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Chemical Structure| 253168-94-4 Chemical Structure| 253168-94-4
Chemical Structure| 253168-94-4

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Product Details of [ 253168-94-4 ]

CAS No. :253168-94-4
Formula : C12H19NO4S
M.W : 273.35
SMILES Code : O=S(CC(N)C1=CC=C(OC)C(OCC)=C1)(C)=O
MDL No. :MFCD27665207
InChI Key :BXUJVINGXQGNFD-UHFFFAOYSA-N
Pubchem ID :11288792

Safety of [ 253168-94-4 ]

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

Calculated chemistry of [ 253168-94-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 18
Num. arom. heavy atoms 6
Fraction Csp3 0.5
Num. rotatable bonds 6
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 70.48
TPSA ?

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

87.0 ?2

Lipophilicity

Log Po/w (iLOGP)?

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

1.85
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

0.5
Log Po/w (WLOGP)?

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

1.89
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.

0.75
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

1.28
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.25

Water Solubility

Log S (ESOL):?

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

-1.7
Solubility 5.45 mg/ml ; 0.0199 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.

-1.9
Solubility 3.46 mg/ml ; 0.0127 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

-3.46
Solubility 0.0939 mg/ml ; 0.000344 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

 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

 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.

-7.61 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)

 2.83

Application In Synthesis [ 253168-94-4 ]

* 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.

  • Downstream synthetic route of [ 253168-94-4 ]

[ 253168-94-4 ] Synthesis Path-Downstream   1~26

  • 1
  • [ 253168-94-4 ]
  • [ 92971-15-8 ]
  • 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-dinitroisoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% In toluene; for 15h;Heating / reflux; [00090] A mixture of 3,4-dinitrophthalic acid (4.63 g, 18.1 mmol) and <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine</strong> (4.94 g, 18.1 g) in toluene (70 mL) was heated to reflux for 15 hours. The water was removed by a Dean-Stark trap. To the reaction mixture was added ethyl acetate (150 mL). The organic layer was extracted with water, sodium hydrogen carbonate (sat), brine (100 mL each), and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was recrystallized from ethanol (300 mL) to give 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-dinitroisoindoline-1,3-dione as an orange solid (4.35 g, 49% yield): mp, 122.0-124.0 C.; 1H NMR (CDCl3) delta1.47 (t, J=6.9 Hz, 3H, CH3), 2.93 (s, 3H, CH3), 3.65 (dd, J=3.9, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.10 (q, J=6.9 Hz, 2H, CH2), 4.56 (dd, J=11.4, 14.1 Hz, 1H, CHH), 5.90 (dd, J=3.9, 11.1 Hz, 1H, NCH), 6.84 (d, J=8.0 Hz, 1H, Ar), 7.07-7.11 (m, 2H, Ar), 8.16 (d, J=8.2 Hz, 1H, Ar), 8.60 (d, J=7.9 Hz, 1H, Ar); 13C NMR (CDCl3) delta14.66, 41.66, 49.57, 53.38, 55.98, 64.61, 111.61, 112.42, 120.64, 123.93, 126.18, 127.85, 131.93, 136.74, 138.10, 142.45, 148.77, 150.17, 161.57, 163.47; Anal Calcd for C20H19N3O10S+0.1 ethyl acetate: C, 48.78; H, 3.97; N, 8.37. Found: C, 48.50; H, 3.77; N, 8.07. (HNMR showed the sample contained 10% eq of ethyl acetate).
  • 2
  • [ 253168-94-4 ]
  • [ 143092-07-3 ]
  • [ 340019-20-7 ]
YieldReaction ConditionsOperation in experiment
70% With sodium acetate; In acetic acid; for 18h;Heating / reflux; A mixture of <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine</strong> (0.69 g, 2.5 mmol), furano[3,4-h]quinoline-1,3-dione (0.50 g, 2.5 mmol) and sodium acetate (0.25 g, 3.1 mmol) in acetic acid (10 ML) was heated to reflux for 18 hours. The solvent was removed in vacuo to give an oil. The resulting oil was stirred in ether/hexane/water (30/5/30 ML) for 18 hours. The suspension was filtered to give a solid. The solid was stirred in hot methanol. The suspension was filtered to give 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-3-pyrrolino[3,4-h]quinoline-1,3-dione as an off-white solid (0.8 g, 70% yield): mp, 223-225 C.; 1H NMR (CDCl3); delta1.47 (t, J=6.8 Hz, 3H, CH3), 2.89 (s, 3H, CH3), 3.79-3.86 (m, 1H, CHH), 3.84 (s, 3H, CH3), 4.12 (q, J=6.9 Hz, 2H, CH2), 4.63 (dd, J=10.4, 14.3 Hz, 1H, CHH), 5.98 (dd, J=4.5, 10.3 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar), 7.19-7.22 (m, 2H, Ar), 7.57 (dd, J=4.2, 8.4 Hz, 1H, Ar), 7.95 (t, J=8.2 Hz, 1H, Ar), 8.17 (d, J=8.3 Hz, 1H, Ar), 8.27 (dd, J=1.4, 8.4 Hz, 1H, Ar), 9.24 (dd, J=1.7, 4.2 Hz, 1H, Ar); 13C NMR (CDCl3) delta14.61, 41.36, 48.90, 54.73, 55.88, 64.47, 11.41, 112.57, 119.55, 120.55, 123.20, 126.89, 129.48, 132.19, 134.43, 135.69, 136.68, 142.79, 148.55, 149.59, 154.30, 167.11, 167.62; Anal Calcd for C23H22N2O6S: C, 60.78; H, 4.88; N, 6.16. Found: C, 60.57; H, 4.79; N, 5.95.
  • 3
  • [ 253168-94-4 ]
  • [ 6296-53-3 ]
  • [ 253168-86-4 ]
YieldReaction ConditionsOperation in experiment
59% In acetic acid; EXAMPLE 1 SYNTHESIS OF 2-[1-(3-ETHOXY-4-METHOXYPHENYL)-2-METHYLSULFONYLETHYL]-4-ACETYLAMINOISOINDOLINE-1,3-DIONE A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144 C.; 1H NMR (CDCl3) delta1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s,3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J=7 Hz, 1H., Ar), 7.64 (t, J=8 Hz, 1H, Ar), 8.74 (d, J=8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) delta14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
59% In acetic acid; 5.1. EXAMPLE 1: SYNTHESIS OF 2-[1-(3-ETHOXY-4-METHOXYPHENYL)-2-METHYLSULFONYLETHYL]-4-ACETYLAMINOISOINDOLINE-1,3-DIONE A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0g, 3.7 mmol) and 3 -acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144C.; 1H NMR (CDCl3) delta1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s,3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J= 7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J= 7 Hz, 1H., Ar), 7.64 (t, J= 8 Hz, 1H, Ar), 8.74 (d, J= 8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) delta14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
59% With acetic acid; for 15h;Reflux; [0110j A stirred solution of 1 -(3 -ethoxy-4-methoxyphenyl)-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144C.; ?H NMR (CDC13) oel.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s,3H, CH3),3.75 (dd, J4.4, 14.3 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J 7Hz, 2H, CH2), 5.87 (dd, J4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J= 7 Hz, 1H., Ar), 7.64 (t, J= 8 Hz, 1H, Ar), 8.74 (d, J= 8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); ?3C NMR (CDC13) oe14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc?d. for C22H24N075: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
59% With acetic acid; for 15h;Reflux; [0093] A stirred solution of l-(3-ethoxy-4-methoxyphenyl)-2- methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144 C; 1H NMR (CDC13) delta: 1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J= 7 Hz, 1H, Ar), 7.64 (t, J= 8 Hz, 1H, Ar), 8.74 (d, J= 8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDC13) delta: 14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S : C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
59% With acetic acid; for 15h;Reflux; Example 1 Synthesis of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144 C.; 1H NMR (CDCl3) delta1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 11-1, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 8.74 (d, J=8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) delta14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
59% With acetic acid; for 15h;Reflux; A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-methylsulfonylethylamine (0607) (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. (0608) Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144C; 1H NMR (CDC13) 51.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s,3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J= 7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J= 7 Hz, 1H., Ar), 7.64 (t, J= 8 Hz, 1H, Ar), 8.74 (d, J= 8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDC13) 514.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
59% With acetic acid; for 15h;Reflux; 10213] A stirred solution of 1-(3-ethoxy-4-methoxyphe- nyl)-2-methyl sulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144 C.; ?H NMR (CDC13) oe: 1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 8.74 (d, J=8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); ?3CNMR (CDC13) oe: 14.61,24.85,41.54,48.44,54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38,169.09, 169.40; Anal Calc?d. for C22H24N075: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
59% With acetic acid; for 15h;Reflux; A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144 C; 1H NMR (CDCl3) delta: 1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J= 7 Hz, 1H, Ar), 7.64 (t, J= 8 Hz, 1H, Ar), 8.74 (d, J= 8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) delta: 14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.

  • 4
  • [ 253168-94-4 ]
  • [ 641-70-3 ]
  • 2-[1-(3-Ethoxy-4methoxyphenyl)-2-methylsunylethyl]-4nitroisoindoline-1,3-dione [ No CAS ]
  • 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-4-nitroisoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% In acetic acid; EXAMPLE 8 2-[1-(3-Ethoxy-4methoxyphenyl)-2-methylsunylethyl]-4nitroisoindoline-1,3-dione A stirred solution 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (640 mg, 2.34 mmol) and 3-nitrophthalic anhydride (460 mg, 2.34 mmol) in acetic acid (10 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-nitroisoindoline-1,3-dione as a yellow solid (850 mg, 81% yield): mp, 110.0-114.0 C.; 1 H NMR (CDCl3); delta 1.47 (t, J=7.0 Hz, 3H, CH3), 2.90 (s, 3H, CH3), 3.71 (dd, J=4.3, 14.4 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.10 (q, J=7.0 Hz, 2H, CH2), 4.58 (dd, J=10.7, 14.4 Hz, 1H, CHH), 5.93 (dd, J=4.2, 10.7 Hz, 1H, NCH), 6.84 (d, J=8.8 Hz, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.89 (t, J=7.8 Hz, 1H, Ar), 8.08-8.13 (m, 2H, Ar); 13 C NMR (CDCl3) delta 14.67, 41.56, 49.19, 53.97, 55.96, 64.56, 111.52, 112.51, 120.62, 123.44, 127.35, 128.65, 128.84, 133.73, 135.48, 145.24, 148.68, 149.92, 162.53, 165.33; Anal Calcd for C20 H20 NO8 S: C, 53.57; H, 4.50; N, 6.23. Found: C, 53.54; H, 4.28; N, 6.32
  • 5
  • [ 253168-94-4 ]
  • [ 5466-84-2 ]
  • 2-[1-(3-Ethoxy-4methoxyphenyl)-2-methylsutfonyletllyl]-5-nitro-iso-indoline-1,3-dione [ No CAS ]
  • [ 253168-80-8 ]
YieldReaction ConditionsOperation in experiment
87% EXAMPLE 6 2-[1-(3-Ethoxy-4methoxyphenyl)-2-methylsutfonyletllyl]-5-nitro-iso-indoline-1,3-dione A stirred mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 4-nitrophthalic anhydride (706 mg, 3.66 mmol) was heated to melt for 6 min. The mixture was allowed to cool to room temperature. Chromatography of the resulting oil gave 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-nitro-iso-indoline-1,3-dione as a solid (1.42 g, 87% yield): mp, 255.0-256.0 C.; 1 H NMR (CDCl3); delta 1.47 (t, J=7 Hz, 3H, CH3), 2.91 (s, 3H, CH3), 3.71 (dd, J=4.2, 14.3 Hz, 1H, CHH), 3.85 (2, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 4.59 (dd, J=11.1, 14.1, Hz, 1H, CHH), 5.94 (dd, J=4.1, 10.9 Hz, 1H, NCH), 6.82-6.86 (m, 2H, Ar), 7.09-7.14 (m, 2H, Ar), 8.01-8.04 (m, 1H, Ar), 8.56-8.65 (m, 1H, Ar), 13 C NMR (CDCl3) delta 14.67, 41.61, 49.16, 53.99, 55.96, 64.54, 111.48, 112.39, 118.98, 120.48, 124.79, 128.73, 129.39, 133.06, 136.03, 148.71, 149.92, 151.79, 165.56, 165.74; Anal Calcd for C20 H20 NO8 S: C, 53.57; H, 4.50; N, 6.23. Found: C, 53.59; H, 4.58; N, 5.88.
  • 6
  • [ 27086-53-9 ]
  • [ 253168-94-4 ]
  • 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonylethyl]-4-dimetilylamino isoindoline-1,3-dione [ No CAS ]
  • [ 253168-88-6 ]
YieldReaction ConditionsOperation in experiment
80% In acetic acid; EXAMPLE 14 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonylethyl]-4-dimetilylamino isoindoline-1,3-dione 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (572 mg, 2.09 mmol) and 3-dimethylaminophthalic anhydride (400 mg, 2.09 mmol) in acetic acid (20 mL). The product was obtained as a yellow solid (740 mg, 80% yield): mp, 94.0-96.0 C.; 1 H NMR (CDCl3) delta 1.46 (t, J=7.0 Hz, 3H, CH3), 2.82 (s, 3H, CH3), 3.08 (s, 6H, CH3), 3.76-3.84 (m, 1H, CHH), 3.82 (s, 3H, CH3), 4.11 (q, J=7.0 Hz, 2H, CH2), 4.54 (dd, J=9.9, 14.5 Hz, 1H, CHH), 5.88 (dd, J=4.8, 9.9 Hz, 1H, NCH), 6.81-6.84 (m, 1H, Ar), 7.04-7.15 (m, 3H, Ar), 7.23-7.27 (m, 1H, Ar), 7.48 (dd, J=7.3, 8.3 Hz, 1H, Ar); 13 C NMR (CDCl3) delta 14.68, 41.47, 43.39, 48.74, 55.20, 55.92, 64.43, 111.34, 112.54, 113.78, 114.41, 120.47, 122.09, 129.97, 134.32, 134.81, 148.46, 149.44, 150.42, 167.06, 168.19; Anal Calcd for C22 H26 NO6 S: C, 59.14; H, 5.91; N, 6.27. Found: C, 59.14; H, 5.91; N, 6.10.
  • 7
  • [ 253168-94-4 ]
  • 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-methyl-isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% EXAMPLE 11 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-methyl-isoindoline-1,3-dione 2- [1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-methylisoindoline-1,3-dione was prepared by the procedure of Example 6 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 4-methylphythalic anhydride (590 mg, 3.7 mmol). The product was obtained as a white solid (710 mg, 46% yield): mp, 87.0-89.0 C.; 1 H NMR (CDCl3) delta 1.45 (t, J=7.0 Hz, 3H, CH3), 2.47 (s, 3H, CH3), 2.84 (s, 3H, CH3), 3.77-3.84 (m, 1H, CHH), 3.84 (s, 3H, CH3), 4.09 (q, J=7.0 Hz, 2H, CH2), 4.54 (dd, J=10.2, 14.4 Hz, 1H, CHH), 5.89 (dd, J=4.7, 10.1 Hz, 1H, NCH), 6.83 (d, J=8.0 Hz, 1H, Ar), 7.09-7.15 (m, 2H, Ar), 7.47 (d, J=7.7 Hz, 1H, Ar), 7.60 (s, 1H, Ar), 7.76 (d, J=7.6 Hz, 1H, Ar); 13 C NMR (CDCl3) delta 14.51, 21.77, 41.31, 48.56, 54.59, 55.73, 64.26, 111.24, 112.31, 120.25, 123.26, 123.86, 128.81, 129.57, 131.79, 134.59, 145.43, 148.34, 149.36, 167.72, 167.87; Anal Calcd for C21 H23 NO6 S: C, 60.42; H, 5.55; N, 3.36. Found: C, 60.34; H, 5.49; N, 3.21.
  • 8
  • [ 253168-94-4 ]
  • [ 14963-96-3 ]
  • [ 253168-91-1 ]
  • 2-[1-(3-Etloxy-4methoxyphenyl)-2-methylsutfonylethyl]-4-methoxy-isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
67% In acetic acid; EXAMPLE 17 2-[1-(3-Etloxy-4methoxyphenyl)-2-methylsutfonylethyl]-4-methoxy-isoindoline-1,3-dione 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-methoxyisoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (580 mg, 2.12 mmol) and 3-methoxyphthalic anhydride (380 mg, 2.13 mmol) in acetic acid (15 mL). The product was obtained as a white solid (620 mg, 67% yield): mp, 162.5-164.5 C.; 1 H NMR (CDCl3) delta 1.45 (t, J=6.9 Hz, 3H, CH3), 2.85 (s, 3H, CH3), 3.78 (dd, J=4.7, 10.5 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 3.99 (s, 3H, CH3), 4.09 (q, J=6.9 Hz, 2H, CH2), 4.54 (dd, J=10.3, 14.4 Hz, 1H, CHH), 5.87 (dd, J=4.6, 10.7 Hz, 1H, NCH), 6.80-6.83 (m, 1H, Ar), 7.10-7.18 (m, 3H, Ar), 7.38 (d, J=7.3 Hz, 1H, Ar), 7.63 (dd, J=7.5, 8.2 Hz, 1H, Ar); 13 C NMR (CDCl3) delta 14.57, 41.32, 48.52, 54.62, 55.82, 56.19, 64.38, 111.35, 112.52, 115.56, 116.75, 117.58, 120.40, 129.58, 133.59, 136.30, 148.41, 149.46, 156.74, 166.43, 167.35; Anal Calcd for C21 H23 NO7 S: C, 58.19; H, 5.35; N, 3.23. Found: C, 58.05; H, 5.35; N, 3.24.
  • 9
  • [ 253168-94-4 ]
  • water(2 mL each) [ No CAS ]
  • [ 22509-74-6 ]
  • 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonyleethyl]isoindoline-1,3-dione [ No CAS ]
  • 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With hydrogenchloride; sodium bicarbonate; In water; acetonitrile; EXAMPLE 5 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonyleethyl]isoindoline-1,3-dione A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (200 mg, 0.73 mmol) and sodium hydrogen carbonate (80 mg, 0.95 mmol) in acetonitrile and water(2 mL each) was stirred under nitrogen at room temperature for 2 minutes. To the resulting solution was added N-ethoxycarbonylphthalimide (170 mg, 0.78 mmol). After 17 hours, the resulting solution was stirred with hydrochloric acid (2 mL, 4 N), and water (30 mL) at room temperature for 30 minutes. The resulting suspension was filtered and the solid was washed with water (2*25 mL), and then dried in a vacuum oven overnight (60 C., <1 torr) to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3dione as a solid (206 mg, 70% yield): mp, 151.0-152.0 C.; 1 H NMR (CDCl3); delta 1.46 (t, J=6.9 Hz, 3H, CH3), 2.84 (s, 3H, CH3), 3.78 (dd, J=4.8, 14.4 Hz, I H, CHH), 3.84 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 4.54 (dd, J=10.1, 14.4 Hz, 1H, CHH), 5.90 (dd, J=4.8, 1 0.1 Hz, 1H, NCH), 6.83 (d, J=8.5 Hz, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.67-7.73 (m, 2H, Ar), 7.80-7.84 (m, 2H, Ar); 13 C NMR (CDCl3) delta 14.63, 41.49, 48.84, 54.82, 55.89, 64.45, 111.43, 112.50, 120.43, 123.51, 129.56, 131.58, 134.17, 148.57, 149.63, 167.80; Anal Calcd for C20 H21 NO6 S: C, 59.54; H, 5.25; N, 3.47. Found: C, 59.66; H, 5.28; N, 3.29.
  • 10
  • [ 253168-94-4 ]
  • 1,2-phthalic dicarboxaldehyde [ No CAS ]
  • 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-metlylsuffonylethyl]isoindolin-1-one [ No CAS ]
  • 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindolin-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% In acetic acid; EXAMPLE 3 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-metlylsuffonylethyl]isoindolin-1-one A stirred mixture 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (100 mg, 0.37 mmol) and 1,2-phthalic dicarboxaldehyde (49 mg, 0.37 mmol) in acetic acid (2 mL) was heated to reflux for 15 min. Removal of solvent in vacuo and chromatography gave an oil which was stirred with ether (2 mL). The resulting suspension was filtered to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindolin-1-one as a light yellow solid (100 mg, 70% yield): mp, 130.0-134.0 C.; 1 H NMR (CDCl3) delta 1.45 (t, J s=7 Hz, 3H, CH3), 2.96 (s, 3H, CH3), 3.70 (dd, J=4.5, 14.7, Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=6.9 Hz, 2H, CH2), 4.25 (d, J=16.5 Hz, 1 H, CHH), 4.31 (dd, J=10.3, 14.5 Hz, 1H, CHH), 4.46 (d, J=16 Hz, 1H, CHH), 5.71 (dd, J=4.5, 10.3 Hz, 1H, NCH), 6.84-7.01 (m, 3H, Ar), 7.38-7.56 (m, 3H, Ar), 7.85 (d, J=6.9 Hz, 1H, Ar); 13 C NMR (CDCl3) delta 14.65, 41.33, 46.27, 52.33, 55.95, 56.00, 65.56, 111.45, 112.28, 119.30, 122.85, 123.85, 128.13, 129.89, 131.80, 132.27, 141.26, 148.88, 149.62, 169.09; Anal Calcd for C20 H23 NO5 S: C, 61.68; H, 5.95; N, 3.60. Found: C, 61.68, H, 6.06; N, 3.62.
  • 11
  • [ 253168-94-4 ]
  • [ 22235-04-7 ]
  • N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)acetamide [ No CAS ]
  • 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-metlylsutfonylethyl]-5-acetamidoisoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
20% EXAMPLE 13 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-metlylsutfonylethyl]-5-acetamidoisoindoline-1,3-dione 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-acetamidoisoindoline-1,3-dione was prepared by the procedure of Example 6 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 4-acetamidophthalic anhydride (751 mg, 3.66 mmol). The product was obtained as a yellow solid (330 mg, 20% yield): mp, 215.0-217.0 C.; 1 H NMR (DMSO-d6) delta 1.32 (t, J=6.9 Hz, 3H, CH3), 2.12 (s, 3H, CH3), 2.99 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.00 (q, J=7.0 Hz, 2H, CH2), 4.12 (dd, J=4.5, 14.3 Hz, 1H, CHH), 4.35 (dd, J=10.5, 14.2 Hz, 1H, CHH), 5.76 (dd, J=4.5, 10.5 Hz, 1H, NCH), 6.90-6.98 (m, 2H, Ar), 7.08 (br s, 1H, Ar), 7.83-7.84 (m, 2H, Ar), 8.19 (br s, 1H, Ar), 10.95 (br s, 1H, NH); 13 C NMR (DMSO-d6) delta 14.66, 24.22, 41.05, 47.35, 53.07, 55.47, 63.80, 111.74, 112.28, 112.72, 123.34, 124.59, 124.66, 129.74, 132.68, 145.00, 147.85, 148.84, 167.00, 167.28, 169.36; Anal Calcd for C22 H24 NO7 S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.13; H, 5.18; N, 5.74.
  • 12
  • [ 253168-94-4 ]
  • [ 6296-53-3 ]
  • [ 253168-86-4 ]
  • 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acedtamidoisoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% In acetic acid; EXAMPLE 12 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetamidoisoindoline-1,3-dione 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acedtamidoisoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL). The product was obtained as a yellow solid (1.0 g, 59% yield): mp, 144.0 C.; 1 H NMR (CDCl3) delta 1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 4.4, 14.3 Hz, 1H, CHH), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 9.49 (br s, 1H, NH), 13 C NMR (CDCl3) delta 14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calcd for C22 H24 NO7 S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
  • 13
  • [ 67-71-0 ]
  • [ 1131-52-8 ]
  • 1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonylethylamine [ No CAS ]
  • [ 253168-94-4 ]
YieldReaction ConditionsOperation in experiment
39% With hydrogenchloride; n-butyllithium; trifluoroborane diethyl ether; In tetrahydrofuran; hexane; lithium hexamethyldisilazane; EXAMPLE 1 1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonylethylamine To a stirred solution of dimethyl sulfone (3.70 g, 39.4 mmol) in tetrahydrofuran (350 mL), was added n-butyllithium (17.5 mL, 2.5 M, 43.8 mmol) under nitrogen at -78 C. and the mixture was stirred at 78 C. for 25 min. To a stirred solution of 3-ethoxy-4-methoxybenzaldehyde (7.10 g, 39.4 mmol) in tetrahydrofuran (40 mL) under nitrogen in a separate flask at 0 C. was added lithium hexamethyldisilazide (43.0 mL, 1.0 M, 43.0 mmol) in hexane. After 15 min, boron trifluoride etherate (10.0 mL, 78.9 mmol) was added to the resulting mixture at 0 C. After 5 min, this solution was added to the -78 C. sulfone solution via syringe. The solution was allowed to warm to room temperature over one hour. The resulting mixture was then quenched with potassium carbonate (32 g) and water (200 mL). The mixture was stirred for 30 min and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), and then dried over magnesium sulfate. The solvent was removed in vacuo and the resulting solid stirred with ether (100 mL) and 4 N hydrochloric acid (100 mL) for 15 min. The aqueous layer was separated and the organic layer extracted with 4 N hydrochloric acid (30 mL). The combined aqueous layers were washed with ether (50 mL), stirred, and cooled in an ice bath and the pH adjusted to 14 with sodium hydroxide (5 N). This solution was extracted with ethyl acetate (3*100 mL) and the combined organic layers were washed with brine (50 mL) and dried over sodium carbonate and sodium sulfate. Removal of solvent in vacuo gave an oil which was stirred with ether (20 mL) for 20 min to give a suspension. The suspension was filtered and the solid was washed with ether (20 mL) and then dried in a vacuum oven to yield 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine as an off-white solid (4.17 g, 39%): mp, 116.5-117.0 C.; 1 H NMR (CDCl3) delta 1.47 (t, J=7 Hz, 3H, CH3), 1.92 (br s 2H, NH2), 2.91 (s, 3H, SO2 CH3), 3.19 (dd, J=3.5, 14 Hz, 1H, CHH), 3.36 (dd, J=9.3, 14 Hz 1H, CHH), 3.87 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 4.60 (dd, J=3.5, 9 Hz, 1H, CH), 6.83-6.93 (m, 3H, Ar); 13 C NMR (CDCl3) delta 14.75, 42.42, 50.94, 55.99, 63.18, 64.44, 110.71, 111.67, 118.21, 135.55, 148.72, 149.09; Anal Calcd for C12 H19 NO4 S: C, 52.73; H, 7.01; N, 5.12. Found: C, 52.82; H, 6.69; N, 4.99.
  • 14
  • [ 253168-94-4 ]
  • [ 1188-21-2 ]
  • [ 608141-43-1 ]
YieldReaction ConditionsOperation in experiment
90% In methanol; at 20℃; for 8h;Reflux; Resolution of racemate; A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3 -ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered andwashed with methanol (250 mL). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried invacuo at 30C. to a constant weight, yielding 49.6 g (90% recovery) of(S)-2-(3-ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine-N-acety l-L-leucine salt (98.4% ee). ChiralHPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies,150 mm 4.6 mm, 0.5 mL/min., 240 nm): 18.4 mm (S-isomer, 99.2%), 25.5 mm (R-isomer,0.8%)
90% General procedure: [0188] A 3 L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-l - (methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C to a constant weight, yielding 49.6 g
90% In methanol; at 20℃; for 4h;Reflux; A mixture of 2-(3-ethoxy-4-meth- oxyphenyl)-i -(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), andmethanol (1.0 L) was charged into a 3-L 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser. Afier the reaction mixture was refluxed for 1 hour, the mixture was allowed to cool to ambient temperature and then stirred for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuum at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% cc). The crude solid (55.0 g) and methanol (440 mE) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mE). The solid was air-dried and then dried in vacuum at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-2-(3-ethoxy- 4-methoxyphenyl)-i -(methylsulphonyl)-eth-2-ylamine-N- acetyl-L-leucine salt (98.4% cc). Chiral HPLC (1/99 EtOH/ 20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mmx4.6 mm, 0.5 mE/mm., 240 nm): 18.4 mm (S-isomer, 99.2%), 25.5 mm (R-isomer, 0.8%).
73.5% at 60 - 70℃; for 2h; In a 500 ml round bottom flask, 200 ml of methanol was added followed by 20 gms of 2-(3-ethoxy-4-methoxyphenyl)-l-(methanesulfonyl)-eth-2-ylamine. The reaction mass was stirred and 76 gms of N-Acetyl-L-Leucine added and reaction mass was stirred. The reaction mass was heated for 2 hours at 60 to 65C, After heating, the reaction masswas cooled at room temperature and it was stirred at room temperature for 3 to 4 hours. The slurry was filtered. Washed with 30 ml methanol, material was unloaded and dried under vacuum for 2 hours at 45C. Yield: 14.36 gm. Further, this material is purified with methanol.
41% In methanol; for 2h;Reflux; A mixture of 27.3 g (100 mmol) of 1- (3-ethoxy-4-methoxy) phenyl-2-methanesulfonyl ethylamine (4), 10.4 g(60 mmol) of N-acetyl-L-leucine was dissolved in 200 mL of methanol, heated under reflux for 2 h, and then cooled to room temperature to a large amountThe slurry was precipitated, filtered and washed with methanol to give the crude product. The crude product was again dissolved in 80 mL of methanol, heated to reflux for 2 h, and cooled againTo a large amount of slurry to the slurry, filter, and wash the filter cake with methanol. The solid was dried in vacuo to give 9.1 g (41% recovery)(S) -1- (3-ethoxy-4-methoxy) phenyl-2-methanesulfonylethylamine N-acetyl-L-leucine salt (97.9% ee).
35% In methanol; for 1h;Inert atmosphere; Reflux; Example 5: Preparation of (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV) A dry 1,000mL glass flask equipped with a mechanical stirrer, a thermometer, and a condenser was added 500g of methanol, 136 g (0.5mol) <strong>[253168-94-4](R,S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine</strong> (E.g. racemate III prepared in Example 1), and 86.5 g (0.5mol) N-acetyl-L-leucine under nitrogen protection. The solution was heated to reflux for 1 hour. The solution was then cooled to 10C and filtered. The resultant filtrate will be used as mother liquor in Example 6. The resulting filter cake was washed with 55g of cold methanol 10C and dried under vacuum to give 78.1 g of white solid (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV). Yield 35.0%, optical purity 99.8%.
In methanol; at 20℃; for 8h;Heating / reflux; A mixture of <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L) was charged into a 3-L 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser. After the reaction mixture was refluxed for 1 hour, the mixture was allowed to cool to ambient temperature and then stirred for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuum at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuum at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 (at)pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm×4.6 mm, 0.5 mL/min., (at)240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).
In methanol; 6.2.3. Resolution of <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm*4.6 mm, 0.5 mL/min., 240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).
In methanol; at 20℃; for 4h;Reflux; [0113j A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-1 - (methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C to a constant weight, yielding 49.6 g (90% recovery) of (S)-2-(3 -ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine -Nacetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150mm x 4.6 mm, 0.5 mL/min., 240 nm): 18.4 mm (S-isomer, 99.2%), 25.5 mm (R-isomer, 0.8%).
49.6 g In methanol; for 1h;Reflux; 6.2.3. Resolution of <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee).
In methanol; for 1h;Reflux; Resolution of 2-(3-ethoxy-4-methoxyphenyl-1-(methylsulphonyl)-eth-2-ylamine A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee).
18 g In methanol; at 25℃; for 4h;Reflux; The compound of formula V 0. 1mol 200mL of methanol was added and the reaction flask was refluxed clear solution was added portionwise N- acetyl-L- leucine (0.06mol ), a large number of the resulting solid was refluxed 1h, cooled to 25 C, stirred 1h, filtered and the filter cake was dried in vacuo at 40 C 5h, to give a white solid 22. 6g; The solid was added to the reaction flask and 180mL of methanol, refluxed for 1h, cooled to 25 C, stirred for 1h, filtered and the filter cake in and dried in vacuo 40 C 5h, to give a white solid 18g, 40 C and dried in vacuo 5h, ee: 98 · 6%
68 g In methanol; at 25℃; for 2h;Reflux; To a reaction mixture of 700 ml methanol and 100 grams (gm) (0.366 moles) of 1-(3-ethoxy-4- methoxy phenyl)-2-(methylsulfonyl) ethanamine, 38gm (0.2196 moles) of N-acetyl-L-leucine was charged. The reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to 25C to 30C and stirred for 1 hour. The product was filtered and washed with 100 ml methanol.The obtained solid material was dried under vacuum at 30C to obtain (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine N-acetyl-L-leucine salt.(Yield = 68.Ogms)R-isomer: 0.5%
35 g In methanol; at 60 - 65℃; for 1h; To 1 liter RBF the product of example 3 or 4 (75 g; 0.2743 moles), N- acetyl-L-leucine (47.5 g ; 0.2743) and methanol (545 mL) were charged and the suspension was stirred at 60 C to 65 C for 1 hour, the suspension was cooled to room temperature and stirred for another 3 hours. The solid was filtered and dried under reduced pressure to obtain 60 g of title compound with chiral purity of 85% desired isomer. It was further purified by methanol to give 35 g of pure title compound having chiral purity 99.5%.
In methanol; at 60 - 65℃; for 1h; To 1 liter round bottom flask, 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine,N-acetyl-L-leucine and methanol were charged and the suspension was stirred at 60 C to 65C for 1 hour, the suspension was cooled to room temperature and stirred for another 3 hours.The solid was filtered and dried under reduced pressure to obtain the title compound withchiral purity of 85 % desired isomer. Yield: 40 %.It was further purified by methanol to give pure title compound having chiral purity 99.5%
49.6 g In methanol; for 1h;Reflux; A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm x 4.6 mm, 0.5 mL/min., 240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).
49.6 g In methanol; for 1h;Reflux; A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm x 4.6 mm, 0.5 mL/min., 240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).

  • 17
  • [ 4792-30-7 ]
  • [ 253168-94-4 ]
  • [ 253168-84-2 ]
  • 18
  • [ 37418-88-5 ]
  • [ 253168-94-4 ]
  • [ 1140885-73-9 ]
  • 19
  • [ 253168-94-4 ]
  • [ 14963-96-3 ]
  • [ 253168-91-1 ]
  • 20
  • [ 253168-94-4 ]
  • [ 641-70-3 ]
  • 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-4-nitroisoindoline-1,3-dione [ No CAS ]
  • 21
  • [ 67-71-0 ]
  • [ 1131-52-8 ]
  • [ 253168-94-4 ]
YieldReaction ConditionsOperation in experiment
91.5% 1) Add Me2SO2 352 g (3.74 mol) to a 5 L dry three-necked bottle. THF (1665 mL), stirring, Replace with nitrogen three times and protect; cool down to - 20 C, Add 1 L (2.5 mol) of n-hexane solution of n-butyllithium, Control within -20 ~ 0 C. After the addition is completed, Continue to control the temperature -20 ~ 0 C reaction for 1 h, prepare the lithium salt R1 of dimethyl sulfone; 2) At the same time as the above operation, Add another 3-ethoxy-4-methoxybenzaldehyde 150 g (0.83 mol) to another 2 L dry three-necked flask. THF (666 mL), Start stirring, replace with nitrogen three times and protect; cool down to - 10 C, Adding lithium hexamethyldisilazide Tetrahydrofuran solution 1 L (1.0 mol) controlled internal temperature -10 ~ 0 C, After the addition is completed, Continue to control the temperature -10 ~ 0 C reaction for 1 h to prepare the lithium imide salt R2; 3) R1 is cooled to -30 ~ -40 C, R2 is dropped into R1, and the internal temperature is controlled at -30 ~ -40 C. After the addition is completed, it is stirred at the same temperature for 1 h; 4) Cool down to -30 ~ -20 C, add 589 g (4.15 mol) of boron trifluoride etherate to the reaction solution, and control the internal temperature -60 ~ -50 C. After the addition is completed, the temperature is naturally raised to 0 C; 5) The reaction solution was quenched by adding 183 g (1.33 mol) of potassium carbonate to a 1.11 L aqueous solution, and the temperature was not more than 15 C. After the addition was completed, the filtrate was separated, and the filtrate was separated. The filter cake was washed twice with DCM 1 L and extracted with water. Combine the organic phases and concentrate to dryness under pressure; 6) Add DCM 600 mL, 4 N HCl 660 mL, Stir at 30 C for 0.5 h, Liquid separation, The organic layer was extracted once with 300 mL of 4 N HCl. Combine the water phase, DCM 600 mL extraction. Add 4 N NaOH to the water layer to adjust the pH to 12 ~ 14, Extract DCM 800mL twice, After concentration, 234.4 g of crude product was obtained, and the yield was 103.3%. The purity is 91.5%; 7) Add the above crude product 234.4 g to a 1 L three-necked flask. Toluene 900 mL, Heat to reflux to dissolve, Cooling to room temperature to precipitate a solid, Crystallization in ice bath for 2 h, Filtration to give 207.7 g of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine. The total yield was 91.5%; The purity is 98.8%.
  • 22
  • [ 67-71-0 ]
  • [ 60758-86-3 ]
  • [ 253168-94-4 ]
YieldReaction ConditionsOperation in experiment
76.1% Dimethylsulfone (191. Ig, 2.03 moles, from Aldrich Chemicals, Milwaukee, WI) and tetrahydrofuran (1.65 L, from Aldrich Chemicals, Milwaukee, WI) were charged to a 12 L three-necked flask at room temperature. The mixture was cooled to 0-5C. n-BuLi (750 ml of 2.5M solution in hexanes, from Aldrich Chemicals, Milwaukee, WI) was added to the flask at a rate such that the reaction mixture was maintained at 0-5C. A line rinse with 150 ml tetrahydrofuran followed. The mixture was stirred at 0-5C for 60-70 minutes. 3-ethoxy-4- methoxybenzonitrile (300.0 g, 1.69 moles, in 750 ml tetrahydrofuran) was then charged to the flask at a rate such that the reaction mixture was maintained at 0-5 C . A line rinse with 300 ml tetrahydrofuran followed. The mixture was stirred at 0-5C for another 10-15 minutes. After warming to room temperature, the reaction mixture was stirred at room temperature for 1.5-2 hours, while purged with nitrogen. NaBH4 (83.1 g, 2.20 moles, from Aldrich Chemicals, Milwaukee, WI) and 150 ml of tetrahydrofuran were then charged to the reaction mixture. The reaction mixture was stirred at 0-50C for 15-30 minutes. HOAc (450 ml, 7.83 moles, from Fisher Scientific, Pittsburgh, PA) was charged to the flask at a rate such that the reaction mixture was maintained at 0-50C. The mixture was stirred at 0-50C for an additional 2-3 hours. The mixture was then charged with 2.25 L of NaOH (2.5N, pH 12 to 13, from Fisher Scientific, Pittsburgh, PA), and stirred at 0-50C for another 15-30 minutes. After warming to room temperature, the reaction mixture was heated to reflux at about 600C. After reflux for 12-14 hours, the mixture was cooled to 35-40C, and 3.0 L of water was added. The mixture was further cooled to 0-5C over a period of 1.5-2 hours. The mixture was filtered under vacuum, and the filtered solid was washed with 2 L of deionized water. The solid was dried in a tray at 50-550C under vacuum. The yield of 2-(3-ethoxy-4-methoxyphenyl)-l-(methanesulfonyl)-eth- 2-ylamine was found to be 352 g (76.1%) based on a 300 g input of 3-ethoxy-4- methoxybenzonitrile (HPLC indicated 99.74% purity by peak area).
65% In a flask, 5 litres of tetrahydrofuran was charged followed by 1.06 kg of dimethylsulfone. This reaction mass was cooled for 25 to 30 minutes at 0C. Aftercooling, 1M potassium-hexamethyldisilazane was added followed by 10 litres of tetrahydrofuran. The reaction mass was stirred for an hour at 0 to 10 C. After stirring, 1 kg of 3-ethoxy-4-methoxybenzonitrile was dissolved in 2 litres tetrahydrofuran and was added to the above reaction mass. The reaction mass was stirred for 30 minutes and cooled. After cooling, 0.433 kg of sodium borohydride was added followed bytetrahydrofuran and 5 litres of acetic acid and the total reaction mass was stirred for 3- 4 hours at 0 to 10 C. After completion of reaction, sodium hydroxide solution was added to it and stirred for 45 minutes. The reaction mass was warmed and further heated for 3 to 4 hours at 60 to 65C. After completion of reaction, the reaction solution was allowed to cool to room temperature for half an hour. The layers were separated. The combinedorganic layer was treated with aq. HC1 and water was added to the concentrated mass. The aqueous layer was treated with ethyl acetate. Finally sodium hydroxide solution was added to the aqueous layer and solid was precipitated. The solid was filtered, washed with water and dried at 50C and further 1.0 kg (65%) of material was unloaded.
50% Dimethyl sulfone (0.639 g, 0.067 mmoles) was added to dimethylsulfoxide (10 ml) and stirred at room temperature for 5-10 minutes. Potassium tertiary butoxide (1.89 g, 0.169 mmoles) was added slowly to the reaction mixture at 30C and stirred for three hours. 3-ethoxy-4-methoxy benzonitrile (1.0 g, 0.056 mmoles) in tetrahydrofuran (2 ml) was added to the reaction mixture over a period of 30 minutes and was stirred for three hours at room temperature. Sodium borohydride (0.213 g,0.056 mmoles) was added to the reaction mixture at 30 C and maintained for one hour. Ammonium chloride (10 ml) was added to the reaction mixture and extracted with ethyl acetate (20 ml). The ethyl acetate layer was washed with water (10 ml). The ethyl acetate layer was distilled at 30 C to provide crude compound. The crude compound was washed with methyl tertiary butyl ether to provide the title compound as pale yellow colored solid.Yield: 750 mg (50%)
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