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Chemical Structure| 854690-87-2 Chemical Structure| 854690-87-2

Structure of 854690-87-2

Chemical Structure| 854690-87-2

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Product Details of [ 854690-87-2 ]

CAS No. :854690-87-2
Formula : C7H7BF2O2
M.W : 171.94
SMILES Code : FC(C1=CC(B(O)O)=CC=C1)F
MDL No. :MFCD09864670
InChI Key :MYJVGNXKXAYCTH-UHFFFAOYSA-N
Pubchem ID :44717244

Safety of [ 854690-87-2 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H228-H302-H314-H412
Precautionary Statements:P210-P240-P241-P260-P264-P270-P273-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P370+P378-P405-P501
Class:8(4.1)
UN#:2921
Packing Group:

Computational Chemistry of [ 854690-87-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 2
Num. H-bond acceptors 4.0
Num. H-bond donors 2.0
Molar Refractivity 41.34
TPSA ?

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

40.46 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
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

1.45
Log Po/w (WLOGP)?

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

0.82
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.

1.21
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

0.13
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.72

Water Solubility

Log S (ESOL):?

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

-2.06
Solubility 1.51 mg/ml ; 0.00876 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.

-1.91
Solubility 2.14 mg/ml ; 0.0124 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

-1.89
Solubility 2.21 mg/ml ; 0.0129 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.

-6.32 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

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)

1.72

Application In Synthesis of [ 854690-87-2 ]

* 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 [ 854690-87-2 ]

[ 854690-87-2 ] Synthesis Path-Downstream   1~12

  • 1
  • [ 787575-92-2 ]
  • [ 854690-87-2 ]
  • [ 854690-78-1 ]
YieldReaction ConditionsOperation in experiment
71% With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; 1,2-dimethoxyethane; at 82℃; PREPARATION 90 7- (3-difluoromethylphenyl)-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide Dissolve [2- (7-bromo-isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert- butyl ester (0.13 g, 0.30 mmol) and 3- (difluoromethyl) phenylboronic acid (0.057 g, 0.33 mmol) in DME-methanol (8: 1,10 ml). To the mixture, add K3P04 (0.13 g, 0.60 mmol), and PdCl2 (dppf) (0.012 g, 0.015 mmol). Heat this mixture at 82 °C overnight. Cool the reaction mixture, dilute with water and extract with EtOAc. Wash with brine and evaporate to dryness. Purify by silica gel chromatography to give the desired compound (0.10 g, 71percent yield) :'H NMR (CDC13): J9. 39 (s, 1H), 8.66 (m, 2H), 8.43 (d, J= 5.7 Hz, 2H), 7.86 (m, 2H), 7.61 (m, 2H), 6. 76 (t, J= 52.1 Hz, 1H), 5.00 (br s, 1H), 3. 18 (m, 2H), 3.03 (m, 2H), 1.37 (s, 9H); ESIMS : m/z 478 (M+H) +.
  • 2
  • [ 854690-87-2 ]
  • [ 1569649-68-8 ]
  • [ 1569649-74-6 ]
YieldReaction ConditionsOperation in experiment
55% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetonitrile; at 75℃; for 2h; General procedure: Preparation 4 5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid A mixture of 5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 3c, 3.00 g, 8.32 mmol, based on 76percent purity), 3-(difluoromethyl)-phenylboronic acid (2.30 g, 13 mmol), 1,1'-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (690 mg, 0.94 mmol) and 2 M aqueous K2CO3 solution (10 mL, 20 mmol) in acetonitrile (20 mL) is heated for 2 h at 75° C. The reaction mixture is diluted with methanol and purified by preparative reversed phase HPLC (XBridge, gradient of acetonitrile in water, 0.3percent NH4OH, 30° C.). Yield: 1.46 g (55percent of theory); ESI mass spectrum: [M+H]+=322; Retention time HPLC: 0.92 min (Z018_S04).
1.46 g With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetonitrile; at 75℃; for 2h; A mixture of 5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 3c, 3.00 g, 8.32 mmol, based on 76percent purity), 3-(difluoromethyl)- phenylboronic acid (2.30 g, 13 mmol), 1,1 '-[bis(diphenylphosphino)ferrocene]- dichloropalladium(II) (690 mg, 0.94 mmol) and 2 M aqueous K2CO3 solution (10 mL, 20 mmol) in acetonitrile (20 mL) is heated for 2 h at 75°C. The reaction mixture is diluted with methanol and purified by preparative reversed phase HPLC (XBridge, gradient of acetonitrile in water, 0.3percent NH4OH, 30°C). Yield: 1.46 g (55 percent of theory); ESI mass spectrum: [M+H]+ = 322; Retention time HPLC: 0.92 min (Z018 S04).
  • 3
  • [ 854690-87-2 ]
  • [ 1570077-28-9 ]
  • [ 1570075-93-2 ]
YieldReaction ConditionsOperation in experiment
42% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetonitrile; at 75℃; for 18h; General procedure: Example 1 5-(3-Difluoromethyl-phenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-(N-cyano-S-methylsulfonimidoyl)-benzylamide To a solution of preparation 1 (70 mg, 0.15 mmol), <strong>[854690-87-2]3-(difluoromethyl)phenylboronic acid</strong> (36 mg, 0.21 mmol) and 1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.015 mmol) in acetonitrile (2.00 mL) is added aqueous K2CO3 solution (2 M, 0.155 mL, 0.31 mmol). After stirring for 18 h at 75° C., the reaction mixture is filtered and the filtrate is purified by preparative reversed phase HPLC(XBridge, gradient of methanol in water, 0.1percent NH4OH, 60° C.). Yield: 32 mg (42percent of theory); ESI mass spectrum: [M+H]+=513; r.t. HPLC: 0.90 min (Z003-001).
42% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetonitrile; at 75℃; for 18h; To a solution of preparation 1 (70 mg, 0.15 mmol), <strong>[854690-87-2]3-(difluoromethyl)phenylboronic acid</strong>(36 mg, 0.21 mmol) and 1, 1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11mg, 0.015 mmol) in acetonitrile (2.00 mL) is added aqueous K2C03 solution (2M, 0.155mL, 0.31 mmol). After stirring for 18 hat 75°C, the reaction mixture is filtered and the filtrate is purified by preparative reversed phase HPLC (XBridge, gradient of methanol inwater, 0.1percent NH40H, 60°C). Yield: 32 mg (42percent oftheory); ESI mass spectrum: [M+Ht= 513; r.t. HPLC: 0.90 min (Z003_001).
  • 4
  • [ 854690-87-2 ]
  • [ 1571135-36-8 ]
  • [ 1571134-60-5 ]
YieldReaction ConditionsOperation in experiment
90 mg With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; acetonitrile; at 75℃; for 18h; To a solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 11, 110 mg, 0.208 mmol), 3-difluoromethyl-phenylboronic acid (48 mg, 0.28 mmol), palladium (0) tetrakis(triphenylphosphine) (32 mg, 0.028 mmol) in acetonitrile (2 mL) is added 2 M aqueous K2CO3 solution (0.21 mL, 0.42 mmol). After stirring for 18 h at 75° C., the reaction mixture is diluted with methanol, acidified with acetic acid and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1percent TFA, 60° C.). Yield: 90 mg (75percent of theory); ESI mass spectrum: [M+H]+=576; Retention time HPLC: 1.03 min (Z018_S04).
90 mg With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; acetonitrile; at 75℃; for 18h; To a solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-l,4-dihydro- pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 11, 110 mg, 0.208 mmol), 3-difluoromethyl-phenylboronic acid (48 mg, 0.28 mmol), palladium (0) tetrakis(triphenylphosphine) (32 mg, 0.028 mmol) in acetonitrile (2 mL) is added 2 M aqueous K2CO3 solution (0.21 mL, 0.42 mmol). After stirring for 18h at 75°C, the reaction mixture is diluted with methanol, acidified with acetic acid and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1percent TFA, 60°C). Yield: 90 mg (75percent of theory); ESI mass spectrum: [M+H]+ = 576; Retention time HPLC: 1.03 min (Z018_S04).
  • 5
  • [ 854690-87-2 ]
  • [ 1571135-36-8 ]
  • [ 1571134-62-7 ]
  • [ 1571134-61-6 ]
  • 6
  • [ 854690-87-2 ]
  • [ 1571135-34-6 ]
  • [ 1571133-56-6 ]
YieldReaction ConditionsOperation in experiment
71% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; acetonitrile; at 75℃; for 18h; To a solution of 5-bromo-l-[l-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-l,4-dihydro- pyridine-3-carboxylic acid methylamide (preparation 9, 100 mg, 0.267 mmol), 3- difluoromethyl-phenylboronic acid (67 mg, 0.390 mmol), palladium (0) tetrakis(triphenylphosphine) (25 mg, 0.022 mmol) in acetonitrile (2 mL) is added 2 M aqueous K2CO3 solution (0.30 mL, 0.60 mmol). After stirring for 18h at 75°C, the reaction mixture is purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1percent NH4OH, 60°C). Yield: 80 mg (71percent of theory); ESI mass spectrum: [M+H]+ = 422; Retention time HPLC: 0.99 min (Z018 S04)
80 mg With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; acetonitrile; at 75℃; for 18h; To a solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid methylamide (preparation 9, 100 mg, 0.267 mmol), 3-difluoromethyl-phenylboronic acid (67 mg, 0.390 mmol), palladium (0) tetrakis(triphenylphosphine) (25 mg, 0.022 mmol) in acetonitrile (2 mL) is added 2 M aqueous K2CO3 solution (0.30 mL, 0.60 mmol). After stirring for 18 h at 75° C., the reaction mixture is purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1percent NH4OH, 60° C.). Yield: 80 mg (71percent of theory); ESI mass spectrum: [M+H]+=422; Retention time HPLC: 0.99 min (Z018_S04).
  • 7
  • [ 854690-87-2 ]
  • 5-(4-chlorophenyl)-2-({5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
  • 5-(4-chlorophenyl)-2-({1-[3-(difluoromethyl)phenyl]-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
47 mg With pyridine; copper diacetate; at 20℃; for 120h; Example 19 5-(4-Chlorophenyl)-2-({1-[3-(difluoromethyl)phenyl]-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (diastereomeric mixture) To a solution of 5-(4-chlorophenyl)-2-({5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (400 mg, 0.74 mmol, 80percent purity) in pyridine (9.6 ml) were added <strong>[854690-87-2][3-(difluoromethyl)phenyl]boronic acid</strong> (254.26 mg, 1.48 mmol) and copper(II) acetate (268.6 mg, 1.48 mmol). The reaction mixture was heated to 60° C. for 2 h and then stirred at room temperature for 5 days. The resulting reaction mixture was concentrated in vacuo, then diluted with ethyl acetate and quenched with aqueous hydrochloric acid (0.5 M). After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC [method 4], and the desired compound (47 mg, 0.08 mmol) was obtained as a mixture of diastereomers (yield 11.3percent). LC/MS [method 1]: Rt=1.04 min; MS [ESIpos]: m/z=559 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta [ppm] 1.47 (d, 3H), 3.85 (dd, 1H), 4.01 (dd, 1H), 4.24-4.36 (m, 1H), 4.81 (q, 1H), 5.02-5.13 (m, 2H), 5.74 (br. s, 1H), 6.89 (br. s, 1H), 7.14 (t, 1H), 7.59-7.65 (m, 2H), 7.69-7.78 (m, 4H), 7.81-7.87 (m, 2H).
  • 8
  • [ 854690-87-2 ]
  • (4S)-7-chloro-8-methyl-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine [ No CAS ]
  • (4S)-7-(3-(difluoromethyl)phenyl)-8-methyl-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine [ No CAS ]
YieldReaction ConditionsOperation in experiment
50.8% A suspension of (4S)-7-chloro-8-methyl-2,3,4,5-tetrahydro-l,4-methanopyrido[2,3- b][l,4]diazepine (400 mg, 1.908 mmol),<strong>[854690-87-2](3-(difluoromethyl)phenyl)boronic acid</strong> (328 mg, 1.908 mmol) and potassium carbonate (791 mg, 5.72 mmol) in 1,4-Dioxane (15 mL) & Water (4 mL) stirred and degassed with argon at room temp for 15 min, PdCl2(dppf)- CH2C12 adduct (1558 mg, 1.908 mmol) was added to the reaction mixture. Then the reaction mixture was stirred 16 hr at 90 C. The reaction mixture was cooled to room temp, and filtered through celite and washed with EtOAc (100 ml). Filtrate was concentrated and dissolved with EtOAc (50 ml).EtOAc layer washed with water (50 ml) followed by brine solution (50 ml) and dried out with Na2S04, filtered and concentrated to get crude product. The crude product was purified by column chromatography using silica gel(100-200) and was eluted with 50% EtOAc in Hexane (gradient system) to afford the desired product (4S)-7-(3-(difluoromethyl)phenyl)-8-methyl-2,3,4,5-tetrahydro-l,4- methanopyrido[2,3-b][l,4]diazepine (300 mg, 0.969 mmol, 50.8 % yield) as a pale yellow solid LCMS (w/z):302.1 1 [M+H]+.
  • 9
  • [ 854690-87-2 ]
  • (4S)-7,8-dichloro-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine [ No CAS ]
  • (4S)-8-chloro-7-(3-(difluoromethyl)phenyl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine [ No CAS ]
YieldReaction ConditionsOperation in experiment
A suspension of (4S)-7,8-dichloro-2,3,4,5-tetrahydro-l,4-methanopyrido[2,3- b][l,4]diazepine (400 mg, 1.738 mmol),<strong>[854690-87-2](3-(difluoromethyl)phenyl)boronic acid</strong> (299 mg, 1.738 mmol) and potassium carbonate (721 mg, 5.22 mmol) in 1,4-Dioxane (10 mL) & Water (1.5 mL) stirred and degassed with argon at room temp for 15 mins, PdCl2(dppf)- CH2C12 adduct (1420 mg, 1.738 mmol) was added to the reaction mixture. Then the reaction mixture was stirred 16 hr at 90 C. The reaction mixture was cooled to room temp, and filtered through celite and washed with EtOAc (100 ml). Take filtrate and concentrated and dissolved with EtOAc (50 ml).EtOAc layer washed with water (100 ml) followed by brine solution (100 ml) and dried out with Na2S04, filtered and concentrated to get crude product. The crude product was purified by column chromatography using silica gel(l 00-200) and was eluted with 50% EtOAc in Hexane (gradient system) to afford the desired product (4S)-8-chloro-7-(3-(difluoromethyl)phenyl)-2,3,4,5-tetrahydro-l,4- methanopyrido[2,3-b][l,4]diazepine (500 mg, 1.554 mmol, 89 % yield) as a pale yellow solid, LCMS (m/z): 302.1 1 [M+H]+.
  • 10
  • [ 854690-87-2 ]
  • N-(5-(3-(difluoromethyl)benzyl)pyridin-2-yl)-1-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-carboxamide [ No CAS ]
  • 11
  • [ 854690-87-2 ]
  • 5-(3-(difluoromethyl)benzyl)pyridin-2-amine [ No CAS ]
  • 12
  • [ 854690-87-2 ]
  • [ 70258-18-3 ]
  • 2-chloro-5-(3-(difluoromethyl)benzyl)pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; acetonitrile; at 50℃; for 1h;Inert atmosphere; To a solution of <strong>[854690-87-2](3-(difluoromethyl)phenyl)boronic acid</strong> (0.405 g, 2.5 mmol) and 2-chloro-5-(chloromethyl)pyridine (0.430 g, 2.5 mmol) and potassium carbonate (0.691 g, 5 mmol) in acetonitrile (70 ml_) and water (10 ml_) was added [1 ,1 '-b/s(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane (0.204 g, 0.25 mmol) under argon. The mixture was stirred at 50 C for 1 h. Volatiles were removed under reduced pressure and water (50 ml_) was added. The aqueous layer was extracted with ethyl acetate (80 ml_ x 3), dried with sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 12/1 ) to give 2-chloro-5-(3-(difluoromethyl)benzyl)pyridine (0.397 g, 1 .45 mmol, 58%) as a colorless oil. LCMS (ESI) m/z: 254.1 [M+H]+.
 

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