1034467-80-5|5-Cyclopropyl-2-fluoropyridine| Ambeed

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Quality Control of [ 1034467-80-5 ] Purity: 97% SDS Specification

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Product Details of [ 1034467-80-5 ]

CAS No. :	1034467-80-5
Formula :	C₈H₈FN
M.W :	137.15
SMILES Code :	FC1=NC=C(C2CC2)C=C1
MDL No. :	MFCD18384289
InChI Key :	HDIKFKIIABQSPW-UHFFFAOYSA-N
Pubchem ID :	57690831

Safety of [ 1034467-80-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H227-H315-H319-H335
Precautionary Statements:	P305+P351+P338

Computational Chemistry of [ 1034467-80-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.38
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	36.66
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.	2.0
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	2.2
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.46
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.	1.91
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	2.86
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.28

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.45
Solubility	0.482 mg/ml ; 0.00351 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.	-2.1
Solubility	1.08 mg/ml ; 0.00786 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	-2.87
Solubility	0.184 mg/ml ; 0.00134 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.	-5.57 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	1.0 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)	1.77

Application In Synthesis of [ 1034467-80-5 ]

* 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.

Downstream synthetic route of [ 1034467-80-5 ]

[ 1034467-80-5 ] Synthesis Path-Downstream 1~35

1
[ 171197-80-1 ]
[ 411235-57-9 ]
[ 1034467-80-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium phosphate;palladium diacetate; In water; toluene; at 100℃; for 4h;	Preparation 46; 5-Cyclopropyl-2-fluoro-pyridine; In a flask, combine 2-fluoro-5-iodo-pyridine (1.12 g, 5 mmol), cyclopropylboronic acid (645 mg, 7.5 mmol), palladium acetate (56 mg, 0.25 mmol), potassium phosphate (3.2 g, 15 mmol), and toluene-water (20: 1, 21 mL). Heat the mixture at 100 0C for 4 hours. Dilute the mixture with chloroform-isopropanol (3: 1, 100 mL). Wash the organic phase with saturated aqueous sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to a brown oil. Purify by column chromatography (20 % ethyl acetate in hexane) to afford the title compound (430 mg, 63 %) as a pale yellow oil. 1H νMR (400 MHz-CDCl3) δ 7.99 (d, J= 3 Hz, IH), 7.39 (td, J= 3, 5 Hz, IH), 6.79 (dd, J= 3, 8 Hz, IH), 0.96-1.02 (m, 2H), 0.63-0.69 (m, 2H).
63%	With potassium phosphate;palladium diacetate; In water; toluene; at 100℃; for 4h;	Preparation 145-Cyclopropyl-2-fluoro-pyridineCombine 2-fluoro-5-iodo-pyridine (1.12 g, 5 mmol), cyclopropylboronic acid (645 mg, 7.5 mmol), palladium acetate (56 mg, 0.25 mmol) and potassium phosphate (3.2 g, 15 mmol) in toluene/water (20: 1, 21 mL). Heat the mixture at 100 0C for 4 h. Dilute the mixture with chloroform-IPA (3:1, 100 mL). Wash the organic phase with saturated aqueous sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to a brown oil. Purify by column chromatography (20 % ethyl acetate in hexane) to afford the title compound as a pale yellow oil (430 mg, 63 %).

References: [1]Patent: WO2008/76705,2008,A1 .Location in patent: Page/Page column 19.
[2]Patent: WO2008/144222,2008,A2 .Location in patent: Page/Page column 13.

2
[ 1034467-80-5 ]
[ 1034467-82-7 ]

Yield	Reaction Conditions	Operation in experiment
68%		Preparation 47; S-Cyclopropyl^-fluoro-S-iodo-pyridine; Cool a solution of 5-cyclopropyl-2-fluoro-pyridine (1.3 g, 9.5 mmol) in THF (20 mL) to -75 0C in a dry ice-acetone bath under nitrogen. Add lithium diisopropylamide (2 M in THF, 6 mL, 12 mmol) over a period of 30 min. Stir the mixture for an additional 3 hours. Add iodine (2.9 g, 11.4 mmol, dissolved in 50 mL of THF) and stir the mixture for 2 hours. Add water (100 mL) and allow the temperature to rise to room temperature over 1 hour while stirring. Treat the mixture with saturated aqueous sodium thiosulfate solution (50 mL). Extract the solution with ether. Concentrate the solution in vacuo to brown oil. Purify by column chromatography (hexane to 20 % ethyl acetate in hexane) to afford the title compound (1.7 g, 68 %) as a yellow oil. 1H NMR (40OMHz-CDCl3) δ 8.03 (dd, J= 3, 8 Hz, IH), 7.99 (s, IH), 0.91-1.00 (m, 2H), 0.71-0.78 (m, 2H).
68%		Preparation 155-Cyclopropyl-2-fluoro-3-iodo-pyridineCool a solution of 5-cyclopropyl-2-fluoro-pyridine (1.3 g, 9.5 mmol) in THF (20 mL) to -75 0C in a dry ice-acetone bath under nitrogen. Add lithium diisopropylamide (2 M in THF, 6 mL, 12 mmol) during a period of 30 min. Stir the mixture for another 3 h before adding iodine (2.9 g, 11.4 mmol, dissolved in 50 mL of THF). Keep stirring for 2 more hours before adding water (100 mL) to the mixture. Then allow to warm to RT during 1 h under stirring. Treat the mixture with a saturated sodium thiosulfate solution (50 mL). Extract the solution with ether. Concentrate the solution in vacuo. Purify by column chromatography (hexane-^ 20% ethyl acetate in <n="15"/>hexane) to afford the title compound as a yellow oil (1.7 g, 68 %). 1H NMR (400 MHz- CDCl3) δ 7.99 (d, J= 3 Hz, IH), 7.39 (td, J= 3, 5 Hz, IH), 6.79 (dd, J= 3, 8 Hz, IH), 0.96-1.02 (m, 2H), 0.63-0.69 (m, 2H).

References: [1]Patent: WO2008/76705,2008,A1 .Location in patent: Page/Page column 20.
[2]Patent: WO2008/144222,2008,A2 .Location in patent: Page/Page column 13-14.

3
[ 1034467-80-5 ]
4-hydroxy-3-(piperidin-4-yl)-4-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridine-6-one [ No CAS ]
3-[1-(5-cyclopropylpyridin-2-yl)piperidin-4-yl]-4-hydroxy-4-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridine-6-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%		(Example 99) 3-[1-(5-Cyclopropylpyridin-2-yl)piperidin-4-yl]-4-hydroxy-4-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one[0795] 4-hydroxy-3-(piperidin-4-yl)-4-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one (385 mg, 1.27 mmol) produced in Reference Example 116, and N,N-diisopropylamine (323 µL, 1.90 mmol) in dimethyl sulfoxide (3 mL) was stirred while irradiated with microwaves at 60C for 1.5 hours using Initiator(R) manufactured by Biotage Japan Ltd. The reaction solution was poured to water, and the precipitate was collected by filtration and dried at 60C under reduced pressure to obtain a crude product (345 mg).[0798] A suspension of a portion (140 mg) of the obtained crude product and iron (71.5 mg, 1.28 mmol) in acetic acid (5 mL) was stirred at 70C for 1 hours and 50 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The resulting solid was filtered off. The filtrate was washed with a saturated sodium bicarbonate aqueous solution and brine in this order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elute: ethyl acetate/methanol = 95/5 - 80/20 (gradient)] and further purified by silica gel chromatography [elute: hexane/ethyl acetate = 88/12 - 0/100 (gradient)] to obtain the title compound (37.2 mg, yield: 14%).[0799] 1H-NMR (DMSO-d6) δ: 12.22 (1H, s), 10.49 (1H, s), 7.96 (1H, d, J = 2 Hz), 7.20 (1H, dd, J = 9, 2 Hz), 6.77 (1H, d, J = 9 Hz), 6.72 (1H, s), 4.41-4.32 (2H, m), 3.25-3.15 (1H, m), 2.89 (1H, d, J = 16 Hz), 2.76-2.68 (2H, m), 2.72 (1H, d, J = 16 Hz), 1.90-1.62 (4H, m), 1.30-1.20 (1H, m), 0.88-0.83 (2H, m), 0.60-0.54 (2H, m); MS (ESI) m/z: 422 (M+H)+.
14%		5-Cyclopropyl-2- fluoropyridine (compounds described in WO2008 / 76 705 pamphlet, 209mg, 1.52mmol) in dichloromethane (3 mL) solution of hydrogen peroxide urea (301 mg, 3.20 mmol) and trifluoroacetic acid anhydride thing (426μL, 3.04mmol) was added, and the mixture was stirred overnight.After the reaction mixture was diluted with dichloromethane, saturated sodium hydrogen carbonate aqueous solution was washed successively with 10% aqueous sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.The resulting residue, prepared in Reference Example 116 was 4-hydroxy-3- (piperidin-4-yl) -4- (trifluoromethyl) -1,4,5,7- tetrahydro -6H- pyrazolo [3 , 4-b] pyridin-6-one (385mg, 1.27mmol), and, N, N- diisopropylamine (323μL, 1.90mmol) of dimethyl sulfoxide (3 mL) solution Biotage Inc. the Initiator (TM) of using, 60 , and the mixture was stirred while being irradiated for 1.5 hours microwave.The reaction mixture was poured into water, collected by filtration and the resulting solid, dried under reduced pressure at 60 , was obtained (345mg).A portion of the resulting crude product (140 mg), and iron (71.5 mg, 1.28 mmol) and acetic acid (5 mL) suspension and stirred for 1 hour 50 minutes at 70 C..The solvent was distilled off under reduced pressure, ethyl acetate was added and the resulting solid was filtered off, the filtrate a saturated aqueous sodium hydrogen carbonate solution, successively washed with saturated brine, dried over anhydrous sodium sulfate under reduced pressure, the solvent It was distilled off.The obtained residue was purified by silica gel column chromatography [NH- silica gel column, eluent: ethyl acetate / methanol = 95 / 5-80 / 20 (gradient)] to give the further silica gel chromatography [eluent: hexane / acetic acid ethyl = 88 / 12-0 / 100 and purified by (gradient)] to give the title compound (37.2 mg, yield: 14%) was obtained.1H-NMR (DMSO-d-. 6) [delta]

References: [1]Patent: EP2862861,2015,A1 .Location in patent: Paragraph 0796; 0797; 0798; 0799.
[2]Patent: JP2015/113323,2015,A .Location in patent: Paragraph 0750 - 0752.

4
[ 1034467-80-5 ]
[ 1338378-32-7 ]
5-cyclopropyl-2-(3-ethoxy-4-iodo-5-methyl-1H-pyrazol-1-yl)-pyridine [ No CAS ]
5-cyclopropyl-2-(3-ethoxy-5-methyl-1H-pyrazol-1-yl)pyridine [ No CAS ]