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Chemical Structure| 101335-11-9 Chemical Structure| 101335-11-9

Structure of 101335-11-9

Chemical Structure| 101335-11-9

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Product Details of [ 101335-11-9 ]

CAS No. :101335-11-9
Formula : C6H3ClFI
M.W : 256.44
SMILES Code : IC1=CC=C(F)C=C1Cl
MDL No. :MFCD00051774
Boiling Point : No data available

Safety of [ 101335-11-9 ]

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

Computational Chemistry of [ 101335-11-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 0.0
Molar Refractivity 44.13
TPSA ?

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

0.0 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.22
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

3.3
Log Po/w (WLOGP)?

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

3.5
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.

4.22
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

3.89
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.43

Water Solubility

Log S (ESOL):?

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

-4.0
Solubility 0.0255 mg/ml ; 0.0000995 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.98
Solubility 0.271 mg/ml ; 0.00106 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

-4.25
Solubility 0.0146 mg/ml ; 0.0000568 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

Low
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.

-5.52 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

1.0
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

2.0 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<0.0
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)

2.27

Application In Synthesis of [ 101335-11-9 ]

* 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 [ 101335-11-9 ]

[ 101335-11-9 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 18640-58-9 ]
  • [ 101335-11-9 ]
  • [ 39249-52-0 ]
  • 2
  • [ 101335-11-9 ]
  • [ 68-12-2 ]
  • [ 146137-84-0 ]
YieldReaction ConditionsOperation in experiment
INT 18 2-Chloro-6-fluoro-3-iodobenzonitrile Step A: 2-Chloro-6-fluoro-3-iodobenzaldehyde A solution of diisopropylamine (870 mg, 8.6 mmol) in anhydrous THF was added n-butyllithium (2.5 M in hexanes, 3.1 mL, 7.8 mmol) dropwise over 5 min under nitrogen at 0 C. After 10 min, the reaction mixture was cooled to -78 C and 2-chloro-4-fluoro-l-iodobenzene (2.0 g, 7.8 mmol) was added dropwise over 5 min. After 1 h at - 78 C, DMF (640 mg, 8.6 mmol) was added dropwise over 5 min. After a further 10 min at -78 C, the reaction mixture was quenched by the rapid addition of acetic acid (2.0 mL), followed quickly by water (50 mL). The cold solution was extracted with diethyl ether and the organic extracts were washed with diluted HCl (0.2 M, 25 mL), water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduce pressure and the resulting residue was then purified by silica gel chromatography to provide 2-chloro-6-fluoro-3-iodobenzaldehyde. 1HNMR (400 MHz, CDC13) delta 10.34 (s, 1H), 8.04 (m, 1H), 6.92 (dd, J = 9.4, 9.4 Hz, 1H).
  • 3
  • [ 877868-59-2 ]
  • [ 101335-11-9 ]
  • C19H12NSO2F2Cl [ No CAS ]
  • 4
  • [ 101335-11-9 ]
  • [ 39249-87-1 ]
  • 5
  • [ 101335-11-9 ]
  • [ 39249-53-1 ]
  • 6
  • [ 101335-11-9 ]
  • [ 5188-07-8 ]
  • [ 779331-06-5 ]
YieldReaction ConditionsOperation in experiment
for 20h; Sodium methanethiolate (5g) was added to a solution of <strong>[101335-11-9]4-fluoro-2-chloro-iodobenzene</strong> (18.3g) and stirred for 20h. The mixture was poured into water, extracted with ether, washed with brine, dried (MgS04) and evaporated. Yield 18. 5g. 1H NMR DMSO-d6: 8 7.81 (d, 1H), 7.43 (dd, 1H), 6.98 (dd, 1H), 3.32 (s, 3H)
  • 7
  • [ 101335-11-9 ]
  • [ 313545-72-1 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; isopropylmagnesium chloride; In tetrahydrofuran; diethyl ether; Trimethyl borate; Intermediate XI A solution of isopropyl magnesium chloride (100 mL, 2.0M in Ethyl Ether) was added to a solution of <strong>[101335-11-9]2-chloro-4-fluoro-1-iodobenzene</strong> (25 g, 97.5 mmol) in 300 mL THF chilled in an ice bath. The solution was then stirred at RT overnight. The solution was chilled in a CO2/acetone bath and trimethyl borate was added (23 mL, 200 mmol). The solution was warmed to RT and stirred for 6 h. The suspension was partitioned between water and ethyl ether (emulsion). The phases were separated and the organic phase concentrated. The residue was treated with 200 mL 2N HCl and stirred overnight. The suspension was then extracted with ethyl ether (2*) and the combined organics washed with brine, dried over MgSO4, filtered and concentrated to give 13.3 g solid. The crude solid was suspended in hexanes, filtered and washed 2* (hexanes) to give 2-chloro-4-fluoro-phenylboronic acid. LC 1: 1.65 min.
  • 8
  • ammonium chloride [ No CAS ]
  • [ 17630-76-1 ]
  • [ 101335-11-9 ]
  • [ 365525-95-7 ]
YieldReaction ConditionsOperation in experiment
With magnesium; In tetrahydrofuran; diethyl ether; Preparation 9 5-Chloro-3-(2-chloro-4-fluorophenyl)-3-hydroxyindolin-2-one, Compound II.10 0.44 g of a 60% dispersion of sodium hydride in oil is added at -40 C. to a cooled suspension of 2 g of 5-chloroindolin-2,3-dione in 60 ml of tetrahydrofuran and the reaction mixture is stirred at 0 C. for 15 minutes. 0.45 g of magnesium and 4.23 g of <strong>[101335-11-9]2-chloro-4-fluoro-1-iodobenzene</strong> in 18 ml of diethyl ether are stirred at reflux for 3 hours. The solution thus obtained is slowly added at -60 C. to the reaction mixture. The reaction mixture is stirred for 30 minutes at 20 C. and a saturated aqueous ammonium chloride solution is added. Extraction is carried out with ethyl acetate, the organic phase is dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with dichloromethane and then with a 95/5 (v/v) dichloromethane/methanol mixture. The solid obtained is crystallized from n-pentane; M.p.=239 C. In the same way, 5-chloro-3-(2,5-dimethoxyphenyl)-3-hydroxyindolin-2-one, compound II,11;
  • 9
  • [ 101335-11-9 ]
  • [ 375853-82-0 ]
  • [ 864830-09-1 ]
  • 10
  • [ 5625-67-2 ]
  • [ 101335-11-9 ]
  • [ 1146411-51-9 ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate;copper(l) iodide; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In 1,4-dioxane; at 100℃; for 20h;Heating / reflux; The 1-(2-chloro-4-fluorophenyl)-2-piperazinone used in the above procedure was prepared as follows: A suspension of 2-piperazinone (1.5 g, 15.0 mmol), <strong>[101335-11-9]2-chloro-4-fluoro-1-iodobenzene</strong> (3.8 g, 15.0 mmol), copper(l) iodide (0.57 g, 3.0 mmol), N,N'-dimethyl-1 ,2- cyclohexanediamine (1.3 g, 6.0 mmol), and potassium phosphate (6.4 g, 44.9 mmol) in 1 ,4-dioxane (20 ml) was heated at reflux (1000C) under argon for 20 hours. The mixture was allowed to cool to room temperature and then diluted with dichloromethane and 0.88M ammonia diluted in water (1 :5). The mixture was extracted into dichloromethane (x3), and then the combined organic extracts were washed with water (x2) and dried over magnesium sulphate. The solvent was evaporated in vacuo and the crude product was purified by flash-silica gel chromatography, eluting with 5% 2M ammonia in methanol in dichloromethane, to give the product 1-(2-chloro-4-fluorophenyl)-2-piperazinone (250mg) as a brown oil which was used without further purification. LC/MS [M+H]+ = 229.
  • 12
  • [ 67888-71-5 ]
  • [ 101335-11-9 ]
  • [ 1131890-69-1 ]
  • 13
  • [ 40475-58-9 ]
  • [ 101335-11-9 ]
  • [ 1131890-65-7 ]
  • 14
  • [ 343866-04-6 ]
  • [ 101335-11-9 ]
  • [ 1131890-71-5 ]
  • 16
  • [ 4746-97-8 ]
  • [ 101335-11-9 ]
  • [ 1247885-64-8 ]
YieldReaction ConditionsOperation in experiment
48% To a solution of 2-chloro-4-fluoro-l-iodobenzene (10.0 g, 39.0 mmol) in dry THF (150 niL) was added /-PrMgCl (29.3 niL, 2.0 N, 58.5 mmol) dropwise at 0 C . After stirring for 1 hr at 0 C , the reaction was warmed to room temperature and stirred for 2 h. 1,4-cyclohexanedione monoethylene acetal (4.87 g, 31.2 mmol) was added and the reaction was stirred at room temperature for 12 h. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (100 mL), then dried over Na2SO4. After concentration in vacuo, the crude material was purified by column chromatography (petroleum ethe?ethyl acetate = 5:1) on silica gel to give the desired product as a white solid (5.38 g, 48%). 1H NMR (400 MHz, CDCl3): delta 7.61-7.57 (m, IH), 7.14-7.11 (m, IH), 6.99- 6.94 (m, IH), 4.00-3.95 (m, AzU), 2.63-2.57 (m, IH), 2.42-2.36 (m, 2H), 2.17-2.10 (m, 2H), 2.05-2.01 (m, 2H), 1.72-1.69 (m, 2H).
  • 17
  • [ 1247885-16-0 ]
  • [ 101335-11-9 ]
  • [ 1247881-06-6 ]
YieldReaction ConditionsOperation in experiment
0.87% With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene; at 150℃; for 3h;Microwave irradiation; 7,7-Dimethyl-2-(pyridin-2-yl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine (460 mg, 2.0 m mol), Pd2(dba)3 (92 mg, 0.1 mmol), X-phos (95 mg, 0.2 mmol), 2-chloro-4- fluoro-1-iodobenzene (768 mg, 3.0 mmol), and Na-OtBu (576 mg, 6.0 mmol) were combined in toluene (15 mL) and heated at 1500C by microwave for 3 h. The reaction was evaporated to dryness, diluted with dichloromethane and extracted with water. The combined organic layer was dried using sodium sulfate, filtered, evaporated, and then purified by prep-TLC to obtain the title compound as a yellow solid. (6 mg, 0.87 %). 1H NMR (400 MHz, CDCl3): delta 8.74-8.76 (m, IH), 8.08-8.11 (m, IH), 7.78-7.72 (m, IH), 7.32-7.36 (m, IH), 7.15-7.20 (m, 2H), 6.96-7.01 (m, IH), 4.06 (s, 2H), 3.12 (s, 2H), 1.46(s, 6H); LC/MS: m/e = 358 (M+H)+.
  • 18
  • [ 1068-55-9 ]
  • [ 59084-16-1 ]
  • [ 101335-11-9 ]
  • [ 946598-81-8 ]
YieldReaction ConditionsOperation in experiment
33% Step 1 1-[4-(2-Chloro-4-fluoro-benzoyl)-piperidin-1-yl]-ethanone <strong>[101335-11-9]2-Chloro-4-fluoro-1-iodobenzol</strong> (5 g, 19 mmol) was solved in THF (3 mL) and at -10 C. isopropyl magnesium chloride-lithium chloride (2M in THF) was added dropwise and the mixture stirred for 30 minutes at 0 C. At -10 C. 1-acetyl-isonipecotoyl chloride was added (3.3 g, 18 mmol) solved in THF (2 mL) and the mixture stirred for 10 minutes to -10 C. and 4 h to 0 C. Water was added and the reaction extracted with dichloromethane. Chromatography with Heptane/EtOAc (2:1) gave the desired compound as a clear orange liquid (1.8 g, 33% yield). (m/e): 284.3 (M+H+).
  • 19
  • [ 1365889-00-4 ]
  • [ 101335-11-9 ]
  • [ 15164-44-0 ]
  • [ 1365889-09-3 ]
  • (Z)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 35Preparation of Compound 110: (E)-Ethyl 3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate hydrochlorideStep 1: (E)-4-(2-(2-Chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1,1-indazol-5-yl)but-1-en-1-yl)benzaldehyde A round-bottom flask equipped with a magnetic stir bar, a reflux condenser, internal thermometer, and a N2 inlet was charged with 5-(but-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (50.0 g, 197 mmol; Intermediate 3), bis(pinacolato)diboron (50.4 g, 199 mmol), and anhydrous 2-methyltetrahydrofuran (393 mL) followed by Pt(PPh3)4 (1.83 g, 1.5 mmol). This mixture was degassed with three vacuum/N2 cycles, heated at 83 C. (internal temperature; oil bath at 95 C.) for 5 h under N2, and then allowed to cool to room temperature. 2-Methyltetrahydrofuran (393 mL), cesium carbonate (128.1 g, 393 mmol), and water (11.8 mL, 1.5% v/v) were added, and the reaction was cooled to 4 C. 4-Iodobenzaldehyde (45.6 g, 197 mmol) and PdCl2(PPh3)2 (6.90 g, 9.8 mmol) were added, and the reaction was degassed with three vacuum/N2 cycles. The mixture was allowed to warm to room temperature and stirred overnight. Aqueous KOH solution (4M, 275 mL, 1100 mmol) and <strong>[101335-11-9]2-chloro-4-fluoroiodobenzene</strong> (70.6 g, 275 mmol) were added. The reaction was degassed with 3 vacuum/N2 cycles, heated at 75 C. (internal temperature; oil bath at 90 C.) for 7 h under N2, and then allowed to cool to room temperature. The layers were separated, and the organic layer was washed with brine (800 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give the title compound (82.6 g, 7:1 mixture of regioisomers) as a pale yellow foam. Data for major isomer; (E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde: 1H NMR (300 MHz, DMSO-d6): delta 9.82 (s, 1H), 8.15 (s, 1H), 7.78-7.71 (m, 2H), 7.61 (d, 2H), 7.43-7.27 (m, 3H), 7.15 (m, 3H), 5.86 (dd, 1H), 3.93-3.85 (m, 1H), 3.79-3.68 (m, 1H), 2.44-2.36 (m, 3H), 2.10-1.96 (m, 2H), 1.81-1.67 (m, 1H), 1.63-1.53 (m, 2H), 0.92 (t, 3H); LCMS: 405 [(M-THP+H)+H]+.
  • 20
  • [ 40138-16-7 ]
  • [ 101335-11-9 ]
  • [ 1421751-51-0 ]
  • 21
  • [ 40138-16-7 ]
  • [ 101335-11-9 ]
  • [ 1421751-75-8 ]
  • 22
  • [ 1428882-00-1 ]
  • [ 101335-11-9 ]
  • [ 1428882-01-2 ]
YieldReaction ConditionsOperation in experiment
7.44% Preparation 9 IB: (2-Chloro-4-fluorophenyl)(3-fluoro-4-(pyrimidin-5-yl)pyridin-2- yl)methanoneTo a solution of 2-chloro-4-fluoro-l-iodobenzene (0.307 g, 1.199 mmol) in THF (Volume: 1.622 ml) cooled to -10 C was added isopropylmagnesium chloride, 2M in THF (0.699 ml, 1.399 mmol) in one portion. After 30 min, 3-fluoro-4-(pyrimidin-5- yl)picolinonitrile (0.200 g, 0.999 mmol) was added. The reaction mixture was stirred at -10 C for 30 min, then allowed to warm to room temperature and stirred overnight. Water and ice were carefully added, followed by acidification with 6 M HC1. After stirring for 1 hr, CH2C12 was added and the pH was adjusted to 8.5 with aqueous 4 M NaOH. The layers were separated. The aqueous phase was extracted with CH2CI2 (5X). Organics combined, dried over Na2S04, filtered, and concentrated to afford an orange residue. The crude material was dissolved in a minimal amount of CH2CI2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 60-100% EtOAc in hexanes over 23 min, tr = 9 min) gave the title compound (0.029 g, 0.074 mmol, 7.44% yield) as an orange solid.
  • 23
  • [ 71-23-8 ]
  • [ 101335-11-9 ]
  • [ 1363438-42-9 ]
YieldReaction ConditionsOperation in experiment
General procedure: To 259 mg (26.9 mmol) pyrimidin-5-ol (J. Chem. Soc. 1956, 2033) in 200 mL DMF are added 108 mg (26.9 mmol) sodium hydride (60% dispersion in mineral oil). The mixture is stirred for 20 mm at r.t.. After that time, 500 mg (22.4 mmol) 2-fluoro-4-iodopyridine are added and the mixture is stirred for 12 h at 80 C. Subsequently the mixture is poured into water and extracted with ethyl acetate (3x). The combined organic layers are washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; heptane/EtOAc, 100/0 - 40/60).C9H6IN3O (M = 299.1 g/mol)ESI-MS: 300 [M+H]+ Rt(HPLC) : 2.87 min (method C) For the example XXVIII.4 6 eq. of the alcohol and 4 eq. of KOtBu as base are used and the reaction mixture is stirred at r.t. for 3 h.
  • 24
  • 2-chloro-4-fluoro-α-(hydroxymethylene)benzeneacetonitrile [ No CAS ]
  • [ 101335-11-9 ]
  • [ 60-34-4 ]
  • [ 1450903-84-0 ]
  • [ 1450903-83-9 ]
YieldReaction ConditionsOperation in experiment
15 mg; 18 mg Step B: Preparation of 4-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole-5-amine and 4-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole-3-amine A stirred solution of (aZ)-2-chloro-4-fluoro-a-(hydroxymethylene)benzeneacetonitrile and (aE)-2-chloro-4-fluoro-a-(hydroxymethylene)benzeneacetonitrile (i.e. the product of Step A, 1.29 g, 6.53 mmol) was cooled in an ice/water bath. Glacial acetic acid (0.486 mL, 8.48 mmol) and methylhydrazine (0.438 mL, 8.16 mmol) were added, and the stirred reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was stirred and heated at 40 C for 6 h, under reflux for an additional 6 h, then stirred at ambient temperature overnight. The reaction mass was concentrated under reduced pressure, diluted with water (50 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic phases were washed with water and brine, dried (MgS04), filtered and concentrated under reduced pressure to give a brown solid (0.45 g, 31% yield). Analysis of the solid by LC/MS showed a single component of mass 226 (AP+). NMR analysis was consistent with a mixture of the two regioisomeric title compounds, in an apparent ratio of approximately 1 : 1. This material was used directly in the next step without further purification. H NMR (acetone-^) delta 7.53 (m, 0.4 H), 7.5 (s, 1H), 7.27-7.34 (m, 1.6 H), 7.08-7.16 (m, 1H total), 5.15, 4.7, and 4.1(br m, ~2H total), 3.71 and 3.73 (two s, 3H total). Step C : Preparation of N,4-bis(2-chloro-4-fluorophenyl)- 1 -methyl- lH-pyrazol- 5-amine and N,4-bis(2-chloro-4-fluorophenyl)- 1 -methyl- lH-pyrazol-3-amine To a solution of 4-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole-5-amine and 4-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole-3-amine (i.e. the product of Step B) (0.45 g, 1.99 mmol) in tert-butyl alcohol (4 mL previously sparged with dry nitrogen gas for 20 min) at room temperature were added 2-chloro-4-fluoro-l-iodobenzene (0.51 g, 1.99 mmol), sodium tert-butoxide (0.21 g, 2.1 mmol), tris(dibenzylideneacetone)- dipalladium(O) complex (3.5 mg, 0.004 mmol) and tri-tert-butylphosphonium tetrafluoro- borate (24 mg, 0.079 mmol). The mixture was sparged with nitrogen gas for an additional 5 min and then heated at 80 C overnight. Additional tris(dibenzylideneacetone)- dipalladium(O) complex (37 mg) and tri-tert-butylphosphonium tetrafluoroborate (230 mg) were added, and the mixture was heated at 75-80 C for 72 h. Additional tris(dibenzylidene- acetone)dipalladium(O) complex (37 mg) and tri-tert-butylphosphonium tetrafluoroborate (230 mg) were added, and the mixture was heated at 80 C for 24 h. The cooled reaction mixture was filtered through a pad of Celite diatomaceous filter aid, and the pad was washed with ethyl acetate (25 mL). The filtrate was washed with water and brine, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (12 g) using an elution gradient of 5% ethyl acetate in hexanes to 100% ethyl acetate to give the desired N,4-bis(2-chloro-4-fluorophenyl)-l-methyl- lH-pyrazol-5-amine (18 mg), a compound of the present invention, along with its regioisomer N,4-bis(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazol-3 -amine (15 mg) as a less-polar component. H NMR delta 7.67 (s, 1H), 7.14-7.20 (m, 2H), 7.07 (m, 1H), 6.91 (m, 1H), 6.76 (m, 1H), 6.26 (m, 1H), 5.71 (br s, 1H), 3.74 (s, 3H).
  • 25
  • [ 101335-11-9 ]
  • [ 1374574-53-4 ]
  • 26
  • [ 101335-11-9 ]
  • [ 1428477-60-4 ]
  • 27
  • [ 20154-03-4 ]
  • [ 101335-11-9 ]
  • [ 1523249-94-6 ]
YieldReaction ConditionsOperation in experiment
4.2 g With potassium carbonate; In N,N-dimethyl-formamide; at 135℃; for 12h; To a solution of 2-chloro-4-fluoro-l-iodo-benzene (3.6 g, 14.3 mmol) and 3-trifluoromethyl-lH-pyrazole (1.9 g, 14.4 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (2.4 g, 17.2 mmol), and the resulting mixture was heated at 135 C for 12 h. The reaction mixture was cooled to room temperature, poured in cold water (80 mL) and extracted with dichloromethane (2 x 40 mL). The combined organic extracts were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10% ethyl acetate in hexanes to afford the title compound (4.2 g) as a white solid. lH NMR delta 10.4 (s, 1H), 7.88 (m, 2H), 7.80 (d, 1H), 7.27 (m, 1H), 6.68 (d, 1H). MS (AP+) 373 amu.
  • 28
  • [ 101335-11-9 ]
  • [ 1523249-98-0 ]
  • 29
  • [ 101335-11-9 ]
  • [ 1523250-04-5 ]
  • 30
  • [ 101335-11-9 ]
  • [ 1523250-01-2 ]
  • 31
  • [ 101335-11-9 ]
  • [ 1523244-75-8 ]
  • 32
  • [ 106-48-9 ]
  • [ 101335-11-9 ]
  • [ 1615678-63-1 ]
  • 33
  • [ 106-48-9 ]
  • [ 101335-11-9 ]
  • [ 1615678-81-3 ]
YieldReaction ConditionsOperation in experiment
47% With caesium carbonate; In N,N-dimethyl-formamide; at 95℃; for 16h; To a solution of 2-chloro-4-fluoro-1 -iodo-benzene (9.0 g, 1 eq.) in DMF (46 ml.) was added cesium carbonate (22.8 g, 2 eq) then 4-chlorophenol (4.5 g, 1 eq.). The mixture was heated at 95 C for 16h. After cooling, an aq. solution of ammonium chloride (230ml_) was added, and extracted 3 times with diethylether. The organic phases were combined and washed successive- lywith an aq. solution of ammonium chloride (2x), aq. solution of NaOH (2%), water, then a saturated aq. solution of sodium chloride. The organic phase was dried and evaporated to give after purification on column chromatography on silica gel, 2-chloro-4-(4-chlorophenoxy)-1 -iodo- benzene as an oil (16,7 g, yield=47%).
  • 34
  • C11H11FN2 [ No CAS ]
  • [ 101335-11-9 ]
  • 2-((1-(2-chloro-4-fluorophenyl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
12.3% With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; at 120℃; for 1h;Inert atmosphere; To a solution of 1 (30mg, 0.157mmol), 2 (81mg, 0.315mmol) and Cs2CO3 (256mg, 0.785mmol) in DMF (2mL) were added 1 mg of Pd(dba)2 and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 120 C for 1hr. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 215 (6.15mg, yield: 12.3%). LCMS: m/z, 319.0(M+H)+; 1HNMR (d-CDCl3, 400MHz): delta 8.62-8.63 (m, 1H), 7.68-7.72 (m, 1H), 7.50-7.52 (m, 1H), 7.28-7.32 (m, 1H), 7.09-7.12 (m, 1H), 6.91-6.93 (m, 2H), 4.06-4.17 (m, 1H), 3.68-3.77 (m, 2H), 3.33-3.38 (m, 1H), 2.46-2.69 (m, 2H).
  • 35
  • (Z)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(thiazol-5-yl)phenyl)but-1-en-1-yl)benzaldehyde [ No CAS ]
  • [ 101335-11-9 ]
  • (E)-4-(2-(2-chloro-4-fluorophenyl)-1-(4-(thiazol-5-yl)phenyl)but-1-en-1-yl)benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
With bis-triphenylphosphine-palladium(II) chloride; potassium hydroxide; In 1,4-dioxane; at 90℃; Step 2: (E)-4-(2-(2-Chloro-4-fluorophenyl)-l-(4-(thiazol-5-yl)phenyl)but-l-en-l- yl)benzaldehyde[00394] A mixture of (Z)-4-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(4-(thiazol-5- yl)phenyl)but-l-en-l-yl)benzaldehyde (99 mg, 0.22 mmol), 2-chloro-4-fluoro-l-iodobenzene (114 mg, 0.44 mmol), Pd(PPh3)2Cl2(15 mg, 0.022 mmol), and KOH (6M, 0.2 mL, 1.32 mmol) in 1,4-dioxane (2.2 mL) was heated to 90C overnight. After cooling, ethyl acetate and brine were added to the reaction mixture and the two layers were separated. The organic layer was washed with more brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel to afford 68 mg of a mixture of the title compound (major) and the undesired regioisomer (minor). 1H NMR (400 MHz, DMSO-d6) of major: delta 9.84 (s, 1H), 9.11 (s, 1H), 8.35 (s, 1H), 7.75 (d, 2H), 7.64 (d, 2H), 7.40-7.33 (m, 4H), 7.17 (m, 3H), 2.45 (q, 2H), 0.93 (t, 3H).
 

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