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Chemical Structure| 881674-56-2 Chemical Structure| 881674-56-2

Structure of 881674-56-2

Chemical Structure| 881674-56-2

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Product Details of [ 881674-56-2 ]

CAS No. :881674-56-2
Formula : C11H8FNO
M.W : 189.19
SMILES Code : O=CC1=CNC(C2=CC=CC=C2F)=C1
MDL No. :MFCD11875867
InChI Key :MQULPEUCGKEHEG-UHFFFAOYSA-N
Pubchem ID :46908593

Safety of [ 881674-56-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 881674-56-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 11
Fraction Csp3 0.0
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 51.57
TPSA ?

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

32.86 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.92
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

1.94
Log Po/w (WLOGP)?

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

3.05
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.

1.57
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

3.63
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.42

Water Solubility

Log S (ESOL):?

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

-2.68
Solubility 0.391 mg/ml ; 0.00207 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.

-2.25
Solubility 1.05 mg/ml ; 0.00557 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

-4.35
Solubility 0.00837 mg/ml ; 0.0000443 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

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.08 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)

1.95

Application In Synthesis of [ 881674-56-2 ]

* 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 [ 881674-56-2 ]

[ 881674-56-2 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 881674-58-4 ]
  • [ 881674-56-2 ]
YieldReaction ConditionsOperation in experiment
95.1% With sodium bromate; sulfuric acid; bromine; sodium bromide; In dichloromethane; water; butan-1-ol; at 0 - 5℃; for 3.5h; Sodium bromate was added 52g (0.34mol) in a beaker, 400ml of water and dissolved with stirring, as a backup solution, the other solution of (5- (2-fluorophenyl) lH-pyrrol-3-yl) in a 3000 ml three-necked flask - methanol (6) 191g (1.0mol), dichloromethane 400ml, n-butanol 400ml, 35% sulfuric acid 20g (0.07mol), sodium bromide 1.2g, ice-salt bath to 0 ~ 5 , bromine was added dropwise sodium stock solution, an ice-salt bath after the addition stirring was continued for 3.5h, TLC detection starting material the reaction is completed, the reaction solution was transferred to a single neck flask, under reduced pressure to remove most of the organic solvent was concentrated under rotation, the precipitated yellow solid was cooled in a water bath with stirring 0.5h, yellow solid was collected by filtration, dried under reduced pressure to give 5- (2-fluorophenyl) lH-pyrrole-3-carbaldehyde 180g, (HPLC content: 98.4%), yield 95.1%.
92% With [bis(acetoxy)iodo]benzene; In dichloromethane; at 20℃; for 12h; In 2000ml reaction flask was added Compound VII 100g, was added methylene chloride 800ml, iodine 177g, stirred at room temperature for 12h, the reaction was completed, filtered through celite, diatomaceous earth leached with 60ml of dichloromethane, The dichloromethane was concentrated to dryness, 400ml isopropanol was added, stirred overnight, a solid precipitated, cooled to 0 ~ 10 C, incubated for 1h, suction filtered to give a brown solid 91 g, namely 5- (2-fluorophenyl ) -1H-pyrrole-3-carbaldehyde in 92% yield and 99.2% purity.
60% With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In acetonitrile; at 20℃; for 1.5h; Reference Example 17 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde; A solution (220 mL) of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (11.6 g) in tetrahydrofuran was cooled to -78 C., and a 1.5 mol/L solution (100 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was stirred at -78 C. for 1 hr and water (10 mL) was added dropwise over 2 min. The mixture was allowed to warm to room temperature and the mixture was stirred for 2 hr. The reaction mixture was filtered by adding celite and anhydrous magnesium sulfate and concentrated under reduced pressure to give a pale-yellow oil (yield 8.3 g). To a solution (220 mL) of the obtained pale-yellow oil (8.30 g) in acetonitrile were added tetra-n-propylammonium perruthenate (1.75 g), N-methylmorpholine N-oxide (13.5 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3?1:1) to give the title compound as yellow crystals (yield 5.6 g, 60%). 1H-NMR (CDCl3) delta: 7.07-7.28 (4H, m), 7.52-7.54 (1H, m), 7.61-7.67 (1H, m), 9.49 (1H, brs), 9.86 (1H, s).
  • 2
  • [ 881674-56-2 ]
  • [ 928324-56-5 ]
YieldReaction ConditionsOperation in experiment
46% With N-chloro-succinimide; In N,N-dimethyl-formamide; at 0 - 60℃; for 2h; Reference Example 114 4-chloro-<strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong>; To a solution (15 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (1.0 g) in N,N-dimethylformamide was added N-chlorosuccinimide (0.71 g) at 0 C., and the mixture was stirred at 60 C. for 2 hr. The mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1?3:1) to give the title compound as a yellow powder (yield 0.55 g, 46%). 1H-NMR (CDCl3) delta: 7.15-7.40 (3H, m), 7.52 (1H, d, J=3.6 Hz), 7.97-8.03 (1H, m), 9.24 (1H, br), 9.96 (1H, s).
  • 3
  • [ 881674-56-2 ]
  • [ 928324-57-6 ]
YieldReaction ConditionsOperation in experiment
13% With 1-fluoro-2,6-dichloropyridinium triflate; In tetrahydrofuran; at 0℃; for 2h; Reference Example 115 4-fluoro-<strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong>; To a solution (60 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (3.1 g) in tetrahydrofuran was added 2,6-dichloro-N-fluoropyridinium triflate (5.6 g) at 0 C., and the mixture was stirred at the same temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as white crystals (yield 0.43 g, 13%). 1H-NMR (CDCl3) delta: 7.11-7.30 (4H, m), 7.80-7.87 (1H, m), 9.14 (1H, brs), 9.88 (1H, s).
  • 4
  • [ 881674-56-2 ]
  • [ 928324-91-8 ]
YieldReaction ConditionsOperation in experiment
14% With N-iodo-succinimide; In N,N-dimethyl-formamide; for 12h; Reference Example 152 5-(2-fluorophenyl)-4-iodo-1H-pyrrole-3-carbaldehyde; 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (2.0 g) was dissolved in N,N-dimethylformamide (60 mL), N-iodosuccinimide (2.38 g) was added and the mixture was stirred at for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, a 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3?1:1) to give the title compound as a pale-brown powder (yield 450 mg, 14%). 1H-NMR (CDCl3) delta: 7.16-7.30 (2H, m), 7.37-7.44 (1H, m), 7.63 (1H, d, J=3.4 Hz), 7.81-7.86 (1H, m), 9.24 (1H, br), 9.81 (1H, s).
  • 5
  • [ 114615-82-6 ]
  • [ 881674-06-2 ]
  • [ 881674-56-2 ]
YieldReaction ConditionsOperation in experiment
With diisobutylaluminium hydride; 4-methylmorpholine N-oxide;silica gel; In tetrahydrofuran; water; toluene; acetonitrile; Reference Example 111 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde A solution (220 mL) of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (11.6 g) in tetrahydrofuran was cooled to -78C, and a 1.5 mol/L solution (100 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was stirred at -78C for 1 hr and water (10 mL) was added dropwise over 2 min. The mixture was allowed to warm to room temperature and stirred for 2 hr. To the reaction mixture were added celite and anhydrous magnesium sulfate and the mixture was filtered. The filtrate was concentrated under reduced pressure to give a pale-yellow oil (yield 8.30 g). To a solution (220 mL) of the obtained pale-yellow oil (8.30 g) in acetonitrile were added tetra-n-propylammonium perruthenate (1.75 g), N-methylmorpholine N-oxide (13.5 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3?1:1) to give the title compound as yellow crystals (yield 5.6 g, 60%). 1H-NMR (CDCl3)delta: 7.07-7.28 (4H, m), 7.52-7.54 (1H, m), 7.61-7.67 (1H, m), 9.49 (1H, brs), 9.86 (1H, s).
  • 6
  • [ 881674-56-2 ]
  • [ 2905-21-7 ]
  • [ 881677-09-4 ]
YieldReaction ConditionsOperation in experiment
78% Reference Example 244 5-(2-Fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde To a solution (25 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (250 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 106 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (583 mg) was added dropwise and the mixture was stirred for 30 min, (2-fluorobenzene)sulfonyl chloride (386 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1?3:2) to give the title compound as colorless crystals (yield 360 mg, 78%). 1H-NMR (CDCl3)delta: 6.67 (1H, d, J=1.8 Hz), 6.86-6.92 (1H, m), 7.03-7.23 (5H, m), 7.33-7.41 (1H, m), 7.59-7.66 (1H, m), 8.21-8.22 (1H, m), 9.91 (1H, s).
In tetrahydrofuran; Reference Example 244 5-(2-Fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde To a solution (25 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (250 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 106 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (583 mg) was added dropwise and the mixture was stirred for 30 min, (2-fluorobenzene)sulfonyl chloride (386 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1?3:2) to give the title compound as colorless crystals (yield 360 mg, 78%). 1H-NMR (CDCl3)delta: 6.67 (1H, d, J=1.8 Hz), 6.86-6.92 (1H, m), 7.03-7.23 (5H, m), 7.33-7.41 (1H, m), 7.59-7.66 (1H, m), 8.21-8.22 (1H, m), 9.91 (1H, s).
  • 7
  • [ 881674-56-2 ]
  • [ 69360-26-5 ]
  • [ 881677-06-1 ]
YieldReaction ConditionsOperation in experiment
77% Reference Example 242 2-[2-(2-Fluorophenyl)-4-formyl-1H-pyrrol-1-yl]sulfonyl}benzonitrile To a solution (28 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (284 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 181 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (992 mg) was added dropwise and the mixture was stirred for 30 min, (2-cyanobenzene)sulfonyl chloride (606 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1?2:3) to give the title compound as colorless crystals (yield 410 mg, 77%). 1H-NMR (CDCl3)delta: 6.70 (1H, d, J=1.7 Hz), 6.83-6.89 (1H, m), 7.08-7.18 (2H, m), 7.32-7.52 (3H, m), 7.70-7.75 (1H, m), 7.82-7.85 (1H, m), 8.39 (1H, d, J=1.7 Hz), 9.94 (1H, s).
In tetrahydrofuran; Reference Example 242 2-[2-(2-Fluorophenyl)-4-formyl-1H-pyrrol-1-yl]sulfonyl}benzonitrile To a solution (28 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (284 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 181 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (992 mg) was added dropwise and the mixture was stirred for 30 min, (2-cyanobenzene)sulfonyl chloride (606 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1?2:3) to give the title compound as colorless crystals (yield 410 mg, 77%). 1H-NMR (CDCl3)delta: 6.70 (1H, d, J=1.7 Hz), 6.83-6.89 (1H, m), 7.08-7.18 (2H, m), 7.32-7.52 (3H, m), 7.70-7.75 (1H, m), 7.82-7.85 (1H, m), 8.39 (1H, d, J=1.7 Hz), 9.94 (1H, s).
  • 8
  • [ 881674-56-2 ]
  • [ 49584-26-1 ]
  • [ 881677-08-3 ]
YieldReaction ConditionsOperation in experiment
79% Reference Example 243 4-[2-(2-Fluorophenyl)-4-formyl-1H-pyrrol-1-yl]sulfonyl}benzonitrile To a solution (28 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (284 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 181 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (992 mg) was added dropwise and the mixture was stirred for 30 min, (4-cyanobenzene)sulfonyl chloride (606 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1?2:3) to give the title compound as colorless crystals (yield 420 mg, 79%). 1H-NMR (CDCl3)delta: 6.69 (1H, d, J=1.8 Hz), 6.98-7.04 (1H, m), 7.16-7.18 (2H, m), 7.42-7.49 (1H, m), 7.51-7.54 (2H, m), 7.67-7.71 (2H, m), 8.12 (1H, d, J=1.8 Hz), 9.90 (1H, s).
In tetrahydrofuran; Reference Example 243 4-[2-(2-Fluorophenyl)-4-formyl-1H-pyrrol-1-yl]sulfonyl}benzonitrile To a solution (28 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (284 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 181 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (992 mg) was added dropwise and the mixture was stirred for 30 min, (4-cyanobenzene)sulfonyl chloride (606 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1?2:3) to give the title compound as colorless crystals (yield 420 mg, 79%). 1H-NMR (CDCl3)delta: 6.69 (1H, d, J=1.8 Hz), 6.98-7.04 (1H, m), 7.16-7.18 (2H, m), 7.42-7.49 (1H, m), 7.51-7.54 (2H, m), 7.67-7.71 (2H, m), 8.12 (1H, d, J=1.8 Hz), 9.90 (1H, s).
  • 9
  • [ 881674-56-2 ]
  • [ 42899-76-3 ]
  • [ 881677-11-8 ]
YieldReaction ConditionsOperation in experiment
82% Reference Example 245 5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde To a solution (96 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (475 mg) in tetrahydrofuran was added sodium hydride (60percent in oil, 503 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (2.77 g) was added dropwise and the mixture was stirred for 30 min, pyridine-3-sulfonyl chloride hydrochloride (1.35 g) was added, and the mixture was further stirred for 3 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3?2:3), and crystallized from diisopropyl ether-ethyl acetate (4:1) to give the title compound as colorless crystals (yield 680 mg, 82percent). 1H-NMR (CDCl3)delta: 6.68 (1H, d, J=1.8 Hz), 6.99-7.05 (1H, m), 7.16-7.19 (2H, m), 7.35-7.39 (1H, m), 7.45-7.51 (1H, m), 7.69-7.73 (1H, m), 8.14 (1H, d, J=1.8 Hz), 8.58-8.59 (1H, m), 8.81-8.83 (1H, m), 9.91 (1H, s).
78% A total of 0.5g, 4-dimethylaminopyridine 90mg, 5ml acetonitrile, take N, N-diisopropylethylamine1.5g with a small amount of acetonitrile dissolved in the above reaction bottle, take pyridine-3-sulfonyl chloride hydrochloride 1.1g, with 5mlAcetonitrile dissolved into the reaction flask, heated to 45 ° C stirring reaction 5h after cooling to room temperature, adding 5ml of water,The pH was adjusted to 5 with 0.5 N hydrochloric acid solution, and 20 ml of water was slowly added dropwise (at this time, a large amount of white solid precipitated)Stirring at room temperature for 0.5h, cooling to below 10 , stirring 1h, filtration, filter cake with a small amount of acetonitrile and water mixtureWashing, 50 ° C drying was V total of 0.69g, yield 78percent.
In tetrahydrofuran; Reference Example 245 5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde To a solution (96 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (475 mg) in tetrahydrofuran was added sodium hydride (60percent in oil, 503 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (2.77 g) was added dropwise and the mixture was stirred for 30 min, pyridine-3-sulfonyl chloride hydrochloride (1.35 g) was added, and the mixture was further stirred for 3 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3-->2:3), and crystallized from diisopropyl ether-ethyl acetate (4:1) to give the title compound as colorless crystals (yield 680 mg, 82percent). 1H-NMR (CDCl3)delta: 6.68 (1H, d, J=1.8 Hz), 6.99-7.05 (1H, m), 7.16-7.19 (2H, m), 7.35-7.39 (1H, m), 7.45-7.51 (1H, m), 7.69-7.73 (1H, m), 8.14 (1H, d, J=1.8 Hz), 8.58-8.59 (1H, m), 8.81-8.83 (1H, m), 9.91 (1H, s).
  • 10
  • [ 881674-56-2 ]
  • [ 5335-40-0 ]
  • [ 881677-02-7 ]
YieldReaction ConditionsOperation in experiment
56% Reference Example 240 5-(2-Fluorophenyl)-1-[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde To a solution (48 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (475 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 302 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (1.66 g) was added dropwise and the mixture was stirred for 30 min, [3-(methylsulfonyl)benzene]sulfonyl chloride (1.28 g) was added, and the mixture was further stirred for 15 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3?2:3), and crystallized from diisopropyl ether· ethyl acetate mixed solvent (4:1) to give the title compound as colorless crystals (yield 576 mg, 56%). 1H-NMR(CDCl3) delta:3.03(3H,s), 6.69(1H,d,J=1.8Hz), 6.97-7.02(1H,m), 7.19-7.22(2H,m), 7.43-7.50(1H,m), 7.63-7.75(2H,m), 7.99-8.00(1H,m), 8.14(1H,d,J=1.8Hz), 8.16-8.19(1H,m), 9.91(1H,s).
In tetrahydrofuran; Reference Example 240 5-(2-Fluorophenyl)-1-[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde To a solution (48 mL) of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (475 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 302 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (1.66 g) was added dropwise and the mixture was stirred for 30 min, [3-(methylsulfonyl)benzene]sulfonyl chloride (1.28 g) was added, and the mixture was further stirred for 15 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3?2:3), and crystallized from diisopropyl ether-ethyl acetate mixed solvent (4:1) to give the title compound as colorless crystals (yield 576 mg, 56%). 1H-NMR(CDCl3) delta:3.03(3H, s), 6.69(1H, d, J=1.8Hz), 6.97-7.02(1H, m), 7.19-7.22(2H, m), 7.43-7.50(1H, m), 7.63-7.75(2H,m),7.99-8.00(1H,m),8.14(1H,d,J=1.8Hz),8.16-8.19(1H,m),9.91(1H,s).
  • 11
  • [ 851449-41-7 ]
  • [ 881674-56-2 ]
  • [ 881681-30-7 ]
YieldReaction ConditionsOperation in experiment
Example 189 1-[5-(2-Fluorophenyl)-1-({3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride Using <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (189 mg) and 3-[(trifluoromethyl)sulfonyl]benzenesulfonyl chloride (432 mg), a procedure as in Example 187 was performed to give the title compound as a solid (yield 78 mg, 15%). 1H-NMR (DMSO-d6)delta: 2.50 (3H, s), 4.00 (2H, s), 6.58 (1H, s), 7.10-7.25 (3H, m), 7.51-7.60 (1H, m), 7.85 (1H, s), 7.90 (1H, s), 8.06-8.11 (1H, m), 8.22-8.25 (1H, m), 8.54-8.56 (1H, m), 8.91 (2H, br).
  • 12
  • [ 881674-56-2 ]
  • [3-(ethylsulfonyl)benzene]sulfonyl chloride [ No CAS ]
  • [ 881677-04-9 ]
YieldReaction ConditionsOperation in experiment
Reference Example 241 1-[3-(Ethylsulfonyl)phenyl]sulfonyl}-<strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> Using <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (147 mg), sodium hydride (60% in oil, 45 mg), 15-crown-5 (205 mg) and [3-(ethylsulfonyl)benzene]sulfonyl chloride (250 mg), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow oil (yield 181 mg, 55%). 1H-NMR (CDCl3)delta: 1.25 (3H, t, J=7.5 Hz), 3.08 (2H, q, J=7.5 Hz), 6.68 (1H, d, J=2.4 Hz), 6.95-7.02 (1H, m), 7.18-7.21 (2H, m), 7.43-7.50 (1H, m), 7.62-7.72 (2H, m), 7.16-7.97 (1H, m), 8.12-8.15 (2H, m), 9.91 (1H, s).
  • 13
  • [ 16133-25-8 ]
  • [ 881674-56-2 ]
  • 1-[5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-yl]-N-methylmethylamine fumaric acid salt [ No CAS ]
  • 16
  • [ 1240948-81-5 ]
  • [ 881674-56-2 ]
  • 17
  • [ 1240948-83-7 ]
  • [ 881674-56-2 ]
  • 18
  • [ 16133-25-8 ]
  • [ 881674-56-2 ]
  • [ 881677-11-8 ]
YieldReaction ConditionsOperation in experiment
90.6% With dmap; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 50℃; for 2h; Take <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> 300 g, 4-dimethylaminopyridine 37.5 g, N,N-diisopropylethylamine 300 g, 1L acetonitrile, and add to the reaction flask.300 g of pyridine-3-sulfonyl chloride was dissolved in 1L of acetonitrile, and added dropwise to the above reaction system at 20-30[deg.] C., and the addition was completed in about 1 hour.After the dripping, the system was heated to 40-50C, and the reaction was continued for 1 hour until the raw material was consumed completely.The system was cooled down to 30 C., and 1.8 L of purified water was added to quench the reaction. The pH was adjusted to 4 to 5 with 0.5 mol/L HCl, and a yellow solid precipitated.To the system, 3.6 L of purified water was added and stirred at 0 to 10C for 1 hour.After suction filtration, the filter cake was washed with 900 ml of acetonitrile: purified water (1:2) and 900 ml of purified water, and dried under reduced pressure at 50 C. to obtain 475 g of a brown powdery solid with a yield of 90.6%.
88.7% With dmap; triethylamine; In acetonitrile; at 45℃; for 1.5h; Example 1 (chlorobenzene solvent) 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0141) Pyridine-3-sulfonic acid (10.7 g, 68.5 mmol) and phosphorus pentachloride (15.7 g, 75.4 mmol) were suspended in chlorobenzene (15 mL) at room temperature. After heating and stirring at an inside temperature of 105±5C for about 3 hr, the mixture was cooled to room temperature. Toluene (50 mL) and water (30 mL) were added into another kolben, and the mixture was cooled to an inside temperature of 5±5C. The reaction solution was added dropwise at not more than an inside temperature of 15C, and the dropping funnel was washed well with a mixed solution of toluene and water (1:1, 20 mL). After cooling to an inside temperature of 5±5C, 50% aqueous potassium carbonate solution (39 mL) was added dropwise at not more than an inside temperature of 20C, and the mixture was adjusted to pH 7.5±0.5. After partitioning at room temperature, the organic layer was washed with 5% brine (40 mL), and concentrated to about 20 mL under reduced pressure. Toluene (40 mL) was added and the mixture was concentrated again to about 20 mL. An operation of adding acetonitrile (40 mL) and concentrating the mixture to about 20 mL was repeated three times to give an acetonitrile solution of pyridine-3-sulfonylchloride (quantified yield 10.7 g, 87.9%, total amount 20.3 g, 52.7 w/w% acetonitrile solution). (0142) To the acetonitrile solution (total amount) of pyridine-3-sulfonylchloride obtained above were added acetonitrile (45 mL), <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (10.0 g, 52.9 mmol), N,N-dimethylpyridin-4-amine (0.646 g, 5.29 mmol) and triethylamine (10.4 mL, 74.1 mmol), and the mixture was heated to an inside temperature of 45±5C. After stirring at an inside temperature of 45±5C for 1.5 hr, the mixture was cooled to room temperature, and water (30 mL) was added dropwise. The mixture was adjusted to pH 4 - 5 with 0.5M hydrochloric acid (about 20 mL). The seed crystal of the title compound was added and, after confirmation of crystal precipitation, water (60 mL) was added dropwise. After stirring at room temperature for 30 min and at 5±5C for 1 hr, the precipitated crystals were collected by filtration. The crystals were washed twice with a mixed solution of acetonitrile and water (1:2, 30 mL) cooled to 5±5C in advance, and dried at an outer temperature of 50C under reduced pressure to give the title compound (15.5 g, isolation yield 88.7%). 1H NMR (500 MHz, CDCl3) delta 6.68 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 8.2 Hz, 1H), 7.14-7.19 (m, 2H), 7.38 (dd, J = 8.2, 4.9 Hz, 1H), 7.44-7.48 (m, 1H), 7.72 (ddd, J = 8.2, 2.5, 1.6 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.82 (dd, J = 4.7, 1.6 Hz, 1H), 9.90 (s, 1H).
87.9% With dmap; N,N-diethyl-N-isopropylamine; In acetonitrile; at 15 - 50℃; for 3h;Large scale; Volonadezan Intermediate II 2.0Kg, N,N-dimethyl-4-aminopyridine 109g, Diethylisopropylamine 1.9Kg Acetonitrile 16L, pyridine-3-sulfonyl chloride 1.9Kg Acetonitrile 6L And then added dropwise at a temperature of 15C to 25C,After dripping, heat to 40C to 50C and stir for 3 hours.After cooling to 0 ~ 10 C, add 12 L of water dropwise, cool to 0 ~ 10 C, and stir for 1 hour.Filtration, drying at 40 C. to 50 C. (-0.08 to -1.0 MPa) for 8 to 12 hours gives Warnarazan Intermediate III 3.07 Kg with a yield of 87.9%, which is directly input to the next step.
87% With dmap; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 40 - 50℃; for 1h; 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (7.0 g, 37.00 mmol), N,N-dimethylpyridine-4-amine (0.902 g, 7.38 mmol), diisopropylethylamine (6.69 g, 51.80 mmol) and acetonitrile (28 mL) were added to a four-necked flask, then pyridine-3-sulfonyl chloride (7.89 g, 44.42 mmol) was added dropwise, and the mixture was washed well with acetonitrile (3.5 mL). The mixture was stirred at an inside temperature of 40-50 C. for about 1 hr, and cooled to an inside temperature of 25-35 C., and water (21 mL) was added dropwise at the same temperature. Then the mixture was adjusted to pH 4-5 at room temperature with 0.5N hydrochloric acid (8 mL), and water (41 mL) was added dropwise at room temperature. After stirring at room temperature for 30 min, the inside temperature was cooled to 0-10 C., and the mixture was stirred for 1 hr. The precipitated crystals were collected by filtration, washed with acetonitrile (14 mL)/water (28 mL) cooled to 5 C., and dried under reduced pressure at 50 C. until a constant weight was reached to give the title compound (10.6 g, yield 87.0%). 1H-NMR (CDCl3, TMS, 500 MHz) delta (ppm): 6.68 (d, J=1.6 Hz, 1H), 7.02 (dd, J=8.2, 8.2 Hz, 1H), 7.14-7.19 (m, 2H), 7.38 (dd, J=8.2, 4.9 Hz, 1H), 7.44-7.48 (m, 1H), 7.72 (ddd, J=8.2, 2.5, 1.6 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.82 (dd, J=4.7, 1.6 Hz, 1H), 9.90 (s, 1H).
86.7% With N-ethyl-N,N-diisopropylamine;dmap; In acetonitrile; at 40 - 50℃; for 1.5h; Example 4 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (5.00 g, 26.43 mmol), N,N-dimethylpyridin-4-amine (0.65 g, 5.29 mmol), diisopropylethylamine (4.78 g, 37.00 mmol) and acetonitrile (18.5 ml) were added in a four neck flask, and a solution of pyridine-3-sulfonyl chloride (5.63 g, 31.71 mmol) in acetonitrile (5 ml) was added. Acetonitrile (1.5 ml) was further added, and the mixture was stirred at the internal temperature of 40-50 C. for 1.5 hr. The internal temperature was cooled to 30 C., and water (15 ml) was added dropwise. The mixture was adjusted to pH 4-5 with 0.5 N hydrochloric acid. Seed crystals (2.5 mg) of the title compound were added, and then water (about 30 ml) was added dropwise. After stirring at the internal temperature of 20-30 C. for 0.5 hr, the internal temperature was cooled to 0-10 C., and the mixture was stirred for 1 hr. The precipitated crystals were collected by filtration, washed with a cold mixed solution of acetonitrile and water (1:2, 7.5 ml), and water (7.5 ml*2), and dried under reduced pressure at 50 C. until a constant weight was reached to give the title compound (7.57 g, yield 86.7%). 1H-NMR (300 MHz, CDCl3) delta (ppm): 6.68 (d, J=1.7 Hz, 1H), 7.01-7.05 (m, 1H), 7.16-7.18 (m, 2H), 7.37-7.40 (m, 1H), 7.45-7.51 (m, 1H), 7.69-7.72 (m, 1H), 8.15 (d, J=1.8 Hz, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.82 (dd, J=4.8, 1.5 Hz, 1H), 9.90 (s, 1H). elemental analysis (C16H11N2O3SF). Calculated: C, 58.17; H, 3.36; N, 8.48; O, 14.53; S, 9.71; F, 5.75.Found: C, 58.32; H, 3.46; N, 8.54; S, 9.76; F, 5.62.melting point 106-108 C.
86.6% With dmap; triethylamine; In dichloromethane; for 2h; 10.00 g of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong>, 1.29 g of 4-dimethylaminopyridine (DMAP), 7.49 g of triethylamine, and 1 L of dichloromethane were put into the reactor, and the temperature was reduced by stirring. 11.26 g of pyridine-3-sulfonyl chloride was added dropwise, and the reaction was stirred for 2 hours after the dropwise addition.Add water 20ml quench reaction, followed by 20ml of water, the mass percentage concentration of 20% sodium chloride solution 20ml washing, distillation, add 70ml 75% ethanol solution to heat the solution, cooling crystallization, filtration, washing, drying to obtain 1-(3- Pyridinesulfonyl)-<strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> 15.12 g.Yield 86.60%.
86.0% With dmap; triethylamine; In acetonitrile; at 50℃;Large scale; Add 2.5kg of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde to a clean 50L reaction kettle,4-dimethylaminopyridine 0.323kg, triethylamine 1.60kg and acetonitrile 7.31kg,A solution of pyridine-3-sulfonyl chloride in acetonitrile was added dropwise with stirring (2.82 kg of pyridine-3-sulfonyl chloride was added with 2.0 kg of acetonitrile). After the dropwise addition was completed, the temperature was raised to 50 C, and the reaction was kept warm.The reaction progress was monitored by TLC (developing agent: PE: EA = 2: 1). After the reaction was completed, the temperature was lowered to 25 C, and 7.5 kg of purified water was added dropwise.Add 0.5 mol / L hydrochloric acid dropwise to adjust the pH of the system to 4, and then dropwise add 15.0 kg of purified water, stir at 25 C for 0.5h, lower the temperature to 10 C, and stir for 1h.After filtration, the filter cake was rinsed with a mixed solution of 1.0 kg of acetonitrile and 2.5 kg of purified water and 7.5 kg of purified water.Drying gave 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carboxaldehyde 3.75 kg with a yield of 86.0%.
78.39% With dmap; triethylamine; In dichloromethane; at 10 - 35℃; for 3h; Put 50.03 g of 5- (2-fluorophenyl) -1H-pyrrole-3-carboxaldehyde into the reaction tank, and add 6.47 g of 4-N, N-dimethylaminopyridine (DMAP), 37.78 g of triethylamine, and dichloro 250 ml of methane, stirred, 56.41 g of pyridine-3-sulfonyl chloride was added dropwise at an internal temperature of 10 to 35 C, and the internal temperature was maintained at 20 ± 5 C after the dropwise reaction. The TLC was monitored to 5- (2-fluorophenyl) -1H-pyrrole- 3- After the basic reaction of formaldehyde is complete (about 3h), add stirring to quench the reaction, separate the liquid, wash it once with water, evaporate to a distillate under reduced pressure, add 90% ethanol, heat, dissolve at reflux for 30min, cool down, and internal temperature 0 Stir and crystallize at -5 C for 2h, filter, wash with 50% ethanol solution, drain, dry at 60-80 C for 3h, weigh to obtain 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) 68.48 g of -1H-pyrrole-3-carboxaldehyde, yield 78.39%.
68% With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 1.08h; 200 mg of intermediate VI-1 was dissolved in 15 ml of anhydrous tetrahydrofuran, and the temperature was lowered to 0 C, then 1.3 ml of 1 M bistrimethylsilylamide lithium was added dropwise, and the reaction was continued at 0 C after the addition was completed. After a minute, 213 mg of pyridine-3-sulfonyl chloride was further added, followed by incubation at 0 C for 5 minutes, and then the reaction was continued to room temperature for 1 hour. After completion of the reaction, the reaction was quenched by the addition of sodium hydrogen carbonate solution, and the mixture was evaporated to dryness. column chromatography to give the compound of formula VII-1, 237 mg of a white solid, yield 68%
15.5 g With dmap; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 40 - 50℃; for 2h; Acetonitrile (50 ml) was added to the reaction flask at room temperature,5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde (10 g)4-dimethylaminopyridine (1.3 g)And N, N-diisopropylethylamine (13 g),40 ~ 50 stirring reaction 2 hours after the thin layer chromatography to complete the reaction.Adding 1mol / L hydrochloric acid solution to the reaction system to adjust pH = 4 ~ 5,Add water (60ml) and stir.filter,dry,To give 5- (2-fluorophenyl) -1 - [(pyridin-3-yl) sulfonyl] -1H-pyrrole-3-carbaldehyde(15.5 g, yellow solid).
15 g With triethylamine; In acetonitrile; at 45℃; for 1.5h; 5- (2-fluorophenyl) pyrrole-3-carbaldehyde 10g, 4- dimethylaminopyridine 1.3g, triethylamine 7.5g and acetonitrile (40ml) added to the reaction flask, stirred at room temperature; pyridine-3-sulfonyl chloride 11.3g and acetonitrile (10ml), the reaction flask was added dropwise; the reaction was heated to 45 1.5 hours; cooled to 25 , was added water (30ml); the system with concentrated hydrochloric acid adjusted to ph 4-5, stirred for half an hour at 25 deg.] C; was cooled to 0-5 deg.] C stirred for 1 hour; the filter cake with acetonitrile: water (1: 2) 30ml rinsed again with water (20ml) was rinsed 2 times, 50 deg.] C and dried in vacuo to give 5- (2-fluorophenyl yl) -1- (pyridin-3-sulfonyl) pyrrole-3-carbaldehyde 15g;
0.83 mol With dmap; sodium carbonate; In acetonitrile; at 60℃; for 5h; Weigh 1 mol of pyridine-3 sulfonyl chloride and 1 mol of <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> in an appropriate amount of acetonitrile solvent, and add 1 mol of an acid-binding agent, and the acid-binding agent is DMAP and The composition of sodium carbonate was uniformly stirred, heated to 60 C, and the temperature was raised to 1 C / min. The temperature was raised to 60 C and then incubated for 5 hours to carry out a nucleophilic substitution reaction. The reaction formula of the nucleophilic substitution reaction is as follows: As shown in the above reaction formula, the product of the nucleophilic substitution reaction is 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde, said 5-(2- Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde is still present in the acetonitrile solvent. Next, the mixture after the above nucleophilic substitution reaction was allowed to stand for 3 h, and gradually cooled to room temperature.The mixture will undergo crystallization during the cooling process to form a solid-liquid mixture, and then the filtration operation is performed.The solid obtained after filtration is the nucleophilic substitution reaction product 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde.It was dried, weighed, and converted to obtain 0.83 mol of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde.

  • 19
  • [ 312307-38-3 ]
  • [ 881674-56-2 ]
  • [ 1240948-77-9 ]
YieldReaction ConditionsOperation in experiment
14.8%; 38.6% With water; hydrogen; acetic acid; In tetrahydrofuran; at 45 - 50℃; for 5h; Example 52 [2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (2.00 g, 9.89 mmol), acetic acid (22 ml) and THF (22 ml) were weighed and dissolved (under an argon atmosphere). Then, Raney-nickel (1 ml) and water (2 ml) were weighed and added, and the mixture was purged with hydrogen. This was reacted at 45-50 C. for about 5 hr. Quantification of the filtrate by HPLC gave 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (718 mg, yield 38.6%) and 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (277 mg, yield 14.8%).
  • 20
  • [ 1240948-77-9 ]
  • [ 881674-56-2 ]
YieldReaction ConditionsOperation in experiment
84.4% With hydrogen; acetic acid; In tetrahydrofuran; water; at 15 - 25℃; for 4h; In a four-necked flask, 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (10.0 g, 53.71 mmol) and THF (30 mL) were added and dissolved, and acetic acid (50 mL) and water (10 mL) were added. After substitution with nitrogen gas, Raney-nickel (Kawaken Fine Chemicals Co., Ltd., NDHT-90, 5 mL) was added. Then, the mixture was vigorously stirred under a hydrogen atmosphere at inside temperature 15-25 C. for about 4 hr. After substitution with nitrogen gas, Raney-nickel was filtered off and the residue was washed with ethyl acetate (64 mL). Ethyl acetate (36 mL) was added, 8N aqueous sodium hydroxide solution (87 mL) was added to the filtrate at an inside temperature 10-40 C. to adjust the pH to 6.5-7.5, and the mixture was partitioned. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and 5% brine (50 mL). To the organic layer was added 5% brine (50 mL), and the mixture was adjusted to pH 3.0-3.5 by adding 6N hydrochloric acid at room temperature, stirred at room temperature for 10 hr, and partitioned. The organic layer was washed with 5% brine (50 mL), and the reaction mixture was concentrated to about 35 g under reduced pressure at not more than 45 C. Furthermore, ethyl acetate (50 mL) was added to the concentrated solution, and the reaction mixture was concentrated to about 35 g under reduced pressure at not more than 45 C. After stirring at room temperature for 1 hr, n-heptane (50 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hr. Successively, the mixture was stirred at an inside temperature of 0-10 C. for 1 hr. The precipitated crystals were collected by filtration, and washed with n-heptane (20 mL)/ethyl acetate (10 mL) cooled to 5 C. The crystals were dried under reduced pressure at 50 C. until a constant weight was reached to give the title compound (8.6 g, yield 84.4%). 1H-NMR (DMSO-d6, TMS, 500 MHz) delta (ppm): 6.91 (d, J=1.6 Hz, 1H), 7.21-7.31 (m, 3H), 7.75-7.80 (m, 2H), 9.76 (s, 1H), 12.17 (brs, 1H).
78% Example 3 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde 5-(2-Fluorophenyl)-1H-pyrrole-3-carbonitrile (5.0 g, 26.9 mmol) and THF (33 ml) were added in a four neck flask, and the mixture was dissolved at the internal temperature of 15-25 C. Acetic acid (55 ml) and water (11 ml) were added. After purging with nitrogen gas, Raney-nickel (Kawaken Fine Chemicals Co., Ltd., NDHT-90, 2.5 ml, wet weight 4 g) was added. Under a hydrogen atmosphere, the mixture was vigorously stirred at the internal temperature of 15-25 C. for about 3 hr. After purging with nitrogen gas, Raney-nickel was filtered off, and washed with ethyl acetate (50 ml). 5 N Aqueous sodium hydroxide solution (about 180 ml) was added to the filtrate at the internal temperature of 10-35 C. to adjust the mixture to pH 7-8 and the mixture was partitioned. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (25 ml) and 5% brine (25 ml). Water (25 ml) was added to the organic layer, and the mixture was adjusted with 6 N hydrochloric acid to pH 3.0-3.5 at the internal temperature of 15-25 C. After stirring overnight, the mixture was partitioned. The organic layer was washed with 5% brine (25 ml), concentrated under reduced pressure to about 18 g. After increasing the internal temperature to 65-70 C., the mixture was cooled to the internal temperature of 45-55 C., and further stirred for 1 hr. After cooling to the internal temperature of 15-25 C., n-heptane (25 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hr. Furthermore, the mixture was stirred at the internal temperature of 0-10 C. for 1 hr. The precipitated crystals were collected by filtration, washed with ethyl acetate:n-heptane (1:2, 15 ml), and dried under reduced pressure at 50 C. until a constant weight was reached to give the title compound (23.9 g, yield 78%). 1H-NMR (300 MHz, DMSO-d6) delta (ppm): 6.91 (d, J=1.6 Hz, 1H), 7.21-7.31 (m, 3H), 7.75-7.80 (m, 2H), 9.76 (s, 1H), 12.17 (brs, 1H). elemental analysis (C11H8NOF). Calculated: C, 69.83; H, 4.26; N, 7.40; O, 8.46; F, 10.04.Found: C, 69.91; H, 4.27; N, 7.33.melting point 123.0-126.0 C. dec.
51.5% With formic acid; water; hydrogen; In tetrahydrofuran; under 750.075 Torr; for 2.5h; Compound (4) (6.62g, 35.6mmol), tetrahydrofuran (45ml), formic acid (36.5 ml), water (15ml), and Raney nickel (397.2um, wet weight 5.3g) was added to the reaction flask. In a hydrogen atmosphere (0.1 MPa) and room humidity, the reaction was stirred for 2.5 hours. After the reaction was complete, the system was purged with nitrogen, the solution was filtered and washed with ethyl acetate (25 ml x 2). The filtrate was adjusted to pH 6 to 7 with 5N aqueous sodium hydroxide under ice-cooling. After phase separation, the ethyl acetate layer was collected and the aqueous layer was extracted again with ethyl acetate (25 ml). The ethyl acetate layers were combined, washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dissolved in ethyl acetate (20 ml), stirred on 100 to 200 mesh silica gel and spin dried. The resulting solution was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5: 1 to 3: 1) and dried under reduced pressure to give a pale yellow solid (3.47 g, yield 51.5%).
42% With hydrogen; acetic acid; In tetrahydrofuran; water; at 20℃; for 2h; 1 g of the intermediate V-1 was dissolved in a mixed solution of 20 ml of tetrahydrofuran, 6 ml of acetic acid and 1 ml of water, then 1 ml of Raney nickel was added, hydrogen gas was introduced, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, to give a compound of Formula VI-1, 427 mg of a white solid, yield 42%

  • 21
  • [ 1240949-27-2 ]
  • [ 881674-56-2 ]
  • 23
  • [ 881674-06-2 ]
  • [ 881674-56-2 ]
YieldReaction ConditionsOperation in experiment
60% Reference Example 111 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde A solution (220 mL) of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (11.6 g) in tetrahydrofuran was cooled to -78C, and a 1.5 mol/L solution (100 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was stirred at -78C for 1 hr and water (10 mL) was added dropwise over 2 min. The mixture was allowed to warm to room temperature and stirred for 2 hr. To the reaction mixture were added celite and anhydrous magnesium sulfate and the mixture was filtered. The filtrate was concentrated under reduced pressure to give a pale-yellow oil (yield 8.30 g). To a solution (220 mL) of the obtained pale-yellow oil (8.30 g) in acetonitrile were added tetra-n-propylammonium perruthenate (1.75 g), N-methylmorpholine N-oxide (13.5 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate= 7:3?1:1) to give the title compound as yellow crystals (yield 5.6 g, 60%). 1H-NMR (CDCl3)delta: 7.07-7.28 (4H, m), 7.52-7.54 (1H, m), 7.61-7.67 (1H, m), 9.49 (1H, brs), 9.86 (1H, s).
60% Diisobutyl aluminum hydride 2.4ml dissolved in toluene, placed at -78 , take 2.3g dissolved in 100ml of tetrahydrofuranWas added dropwise to the reactor. After stirring for 1 hour, 2 ml of water was added slowly, and the mixture was stirred at room temperature for 1 hour.Adding anhydrous magnesium sulfate, filtering and concentrating the filtrate to dryness, dissolving in 45ml of acetonitrile, adding 2.36g of NMO,0.46g TPAP, molecular sieves, reaction at room temperature for 1.5 hours, the filtrate filtered diatomite, vacuum concentration, eluentWith hexane: ethyl acetate = 4: 1-1: 1 over the column that 1.1g, 60% yield.
  • 24
  • [ 881674-56-2 ]
  • 1-[5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-yl]-N-methylmethylamine fumaric acid salt [ No CAS ]
  • 25
  • [ 881674-56-2 ]
  • 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine [ No CAS ]
  • 29
  • [ 881674-56-2 ]
  • 1-[5-(2-fluorophenyl)-1-[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride [ No CAS ]
  • 30
  • [ 881674-56-2 ]
  • 2-[2-(2-fluorophenyl)-4-[(methylamino)methyl]-1H-pyrrol-1-yl]sulfonyl}benzonitrile hydrochloride [ No CAS ]
  • 31
  • [ 881674-56-2 ]
  • 4-[2-(2-fluorophenyl)-4-[(methylamino)methyl]-1H-pyrrol-1-yl]sulfonyl}benzonitrile hydrochloride [ No CAS ]
  • 32
  • [ 881674-56-2 ]
  • 1-{5-(2-fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine hydrochloride [ No CAS ]
  • 33
  • [ 881674-56-2 ]
  • 3-(ethylsulfonyl)benzene-1-sulfonyl chloride [ No CAS ]
  • [ 881677-04-9 ]
YieldReaction ConditionsOperation in experiment
Reference Example 241 1-[3-(Ethylsulfonyl)phenyl]sulfonyl}-<strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> Using <strong>[881674-56-2]5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde</strong> (147 mg), sodium hydride (60% in oil, 45 mg), 15-crown-5 (205 mg) and [3-(ethylsulfonyl)benzene]sulfonyl chloride (250 mg), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow oil (yield 181 mg, 55%). 1H-NMR (CDCl3)delta: 1.25 (3H, t, J=7.5 Hz), 3.08 (2H, q, J=7.5 Hz), 6.68 (1H, d, J=2.4 Hz), 6.95-7.02 (1H, m), 7.18-7.21 (2H, m), 7.43-7.50 (1H, m), 7.62-7.72 (2H, m), 7.16-7.97 (1H, m), 8.12-8.15 (2H, m), 9.91 (1H, s).
  • 34
  • [ 881674-56-2 ]
  • ethyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate [ No CAS ]
  • 35
  • [ 881674-56-2 ]
  • 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetic acid [ No CAS ]
 

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