12.4 ml of methyl formate (200 mmol, 2 equivalents), dissolved in 23 ml of THF, were then quickly added dropwise. After 1.5 h at -70° C., the reaction solution was quickly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with in each case 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. This gave 11.6 g (81percent of theory) of the title compound, which were directly reacted further. GC-MS (Method 14): Rt=1.82 min MS (ESpos): m/z=144.0 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=8.75 (br. s, 2H), 10.24 (br. s, 1H).
		3,5-Difluoro-pyridine-4-carboxaldehyde Diisopropylamine (13.4 mL, 95.6 mmol) in THF (40 mL) was stirred at about 0 °C under an atmosphere of nitrogen and n-butyllithium (1.6M in hexanes, 60 mL, 96 mmol) was added while maintaining reaction temperature below about 10 °C. The mixture was stirred for about 30 minutes at about 0 °C and then was diluted with THF (150 mL) and cooled to about-78 °C. A solution of <strong>[71902-33-5]3,5-difluoro-pyridine</strong> (10.0 g, 86.9 mmol) in THF (100 mL) was added dropwise while maintaining the reaction temperature below about-75 °C. The solution was stirred at about-78 °C for about 1 hour and a solution of methyl formate (10.7 mL, 174 mmol) in THF (30 mL) was added over about 30 minutes. The mixture was stirred for about 0.75 hr and then transferred via cannula to a stirred solution of saturated aqueous NaHC03 (200 mL) held at about 0 °C. The product was extracted with EtOAc (100 mL) and the combined organic extracts were washed with saturated aqueous brine solution (2 x 100 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure (165 mbar, bath temperature about 30 °C). The crude material was purified by flash chromatography on silica gel using DCM as the mobile phase. Fractions containing the desired product were combined and concentrated under reduced pressure. Crystallization from heptane afforded 3,S-difluoro-pyridine-4-carboxaldehyde as an off-white solid (4.44 g, 31.0 mmol) ; (at)H NMR (DMSO-d6, 300 MHz) 10.23 (s, 1H), 8.75 (s, 2H) ; RP-HPLC (Table 1, Method m) Rt 0.62 min.

References: [1]Patent: US2014/128386,2014,A1 .Location in patent: Paragraph 1410; 1411; 1412; 1413; 1414.
[2]Patent: US2017/57954,2017,A1 .Location in patent: Paragraph 0630; 0631; 0632; 0633; 0634.
[3]Patent: US2009/286800,2009,A1 .Location in patent: Page/Page column 107-108.
[4]Patent: WO2013/64521,2013,A1 .Location in patent: Page/Page column 112.
[5]Patent: US2017/217954,2017,A1 .
[6]Patent: WO2005/110410,2005,A2 .Location in patent: Page/Page column 79-80.

23
[ 1461-22-9 ]
[ 71902-33-5 ]
[ 765916-82-3 ]

Yield	Reaction Conditions	Operation in experiment
88%		INTERMEDIATE 63 : 3, 5-Difluoro-4-tributylstannanyl-pyridine [00224]. n-Butyl lithium (1.0 eq, 76 mmol, 47.6 mL, 1.6 M in hexanes) was added via dropping funnel to a solution of diisopropylamine (1.05 eq, 80 mmol, 11.2 mL) in THF (300 mL) at-78 °C under nitrogen (N2). The solution was stirred for 30 min at-78 °C, then a solution of 3,5- difluoropyridine (1.05 eq, 80 mmol, 9.2 g) in THF (20 mL) was added dropwise via syringe. A beige precipitate was observed to form. The reaction stirred at-78 °C for 90 min then tributyltin chloride (1.0 eq, 76 mmol, 20.7 mL) was added dropwise via syringe and the resulting solution allowed to warm to RT over 2 h. Water (5 mL) was added, then roughly 250 mL of THF was removed on a rotary evaporator. The resulting material was diluted with diethyl --139-- ether (350 mL) and washed successively with water (2X200 mL), saturated sodium chloride solution (1X150 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the 3,5-Difluoro-4-tributylstannanyl-pyridine as a colourless oil (27.5 g, 88percent). This material was used crude without further purification. Retention Time (LC, method: ammonium acetate standard): 3.35 min. MS (M+H+) : 406.
88%		Intermediate 63: 3,5-Difluoro-4-tributylstannanyl-pyridine n-Butyl lithium (1.0 eq, 76 mmol, 47.6 mL, 1.6 M in hexanes) was added via dropping funnel to a solution of diisopropylamine (1.05 eq, 80 mmol, 11.2 mL) in THF (300 mL) at -78° C. under nitrogen (N2). The solution was stirred for 30 min at -78° C., then a solution of <strong>[71902-33-5]3,5-difluoropyridine</strong> (1.05 eq, 80 mmol, 9.2 g) in THF (20 mL) was added dropwise via syringe. A beige precipitate was observed to form. The reaction stirred at -78° C. for 90 min then tributyltin chloride (1.0 eq, 76 mmol, 20.7 mL) was added dropwise via syringe and the resulting solution allowed to warm to RT over 2 h. Water (5 mL) was added, then roughly 250 mL of THF was removed on a rotary evaporator. The resulting material was diluted with diethyl ether (350 mL) and washed successively with water (2200 mL), saturated sodium chloride solution (1150 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the 3,5-Difluoro-4-tributylstannanyl-pyridine as a colourless oil (27.5 g, 88percent). This material was used crude without further purification. Retention Time (LC, method: ammonium acetate standard): 3.35 min. MS (M+H+): 406.

References: [1]Patent: WO2004/92167,2004,A1 .Location in patent: Page 138.
[2]Patent: US2005/239781,2005,A1 .Location in patent: Page/Page column 85; 106.

24
[ 700-16-3 ]
[ 2875-18-5 ]
[ 2693-66-5 ]
[ 76469-41-5 ]
[ 71902-33-5 ]

References: [1]Tetrahedron Letters,2010,vol. 51,p. 2265 - 2268.

25
[ 109384-19-2 ]
[ 71902-33-5 ]
[ 1189551-57-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 17h;	t-Butyl 4-hydroxypiperidine-1-carboxylate (1.04 g, 5.00 mmol) was added to a N,N-dimethylformamide suspension (5.0 ml) of 60percent sodium hydride (229 mg, 6.00 mmol), at 0°C, and stirring was carried out at room temperature for 30 minutes. Further, at 0°C, <strong>[71902-33-5]3,5-difluoropyridine</strong> (645 mg, 5.50 mmol) was added, and stirring was carried out for 16.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed sequentially with water and saline, and then dried over anhydrous sodium sulfate. The organic layer was concentrated and the resulting residue was purified by silica gel column chromatography to afford t-butyl 4-[(5-fluoropyridin-3-yl)oxy]piperidine-1-carboxylate (1.48 g, yield 99percent) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) delta: 8.16-8.11 (2H, m), 6.96 (1H, dt, J=10.2, 2.3 Hz), 4.52-4.47 (1H, m), 3.73-3.67 (2H, m), 3.39-3.33 (2H, m), 1.99-1.73 (4H, m), 1.47 (9H, s). MS (ESI, m/z): 297 (M+H)+.

References: [1]Patent: EP2258697,2010,A1 .Location in patent: Page/Page column 107-108.

26
[ 1942-45-6 ]
[ 71902-33-5 ]
[ 1092526-19-6 ]

References: [1]Dalton Transactions,2010,vol. 39,p. 10483 - 10494.

Historical Records

Technical Information

• Alkyl Halide Occurrence • Preparation of Amines

Related Functional Groups of
[ 71902-33-5 ]

Fluorinated Building Blocks

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[ 71902-33-5 ]

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