[ CAS No. 6296-53-3 ] {[proInfo.proName]}

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2D 3D

Structure of 6296-53-3 * Storage: {[proInfo.prStorage]}

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Quality Control of [ 6296-53-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 6296-53-3 ]

SDS Specification

Alternatived Products of [ 6296-53-3 ]

Product Details of [ 6296-53-3 ]

CAS No. :	6296-53-3	MDL No. :	MFCD00453138
Formula :	C₁₀H₇NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PAUAJOABXCGLCN-UHFFFAOYSA-N
M.W :	205.17	Pubchem ID :	226121
Synonyms :

Calculated chemistry of [ 6296-53-3 ] Expand+

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.1
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	50.5
TPSA :	72.47 ?2

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.31
Log Po/w (XLOGP3) :	1.02
Log Po/w (WLOGP) :	0.76
Log Po/w (MLOGP) :	0.78
Log Po/w (SILICOS-IT) :	1.37
Consensus Log Po/w :	1.05

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.92
Solubility :	2.47 mg/ml ; 0.0121 mol/l
Class :	Very soluble
Log S (Ali) :	-2.13
Solubility :	1.52 mg/ml ; 0.00739 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.86
Solubility :	0.283 mg/ml ; 0.00138 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.99

Safety of [ 6296-53-3 ]

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

Application In Synthesis of [ 6296-53-3 ]

* 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 [ 6296-53-3 ]
Downstream synthetic route of [ 6296-53-3 ]

[ 6296-53-3 ] Synthesis Path-Upstream 1~1

1
[ 6296-53-3 ]
[ 102308-43-0 ]

Reference： [1] Bulletin de la Societe Scientifique de Bretagne, 1951, vol. 26, p. Sonderheft 5, S. 7, 96[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1952, vol. 235, p. 962

[ 6296-53-3 ] Synthesis Path-Downstream 1~8

1
[ 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.

Reference： [1]Patent: US2003/187052,2003,A1
[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
[5]Patent: US9272035,2016,B2 .Location in patent: Page/Page column 22
[6]Patent: WO2015/175956,2015,A1 .Location in patent: Paragraph 0185
[7]Patent: US2016/128981,2016,A1 .Location in patent: Paragraph 0213
[8]Patent: EP3096749,2019,B1 .Location in patent: Paragraph 0078
[9]Journal of Medicinal Chemistry,2009,vol. 52,p. 1522 - 1524

2
[ 253168-94-4 ]
[ 6296-53-3 ]
[ 253168-86-4 ]
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acedtamidoisoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Patent: US6011050,2000,A

3
[ 6296-53-3 ]
[ 608141-42-0 ]
[ 608141-41-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With acetic acid; for 1h;Reflux; Large scale;	The unbaked product (728 g after drying), glacial acetic acid (4. 2 L), (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethanamine(1570 g, 99.3%) Followed by adding the reaction flask, heating to reflux reaction for 1 hour, After the TLC was detected, the reaction was stopped and the reaction was terminated. The reaction was terminated under reduced pressure, and 10L of methylene chloride was dissolved. After washing with 5 L of water, 5 L of water saturated with aqueous sodium bicarbonate, 5 L of saturated sodium chloride, dried over anhydrous magnesium sulfate, Concentrated to dry, add anhydrous ethanol 10L, reflux 30 minutes, filtration, ethanol washing, 60 C drying to obtain product 1584g, the yield of 97%, HPLC 99. 8% or more, 99.2%.
94%	With acetic acid; In acetonitrile; at 40℃; for 6h;Reflux;	<strong>[608141-42-0](1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine</strong> (Compound IX,328.2 g, 1.20 mol) was dissolved in Acetonitrile (1800 mL) at 40C. The solution was added to a suspension of 3-acetamidophthalic anhydride (compound X) (246.0 g, 1.20 mol) in Acetonitrile (550 mL) at 40C. Acetic acid was added (72 mL) and heated to reflux temperature. The solution was kept at this temperature for mm. 6 hours. Acetonitrile (1800 mL) was evaporated from solution. The remaining reaction mixture was cooled to 35C and ethanol (2400 mL) was added to the solution in 2 hours. After ethanol addition the suspension was stirred for 10 hours. The suspension was cooled to 0-5C and kept at this temperature for 2 hours. The suspension was filtered, washed with cooled (0-5C) ethanol (1200 mL) and dried under vacuum at 50C overnight. Product: 517 g (yield: 94%). HPLC purity: 99.92 Area%. Assay: 99.0%
92%	With acetic acid; for 3h;Reflux;	1.21 g (4.43 mmol; 97% ee) of (S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethylamine (5)-i (obtained using the process of Example 16), 954 mg (4.65 mrnol) of 3-acetamidophthalic anhydride 4 and 18 ml of glacial acetic acid were charged into a 50m1 flask. The mixture was refluxed for 3 h and cooled down to 20C. After that, 35 ml ofwater was gradually added, under continuous stirring the mixture was inoculated with crystals of Aprernilast 3 (10 mg) and stined at 20C for another 15 hours. The separated crystals were aspirated, washed with a mixture of acetic acid - water (volume ratio 2:5) and dried at a reduced pressure. The amount of 1.875 g of yellowish crystals of the product 3 was obtained (yield 92%, 98% ee, HPLC 99.1%).

91.5%	In toluene; at 90℃; for 5h;	148.7 g of N-acetyl-L-leucinate (0.4% isomer content) of chiral amine intermediate II, 71.38 g of anhydride intermediate III, 1487 ml of toluene were charged into the reaction flask;Heated to 90 ± 5 , incubated for 5 hours, concentrated under reduced pressure to remove toluene; added to 3000ml of ethanol, heating; steamed out of ethanol until evaporated to dryness;Add 1000mL of ethanol, 500mL acetone, heated to reflux, dissolved until clear, add 1.5g activated carbon decolorization, slowly cooled to 15 ; incubated at 10 ± 5 for 6 hours;Filter and wash the filter cake with 200 mL of ethanol. Drying in vacuo at 50 ± 5 C for 4 hours afforded 139.1 g of aphthous (I) in 91.5% yield.After testing, Purcert purity of 99.94%, 0.05% isomer content, crystal form B (see Figure 1).
89%	With perchloric acid; acetic acid; at 85℃; for 2.5h;Reflux;	Example 8: Preparation of S-apremilast (I) In a dry 250mL glass flask was added 2.5g of 3-acetamidophthalicanhydride, 25g of glacial acetic acid, 0.2g of perchloric acid, and 2.7g of (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (II) (prepared in Example 7). The reaction was heated at 80-85C for 30 minutes then heated at reflux for 2 hours. Glacial acetic acid was recovered through vacuum distillation. The remaining material was then cooled to room temperature 20C. 10g of saturated brine and 20g of ethyl acetate were added and allowed to seperate under stirring. The organic phase was separated. The aqueous phase was extracted once with 20 g of ethyl acetate. The combined organic phases, recovered by distillation of ethyl acetate, gave 4.1g of solid S-apremilast (I). Yield 89.0%, e.e% to 99.8%.
89%	With acetic acid; for 3h;Reflux;	3.17 g (11,6 mmol; 99.4 % ee) of (S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethylamine of formula (S)-2a (see Example 9), 2.50 g (12.2 mmol) of 3- acetamidopbtalic anhydride of formula S and 52 ml of glacial acetic acid were placed into a250 ml flask. The mixture was refluxed for 3 h and cooled down to 20C. After that, 4 x 25 ml of water were gradually added, under continuous stirring the mixture was inoculated with crystals of Apremilast of formula 1 and stirred at 20 C. The separated crystals were aspirated, washed with a mixture of acetic acid - water (volume ratio 2:5) and dried at a reduced pressure. The amount of 4.75 g of yellowish crystals of the product of formula 1 was obtained(yield 89%, >99% ee, HPLC 99.1%).
84%	With acetic acid; at 120℃;	1 Anhydride (4.16 g, 20.26 mmol), chiral amine (19.3 mmol) were added to a 250 mL reaction flask, glacial acetic acid (65 mL) was added, refluxed at 120 C., and thin layer chromatography (TLC) detection reaction ( Methanol: Dichloromethane volume fraction ratio = 1:10). The chiral amine material was completely reacted (about 5-6 h). Acetic anhydride (60 mmol) was added. The reaction was continued for 1 h. The glacial acetic acid was distilled off, and the residue was poured into 100 mL. Intensely stirred water forms a suspension. After suction filtration, the filter cake was washed with 4×50 mL of water, and the filter cake was dried in a drying oven at 50 C. for approximately 4-5 h to obtain 8.0 g of crude yellow appress. The purity was 98.8 by HPLC. %, the deacetylated by-product content is about 0.05%.The above crude product was added to ethanol (70 mL), heated to reflux for 2 h, and then slowly lowered to room temperature with stirring. The solid precipitated and was filtered under suction. The filter cake was washed with ethanol (2×10 mL) and dried (60 C., dried for 3 h). ,getApstThe product is 7.5g, and the total yield is 84%.
81.5%	With acetic acid; for 6h;Reflux;	The reaction flask was charged with 350 mL of glacial acetic acid,(0.22 mol) of (1S) -1- (3-ethoxy-4-methoxybenzene) Yl) -2- (methylsulfonyl) ethylamine (formula V)57.4 g (0.28 mol) of 3-acetylaminophthalic anhydride,Stir well, reflux reaction for 6 hours,The reaction was stopped and the residue after dissolution was dissolved in 400 ml of ethyl acetate,Washed with saturated aqueous sodium carbonate (300 mL x 2 times)Washed with brine (150 mL x 1 time).After further desolvation, a mixed solvent of 400 mL of absolute ethanol and 150 mL of acetone was added and stirred for 5 hours,Filter, filter cake with 100mL anhydrous ethanol washing, drying was 82.6g products,The molar yield was 81.5%, the HPLC purity was 98.3%Ee value of 97.9%.
73.1%	With acetic acid; at 115 - 125℃;	(1S)-i -(3 -ethoxy-4-methoxy-phenyl)-2-methanesulfonyl- ethyl amine (Formula-V) (125gm) and N-(1, 3-dioxo-1, 3dihyro-2-benzofuran-4-yl) acetamide (Formula-IV) (98.5gm) in to methyl isobutyl ketone (lSOOml) and acetic acid (SSOml) mixture of solvent at ambient temperature. Raise temperature up to 115-120C (115-125C). Remove the water formed during the reaction. After completion of reactiondistill out reaction mass completely. Charge ethyl acetate for extraction and wash with sodium bicarbonate solution and sodium chloride solution. Distill out reaction mass completely and charge acetone followed by ethanol. Raise temperature up to reflux and maintain 1 hr. Reaction gradually cool to ambient temperature and maintain reaction mass and stir for 7-8 hr. Filter the product and wash with ethanol. Charge wet cake into acetone followed by ethanol. Raise temperature up to reflux and maintain 1 hr. Reaction gradually cool to ambient temperature and maintain reaction mass and stir for 7-8 hr. Filter the product and wash with ethanol resulting Formula I with 73.1%yield and 99.98% HPLC purity and 99.99 Chiral purity. The titled product having XRPD values as, 10.1, 12.4, 13.5, 20.8, 22.5, 24.7, and 27.0 ±0.2 (Form-B).
64%	With acetic acid;Reflux;	Example 8: Preparation of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl)-4-amino- isoindoline-1 ,3-dione (apremilast) from the compound of formula VII Into a reaction vessel equipped with magnetic stirrer and condenser was placed (S)-1 -(3- ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (2.24 mmol, 1 g) and was dissolved in 10 mL of glacial acetic acid. Afterwards 3-acetamidophthalic anhydride was added (2.35 mmol, 0.48 g) and reaction mixture was vigorously stirred at reflux overnight. Reaction system was cooled down to room temperature and acetic acid was evaporated under reduced pressure. The organic residue was extracted with dichloromethane, organic phases were washed with water, dried over Na2S04 and solvent was evaporated. The residue was recrystallized from acetone/ethanol mixture, solid material was filtered off and dried in vacuo at 60 C affording 0.66 g (64% Yield) of final product with > 99% ee. 1 H NMR analysis was in agreement with known data.
64%	With acetic acid;Reflux;	Example 11 : Preparation of (S)-1 -(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl)-4-amino- isoindoline-1 ,3-dione (apremilast) from the compound of formula 5S Into a reaction vessel equipped with magnetic stirrer and condenser was placed (S)-1 -(3- ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (2.24 mmol, 1 g) and was dissolved in 10 mL of glacial acetic acid. Afterwards 3-acetamidophthalic anhydride was added (2.35 mmol, 0.48 g) and reaction mixture was vigorously stirred at reflux overnight. Reaction system was cooled down to room temperature and acetic acid was evaporated under reduced pressure. The organic residue was extracted with dichloromethane, organic phases were washed with water, dried over Na2S04 and solvent was evaporated. The residue was recrystallized from acetone/ethanol mixture, solid material was filtered off and dried in vacuo at 60 C affording 0.66 g (64% Yield) of final product with > 99% ee. 1 H NMR analysis was in agreement with known data.
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.
	With acetic acid;Reflux;	N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide, which may be obtained via techniques known in the art, (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine, and glacial acetic acid is refluxed overnight and then cooled to <50 C. The solvent is then removed in vacuo, and the residue is dissolved in ethyl acetate. The resulting solution is washed with water, saturated aqueous NaHCO3, brine, and dried over sodium sulphate. The solvent is evaporated in vacuo, and the residue is recrystallized from a binary solvent containing ethanol and acetone. The solid is isolated by vacuum filtration and washed with ethanol. The product is then dried to afford H-CH2-CH3-Compound A.
8.5 g	With acetic acid; In toluene; at 100 - 105℃;	(S)- 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine (6.5 g, 0.023 moles) were added to toluene (120 ml) and stirred at room temperature. Acetic acid (30 ml) and N-acetylphthalic anhydride (5.12 g, 0.024 moles) was added to the reaction mixture at room temperature. The temperature of reaction mixture was raised to 100-105C and maintained for 8-10 hours. Distilled the solvent at below 60C under vacuum and cooled the reaction mixture to room temperature. Methyl ethyl ketone (150 ml) was added to the reaction mixture at room temperature. The temperature of reaction mixture was raised to 50-60C and 10% sodium bicarbonate solution (150 ml) was added followed by water (50 ml). The layers were separated and the organic layer was distilled upto one-fourth of its initial volume under vacuum and cooled to 0-5C. The reaction mixture was maintained at 0-5C for 1-2 hours. The solid was filtered, washed with methyl ethyl ketone (15 ml) and dried in oven to provide apremilast as product.Yield: 8.5 g
		A reaction vessel was charged with glacial acetic acid (300 ml_), Tri ethyl amine (40.72 g), (S) - 1 -(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (100 g) and 3-Acetamido phthalic anhydride (75.05g). Reaction mass was heated for 1.0 hour at 90±3C. After completion of the reaction; reaction mass was cooled to 27 ± 3C. Process water (500 ml_) and dichloromethane (300 ml_) were added in to the reaction mass. Reaction mass was stirred and settled. Layers were separated. Acetyl chloride (17.23 g) was charged in to the organic layer and was heated for 15-20 min at 40 ± 3C. The organic layer was cooled to 27 ± 3C and washed with sodium bicarbonate solution in water. Benzyl alcohol (1 18.68 g) was charged into the organic layer and solvent was distilled out completely under reduced pressure at 42 ± 3C. Methanol (200 ml_) was charged into reaction mass at below 40C. Reaction mass was stirred for 15-20 min. at 52 ± 3C and 1 hour at 27 ± 3C. The solid was filtered and washed with methanol.
	With acetic acid; at 85℃; for 5h;	In a three-neck flask, 500 g of chiral amine and 412 g of anhydride were added.Glacial acetic acid 4L, heated at 85 C under reflux for 5 h.The system was cooled to room temperature and extracted and washed.The solvent was evaporated to dryness to obtain 750 g of crude Apstar.Purity (HPLC) 96%;_(2)Crude refiningThe crude product (200 g) was added to 2-butanone (3L) and water (1L).Heat to 50-60C to dissolve the solids.Cool to 0 ~ 10 C crystallized 1h, suction filtration,175g of refined white crystals are dried at 50C.Yield 87.5%, purity (HPLC) 99.8%,The largest single miscellaneous 0.02%.

Reference： [1]Patent: CN105294534,2016,A .Location in patent: Paragraph 0030; 0031
[2]Patent: WO2017/59040,2017,A1 .Location in patent: Paragraph 00120
[3]Patent: WO2016/192694,2016,A1 .Location in patent: Page/Page column 22
[4]Patent: CN106995401,2017,A .Location in patent: Paragraph 0016; 0063; 0064; 0066-89
[5]Patent: CN105348172,2016,A .Location in patent: Paragraph 0068; 0069
[6]Patent: WO2016/161996,2016,A1 .Location in patent: Page/Page column 24
[7]Patent: CN105085373,2018,B .Location in patent: Paragraph 0030; 0033; 0034
[8]Patent: CN106866493,2017,A .Location in patent: Paragraph 0047-0048
[9]ChemCatChem,2019,vol. 11,p. 5808 - 5813
[10]Journal of Medicinal Chemistry,2009,vol. 52,p. 1522 - 1524
[11]Patent: WO2018/203192,2018,A1 .Location in patent: Page/Page column 12; 13
[12]Patent: WO2016/202806,2016,A1 .Location in patent: Page/Page column 20
[13]Patent: WO2017/46319,2017,A1 .Location in patent: Page/Page column 21
[14]Patent: EP3157520,2019,B1 .Location in patent: Paragraph 0097
[15]Patent: US2014/81032,2014,A1 .Location in patent: Paragraph 0320; 0321
[16]Patent: WO2016/199031,2016,A1 .Location in patent: Paragraph 33; 34; 35
[17]Patent: WO2017/85568,2017,A1 .Location in patent: Page/Page column 20
[18]Patent: CN107698485,2018,A .Location in patent: Paragraph 0027; 0028; 0029; 0030; 0031

4
[ 253168-94-4 ]
[ 6296-53-3 ]
[ 608141-41-9 ]

Yield	Reaction Conditions	Operation in experiment
73.4%	With acetic acid; at 50℃;Reflux;	According to the synthetic method of Patent Document W02009120167A1 Example 2, Aster was synthesized, in particular: (3-ethoxy-4-methoxyphenyl) -1- (methylsulfonyl) -ethan-2-yl-amine as the N-acetyl-L-leucine salt (25 g, 56 mmol), 3-acetamidophthalic anhydride (12. lg, 58.8 mmol) and glacial acetic acid (250 mL) The mixture was refluxed overnight and the mixture was reduced to less than 50 C. The solvent was removed in vacuo and the resulting solid was dissolved in ethyl acetate, The resulting solution was washed with water (250 mL X2), saturated aqueous sodium bicarbonate solution (250 mL x2) and saturated aqueous sodium chloride solution (250 mL x 2). The solution was dried over anhydrous sodium sulfate and the solvent was evaporated to dryness. The resulting solid was purified in ethanol (150 mL) and Acetone (75 mL) was stirred for 3 hours, the filtrate was filtered and the filter cake was rinsed with ethanol (100 mL x 2). Get solid The body was dried overnight at 60 C to give 19.0 g (2- (l- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl ethyl) -4-acetamidoisoindoline-1,3-dione, The rate was 73.4%.
59%	In acetic acid; for 15h;Reflux;	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 C22H24N07S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.

Reference： [1]Patent: CN105461610,2016,A .Location in patent: Paragraph 0059
[2]Patent: WO2014/151180,2014,A1 .Location in patent: Paragraph 0071
[3]ChemCatChem,2019,vol. 11,p. 5808 - 5813

5
[ 108-24-7 ]
[ 6946-22-1 ]
[ 6296-53-3 ]

Yield	Reaction Conditions	Operation in experiment
94 g	In water; at 100℃; for 15h;	The compound of formula VII 0. 55mol, and 37percent concentrated hydrochloric acid was added 500mL one-neck flask 1L, 25 ° C was stirred for 15h, the water distilled off under reduced pressure, slurried with 300mL tetrahydrofuran 10min, the solvent was distilled off under reduced pressure was repeated twice to give an off-white solid 120g, Karl Fischer determination of water 0.5percent. This solid was added to a 2L four-neck flask, was added acetic anhydride 1. 2L, 100 ° C 15h reaction, acetic anhydride was distilled off under reduced pressure, cooling the residue was added 200 mL of methyl tert-butyl ether, heating 10min, filtered, washed with methyl tert-butyl ether was washed with 20mL solid was filtered, the filter cake was dried in vacuo at 40 ° C 5H, 94g of off-white solid, a yield of 83.3percent.
45 g	at 110℃; for 2h;	A stirred solution of <strong>[6946-22-1]<strong>[6946-22-1]3-aminophthalic acid</strong> hydrochloride</strong> (65.0gm) in acetic anhydride (195 ml) was heated to 110°C and maintained for 2.0 hr. The reaction mass was cooled to 5°C. The product was filtered, washed with cyclohexane and dried at 40°C for 6.0 hr to obtain 45.0gm of 3-acetamidophthalic anhydride.

Reference： [1]Patent: CN105622380,2016,A .Location in patent: Paragraph 0064; 0065; 0066; 0067
[2]Patent: WO2017/33116,2017,A1 .Location in patent: Paragraph 00114

6
[ 109-99-9 ]
[ 6296-53-3 ]
[ 608141-42-0 ]
2C₂₂H₂₄N₂O₇S*C₄H₈O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With acetic acid; for 4h;Reflux;	600 g (2.195 mol) of (S)-l-(3-emoxy-4-memoxyphenyi)-2-(memylsulfonyl)-e larnine (S)-3 and 468 g (2.281 mmol) of 3-acetamidophtalic anhydride (5) were refluxed in a mixture of 1200 ml of acetic acid and 2220 ml of THF for 4 h. Then, the reaction rnixture was gradually cooled down to 40C and 2100 ml of MTBE was added. At 30C, the mixture was seeded and subsequently cooled down to -5C during 1.5 h and stirred at -5C for another two hours. The separated product was filtered off, washed with 3 x 850 ml of icy MTBE and dried at 40-45X in vacuo. 964.3 g of white crystals of the title compound was obtained; yield 87%, HPLC >99.99%, NMR apremilast/THF 1:0.6, XRPD-THF solvate.

Reference： [1]Patent: WO2016/169533,2016,A1 .Location in patent: Page/Page column 13

7
[ 253168-94-4 ]
[ 6296-53-3 ]
[ 64-19-7 ]
C₄₅H₄₈N₄O₁₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 98 - 100℃; for 3h;	Racemic amino sulfone of formula (II) (150 g) obtained after distillation the solvent from mother liquor from one of the plant batches, N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (113 g) , methyl isobutyl ketone (300 mL) and acetic acid (700 mL) were charged into a round bottom flask and stirred at room temperature. The mixture was heated to 98-100C and maintained for 3 hours. The solvent from the reaction mass was evaporated under vacuum at below 60C. Dichloromethane (300 mL) water (200 mL) were charged to the reaction mass at room temperature and stirred for 10 minutes. The organic layers were separated and washed with water (2X200mL).The combined organic layer was distilled under vacuum. Methyl isobutyl ketone (750 mL) was added to the residue and maintained for 15 hours at room temperature. The solid was filtered and washed with methyl isobutyl ketone (100 mL) and dried under vacuum at 85C for 10-12 hours. Dried compound was adsorbed on silica gel and subjected to flash column chromatography and impurity was separated by collecting the required fraction.1H NMR (400 IVIHz, CDC13) oe (ppm): 1.45 (s, 6H), 9.4 (2NH), 8.75 (d, 2H), 7.65(t, 2H) 7.48 (d,2H), 5.85 (m, 2H), 4.6 & 3.65 (m, 4H), 4.1 (4H), 7.15 (d, 4H), 6.8 (d, 2H), 3.8 (6H), 3.15 (t, 4H),2.4 (m, 2H), 2.25 (s, 6H);Mass Spectral data: m/Z = 931 (M-1) and m/Z = 955 (Na adduct).

Reference： [1]Patent: WO2016/199031,2016,A1 .Location in patent: Page/Page column 36; 37

8
[ 6296-53-3 ]
[ 608141-42-0 ]
[ 635705-72-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With perchloric acid; acetic acid; at 65 - 85℃; for 2.5h;Inert atmosphere; Reflux;	Under nitrogen, to a dry 1000 ml glass flask, (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine 60.0 g (0.22 mol, 99.4% ee), 3-acetamido-phthalic anhydride (49.0 g, 0.23 mol) and glacial acetic acid 500 g. After stirring evenly, add 3 grams of perchloric acid to 30 minutes, keep the internal temperature between 65 C and 85 C for 30 minutes and then heated to reflux for 2 hours, then vacuum distillation to recover glacial acetic acid, and then the remaining material cooled to room temperature, respectively, by adding 200 grams of saturated salt water and 300 grams of ethyl acetate dissolved, stirring stratification. The organic phase was taken off and evaporated to dryness under reduced pressure. The residue was recrystallized from isopropanol to give 82.8 g of a solid (80% yield), (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-4-aminoisoindoline-1,3-dione, optical purity 99.1%, purity 99.5%.

Reference： [1]Patent: CN104447445,2016,B .Location in patent: Paragraph 0086; 0087

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Technical Information

? Acyl Group Substitution ? Baeyer-Villiger Oxidation ? Barbier Coupling Reaction ? Baylis-Hillman Reaction ? Bouveault-Blanc Reduction ? Bucherer-Bergs Reaction ? Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions ? Catalytic Hydrogenation ? Chan-Lam Coupling Reaction ? Clemmensen Reduction ? Complex Metal Hydride Reductions ? Corey-Bakshi-Shibata (CBS) Reduction ? Corey-Chaykovsky Reaction ? Ester Cleavage ? Fischer Indole Synthesis ? Grignard Reaction ? Henry Nitroaldol Reaction ? Horner-Wadsworth-Emmons Reaction ? Hydride Reductions ? Lawesson's Reagent ? Leuckart-Wallach Reaction ? Mannich Reaction ? McMurry Coupling ? Meerwein-Ponndorf-Verley Reduction ? Passerini Reaction ? Paternò-Büchi Reaction ? Petasis Reaction ? Peterson Olefination ? Pictet-Spengler Tetrahydroisoquinoline Synthesis ? Preparation of Aldehydes and Ketones ? Preparation of Amines ? Prins Reaction ? Reactions of Aldehydes and Ketones ? Reactions of Amines ? Reactions with Organometallic Reagents ? Reformatsky Reaction ? Robinson Annulation ? Schlosser Modification of the Wittig Reaction ? Schmidt Reaction ? Specialized Acylation Reagents-Carbodiimides and Related Reagents ? Specialized Acylation Reagents-Ketenes ? Specialized Acylation Reagents-Vilsmeier Reagent ? Stobbe Condensation ? Tebbe Olefination ? Ugi Reaction ? Wittig Reaction ? Wolff-Kishner Reduction

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P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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[ CAS No. 6296-53-3 ] {[proInfo.proName]}

Quality Control of [ 6296-53-3 ]

Related Doc. of [ 6296-53-3 ]

Product Details of [ 6296-53-3 ]

Calculated chemistry of [ 6296-53-3 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 6296-53-3 ]

Application In Synthesis of [ 6296-53-3 ]

[ 6296-53-3 ] Synthesis Path-Upstream 1~1

[ 6296-53-3 ] Synthesis Path-Downstream 1~8

Technical Information

Related Functional Groups of [ 6296-53-3 ]

Anhydrides

Amides

Esters

Amines

Related Parent Nucleus of [ 6296-53-3 ]

Benzofurans

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 6296-53-3 ]

Related Parent Nucleus of
[ 6296-53-3 ]