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Chemical Structure| 1221819-46-0

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Product Details of [ 1221819-46-0 ]

CAS No. :1221819-46-0
Formula : C10H10O3S
M.W : 210.25
SMILES Code : O=S(C=C1COC1)(C2=CC=CC=C2)=O
MDL No. :MFCD16652327
InChI Key :NCHCTLRZIXTLPI-UHFFFAOYSA-N
Pubchem ID :46203852

Safety of [ 1221819-46-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Computational Chemistry of [ 1221819-46-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 2
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 52.45
TPSA ?

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

51.75 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.71
Log Po/w (XLOGP3)?

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

0.36
Log Po/w (WLOGP)?

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

2.46
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.

1.11
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.77
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.48

Water Solubility

Log S (ESOL):?

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

-1.56
Solubility 5.85 mg/ml ; 0.0278 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-1.01
Solubility 20.5 mg/ml ; 0.0974 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

-2.93
Solubility 0.248 mg/ml ; 0.00118 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.

-7.33 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<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)

2.66

Application In Synthesis of [ 1221819-46-0 ]

* 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 [ 1221819-46-0 ]

[ 1221819-46-0 ] Synthesis Path-Downstream   1~13

  • 1
  • [ 6704-31-0 ]
  • [ 3112-85-4 ]
  • [ 1221819-46-0 ]
YieldReaction ConditionsOperation in experiment
82% To a solution of (methylsulfonyl)benzene (2.2 g, 13.9 mmol) in THF (38 mL) at 0 was added n-BuLi (2.5 M in hexanes, 12.2 mL, 30.6 mmol) dropwise over 10 minutes. After the mixture was stirred for 30 min, chlorodiethylphosphonate (2.4 mL, 16.7 mmol) was added dropwise to the reaction. After 30 minutes, a solution of oxetan-3-one (1.0 g, 13.9 mmol) in THF (2 mL) was added dropwise to the reaction mixture at -78 . The reaction mixture was stirred at -78 for 2 hours, then diluted with aqueous NH4Cl (100 mL) and extracted with EtOAc (100 mL x 2) . The combined organic layers were concentrated and the residue was purified by silica gel chromatxography column (petroleum ether/EtOAc = 3/1) to give the title compound (2.4 g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3) : delta7.90-7.88 (m, 2H) , 7.68-7.64 (m, 1H) , 7.57 (t, J= 7.6 Hz, 2H) , 6.13-6.11 (m, 1H) , 5.66-5.64 (m, 2H) , 5.30-5.27 (m, 2H).
75% 3-((Phenylsulfonyl)methylene)oxetane To an oven-dried vial was added (methylsulfonyl)benzene (0.570 g, 3.65 mmol) and the vial was evacuated with argon 3 times. The dry THF (17 mL) was added and the reaction was cooled to 0 C. The 2.5 M BuLi in hexanes (3.21 mL, 8.03 mmol) was added dropwise and the reaction began to stir at 0 C. and stirred for 45 minutes. The diethyl chlorophosphate (0.528 mL, 3.65 mmol) was then added at 0 C. and the reaction stirred for 30 minutes. The reaction was then cooled to -78 C. and the oxetan-3-one (0.330 mL, 5.15 mmol) was then added dropwise and the reaction stirred for 2 h. The reaction was then warmed to rt and filtered through a silica plug. The reaction was then concentrated onto silica and purified by MPLC (20 min, 0-40% EtOAc:hex) to provide pure 3-((phenylsulfonyl)methylene)oxetane (0.579 g, 2.75 mmol, 75% yield). 1H NMR (400 MHz, CDCl3): delta 7.91-7.87 (m, 2H), 7.69-7.64 (m, 1H), 7.60-7.55 (m, 2H), 6.12 (quintet, J=2.3 Hz, 1H), 5.66-5.63 (m, 2H), 5.30-5.27 (m, 2H).
74% To a stirred solution of methyiphenylsulfone (3 g, 19.2 mmol) in dry tetrahydrofuran (15 mL) was added n-butyllithium (2.5 M in tetrahydrofuran; 15.4 mL, 38.4 mmol) at 0 C. Thereaction mixture was stirred for 30 mi Diethyl chiorophosphate (4 mL, 27.8 mmol) wasadded, and the mixture was stirred at 0 C for an additional 30 mm. It was then cooled to -78C, and a solution of 3-oxetanone (1.38 g, 19.2 mmol) in dry tetrahydrofuran (3 mL) wasadded. The mixture was stirred at -78 C for 1.5 h and filtered through a silica plug to give 3-((phenylsulfonyl)methylene)oxetane as a white solid (3 g, 74%). ?H NMR (400 MHz, CDC13)oe 7.90 - 7.87 (m, 2H), 7.66 - 7.64 (m, 1H), 7.59 - 7.56 (m, 2H), 6.12 (s, 1H), 5.65 (d, J =6.0Hz, 2H), 5.29 (d, J =5.6 Hz, 2H).
Example 1313-A. 3-((Phenylsulfonyl)methylene)oxetane.A solution of BuLi (2.5 M in hexanes, 22.5 mL, 56.3 mmol) was added over 10 min to a solution of methylphenylsulfone (4.00 g, 25.6 mmol) in THF (70 mL) at 0 C. The solution went from clear to light green to a heterogeneous yellow suspension. The mixture was stirred for 30 min at 0 C and then chlorodiethylphosphonate (4.46 mL, 30.7 mmol) was added dropwise and the stirring was continued for 30 min, at which point the solution turned clear orange. The reaction mixture was then cooled to -78 C and oxetan-3-one (1.85 g, 25.6 mmol) was added in THF (3 mL). The reaction mixture turned pale brown/yellow in color. After stirring for another 1.5 h, the reaction mixture was filtered through a plug of silica gel. The filtrate was triturated with solid NH4C1 until pH reached 7. The mixture was then filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-60%EtOAc/heptane) to provide 3-((phenylsulfonyl)methylene)oxetane. 1H NMR (400 MHz, CD2C12) delta ppm 7.86 - 7.99 (m, 2 H) 7.68 - 7.77 (m, 1 H) 7.57 - 7.68 (m, 2 H) 6.18 (t, J=2.40 Hz, 1 H) 5.59 - 5.70 (m, 2 H) 5.30 (td, J=3.41, 2.27 Hz, 2 H)
Example 34 Preparation of 3-(phenylsulfonylmethylene)oxetane [0275] In a dry 100 mL flask, methylsulfonylbenzene (1.00 g, 6.41 mmoles) in a solution of dry tetrahydrofuran was 2.5 M n-buLi added at 0C over 10 mins then stirred for 30 mins. Chlorodiethylphosphonate (1.1 mL) was added dropwise and continued to stir for 30 mins before cooling to -78C. Oxetan-3-one (0.65 g, 9.04 mmoles) in dry diethylether (1.0 mL) was added and stirred for 1.5h. The reaction was filtered through a silica plug and to get pure product.

  • 2
  • [ 2759-28-6 ]
  • [ 1221819-46-0 ]
  • C21H26N2O3S [ No CAS ]
  • 3
  • [ 1221819-46-0 ]
  • [ 100-46-9 ]
  • C17H19NO3S [ No CAS ]
  • 4
  • [ 1221819-46-0 ]
  • [ 98-80-6 ]
  • [ 1221819-57-3 ]
  • 5
  • [ 1221819-46-0 ]
  • [ 216019-35-1 ]
  • [ 1421253-20-4 ]
YieldReaction ConditionsOperation in experiment
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; potassium hydroxide; In 1,4-dioxane; water; at 20℃; 13-B. 2-Methyl-5-(3-((phenylsulfonyl)methyl)oxetan-3-yl)phenol.A solution of KOH (1.5 M in water, 14.2 mL, 21.3 mmol) was added to a solution of [Rh(cod)Cl]2 (0.525 g, 1.07 mmol) in dioxane (60 mL). The resulting yellow solution was stirred for 1 min. Then, 3-hydroxy- 4-methylphenyl boronic acid (6.48 g, 42.6 mmol) and a solution of <strong>[1221819-46-0]3-((phenylsulfonyl)methylene)oxetane</strong> (4.48 g, 21.3 mmol) in dioxane (40 mL) were added in that order. After 1 h, a solution of KOH (1.5 M in water, 14.2 mL, 21.3 mmol) was added. After another 10 min, [Rh(cod)Cl]2 (0.525 g, 1.07 mmol) was added. The resulting mixture was stirred at room temperature overnight, and then partitioned between Et20 and aqueous NH4C1. The aqueous layer was extracted with Et20 (3X). (During extractions, some solids crashed out in the organic layer, but went back into solution over time). The combined organic layers were dried (Na2S04), filtered, and concentrated. The dark orange residue was purified by silica gel chromatography (30-100% EtOAc/heptane) to provide 2-methyl-5-(3-((phenylsulfonyl)methyl)oxetan-3- yl)phenol. lU NMR (400 MHz, CD2C12) delta ppm 7.52 - 7.63 (m, 3 H) 7.41 (t, J=T Hz, 2 H) 6.99 (d, J=7.83 Hz, 1 H) 6.57 (dd, J=7.83, 1.77 Hz, 1 H) 6.50 (d, J=2.02 Hz, 1 H) 4.99 (d, J=6.57 Hz, 2 H) 4.91 (d, J=6.57 Hz, 2 H) 4.03 (s, 2 H) 2.20 (s, 3 H)
  • 6
  • [ 2759-28-6 ]
  • [ 1221819-46-0 ]
  • [ 1221819-58-4 ]
YieldReaction ConditionsOperation in experiment
19% To a stirred solution of 3-(Q,henylsulfonyl)methylene)oxetane (1 g, 4.76 mmol) in methanol(25 mL) was added 1-benzylpiperazine (922 mg, 5.23 mmol). The reaction mixture wasstirred at 50 C for 24 h. Magnesium turnings (650 mg, 27.1 mmol) were added, and the mixture was stirred at 20 C for 12 h. Petroleum ether (50 mL) was added, followed by sodium sulfate decahydrate (2 g). The mixture was stirred at 20 C for 20 mm and filtered. The filtrate was dried over anhydrous sodium sulfate, concentrated and purified by silica gelchromatography (eluting gradient: 0-5% methanol in dichloromethane) to give 1-benzyl-4-(3- methyloxetan-3-yl)piperazine (220 mg, 19% yield) as a white solid. ?H NMR (400 MHz, CDC13) oe 7.73 - 7.26 (m, 5H), 4.59 (d, J =5.6 Hz, 2H), 4.22 (d, J =5.6 Hz, 2H), 3.54 (s, 2H), 2.60 - 2.45 (m, 4H), 2.41 - 2.38 (m, 4H), 1.38 (s, 3H).
Example 35 Preparation of l-benzyl-4-(3-methyloxetan-3-yl)piperazine [0276] A solution of N-benzyl piperazine (0.19 g, 1.09 mmoles) and 3- (phenylsulfonylmethylene)oxetane (0.21 g, 1.00 mmoles) in methanol (5.0 mL) was stirred for 20h at 50C. Mg turnings (0.13 g, 4.99 mmoles) were added and the mixture stirred in ultrasound bath to start reaction (slight bubbling) and stirred ovn. Additional Mg turnings (0.13 g, 4.99 mmoles) was added and stirred for an additional 16hours. diethylether (15 mL) was added, followed by sodium sulfate hydrate (Na2SC>4*10 H20) and stirred for 20 minutes, filtered, dried over sodium sulfate, filtered and concentrated. The crude material was purified using a 12 g silica column and eluted with a gradient from 0-40% ethyl acetate-hexane. The desired fractions were combined and concentrated to dryness under reduced pressure to provide the title compound.
  • 7
  • [ 1221819-46-0 ]
  • 4-(3-((phenylsulfonyl)methyl)oxetan-3-yl)phenethyl 4-methylbenzenesulfonate [ No CAS ]
  • 8
  • [ 1221819-46-0 ]
  • (1-(4-(3-((phenylsulfonyl)methyl)oxetan-3-yl)phenethyl)piperidin-4-yl)diphenylmethanol [ No CAS ]
  • 9
  • [ 137756-89-9 ]
  • [ 1221819-46-0 ]
  • 2-(4-(3-((phenylsulfonyl)methyl)oxetan-3-yl)phenyl)ethanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With chloro(1,5-cyclooctadiene)rhodium(I) dimer; potassium hydroxide; In 1,4-dioxane; water; at 100℃; for 0.5h;Microwave irradiation; 2-(4-(3-((Phenylsulfonyl)methyl)oxetan-3-yl)phenyl)ethanol To a vial was added the chloro(1,5-cyclooctadiene)rhodium(I), dimer (0.012 g, 0.025 mmol) and 1,4-dioxane (10 mL). The 1.5 M aqueous KOH (0.496 mL, 0.745 mmol) was then added and the reaction stirred for 1 minute at rt. Then the (4-(2-hydroxyethyl)phenyl)boronic acid (0.103 g, 0.621 mmol) and <strong>[1221819-46-0]3-((phenylsulfonyl)methylene)oxetane</strong> (<strong>[1221819-46-0]KSC-352-099</strong>) (0.052 g, 0.248 mmol) in 1 mL dioxane was added and the reaction stirred for 30 minutes at 100 C. in muwaves. The reaction was then cooled to rt and diluted with EtOAc and washed with 1.0 M HCl. The water layer was extracted with EtOAc (3*15 mL). The EtOAc layer was collected and the water was extracted with EtOAc again. The EtOAc layers were combined and dried with MgSO4, filtered and concentrated then purified by reverse-phase MPLC (30 min, 10-100% MeCN:water) to produce pure 2-(4-(3-((phenylsulfonyl)methyl) oxetan-3-yl)phenyl)ethanol (0.063 g, 0.190 mmol, 76% yield). 1H NMR (400 MHz, CDCl3): delta 7.55-7.52 (m, 2H), 7.50-7.46 (m, 1H), 7.36-7.31 (m, 2H), 7.09 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.3 Hz, 2H), 5.03 (d, J=6.4 Hz, 2H), 4.93 (d, J=6.4 Hz, 2H), 4.03 (s, 2H), 3.82 (t, J=7.3 Hz, 2H), 2.80 (t, J=7.3 Hz, 2H).
  • 10
  • [ 1221819-46-0 ]
  • [ 93102-05-7 ]
  • 6-benzyl-8-(phenylsulfonyl)-2-oxa-6-azaspiro[3.4]octane [ No CAS ]
  • 11
  • [ 6704-31-0 ]
  • [ 56069-39-7 ]
  • [ 1221819-46-0 ]
  • 12
  • [ 5382-16-1 ]
  • [ 75-77-4 ]
  • [ 1221819-46-0 ]
  • 1-(3-methyloxetan-3-yl)piperidin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
A solution of <strong>[1221819-46-0]3-(phenylsulfonylmethylene)oxetane</strong> (2.1 g, 10 mmol) and piperidin-4-ol (1.11 g, 11 mmol) in methanol (100 mL) was stirred at 50 C. for 5 hours. LCMS shows desired product, trace starting material. Reaction mixture was telescoped into next reaction. Magnesium turnings (1.2 g, 50 mmol) were treated with chloro trimethylsilane (0.5 mL), followed by anhydrous methanol (5 mL). The mixture was gently swirled resulting in vigorous bubbling. After 30 seconds, mixture was decanted, anhydrous methanol (5 mL) was added, swirled for 30 seconds and decanted. The activated magnesium was added to above reaction mixture and stirred at 50 C. for 12 h. LCMS shows desired product mass. Reaction mixture was diluted with methanol, filtered through a pad of Celite and the filtrate concentrated. Crude 1-(3-methyloxetan-3-yl)piperidin-4-ol was dissolved in methanol and was applied to a Amberlite column. The column was washed with methanol and product was eluted off using 2M ammonia in methanol. Product containing fractions were concentrated and dried under house vacuum to give a yellow residue. LCMS-ESI+: calc'd for C9H18NO2: 172.1 (M+H)+; found: 172.2 (M+H)+.
  • 13
  • [ 1221819-46-0 ]
  • 5-methyl-6-(piperidin-4-yl)-1H-indazole [ No CAS ]
  • 5-methyl-6-(1-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperidin-4-yl)-1H-indazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% In methanol; at 50℃; To a stirred solution of <strong>[1221819-46-0]3-((phenylsulfonyl)methylene)oxetane</strong> (630 mg, 2.99 mmol) in MeOH (5 ml) was added 5-methyl-6- (piperidin-4-yl) -1H-indazole (500 mg, 2.32 mmol). The reaction mixture was stirred at 50 overnight, then concentrated. The purification via column chromatography afforded the desired product as a white solid (816 mg, yield: 82%). LC-MS [mobile phase: from 90%water (0.1%FA) and 10%CH3CN (0.1%FA) to 5%water (0.1%FA) and 95%CH3CN (0.1%FA) in 2.0 min] : Rt = 1.31 min; MS Calcd: 425, MS Found: 426 [M + H]+.
 

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Technical Information

Categories

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