[ CAS No. 253168-94-4 ] {[proInfo.proName]}

Name: 253168-94-4|1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine|97%
Brand: Ambeed
SKU: A140530
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Quality Control of [ 253168-94-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 253168-94-4 ]

Product Details of [ 253168-94-4 ]

CAS No. :	253168-94-4	MDL No. :	MFCD27665207
Formula :	C₁₂H₁₉NO₄S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BXUJVINGXQGNFD-UHFFFAOYSA-N
M.W :	273.35	Pubchem ID :	11288792
Synonyms :

Calculated chemistry of [ 253168-94-4 ]

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 :	87.0 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.61 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.85
Log Po/w (XLOGP3) :	0.5
Log Po/w (WLOGP) :	1.89
Log Po/w (MLOGP) :	0.75
Log Po/w (SILICOS-IT) :	1.28
Consensus Log Po/w :	1.25

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.7
Solubility :	5.45 mg/ml ; 0.0199 mol/l
Class :	Very soluble
Log S (Ali) :	-1.9
Solubility :	3.46 mg/ml ; 0.0127 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.46
Solubility :	0.0939 mg/ml ; 0.000344 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.83

Safety of [ 253168-94-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 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.

Upstream synthesis route of [ 253168-94-4 ]
Downstream synthetic route of [ 253168-94-4 ]

[ 253168-94-4 ] Synthesis Path-Upstream 1~4

1
[ 253168-94-4 ]
[ 1188-21-2 ]
[ 608141-43-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	at 20℃; for 8 h; 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 (98percent yield) of the crude product (85.8percent 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 30°C. to a constant weight, yielding 49.6 g (90percent recovery) of(S)-2-(3-ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine-N-acety l-L-leucine salt (98.4percent ee). ChiralHPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies,150 mm4.6 mm, 0.5 mL/min., 240 nm): 18.4 mm (S-isomer, 99.2percent), 25.5 mm (R-isomer,0.8percent)
90%	Stage #1: for 1 h; Reflux Stage #2: at 20℃; for 4 h; Reflux	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 (98percent yield) of the crude product (85.8percent 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%	at 20℃; for 4 h; 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 (98percent yield) of the crude product (85.8percent 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 (90percent recovery) of (S)-2-(3-ethoxy- 4-methoxyphenyl)-i -(methylsulphonyl)-eth-2-ylamine-N- acetyl-L-leucine salt (98.4percent 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, 99.2percent), 25.5 mm (R-isomer, 0.8percent).

73.5%	at 60 - 70℃; for 2 h;	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 65°C, 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 45°C. Yield: 14.36 gm. Further, this material is purified with methanol.
41%	for 2 h; 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 (41percent recovery)(S) -1- (3-ethoxy-4-methoxy) phenyl-2-methanesulfonylethylamine N-acetyl-L-leucine salt (97.9percent ee).
35%	for 1 h; 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) (R,S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (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 10°C 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 10°C 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 35.0percent, optical purity 99.8percent.
98.4 % ee	at 20℃; for 8 h; Heating / reflux	A mixture of 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) 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 (98percent yield) of the crude product (85.8percent 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 (90percent recovery) of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine-N-acetyl-L-leucine salt (98.4percent ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 (at)pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm.x.4.6 mm, 0.5 mL/min., (at)240 nm): 18.4 min (S-isomer, 99.2percent), 25.5 min (R-isomer, 0.8percent).
49.6 g	for 1 h; Reflux	6.2.3. 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 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 (98percent yield) of the crude product (85.8percent 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 (90percent recovery) of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine-N-acetyl-L-leucine salt (98.4percent ee).
18 g	at 25℃; for 4 h; 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 · 6percent
68 g	at 25℃; for 2 h; 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 25°C to 30°C and stirred for 1 hour. The product was filtered and washed with 100 ml methanol.The obtained solid material was dried under vacuum at 30°C to obtain (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine N-acetyl-L-leucine salt.(Yield = 68.Ogms)R-isomer: 0.5percent
35 g	at 60 - 65℃; for 1 h;	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 85percent desired isomer. It was further purified by methanol to give 35 g of pure title compound having chiral purity 99.5percent.

Reference： [1] Patent: WO2014/74846, 2014, A1, . Location in patent: Page/Page column 21
[2] Patent: WO2015/175956, 2015, A1, . Location in patent: Paragraph 0188
[3] Patent: US9387195, 2016, B2, . Location in patent: Page/Page column 27
[4] Patent: WO2016/189486, 2016, A1, . Location in patent: Page/Page column 14; 15; 16
[5] Patent: CN106543050, 2017, A, . Location in patent: Paragraph 0046; 0047; 0053; 0054
[6] Patent: CN105348172, 2016, A, . Location in patent: Paragraph 0061; 0062
[7] Patent: US2007/155791, 2007, A1, . Location in patent: Page/Page column 14
[8] Patent: US2012/276087, 2012, A1,
[9] Patent: WO2015/175773, 2015, A1, . Location in patent: Paragraph 0113
[10] Patent: US9272035, 2016, B2, . Location in patent: Page/Page column 23
[11] Patent: US2016/128981, 2016, A1, . Location in patent: Paragraph 0216
[12] Patent: CN105622380, 2016, A, . Location in patent: Paragraph 0072; 0073; 0074; 0075
[13] Patent: WO2016/146990, 2016, A1, . Location in patent: Page/Page column 17; 18
[14] Patent: WO2017/94031, 2017, A2, . Location in patent: Page/Page column 15
[15] Patent: WO2018/61034, 2018, A1, . Location in patent: Page/Page column 12

2
[ 253168-94-4 ]
[ 1188-21-2 ]
[ 608141-43-1 ]
[ 1382429-55-1 ]

Reference： [1] Patent: WO2015/175956, 2015, A1, . Location in patent: Paragraph 0188

3
[ 253168-94-4 ]
[ 608141-42-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 6, p. 1522 - 1524
[2] Patent: US2012/276087, 2012, A1,
[3] Patent: WO2015/175773, 2015, A1,
[4] Patent: US9272035, 2016, B2,
[5] Patent: CN105348172, 2016, A,
[6] Patent: WO2016/161996, 2016, A1,
[7] Patent: WO2016/161996, 2016, A1,
[8] Patent: WO2016/199031, 2016, A1,
[9] Patent: WO2016/192694, 2016, A1,
[10] Patent: WO2016/192694, 2016, A1,
[11] Patent: WO2016/192694, 2016, A1,
[12] Patent: WO2017/85568, 2017, A1,
[13] Patent: EP2431371, 2012, A1,
[14] Patent: WO2015/175956, 2015, A1,
[15] Patent: WO2015/175956, 2015, A1,

4
[ 253168-94-4 ]
[ 608141-42-0 ]
[ 608142-27-4 ]

Reference： [1] Patent: WO2016/161996, 2016, A1,
[2] Patent: WO2016/161996, 2016, A1,

[ 253168-94-4 ] Synthesis Path-Downstream 1~88

1
[ 253168-94-4 ]
[ 92971-15-8 ]
2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-dinitroisoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation 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).

Reference： [1]Patent: US6667316,2003,B1 .Location in patent: Page column 14

2
[ 253168-94-4 ]
[ 143092-07-3 ]
[ 340019-20-7 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Patent: US6667316,2003,B1 .Location in patent: Page column 16

3
[ 253168-94-4 ]
[ 6296-53-3 ]
[ 253168-86-4 ]

Yield	Reaction Conditions	Operation 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.

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[2]Patent: EP2962690,2016,A1
[3]Patent: WO2015/175773,2015,A1 .Location in patent: Paragraph 0110
[4]Patent: WO2016/25686,2016,A1 .Location in patent: Paragraph 0093
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[ 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 ]