[ CAS No. 6296-53-3 ] N-(1,3-Dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide

Cat. No.: A313057

2D 3D

Structure of 6296-53-3 * Storage: Inert atmosphere,Room Temperature

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* Storage: Inert atmosphere,Room Temperature

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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+

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

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[ 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

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[ 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

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[ 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

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[ 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%.

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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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 Å²

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

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

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

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

[ CAS No. 6296-53-3 ] N-(1,3-Dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide

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