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Product Details of [ 1195768-19-4 ]

CAS No. :1195768-19-4
Formula : C14H10F3NO4S
M.W : 345.29
SMILES Code : O=C(OC)C1=CC=CC(NS(=O)(C2=C(F)C=CC=C2F)=O)=C1F
MDL No. :MFCD18447698
Boiling Point : No data available
InChI Key :COSCWKICERLCEK-UHFFFAOYSA-N
Pubchem ID :57989692

Safety of [ 1195768-19-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 1195768-19-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 23
Num. arom. heavy atoms 12
Fraction Csp3 0.07
Num. rotatable bonds 5
Num. H-bond acceptors 7.0
Num. H-bond donors 1.0
Molar Refractivity 74.71
TPSA ?

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

80.85 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.2
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

2.6
Log Po/w (WLOGP)?

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

4.84
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.

3.23
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

2.74
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.12

Water Solubility

Log S (ESOL):?

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

-3.67
Solubility 0.073 mg/ml ; 0.000211 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.

-3.95
Solubility 0.039 mg/ml ; 0.000113 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

-5.77
Solubility 0.000588 mg/ml ; 0.0000017 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

No
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

Yes
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.

-6.56 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

0.0
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

0.0 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)

2.51

Application In Synthesis of [ 1195768-19-4 ]

* 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.

  • Upstream synthesis route of [ 1195768-19-4 ]
  • Downstream synthetic route of [ 1195768-19-4 ]

[ 1195768-19-4 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 1195768-18-3 ]
  • [ 60230-36-6 ]
  • [ 1195768-19-4 ]
YieldReaction ConditionsOperation in experiment
91% With pyridine In dichloromethane at 15 - 25℃; tep A: methyl 3-[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoateMethyl 3-amino-2-fluorobenzoate (50 g, 1 eq) was charged to reactor followed by dichloromethane (250 mL, 5 vol). The contents were stirred and cooled to ~15°C and pyridine (26.2 mL, 1 .1 eq) was added. After addition of the pyridine, the reactor contents were adjusted to ~15°C and the addition of 2,6-diflurorobenzenesulfonyl chloride (39.7 mL, 1 .0 eq) was started via addition funnel. The temperature during addition was kept <25°C. After complete addition, the reactor contents were warmed to 20-25°C and held overnight. Ethyl acetate (150 mL) was added and dichloromethane was removed by distillation. Once distillation was complete, the reaction mixture was then diluted once more with ethyl acetate (5 vol) and concentrated. The reaction mixture was diluted with ethyl acetate (10 vol) and water (4 vol) and the contents heated to 50-55°C with stirring until all solids dissolve. The layers were settled and separated. The organic layer was diluted with water (4 vol) and the contents heated to 50-55° for 20-30 min. The layers were settled and then separated and the ethyl acetate layer was evaporated under reduced pressure to ~3 volumes. Ethyl Acetate (5 vol.) was added and again evaporated under reduced pressure to ~3 volumes.Cyclohexane (9 vol) was then added to the reactor and the contents were heated to reflux for 30 min then cooled to 0 °C. The solids were filtered and rinsed with cyclohexane (2 x 100 mL). The solids were air dried overnight to obtain methyl 3-[(2,6- difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (94.1 g, 91 percent).
91% With pyridine In dichloromethane at 15 - 25℃; Methyl 3-amino-2-fluorobenzoate (50 g, 1 eq) was charged to reactor followed by dichloromethane (250 mL, 5 vol). The contents were stirred and cooled to ~15°C and pyridine (26.2 mL, 1.1 eq) was added. After addition of the pyridine, the reactor contents were adjusted to ~15°C and the addition of 2,6-diflurorobenzenesulfonyl chloride (39.7 mL, 1.0 eq) was started via addition funnel. The temperature during addition was kept <25°C. After complete addition, the reactor contents were warmed to 20-25°C and held overnight. Ethyl acetate (150 mL) was added and dichloromethane was removed by distillation. Once distillation was complete, the reaction mixture was then diluted once more with ethyl acetate (5 vol) and concentrated. The reaction mixture was diluted with ethyl acetate (10 vol) and water (4 vol) and the contents heated to 50-55°C with stirring until all solids dissolve. The layers were settled and separated. The organic layer was diluted with water (4 vol) and the contents heated to 50-55° for 20-30 min. The layers were settled and then separated and the ethyl acetate layer was evaporated under reduced pressure to ~3 volumes. Ethyl Acetate (5 vol.) was added and again evaporated under reduced pressure to ~3 volumes. Cyclohexane (9 vol) was then added to the reactor and the contents were heated to reflux for 30 min then cooled to 0 °C. The solids were filtered and rinsed with cyclohexane (2 x 100 mL). The solids were air dried overnight to obtain methyl 3-[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (94.1 g, 91percent).
91% With pyridine In dichloromethane at 15 - 25℃; Methyl 3-amino-2-fluorobenzoate (50 g, 1 eq) was charged to reactor followed by dichloromethane (250 mL, 5 vol). The contents were stirred and cooled to ~15°C and pyridine (26.2 mL, 1.1 eq) was added. After addition of the pyridine, the reactor contents were adjusted to ~15°C and the addition of 2,6-diflurorobenzenesulfonyl chloride (39.7 mL, 1.0 eq) was started via addition funnel. The temperature during addition was kept<25°C. After complete addition, the reactor contents were warmed to 20-25°C and held overnight. Ethyl acetate (150 mL) was added and dichloromethane was removed by distillation. Once distillation was complete, the reaction mixture was then diluted once more with ethyl acetate (5 vol) and concentrated. The reaction mixture was diluted with ethyl acetate (10 vol) and water (4 vol) and the contents heated to 50-55°C with stirring until all solids dissolve. The layers were settled and separated. The organic layer was diluted with water (4 vol) and the contents heated to 50-55° for 20-30 min. The layers were settled and then separated and the ethyl acetate layer was evaporated under reduced pressure to ~3 volumes. Ethyl Acetate (5 vol.) was added and again evaporated under reduced pressure to ~3 volumes. Cyclohexane (9 vol) was then added to the reactor and the contents were heated to reflux for 30 min then cooled to 0 °C. The solids were filtered and rinsed with cyclohexane (2 x 100 ml_). The solids were air dried overnight to obtain methyl 3-[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (94.1 g, 91 percent).
91% With pyridine In dichloromethane at 15 - 25℃; Step A: methyl 3-[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate Methyl 3-amino-2-fluorobenzoate (50 g, 1 eq) was charged to reactor followed by dichloromethane (250 mL, 5 vol). The contents were stirred and cooled to ~15°C and pyridine (26.2 mL, 1.1 eq) was added. After addition of the pyridine, the reactor contents were adjusted to ~15°C and the addition of 2,6-diflurorobenzenesulfonyl chloride (39.7 mL, 1.0 eq) was started via addition funnel. The temperature during addition was kept <25°C. After complete addition, the reactor contents were warmed to 20-25°C and held overnight. Ethyl acetate (150 mL) was added and dichloromethane was removed by distillation. Once distillation was complete, the reaction mixture was then diluted once more with ethyl acetate (5 vol) and concentrated. The reaction mixture was diluted with ethyl acetate (10 vol) and water (4 vol) and the contents heated to 50-55°C with stirring until all solids dissolve. The layers were settled and separated. The organic layer was diluted with water (4 vol) and the contents heated to 50-55° for 20-30 min. The layers were settled and then separated and the ethyl acetate layer was evaporated under reduced pressure to ~3 volumes. Ethyl Acetate (5 vol.) was added and again evaporated under reduced pressure to ~3 volumes. Cyclohexane (9 vol) was then added to the reactor and the contents were heated to reflux for 30 min then cooled to 0 °C. The solids were filtered and rinsed with cyclohexane (2 x 100 mL). The solids were air dried overnight to obtain methyl 3-[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (94.1 g, 91percent).
91% With pyridine In dichloromethane at 15 - 25℃; Step A: methyl 3-[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate: Methyl 3-amino-2-fluorobenzoate (50 g, 1 eq) was charged to reactor followed by dichloromethane (250 mL, 5 vol). The contents were stirred and cooled to -15 °C and pyridine (26.2 mL, 1.1 eq) was added. After addition of the pyridine, the reactor contents were adjusted to ~15°C and the addition of 2,6-diflurorobenzenesulfonyl chloride (39.7 mL, 1.0 eq) was started via addition funnel. The temperature during addition was kept <25 °C. After complete addition, the reactor contents were warmed to 20-25 °C and held overnight. Ethyl acetate (150 mL) was added and dichloromethane was removed by distillation. Once distillation was complete, the reaction mixture was then diluted once more with ethyl acetate (5 vol) and concentrated. The reaction mixture was diluted with ethyl acetate (10 vol) and water (4 vol) and the contents heated to 50-55 °C with stirring until all solids dissolve. The layers were settled and separated. The organic layer was diluted with water (4 vol) and the contents heated to 50-55 °C for 20-30 min. The layers were settled and then separated and the ethyl acetate layer was evaporated under reduced pressure to ~3 volumes. Ethyl Acetate (5 vol.) was added and again evaporated under reduced pressure to ~3 volumes. Cyclohexane (9 vol) was then added to the reactor and the contents were heated to reflux for 30 min then cooled to 0 °C. The solids were filtered and rinsed with cyclohexane (2 x 100 mL). The solids were air dried overnight to obtain methyl 3- [(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (94.1 g, 91percent).
87% With pyridine In dichloromethane at 20℃; Step C: Methyl 3-[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate; In a 500 mL flask was placed methyl 3-amino-2-fluorobenzoate (5.5 g, 32.5 mmol) and DCM (100 mL), and pyridine (2.9 mL, 35.8 mmol) was added. 2,6-Difluorobenzenesulfonyl chloride (7.6 g, 35.8 mmol) in DCM (50 mL) was added dropwise via addition funnel and the reaction mixture was allowed to stir at rt overnight. The reaction mixture was stripped onto silica and column chromatographed on silica with 5percent to 100percent EtOAc:Hexane to give 9.75 g (87percent) of the title compound of Step C. 1H-NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.64-7.82 (m, 3H), 7.46-7.61 (m, 1H), 7.29 (t, J=8.8 Hz, 2H), and 3.81 (s, 3H). MS (ESI): 346 [M+H]+.
87% With pyridine In dichloromethane at 20℃; Inert atmosphere In a 500 mL flask was placed methyl 3-amιno-2-fluorobenzoate (5 5 g, 32 5 mmol) and DCM (100 mL) and pyridine (2 9 mL, 35 8 mmol) was added 2,6-10 Difluorobenzenesulfonyl chloride (7 6 g, 35 8 mmol) in DCM (50 mL) was added dropwise via addition funnel and the reaction mixture was allowed to stir at rt overnight The reaction mixture was stripped onto silica and column chromatographed on silica with 5percent to 100percent EtOAc Hexane to give 9 75 g (87percent) of the title compound of Step C 1H-NMR (400 MHz, DMSO-ds) δ 10 98 (s, 1 H), 7 64 -15 7 82 (m, 3 H), 746 - 7 61 (m, 1 H), 7 29 (t, J = 8 8 Hz, 2 H), and 3 81 (s, 3 H) MS (ESI) 346 [M+H]+
82% With pyridine; dmap In dichloromethane at 20℃; for 12 h; Inert atmosphere thane (100 mL), pyridine (3.2 g, 0.040 mol) and DMAP (0.1 g), nitrogen , under ice-cooling was added with a dropping funnel, 2,6-difluorophenyl 1-sulfonyl chloride (7.2 g, 0.034 mol).After the addition was complete, slowly warm to room temperature and stirred for 12 hours.The organic phase was washed with water three times (20 mL × 3), dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) was isolated as the product (9.5 g, yield 82percent)
62% With pyridine In dichloromethane at 0 - 20℃; A solution of Methyl 3-amino-2-fluorobenzoate (2.0g, 11.82mmol) in DCM (40mL) was treated at 0°C with pyridine (1.91mL, 23.65mmol) and with 2,6-difluorobenzenesulfonyl chloride (2.40mL, 17.17mmol). The reaction mixture was stirred at room temperature overnight. The medium was poured onto water, and aqueous HC1 (1M) was added. The aqueous layer was extracted with DCM. Combined organics were washed with saturated aqueous sodium bicarbonate, dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (DCM/cHex 8/2 to 10/0) afforded the title compound (2.55g, 62percent). LC/MS (ES"): 344.2 (M-l).
6.91 g at 15 - 20℃; To a cooled solution of 1,3-difluorobenzene (9.4 g, 82 mmol) in diethyl ether (120 mL) was added n-BuLi in hexane (32.3 mL, 81 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 3 h. Sulfur dioxide (106 g, 1648 mmol) was flushed into the solution and stirred at −60° C. for 20 mins, which produced a white solid. NCS (12.10 g, 91 mmol) was added and the reaction mixture was warmed to rt and for 1 h. The reaction mixture with white solid changed to pale brown solution. The reaction mixture was filtered and concentrated to give crude No.34   2,6-difluorobenzenesulfonyl chloride, which was added dropwise into No.35   methyl 3-amino-2-fluorobenzoate (5.19 g, 30.7 mmol) in No.36   pyridine (50 mL) at 15° C. After the addition, the reaction mixture was stirred at room temperature overnight. No.38   Ethyl acetate (100 mL) was added to the reaction mixture and then followed by 40 mL of cold No.10   water. The mixture was heated to 55° C. with stirring until all red solids dissolved. The upper layer was organic layer which was isolated and washed again with water. The organic layer was dried and evaporated under reduced pressure. Petro ether was added to the crude product and heated to reflux and then cooled to 5° C. The solids were filtered and rinsed with petro ether to afford No.39   methyl 3-(2,6-difluorophenylsulfonamido)-2-fluorobenzoate (6.91 g, 10.35 mmol, 12.56percent yield) as orange solid. LCMS: [M+NH4]+=363.0.

References: [1] Patent: WO2011/47238, 2011, A1, . Location in patent: Page/Page column 17-18.
[2] Patent: WO2014/66606, 2014, A2, . Location in patent: Page/Page column 20-21.
[3] Patent: WO2014/195852, 2014, A1, . Location in patent: Page/Page column 28-29.
[4] Patent: WO2015/87279, 2015, A1, . Location in patent: Page/Page column 21; 22.
[5] Patent: WO2017/37587, 2017, A1, . Location in patent: Page/Page column 31-32.
[6] Patent: US2009/298815, 2009, A1, . Location in patent: Page/Page column 53.
[7] Patent: WO2010/104899, 2010, A1, . Location in patent: Page/Page column 163.
[8] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 3, p. 358 - 362.
[9] Patent: CN103936728, 2016, B, . Location in patent: Paragraph 0211; 0222; 0223; 0224.
[10] Patent: WO2018/55097, 2018, A1, . Location in patent: Page/Page column 35; 36.
[11] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 15, p. 4436 - 4440.
[12] Patent: US2013/53562, 2013, A1, . Location in patent: Paragraph 0073.
  • 2
  • [ 1042055-86-6 ]
  • [ 1195768-19-4 ]
References: [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 3, p. 358 - 362.
  • 3
  • [ 206551-41-9 ]
  • [ 1195768-19-4 ]
References: [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 3, p. 358 - 362.
  • 4
  • [ 161957-56-8 ]
  • [ 1195768-19-4 ]
References: [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 3, p. 358 - 362.
  • 5
  • [ 914223-43-1 ]
  • [ 1195768-19-4 ]
References: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 15, p. 4436 - 4440.
[2] Patent: WO2018/55097, 2018, A1, .
  • 6
  • [ 946126-94-9 ]
  • [ 1195768-19-4 ]
References: [1] Patent: CN103936728, 2016, B, .
  • 7
  • [ 317-46-4 ]
  • [ 1195768-19-4 ]
References: [1] Patent: CN103936728, 2016, B, .
 

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