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Chemical Structure| 402-69-7 Chemical Structure| 402-69-7

Structure of 402-69-7

Chemical Structure| 402-69-7

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Product Details of [ 402-69-7 ]

CAS No. :402-69-7
Formula : C6H4FNO2
M.W : 141.10
SMILES Code : C1=CC=C(F)N=C1C(=O)O
MDL No. :MFCD02181193
InChI Key :DIEMCUFYSOEIDU-UHFFFAOYSA-N
Pubchem ID :226027

Safety of [ 402-69-7 ]

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

Computational Chemistry of [ 402-69-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 31.15
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

50.19 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.89
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.97
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.34
Log Po/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.

-0.69
Log Po/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

1.17
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.74

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.7
Solubility 2.79 mg/ml ; 0.0198 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.

-1.61
Solubility 3.45 mg/ml ; 0.0244 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

-1.65
Solubility 3.15 mg/ml ; 0.0223 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.

-6.47 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.

0.56

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)

1.5

Application In Synthesis of [ 402-69-7 ]

* 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 [ 402-69-7 ]

[ 402-69-7 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 407-22-7 ]
  • [ 402-69-7 ]
YieldReaction ConditionsOperation in experiment
53% With potassium permanganate; In water; for 3h;Heating / reflux; To [A] solution of 2-fluoro-6-methyl-pyridine (2.5g, 22.5 [MMOL)] in water (170 ml) was added portionwise [KMN04] (2g, 12.65 mmol) and the mixture was heated to reflux. Then [KMN04] (8g, 50.63 [MMOL)] was added portionwise and the mixture was heated under reflux for 3 hours. On cooling, the precipitate was filtered and the filtrate was acidified with a solution of HCI and then concentrated under reduced pressure. The residue was triturated with hot EtOH, the solid was filtered and the filtrate was concentrated to dryness under reduced pressure. The title compound was obtained as a white solid (1.7g, 53percent); m. p. [137°C.]
53% With potassium permanganate; In water; for 3h;Heating / reflux; To a solution of 2-fluoro-6-methyl-pyridine (2.5g, 22.5 [MMOL)] in water (170 ml) was added portion-wise [KMN04] (2g, 12.65 [MMOL)] and the mixture was heated to reflux. [KMN04] [(8G,] 50.63 [MMOL)] was added portion-wise and the mixture was heated under reflux for 3 hours and then cooled. The precipitate was filtered and the filtrate was acidified with a solution of HCI and then concentrated under reduced pressure. The residue was triturated with hot [ETOH,] the solid filtered and the filtrate was concentrated to dryness under reduced pressure. The title compound was obtained as a white solid (1.7g, 53percent); m. p. [137°C.]
  • 2
  • [ 186581-53-3 ]
  • [ 402-69-7 ]
  • [ 455-71-0 ]
  • 3
  • [ 402-69-7 ]
  • [ 541-41-3 ]
  • C9H8FNO4 [ No CAS ]
  • 4
  • [ 792903-64-1 ]
  • [ 402-69-7 ]
  • 6-fluoro-N-{(1S)-3-[((1S)-2-methyl-1-[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-1carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-2-pyridinecarboxamide [ No CAS ]
  • 5
  • [ 402-69-7 ]
  • 4-chloro-2-(difluoromethyl)-1-[5-(6-fluoro-2-pyridinyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indole-5-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% B. 4-Chloro-2-(difluoromethyl)-1 -[5-(6-fluoro-2-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl}-1H-indole-5-carbonitrile; <n="96"/>To a solution of beta-fluoro^-pyridinecarboxylic acid (0.006 g, 0.043 mmol) in MeCN (2 ml_), under N2, was added EDCI (0.0085 g, 0.044 mmol). After 5 min, 2- [4-chloro-5-cyano-2-(difluoromethyl)-1/-/-indol-1-yl]acetohydrazide (0.012 g, 0.040 mmol) was added. After 1 h, additional beta-fluoro^-pyridinecarboxylic acid (0.003 g, 0.02 mmol) and EDCI (0.0077 g, 0.040 mmol) were added. After another 15 min, additional <strong>[402-69-7]6-fluoro-2-pyridinecarboxylic acid</strong> (0.0014 g, 0.01 mmol) and EDCI (0.0046 g, 0.02 mmol) were added. After another 10 min, TsCI (0.009 g, 0.048 mmol) and P-BEMP (loading 2.2 mmol/g, 0.073 g, 0.16 mmol) were added and the mixture was heated at 12O0C for 20 min. Upon cooling, additional TsCI (0.0046 g, 0.024 mmol) and P-BEMP (0.037 g, 0.08 mmol) were added and the mixture was heated at 12O0C for another 20 min. Upon cooling, the resin was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (0-50percent EtOAc-hexanes gradient) and the product was crystallized from CH2CI2-hexanes to give the title compound as a white solid (0.005 g, 31 percent yield): MS (ES) m/z 404 (M+1 ).
  • 6
  • [ 402-69-7 ]
  • [ 315180-17-7 ]
  • 7
  • [ 402-69-7 ]
  • 6-(6-fluoro-pyridin-2-ylmethoxy)-9<i>H</i>-purin-2-ylamine [ No CAS ]
  • 9
  • [ 402-69-7 ]
  • [ 369-03-9 ]
  • 10
  • [ 2369-19-9 ]
  • [ 7732-18-5 ]
  • [ 402-69-7 ]
YieldReaction ConditionsOperation in experiment
With potassium permanganate; at 100℃; for 4h;Heating / reflux; Add potassium permanganate (12.8 g, 81.0 mmol) to a solution of 2-fluoro-5-methylpyridine (3.0 g, 27.0 mmol) in water (135 ml). Heat the reaction to 100 C for 4hours. While the reaction is hot, filter through Celite Rinse the filter cake with hot water (2 x 50ml) and concentrate the combined aqueous solutions in vacuo to a volume of 50 ml. Acidify with concentrated HCl and concentrate to dryness in vacuo to provide the title compound as a white solid which is used directly in the next step. MS APCI+ m/e 142 (M+1)
  • 11
  • [ 402-69-7 ]
  • [ 64197-03-1 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride; for 3h;Heating / reflux; Intermediate 20 (1g, 7.09 [MMOL)] was added portionwise to thionyl chloride (3 ml) and the mixture was heated under reflux for 3 hours and then concentrated under reduced pressure. Isopropanol (3 ml) was added to the residue and the mixture was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was treated with a saturated solution of NaHCO3, extracted with ethyl acetate, the organic phase was dried over [NA2SO4] and concentrated under reduced pressure. The title compound was obtained as an cream oil (1.2g, 93percent); [[APCI] MS] m/z: 184 (MH+).
With thionyl chloride; for 5h;Reflux; 2-fluoro-pyridine-6-carboxylic acid in thionyl chloride (2ml) (86mg, 0.448mmol) was heated under reflux for 5 hours stirred suspension of. Then excess reagent was removed under reduced pressure to give a crude solid. The crude solid, 4- (6-methyl-imidazo [1,2-a] pyridin-2-yl) aniline (100 mg, 0.448 mmol) and dry THF (20 ml) and diisopropylethylamine (94mul, 0.539mmol) in the amide prepared as described in the section amide coupling using, work-up and flash chromatography: the (2 1 EtOAc / hexanes) after to give the title compound 85 mg, 55percent) of a colorless solid .
  • 12
  • [ 748807-42-3 ]
  • [ 402-69-7 ]
  • [ 748807-43-4 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; EDCI (80 mg) and DMAP (20 mg) are added to a stirred solution of (4,6-diethoxy- PYRIDAZIN-3-YLMETHYL)-3-METHYL-BYTYL)-AMINE (93.5 mg) and fluoropyridinyl acid (59 mg) in DCM (10ML). The mixture is stirred at room temperature overnight. DCM (10 ml) is added to dilute the mixture. The mixture is washed with water (5 mL), dried (NA2S04), and evaporated. Preparative TLC purification of the residue (2: 1 of hexane: ethyl acetate) provides the title product (Compound 2). HL NMR 6 (CDCI3) 7.80-7. 92 (M, 1H), 7.60-7. 68 (M, 1H), 6.95-7. 02 (M, 1H), 6.22 (s, 2H), 4.98 (s, 2H), 4.56 (q, 2H, J = 7.2 Hz), 4.12.
  • 13
  • [ 748807-47-8 ]
  • [ 402-69-7 ]
  • 6-fluoro-pyridine-2-carboxylic acid (6-chloro-4-propyl-pyridazin-3-ylmethyl)-isobutyl-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; To a stirred solution of (6-chloro-4-propyl-pyridazin-3-ylmethyl)-isobutyl-amine (940 mg, 3.89 mmol) and <strong>[402-69-7]6-fluoro-pyridine-2-carboxylic acid</strong> (663 mg, 4.7 mmol) in CH2C12 (LOML) is added EDCI (783 mg, 4.7 mmol) and DMAP (244 mg, 2 mmol). The mixture is stirred at room temperature overnight. Water (10 ml) is added and the layers are separated. The organic layer is washed with brine (10 ml), then dried (NA2S04) and evaporated. Flash column purification of the residue (2: 1 of hexane : ethyl acetate) provides the title PRODUCT. 1H NMR (CDCI3) (mixture of rotamers) 7.89 (q, 0.7H), 7.81 (q, 0.3H), 7.69 (dd, 0.3H), 7.53 (dd, 0.7H), 7.34 (s, 0.7H), 7.20 (s, 0. 3H), 6.99 (dd, 0.7H), 6.91 (dd, 0.3H), 5.19 (s, 0.6H), 5.07 (s, 1.4H), 3.41 (d, 0.6H), 3.31 (d, 1.4H), 2.75 (t, 1.4H), 2.48 (t, 0.6H), 2.08-2. 17 (M, 1H), 1.69-1. 75 (M, 1.4H), 1.54-1. 60 (M, 0.6H), 1.02 (t, 2. 1H), 0.99 (d, 1.8 H), 0.97 (t, 0.9H), 0.80 (d, 4.2H).
  • 14
  • [ 748807-58-1 ]
  • [ 402-69-7 ]
  • [ 748807-56-9 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; To a stirred solution of (6-CHLORO-5-PROPYL-PYRIMIDIN-4-YLMETHYL)- (3-METHYL-BUTYL)- amine (0.715 g, 2.8 mmol) and 6-FLUORO-PYRIDINE-2-CARBOXYLIC acid (0.47g, 3.34 mmol) in DCM (LOML) is added EDCI (0.61 g) and DMAP (0.153 g). The mixture is stirred at room temperature overnight. DCM (10 ml) is added to dilute the mixture. The mixture is washed with water (5 mL), dried (NA2S04) and solvent evaporated. Preparative TLC purification of the residue (2: 1 of hexane : ethyl acetate) provides the title product. HL NMR 6 (CDC13) 8.69 and 8.75 (s, 1H), 7.71- 7.97 (m, LH), 7.58-60 (m, 1H), 4.79 and 5.07 (s, 2H), 3.50-3. 64 (m, 2H), 2.59-2. 87 (m, 2H), 1.45- 1.72 (m, 5H), 0.92-1. 09 (m, 4H), 0.81 (d, 6H).
  • 15
  • [ 748807-64-9 ]
  • [ 402-69-7 ]
  • [ 919991-01-8 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; To a stirred solution of ISOBUTYL- (8-PROPYL- [1, 2,4] triazolo [1, 5-c] pyrimidin-7-ylmethyl)- amine (2.8 mmol) and <strong>[402-69-7]6-fluoro-pyridine-2-carboxylic acid</strong> (0.47g, 3.34 mmol) in DCM (10ML) is added EDCI (0.61 g) and DMAP (0.153 g). The mixture is stirred at room temperature overnight. DCM (10 ml) is added to dilute the mixture. The mixture is washed with water (5 mL), dried (NA2S04) and solvent evaporated. Preparative TLC purification of the residue (2: 1 of hexane: ethyl acetate) provides the title product. HL NMR 6 (CDC13) (mixture of rotamers) 9.25 (s, 0. 5H), 9.18 (s, 0. 5H), 8.39 (s, 0. 5H), 8.36 (s, 0. 5H), 7.78-7. 93 (M, 1H), 7.68 (d, 0. 5H), 7.57 (d, 0. 5H), 6.99 (d, 0. 5H), 6.92 (d, 0. 5H), 5.03 (s, 1H), 4.89 (s, 1H), 3.52 (d, 1H), 3.35 (d, 1H), 3.12 (t, 1H), 2.83 (t, 1H), 1.95-2. 20 (M, 1H), 1.59-1. 85 (M, 2H), 0.88-1. 10 (M, 6H), 0.82 (t, 3H).
  • 16
  • [ 407-22-7 ]
  • [ 67-63-0 ]
  • [ 402-69-7 ]
YieldReaction ConditionsOperation in experiment
45% With potassium permanganate; In chloroform; water; PREPARATION 233 6-Fluoropyridine-2-carboxylic acid To a heterogeneous solution of 2-fluoro-6-methyl-pyridine (9.65 g, 86.8 mmol) in water (400 mL) was added potassium permanganate (31.6 g, 200 mmol), and the reaction was heated to approximately 100° C. After 30 minutes, additional potassium permanganate (16.5 g, 104 mmol) was added, and the reaction heated at 100° C. overnight. The reaction was filtered through celite to remove manganese salts. The mother liquor was washed with ethyl ether (200 mL*3), neutralized to pH 7, and concentrated down to approximately 100 mL total volume. The aqueous solution was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate, followed by 20percent i-PrOH/CHCl3 (*3). The combined organic layers were dried over MgSO4 and concentrated. The solids were suspended in chloroform, sonicated, then filtered to remove remaining side products. The mother liquor was concentrated to give 5.47 g as a white crystalline solid, 45percent yield. 1H NMR: consistent with structure. MS (ion spray) 140 (M-).
  • 17
  • [ 79-37-8 ]
  • [ 402-69-7 ]
  • [ 64197-03-1 ]
YieldReaction ConditionsOperation in experiment
97% N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 24h; Oxalyl chloride (1.35 g, 10.6 mmol) was added to a stirred solution of <strong>[402-69-7]6-fluoropicolinic acid</strong> (1.0 g, 7.09 mmol) in CH2Cl2 (25 mL) at rt under argon atmosphere. A drop of DMF was added to initiate reaction. After stirring for 24 h at rt, the solvents were removed in vacuo to yield the acid chloride as a colorless solid (1.35 g, 97percent).
  • 18
  • [ 402-69-7 ]
  • [ 57260-71-6 ]
  • [ 1071521-56-6 ]
YieldReaction ConditionsOperation in experiment
84% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h; General procedure D. 4-(6-Fluoro~pyridine-2-carbonyI)-piperazine-l- carboxylic acid tert-butyl esterTo a stirred solution of 6-fluoro-2-pyridine carboxylic acid (leqv, 2.00 g, 14.2 mmol), N-boc-piperazine (1.15eqv, 3.04 g, 16.3 mmol) and DIPEA (2.5 eqv, 6.12 ml, 35.4 mmol) in DCM (100 ml) at room temperature was added portionwise EDC (1.2eqv, 3.09 g, 17.0 mmol) and HOBt (0.2eqv, 0.383 g, 2.83 mmol). The reaction mixture was stirred at room temperature for 16 hrs then concentrated at reduced pressure. The crude material was purified by chromatography [SiO2, EtOAc / heptane, 1 :1] to give pure product (4.40 g, 84percent, 11.93 mmol) as colourless oil. LC/MS: 95percent MH+, m/z 310, Rt = 0.97 mins.
  • 19
  • [ 402-69-7 ]
  • [ 6638-79-5 ]
  • [ 676343-47-8 ]
YieldReaction ConditionsOperation in experiment
85% To <strong>[402-69-7]6-fluoropicolinic acid</strong> (980 mg, 6.95 mmol) was in DCM (50 mL) was added DMF (50 mu., 0.65 mmol), followed by dropwise addition of oxalyl chloride (650 mu, 7.43 mmol). After 1.2 h, N,O-dimethylhydroxyl amine HC1 (1.05 g, 10.8 mmol) was added and the reaction mixture was cooled to 0°C. Pyridine (2.6 mL, 32 mmol) was added and the reaction mixture was allowed to warm to room temperature and stir 72 h. The reaction mixture was quenched by the addition of water and the layers were partitioned. The aqueous phase was extracted with dichlorom ethane and the combined organic layer was washed with brine, dried (MgS04), filtered and concentrated under reduced pressure to afford 6-fluoro-N-methoxy-N-methylpicolinamide (1.09 g, 85.0 percent yield) as a clear pale yellow oil. NMR (500 MHz, CD3C1) delta 7.88 (q, J=7.8 Hz, 1 H), 7.56 (br. s., 1 H), 7.02 (dd, J=8.2, 2.4 Hz, 1 H), 3.79 (br. s., 3 H), 3.37 (br. s., 3 H). LCMS m/z = 185.0 (M+H).+
84% Step A-6-Fluoro-N-methyl-M-(methyloxy)-2-pyridinecarboxamide 2-Fluoropyridine-6-carboxylic acid (1.00 g, 7.09 mmol) was dissolved in 50 mL of DCM with stirring. DMF (3 drops) was added. Gxalyi chloride (4.3 mL, 2M in DCM, 8.6 mmol) was added dropwise via syringe. The reaction was stirred for 1 h and cooled to 0° C. N,O-Dimethylhydroxylamine hydrochloride (0.761 g, 7.80 mmol) was added in a single portion. Pyridine (1.26 mL, 15.6 mmol) was added via syringe, and the reaction was allowed to warm to room temperature. The reaction was stirred for 16 h and poured into half-saturated NaHCO3 solution and DCM. The layers were separated, and the aqueous layer was washed with EtOAc, The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography provided 1.10 g (84percent) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta 8.11 (m, 1H), 7.56 (m, 1H), 7.32 (dd, J=8.2, 2.4 Hz, 1H), 3.65 (s, 3H), 3.25 (s, 3H).
67% A solution of 6-methoxypicolinic acid (2.018g,13.2 mmol) in DCM (70 mL) was treated with DMF (0.1 mL, 1.3 mmol) and oxalylchloride (1.34 mL, 15.8 mmol), after 1 h the solution was cooled to 0 °C and N,O-dimethylhydroxylamineHCl (1.42 g, 14.6 mmol) and pyridine (2.34 mL, 28.9 mmol) were added. Themixture was stirred at room temperature for 18 h, sat. aq. NaHCO3 (200mL) was added and the mixture was partitioned between DCM and water. Theorganic fractions were dried and evaporated, column chromatography (97.5:2.5DCM:MeOH) gave N,6-dimethoxy-N-methylpicolinamide (2.372 g, 92percent) asan oil. 1H NMR (CD3SOCD3) delta 7.86 (dd, J = 8.3, 7.3 Hz, 1H), 7.66 (dd, J = 7.3, 0.7 Hz, 1H), 7.05 (dd, J = 8.3, 0.7 Hz, 1H), 3.90 (s, 3H), 3.28(bs, 3H). Found: [M+H] = 197.2.
With triethylamine; HATU; In dichloromethane; at 20℃; for 24h; A solution of <strong>[402-69-7]6-fluoropicolinic acid</strong> (20.0 g, 142 mmol), Nu,Omicron- dimethylhydroxylamine hydrochloride (16.6 g, 170 mmol), 0-(7-azabenzotriazol-l-yl)- Nu,Nu,Nu,Nu-tetramethyluronium hexafluorophosphate (HATU) (80.8 g, 213 mmol) and triethylamine (59.1 mL, 425 mmol) in dichloromethane (500 mL) was stirred for 24 h at RT and treated with 200 mL of saturated aq. H4CI solution. The resulting solution was extracted with dichloromethane (2 x 500 mL). The organic layers were combined, dried over Na2S04 and concentrated. The residue obtained was purified on silica gel with EtO Ac/petroleum ether (15-50percent) to give the title compound as a yellow oil. LCMS, ESI pos. : Calcd. for C8H9FN2O2: 185.0 (M+H)+; found: 184.9.

  • 20
  • [ 4926-28-7 ]
  • [ 402-69-7 ]
  • [ 656239-43-9 ]
YieldReaction ConditionsOperation in experiment
36% To a solution of 2-bromo-4-methyl-pyridine (2.58g, 15 [MMOL)] in anhydrous THF (50 [ML) AT-30°C,] was added dropwise [NAHMDS] (solution 2M in THF, 15ml, 30 [MMOL)] and the mixture was stirred [AT-30°C] for 2 hours. A solution of intermediate 20 (2.74g, 15 [MMOL)] in THF (50 ml) was added dropwise and the mixture was stirred at -30°C for 1 hour and then poured into water. After extraction with EtOAc, the organic phase was dried over [NA2SO4] and concentrated under reduced pressure. The residue was purified by chromatography on silica gel [(CH2CI2/MEOH,] 99: 1). The title compound was obtained as a yellow solid (1.6g, 36percent); [[APCI] MS] m/z=295 (MH+).
  • 21
  • [ 402-69-7 ]
  • [ 67-63-0 ]
  • [ 656239-36-0 ]
YieldReaction ConditionsOperation in experiment
93% Intermediate 4 (1g, 7.09 [MMOL)] was added portion-wise to [THIONYL] chloride (3 [ML)] and the mixture was heated under reflux for 3 hours and then concentrated under reduced pressure. Isopropanol (3 ml) was added to the residue and the mixture was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was treated with a saturated aqueous solution of [NAHCO3] and extracted with ethyl acetate. The combined organic phases were dried over [NA2SO4] and concentrated under reduced pressure. The title compound was obtained as an oil (1. [2G,] 93percent); [[APCI] MS] m/z: 184 (MH+).
  • 22
  • [ 402-69-7 ]
  • [ 6638-79-5 ]
  • 6-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
18% Add N-methylmorpholine (6 ml, 52 mmol) and isobutylchloroformate (3.5 ml, 26.9 mmol) to a solution of <strong>[402-69-7]6-fluoropyridine-2-carboxylic acid</strong> (3.8 g, 26.9 mmol) in methylene chloride at 0 C. After 15 minutes add O,N-dimethylhydroxylamine hydrochloride (2.6 g, 26.9 mmol) and N-methylmorpholine (3 ml, 26.9 mmol). Stir the reaction at 0 C for 15 minutes and then room temperature for 17 hours. Dilute the reaction with methylene chloride and wash sequentially with water (1 x 50 ml), 10 percent aqueous citric acid (1 x 50 ml), brine (1 x 50 ml), saturated aqueous sodium bicarbonate (1 x 50 ml), and brine (1 x 50 ml). Dry the resulting organic solution with Na2SO4, filter, and purify by flash column chromatography (Silica Gel, 20 percent acetone/hexanes) to provide the title compound 0.97g (18 percent from 2-fiuoro-5-methylpyridine) as a clear, yellow oil. MS APCI+ m/e 185 (M+1). TLC (SiO2): Rf 0.40 (1:3 acetone/hexanes)
  • 23
  • [ 352553-60-7 ]
  • [ 402-69-7 ]
  • [ 125700-67-6 ]
  • [ 913961-51-0 ]
YieldReaction ConditionsOperation in experiment
61% With N-ethyl-N,N-diisopropylamine; In dichloromethane; water; Example 60 N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-6-fluoro-2-pyridinecarboxamide To a solution of 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine (0.15 g, 0.68 mmol), DIPEA (0.165 mL, 0.123 g, 0.95 mmol) and 2-fluoro-6-pyridine carboxylic acid (0.115 g, 0.816 mmol) in dichloromethane (5 mL) was added O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 0.26 g, 0.81 mmol) and the mixture was stirred at ambient temperature for 2 h. Water was added and after 10 min, the organic phase was separated and washed with saturated NaHCO3/water, dried (Na2SO4), evaporated, and chromatographed (Silica gel, EtOAc/hexanes, 0-30percent) to provide the title compound as an off-white solid (0.13 g, 61percent yield). 1H-NMR (DMSO-d6): delta 10.92 (s, 1H), 8.8 (d, 1H), 8.2 (quartet, 1H), 8.04 (dd, 1H), 7.43 (m, 2H), 7.28 (d, 1H), 7.0 (dd, 1H), 5.37 (quartet, 1H), 2.62 (m, 2H), 2.0 (m, 3H), 1.8 (m, 1H); MS m/z 365 (M+Na).
  • 24
  • [ 1198409-41-4 ]
  • [ 402-69-7 ]
  • 6-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
psi-Fluoro^-pyridinecarboxylic acid (available from Asymchem Laboratories, 570mg, 4.0mmol) and O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate(1531 mg, 4.0mmol) were dissolved in DMF (15ml) and treated withDIPEA (2.11 ml). The mixture was stirred at room temperature for 30mins then 6-(1H- indol-4-yl)-1 H-indazol-4-amine (500mg, 2.0mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to approx. 5ml which was added to 2 x 5Og aminopropyl cartridges that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The mixture was concentrated in vacuo to give an orange oil. DCM (5ml) was added and the resultant precipitate was collected by filtration to give the title compound (235mg) as a yellow solid. LCMS (Method B) R1 = 1.04 mins, MH+ = 372
  • 25
  • [ 1239013-81-0 ]
  • [ 402-69-7 ]
  • [ 1239013-51-4 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; N,N-dimethyl-formamide; at 20 - 50℃; for 12.25h; To each of the reaction test tubes with the appropriate carboxylic acid (1.0 equivalent) in dry l,4-dioxane:DMF:DIEA (2:2: 1, 0.3M) at room temperature was charged with HOBt (1.0 equivalent) and EDCI (1.5 equivalents). After 15 min, the HCl salt (3, 1.0 equivalent) was added and the heterogeneous mixture was heated to 50 0C. After 12 h, the reaction mixture was added to EtOAc:water (1: 1). The organic layer was separated and sequentially washed with water, brine and dried. The residue was purified by mass-directed preparative HPLC. Following the General Procedure 2, 6-fluoro-Nu-(4-(l,l,3,3-tetraoxidobenzo[d][l,3,2]dithiazol-2- yl)phenyl)picolinamide was obtained as an white solid.LCMS: RT = 3.178 min, >;98percent (at) 214 nM, m/z = 434.0 [M + H]+ 1H NMR (400 MHz, (Z6-DMSO): delta 10.90 (br s, IH), 8.61-8.59 (m, 2H), 8.29 (dd, J = 15.6, 8.0 Hz, IH), 8.24-8.22 (m, 2H), 8.20 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 6.4 Hz, IH), 7.60 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 7.6 Hz, IH)HRMS, calc'd for Ci8H13N3O5FS2 (M+H+), 434.0281; found 434.0281.
  • 26
  • [ 402-69-7 ]
  • [ 75-65-0 ]
  • [ 1053656-65-7 ]
YieldReaction ConditionsOperation in experiment
83% With pyridine; p-toluenesulfonyl chloride; at 0 - 20℃; for 12h; Tosyl chloride (915 mg, 4.8 mmol) was added to a solution of 2-fiuoro- picolinic acid (254 mg, 2 mmol) and pyridine (1.08 mL, 13.4 mmol) in 3.6 mL of t-BuOH at 00C. The reaction was then stirred at room temperature for 12 hours. An aqueous solution of NaHCO3 was then added and the mixture was extracted with ethyl acetate (3 times). The combined organic phases were washed with brine and dried over Na2SO4. The crude compound was purified by flash chromatography using SiO2 (Petroleum Ether/EtOAc 100:0 to 90: 10). The product 120A was obtained as a white solid (m = 326 mg, 83percent): 1H NMR (ppm, CDCl3) 1.6 (s, 9H), 7.05-7.11 (m, IH), 7.85-7.93 (m, 2H).
  • 27
  • [ 1158975-01-9 ]
  • [ 402-69-7 ]
  • [ 1254364-41-4 ]
  • 28
  • [ 870-46-2 ]
  • [ 402-69-7 ]
  • [ 1254073-98-7 ]
YieldReaction ConditionsOperation in experiment
6-Fluoro-2-pyridinecarboxylic acid (2.83 g, 20.06 mmol, CAS[402-69-7], commercially available e.g. from Sigma-Aldrich or Apollo Scientific) was dissolved inDichloromethane (DCM) (100 ml.) at 0 0C. Oxalyl chloride (2.107 ml_, 24.07 mmol) and a drop of Lambda/,Lambda/-dimethylformamide (DMF) was added and the mixture was stirred for 2 hours. The solvents were removed in vacuo and azeotroped with toluene (3x20ml). The residue was dissolved in dichloromethane (DCM) (100 ml) whereupon 1 ,1-dimethylethyl hydrazinecarboxylate (2.92 g, 22.06 mmol) and Lambda/,Lambda/-diisopropylethylamine (DIPEA) (7.71 ml_, 44.1 mmol) were added. The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and saturated sodium bicarbonate solution (50 ml). The aqueous phase was extracted with ethyl acetate (3x100ml), the combined organic extracts were washed with brine (50 ml), were dried over anhydrous sodium sulphate and were concentrated in vacuo. The residue was purified by flash chromatography (Biotage SP4, 40+M, 0-100percent ethyl acetate/iso- hexane) to afford 1 ,1-dimethylethyl 2-[(6-fluoro-2- pyridinyl)carbonyl]hydrazinecarboxylate (5.04 g, 19.75 mmol).LC/MS = 156 (M+H-BOC)+, retention time = 0.81 minutes (2 minute method).
  • 29
  • [ 1269074-30-7 ]
  • [ 402-69-7 ]
  • [ 76-05-1 ]
  • [ 1269072-32-3 ]
YieldReaction ConditionsOperation in experiment
To a stirred solution of 2-(4-amino-2-chlorophenyl)tetrahydroimidazo[ 1 ,5- a]pyridine-l,3(2H,5H)-dione (0.03 g, 0.107 mmol), HATU (0.045 g, 0.119 mmol), DIEA (0.041 mL, 0.236 mmol) in DMF (1 mL) was added 2-fluoro-6-pyridine carboxylic acid (0.017 g, 0.118 mmol). The reaction mixture was stirred at room temperature for 15 h. The reaction was diluted with water (4 mL) and extracted with ethyl acetate (2 x 3 mL). The organic extracts were combined and concentrated. The residue was purified by reverse phase HPLC to give N-(3- chloro-4-(l,3-dioxotetrahydroimidazo[l,5-a]pyridin-2(lH,3H,5H)-yl)phenyl)-6- fluoropicolinamide (TFA), 1.3.4.LCMS: >98percent (at) 214 nm, RT = 2.85 min., m/z = 403.1 [M + H]+.
  • 30
  • [ 402-69-7 ]
  • [ 1319649-66-5 ]
  • 31
  • [ 402-69-7 ]
  • [ 208110-81-0 ]
  • 32
  • [ 1312308-77-2 ]
  • [ 402-69-7 ]
  • [ 1312306-87-8 ]
  • 33
  • [ 1312308-77-2 ]
  • [ 402-69-7 ]
  • [ 1312308-88-5 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; The compound 1 (the same compound as that described in Reference Example 2) (300 mg) was dissolved in methylene dichloride (5.3 ml), and thereto were added 6-fluoro-2-pyridine carboxylic acid (156 mg), EDCI-HCl (304 mg) and HOBt-H2O (267 mg). After stirring the solution all day and all night, water and potassium carbonate were added thereto, and insoluble materials were filtrated. The organic layer was washed with water, followed by evaporation of the solvent in vacuo, and the residue was purified by the silica gel column chromatography affording the compound 2 (289 mg).
  • 34
  • [ 402-69-7 ]
  • [ 455936-94-4 ]
  • 35
  • [ 402-69-7 ]
  • [ 698-75-9 ]
 

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