[ CAS No. 6296-53-3 ]

Name: 6296-53-3|N-(1,3-Dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide|97%
Brand: Ambeed
SKU: A313057
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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 g/mol	Pubchem ID :	226121
Synonyms :

Calculated chemistry of [ 6296-53-3 ]

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 Å²

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 1~8

1
[ 603-11-2 ]
[ 108-24-7 ]
[ 6296-53-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	at 80 - 115℃; Autoclave	2-nitrophthalic acid (100. 0 g), acetic anhydride (1 L) was added to a hydrogenation kettle, heated to 80 ° C,After the raw material disappeared, the mixture was cooled to room temperature, 10percent Pd / C (3 g) was added, replaced with nitrogen twice, hydrogen was introduced to IMPa,The reaction is maintained at room temperature until no hydrogen is absorbed, vented, blown with nitrogen,Heated to 110-115 ° C reaction to the raw material or intermediate state disappeared,Hot filter, cooled to 0-5 ° C, filtered, washed with glacial acetic acid to give pale yellow crystals, dried 80. 6g, yield 83percent, HPLC 99. 0percent.

Reference： [1] Patent: CN105294534, 2016, A, . Location in patent: Paragraph 0036; 0037

2
[ 5434-20-8 ]
[ 108-24-7 ]
[ 6296-53-3 ]

Yield	Reaction Conditions	Operation in experiment
78.5%	for 4 h; Reflux	Example 2;- The Example 1 of the 3-amino-phthalic acid 28.0g (0.15mol) by adding 250 ml of the flask, then adding acetic anhydride 100 ml, was heated to reflux for 4h. The reaction followed by TLC to obtain 3-acetamido-phthalic anhydride. After completion of the reaction, the reaction flask placed in an ice water bath and stirred for 15min, then the solid separated; of diethyl ether was added with stirring, suction filtered and washed with diethyl ether to give a pale yellow flaky solid obtained after drying weighed 24. 9g, yield 78 . 5percent. mp: 180~182 ° C. IR (KBr): 3351,1841 ; 1766 ; 1700 ; 1603 cm -1. 1 HNMR (400MHz, CDCl 3): 2.34 (s, 3H), 7.69 (d, J=7.3Hz, 1H), 7.82-7.93 (m, 1H), 8.97 (d, J=8.5Hz, 1H), 9.12 (s, 1H) .MS (EI): 205 [M +].
61%	at 0 - 5℃; for 4 h; Heating / reflux	A mixture of 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL) was charged into a 1-L 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser. The reaction mixture was refluxed for 3 hours, cooled to ambient temperature, and kept at 0-5° C. for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuum at ambient temperature to a constant weight to yield 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. The product in CDCl₃was characterized by a ¹H NMR spectrum showing the following chemical shifts (δ in ppm): 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
61%	for 3 h; Reflux	A 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer,and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550mL). The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature andfurther to 0-5 ° C. for another 1 hour. The crystalline solid was collected by vacuum filtrationand washed with ether. The solid product was dried in vacua at ambient temperature to a constant weight, giving 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. ‘H-NMR (CDC13) ö: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).

61%	for 3 h; Reflux	A I L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to about 25 °C and further to 0-5 °C for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuo at ambient temperature to a constant weight, giving 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDCls) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
61%	for 3 h; Reflux	[0112j A 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3 -aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature and further to 0-5°C for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuo at ambient temperature to a constant weight, giving 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. ‘H-NMR (CDC13) ö: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
61%	for 3 h; Reflux	A I L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3- aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to about 25 °C and further to 0-5 °C for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuo at ambient temperature to a constant weight, giving 75 g (61 > yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDCI3) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
61%	for 3 h; Reflux	6.2.2. Preparation of 3-Acetamidophthalic Anhydride A 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature and further to 0-5° C. for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuo at ambient temperature to a constant weight, giving 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. ¹H-NMR (CDCl₃) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
61%	for 3 h; Reflux	[0187] A I L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature and further to 0-5°C for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuo at ambient temperature to a constant weight, giving 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDC1₃) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
61%	for 3 h; Reflux	10215] A 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to about 25° C. and thrther to 0-5°C. for another 1 hout The crystalline solid was collected by vacuum filtration and washed with ethet The solid product was dried in vacuo at ambient temperature to a constant weight, giving 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. ‘H-NMR (CDC13) ö: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
61%	for 3 h; Reflux	A mixture of 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mE) was charged into a 1 -L 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser. The reaction mixture was refluxed for 3 hours, cooled to ambient temperature, and kept at 0-5° C. for another 1 hout The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuum at ambient temperature to a constant weight toyield 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. The product in CDC13 was characterized by a ‘H NMR spectrum showing the following chemical shifts (ö in ppm): 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
728 g	Reflux	The unbaked product obtained in Example 1 was transferred to a 5 L three-necked flask, acetic anhydride (4. 5 L) was added,Heated to reflux for 1-2 hours, filtered while hot, washed with glacial acetic acid and then cooled to 0-5 ° C,Stir until the product is fully precipitated, filtered, washed with acetic acid,827 g of yellow needle-like crystals, about 12percent solvent, 728 g after drying, 75percent in two steps, HPLC 99.8percent.

Reference： [1] Patent: CN105330587, 2016, A, . Location in patent: Paragraph 0035; 0036
[2] Patent: US2007/155791, 2007, A1, . Location in patent: Page/Page column 14
[3] Patent: WO2014/74846, 2014, A1, . Location in patent: Page/Page column 20; 21
[4] Patent: WO2014/151180, 2014, A1, . Location in patent: Paragraph 0073
[5] Patent: WO2015/175773, 2015, A1, . Location in patent: Paragraph 0112
[6] Patent: WO2016/25686, 2016, A1, . Location in patent: Paragraph 0095
[7] Patent: US9272035, 2016, B2, . Location in patent: Page/Page column 23
[8] Patent: WO2015/175956, 2015, A1, . Location in patent: Paragraph 0187
[9] Patent: US2016/128981, 2016, A1, . Location in patent: Paragraph 0215
[10] Patent: US9387195, 2016, B2, . Location in patent: Page/Page column 27
[11] Journal of the American Chemical Society, 1909, vol. 31, p. 489
[12] Patent: WO2016/174685, 2016, A1, . Location in patent: Page/Page column 11
[13] Patent: CN105294534, 2016, A, . Location in patent: Paragraph 0028; 0029

3
[ 5434-20-8 ]
[ 6296-53-3 ]

Reference： [1] Patent: US2003/187052, 2003, A1,
[2] Patent: US4456595, 1984, A,
[3] Patent: US2012/276087, 2012, A1,
[4] Patent: EP2962690, 2016, A1,
[5] Patent: CN105622380, 2016, A,

4
[ 108-24-7 ]
[ 6946-22-1 ]
[ 6296-53-3 ]

Yield	Reaction Conditions	Operation in experiment
94 g	at 100℃; for 15 h;	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 2 h;	A stirred solution of 3-aminophthalic acid hydrochloride (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

5
[ 603-11-2 ]
[ 6296-53-3 ]

Reference： [1] Journal of the American Chemical Society, 1909, vol. 31, p. 489
[2] Patent: US2012/276087, 2012, A1,
[3] Patent: WO2014/74846, 2014, A1,
[4] Patent: WO2015/175956, 2015, A1,
[5] Patent: WO2014/151180, 2014, A1,
[6] Patent: WO2015/175773, 2015, A1,
[7] Patent: WO2016/25686, 2016, A1,
[8] Patent: US9272035, 2016, B2,
[9] Patent: CN105330587, 2016, A,
[10] Patent: WO2016/174685, 2016, A1,
[11] Patent: CN105294534, 2016, A,
[12] Patent: WO2017/33116, 2017, A1,

6
[ 641-70-3 ]
[ 6296-53-3 ]

Reference： [1] Annales Pharmaceutiques Francaises, 1958, vol. 16, p. 421,425

7
[ 6296-53-3 ]
[ 59434-19-4 ]

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
[3] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1950, vol. 231, p. 912

8
[ 6296-53-3 ]
[ 102308-43-0 ]

[ 6296-53-3 ] Synthesis Path-Downstream 1~59

1
[ 6296-53-3 ]
[ 60-29-7 ]
[ 506-82-1 ]
4-acetylamino-3,3-dimethyl-phthalide [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 1909

2
[ 6296-53-3 ]
[ 60-29-7 ]
[ 506-82-1 ]
[ 123573-16-0 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 1909

3
[ 6296-53-3 ]
[ 95-51-2 ]
[ 132466-65-0 ]

Reference： [1]Ricerca Scientifica,1958,vol. 28,p. 105,108, 109

4
[ 6296-53-3 ]
[ 100-63-0 ]
N-(2-anilino-1,3-dioxo-isoindolin-4-yl)-acetamide [ No CAS ]

Reference： [1]Journal of the Chemical Society,1937,p. 26,31

5
[ 6296-53-3 ]
[ 60-34-4 ]
N-(2-methyl-1,4-dioxo-1,2,3,4-tetrahydro-phthalazin-5-yl)-acetamide [ No CAS ]
N-(3-methyl-1,4-dioxo-1,2,3,4-tetrahydro-phthalazin-5-yl)-acetamide [ No CAS ]

Reference： [1]Journal of the Chemical Society,1937,p. 1841,1846

7
[ 6296-53-3 ]
[ 71-43-2 ]
7-amino-3,3-diphenyl-phthalide [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1920,vol. 42,p. 1876

8
[ 6296-53-3 ]
[ 103260-67-9 ]
[ 103260-68-0 ]

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

9
[ 6296-53-3 ]
[ 14056-15-6 ]

Reference： [1]Journal of the Chemical Society,1937,p. 26,31

10
[ 6296-53-3 ]
N-ethyl-2,3-bis-hydroxymethyl-aniline [ No CAS ]

Reference： [1]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1954,vol. 238,p. 2246

11
[ 641-70-3 ]
[ 6296-53-3 ]

Reference： [1]Annales Pharmaceutiques Francaises,1958,vol. 16,p. 421,425

12
[ 6296-53-3 ]
[ 39905-45-8 ]
[ 943430-49-7 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 6642 - 6653

13
[ 6296-53-3 ]
[ 151237-05-7 ]
3-acetylamino-N-(3,4,5-tridodecyloxyphenyl)phthalimide [ No CAS ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 6642 - 6653

14
[ 6296-53-3 ]
[ 62-53-3 ]
[ 20871-13-0 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 6642 - 6653

15
[ 6296-53-3 ]
[ 943430-53-3 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 6642 - 6653

16
[ 6296-53-3 ]
[ 943430-54-4 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 6642 - 6653

17
[ 6296-53-3 ]
C₂₈H₁₇N₃O₄ [ No CAS ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 6642 - 6653
[2]Tetrahedron,2007,vol. 63,p. 6642 - 6653

18
[ 6296-53-3 ]
C₄₄H₄₉N₃O₆ [ No CAS ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 6642 - 6653
[2]Tetrahedron,2007,vol. 63,p. 6642 - 6653

19
[ 6296-53-3 ]
C₄₂H₂₅N₅O₆ [ No CAS ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 6642 - 6653

20
[ 6296-53-3 ]
C₆₆H₇₃N₅O₉ [ No CAS ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 6642 - 6653

21
[ 6296-53-3 ]
[ 20579-79-7 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 6642 - 6653

22
[ 6296-53-3 ]
[ 59434-19-4 ]

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

23
[ 6296-53-3 ]
[ 3883-64-5 ]

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

24
[ 6296-53-3 ]
[ 13161-32-5 ]

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

25
[ 6296-53-3 ]
[ 105694-45-9 ]

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

26
[ 6296-53-3 ]
[ 4792-33-0 ]

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

27
[ 6296-53-3 ]
[ 70097-45-9 ]

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

28
[ 6296-53-3 ]
[ 105694-44-8 ]

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

29
[ 6296-53-3 ]
[ 105694-46-0 ]

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

30
[ 6296-53-3 ]
[ 705281-76-1 ]

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

31
[ 6296-53-3 ]
4-benzoylamino-phthalide [ No CAS ]

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

32
[ 6296-53-3 ]
[ 633337-83-4 ]

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

33
[ 6296-53-3 ]
[ 197715-03-0 ]

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

34
[ 6296-53-3 ]
3-bromo-2-hydroxymethyl-benzoic acid hydrazide [ No CAS ]

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

35
[ 6296-53-3 ]
3-amino-2-hydroxymethyl-benzoic acid hydrazide [ No CAS ]

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

36
[ 6296-53-3 ]
2-chloro-6-hydroxymethyl-benzoic acid hydrazide [ No CAS ]

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

37
[ 6296-53-3 ]
2-bromo-6-hydroxymethyl-benzoic acid hydrazide [ No CAS ]

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

38
[ 340019-38-7 ]
[ 6296-53-3 ]
N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine; In DMF (N,N-dimethyl-formamide); at 80 - 90℃; for 7h;	A mixture of 4-amino-4-(3-ethoxy-4-methoxyphenyl)butan-2-ol hydrochloride (0.5 g, 1.81 mmol), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (0.37 g, 1.81 mmol) and triethylamine (0.18 g, 1.81 mmol) in dimethylformamide (10 ML) was heated at 80-90° C. for 7 hours. The mixture was concentrated in vacuo to an oil. The oil was dissolved in ethyl acetate, washed with water, brine, dried, filtered and concentrated to an oil. This oil was purified by chromatography (silica gel, methylene chloride/ethyl acetate 8:2) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid (0.5 g, 65percent); mp 132-134° C.; 1H NMR (CDCl3) delta9.54 (s, 1H), 8.73 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.4 Hz, 1H), 7.46 d, J=7.3 Hz, 1H), 7.12-7.08 (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 5.46 (t, J=7.8 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 3.80 (m, 1H), 2.59-2.42 (m, 2H), 2.25 (s, 3H), 1.65 (s, 1H), 1.45 (t, J=7.0 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H); 13C NMR (CDCl3) delta170.36, 169.20, 167.96, 149.04, 148.26, 137.29, 135.70, 131.50, 131.35, 124.60, 120.61, 117.85, 113.10, 111.25, 66.00, 64.39, 55.89, 52.43, 40.19, 24.92, 24.33, 14.73; Anal. Calcd. For C23H26N2O6: C, 64.78; H, 6.15; N, 6.57. Found: C, 64.86; H, 6.10; N, 6.46.

Reference： [1]Patent: US6667316,2003,B1 .Location in patent: Page column 24

39
[ 340020-06-6 ]
[ 6296-53-3 ]
N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxypentyl]-1,3-dioxoisoindolin-4-yl}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With triethylamine; In DMF (N,N-dimethyl-formamide); at 80 - 90℃; for 6h;	A stirred mixture of 5-amino-5-(3-ethoxy-4-methoxyphenyl)pentan-3-ol hydrochloride(1.15 g, 3.97 mmol), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (0.82 g, 3.97 mmol) and triethylamine (0.4 g, 3.97 mmol) in DMF (20 ML) was heated at 80-90° C. for 6 hours. The mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (80 ML), washed with water (30 ML), brine (30 ML) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride:ethyl acetate 8:2) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxypentyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.35 g, 77percent); 1H NMR (CDCl3) delta9.52 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.09-7.07 (m, 2H), 6.83-6.80 (m, 1H), 5.61-5.55 (J=3.9, 11.9 Hz, 1H), 4.11 (q, J=6.9 Hz, 2H), 3.84 (s, 3H), 3.47 (m, 1H), 2.97-2.86 (m, 1H), 2.25 (s, 3H), 2.06-1.95 (m, 1H), 1.78 (b, 1H), 1.62-1.52 (m, 2H), 1.45 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3) delta170.39, 169.23, 168.11, 148.94, 148.14, 137.32, 135.83, 131.81, 131.19, 124.72, 120.30, 117.94, 115.31, 112.87, 111.09, 70.01, 64.36, 55.86, 51.29, 37.92, 30.46, 24.92, 14.73, 9.90.

Reference： [1]Patent: US6667316,2003,B1 .Location in patent: Page column 46

40
[ 340020-00-0 ]
[ 6296-53-3 ]
N-{2-[1-(R)-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; at 80 - 90℃; for 7h;	A mixture of R-4-amino-4-(3-ethoxy-4-methoxyphenyl)butan-2-ol (1.5 g, 5.44 mmol), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (1.11 g, 5.44 mmol) and triethylamine (0.55 g, 5.44 mmol) was heated at 80-90° C. for 7 hours. The mixture was concentrated in vacuo to an oil. The oil was dissolved in ethyl acetate and washed with water, brine, dried and concentrated. The residue was purified by chromatograhpy (silica gel, methylene chloride:ethyl acetate 8:2) to give N-{2-[1R-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid (1.87 g, 80percent); 1H NMR (CDCl3) delta9.61 (s, 1H), 8.75 (d, J=8.4 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.06 (m, 2H), 6.83-6.80 (m, 1H), 5.58-5.51 (dd, J=4.2 and 11.7 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 3.84 (s, 3H), 3.80-3.73 (m, 1H), 2.92-2.80 (m, 1H), 2.25 (s, 3H), 2.12-2.01 (m, 1H), 1.45 (t, J=7.0 Hz, 3H), 1.29 (d, J=6.1 Hz, 3H); 13C NMR (CDCl3) delta170.39, 169.21, 167.96, 149.01, 148.17, 137.36, 135.86, 131.61, 131.19, 124.75, 120.35, 117.95, 115.30, 112.90, 111.13, 64.88, 64.39, 55.88, 51.32, 39.92, 24.93, 23.77, 14.74.

Reference： [1]Patent: US6667316,2003,B1 .Location in patent: Page column 25

41
[ 340020-08-8 ]
[ 6296-53-3 ]
N-{2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; In DMF (N,N-dimethyl-formamide); at 80 - 90℃; for 7h;	A stirred mixture of 4-amino-4-(3-cyclopentyloxy-4-methoxyphenyl)butan-2-ol hydrochloride(1.20 g, 3.80 mmol), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (0.78 g, 3.80 mmol) and triethylamine (0.38 g, 3.80 mmol) in DMF (15 ML) was heated at 80-90° C. for 7 hours. The mixture was allowed to cool to room temperature and poured into water (80 ML). The resulting mixture was extracted with EtOAC (3*30 ML). The combined ethyl acetate extracts were washed with water (30 ML), brine (30 ML) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride: EtOAC 8:2) to give N-{2-1-(3-cyclopentyloxy-4-meth-oxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.3 g, 73percent) as a white solid: 1H NMR (CDCl3) delta9.53 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.08-7.03 (m, 2H), 6.82 (d, J=8.2 Hz, 1H), 5.57-5.51 (dd, J=4.2, 11.6 Hz, 1H), 4.78 (m, 1H), 3.81 (s, 3H), 3.77-3.74 (m, 1H), 2.91-2.81 (m, 1H), 2.25 (s, 3H), 2.13-1.60 (m, 10H), 1.29 (d, J=6.1 Hz, 3H); 13C NMR (CDCl3) delta170.38, 169.21, 168.06, 149.70, 147.50, 137.33, 135.84, 131.54, 131.20, 124.71, 120.28, 117.93, 115.31, 115.07, 111.55, 80.45, 64.89, 55.97, 51.35, 39.92, 32.73, 24.91, 24.04, 23.76, 21.02.

Reference： [1]Patent: US6667316,2003,B1 .Location in patent: Page column 47; 48

42
[ 340020-01-1 ]
[ 6296-53-3 ]
N-{2-[1S-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine; In DMF (N,N-dimethyl-formamide); at 80 - 90℃; for 7h;	A mixture of S4-amino-4-(3-ethoxy-4-methoxyphenyl)butan-2-ol (1.5 g, 5.44 mmol), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (1.11 g, 5.44 mmol) and triethylamine (0.55 g, 5.44 mmol) in dimethylformamide (20 ML) was heated at 80-90° C. for 7 hours. The mixture was concentrated in vacuo to an oil. The oil was dissolved in ethyl acetate and washed with water, brine, dried and concentrated. The crude product was purified by chromatography (silica gel, methylene chloride:ethyl acetate 8:2) to give N-{2-[1S-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid (1.81 g, 78percent); 1H NMR (CDCl3) delta9.54-9.52 (d, 1H), 8.76-8.70 (m, 1H), 7.66-7.58 (m, 1H), 7.49-7.43 (m, 1H), 7.12-7.05 (m, 2H), 6.85-6.80 (m, 1H), 5.58-5.43 (m, 1H), 4.16-4.04 (q, 2H), 3.84 (s, 3H), 3.80-3.74 (m, 1H), 2.95-2.82 (m, 1H), 2.57-2.44 (m, 1H), 2.26 (s, 3H), 1.47 (t, 3H), 1.25 (d, 3H).

Reference： [1]Patent: US6667316,2003,B1 .Location in patent: Page column 25; 26

43
C₂H₄O₂*C₁₅H₂₀N₂O₂ [ No CAS ]
[ 6296-53-3 ]
[ 882052-96-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With acetic acid; for 17h;Heating / reflux;	Example 10 N-{2-[Cyano(3-cyclopentyloxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide A mixture of 2-amino-2-(3-cyclopentyloxy-4-methoxyphenyl)ethanenitrile acetate (3.5 g, 11.0 mmol) and <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (2.3 g, 11.0 mmol) in glacial acetic acid (40 mL) was heated to reflux for 17 hours. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in EtOAc and washed with water, brine and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 98:2) to give 3.1 g (62percent) of N-{2-[cyano(3-cyclopentyloxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide as white solid; mp 124-126° C.; 1H NMR (CDCl3) delta 9.44 (s, 1H), 8.76 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.03-6.99 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 5.60-5.53 (dd, J=6.2 and 10.4 Hz, 1H), 4.79-4.74 (m, 1H), 3.86-3.75 (m, 1H), 3.82 (s, 3H), 3.29-3.20 (dd, J=6.4 and 17 Hz, 1H), 2.72 (s, 3H0, 1.97-1.56 (m, 8H); 3C NMR (CDCl3) delta 169.58, 169.11, 167.18, 150.61, 147.98, 137.72, 136.28, 130.89, 128.66, 125.09, 119.80, 118.29, 116.78, 114.19, 111.90, 80.68, 56.02, 51.10, 32.73, 24.92, 24.03, 21.07. Analy. Calculated for C25H25N3O5: C, 67.10; H, 5.63; N, 9.39. Found: C, 66.89; H, 5.42; N, 9.26.

Reference： [1]Patent: US2006/84815,2006,A1 .Location in patent: Page/Page column 22-23

44
[ 882053-06-7 ]
[ 6296-53-3 ]
[ 882052-99-5 ]

Yield	Reaction Conditions	Operation in experiment
21%	With sodium acetate; acetic acid;Heating / reflux;	Example 13 N-{2-[1-(3-Cyclopropylmethoxy-4-methoxy-phenyl)2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide To a solution of i-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1.0 g, 3.3 mmol) in acetic acid (10 mL), was added 3acetamido-phthalic anhydride (1.37 g, 6.7 mmol) and sodium acetate (0.54 g, 6.7 mmol). The mixture was heated at reflux temperature overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with water (30 mL*2) and brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel column to give N-{2-[1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (340 mg, 21percent): mp 102-104° C.; 1H-NMR (CDCl3) delta 0.35-0.37 (m, 2H, c-CH2), 0.62-0.67 (m, 2H, c-CH2), 0.88-0.93 (m, 2H, c-CH2), 1.25-1.32 (m, 1H, c-CH), 2.25 (s, 3H, CH3), 2.87 (s, 3H,CH3), 3.75 (dd, J=4, 15 Hz, 1H, CHH), 3.83-3.85 (m, 5H, OCH2+OCH3), 4.53 (dd, J=10, 15 Hz, 1H, CH2), 5.85 (dd, J=4, 10 Hz, 1H, NCH), 6.84 (d, J=8 Hz, 1H, Ar), 7.07-7.10 (m, 2H, Ar), 7.45 (d, J=5 Hz, 1H, Ar), 7.62 (t, J=8 Hz, 1H, Ar), 8.72 (d, J=8 Hz, 1H, Ar), 9.45 (s, 1H, NHCO); 13C NMR (CDCl3) delta 1.6, 3.2, 3.3, 24.7, 41.4, 48.3, 54.2, 55.8, 73.9, 111.5, 113.1, 115.0, 118.0, 120.3, 124.7, 129.1, 130.9, 135.9, 137.2, 148.6, 149.8, 167.2, 169.0, 169.3. Analy. Calculated for C24H26N2O7S: C, 59.25; H, 5.39; N, 5.76. Found: C, 59.00; H, 5.36; N, 5.55.

Reference： [1]Patent: US2006/84815,2006,A1 .Location in patent: Page/Page column 23

45
C₂H₄O₂*C₁₂H₁₆N₂O₂ [ No CAS ]
[ 6296-53-3 ]
[ 882052-94-0 ]

Yield	Reaction Conditions	Operation in experiment
83%	With acetic acid; for 17h;	Example 8 N-{2-[Cyano(3-ethoxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide To a mixture of 2-amino-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile acetate (4.1 g, 14.6 mmol) and <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (3.0 g, 14.6 mmol) in glacial acetic acid (60 mL), was heated to reflux for 17 hours. The mixture was concentrated in vacuo to provide an oil. The oil was dissolved in EtOAc and washed with water, brine and dried over MgSO4. Solvent was removed, and the residue was purified by chromatography (SiO2, Hexane:EtOAc 6:4) to give 4.9 g (83percent) of N-{2-[cyano(3-ethoxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid; mp 118-120° C.; 1H NMR(CDCl3) delta 9.43 (s, 1H), 8.76 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.05-6.82 (m, 3H), 5.60-5.54 (dd, J=6.63 and 10.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 2H), 3.81 (s, 3H), 3.81-3.74 (m, 1H), 3.29-3.20 (dd, J=6.2 and 16.8 Hz, 1H), 2.27 (s, 3H), 1.46 (t, J=7 Hz, 3H); 13C NMR (CDCl3) delta 169:56, 169.12, 167.19, 149.92, 148.64, 137.73, 136.30, 130.87, 128.70, 125.11, 119.92, 118.29, 116.76, 114.94, 112.14, 111.98, 64.56, 55.94, 51.08, 24.92, 21.04, 14.68. Aanly. Calculated for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 65.01; H, 5.10; N, 10.19.

Reference： [1]Patent: US2006/84815,2006,A1 .Location in patent: Page/Page column 21

46
[ 5434-20-8 ]
[ 6296-53-3 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic anhydride;	Preparation of 3-acetamidophthalic Anhydride A 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature and further to 0-5° C. for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacua at ambient temperature to a constant weight, giving 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDCl3) delta: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
	With acetic anhydride;	(b) 3-Acetamidophthalic anhydride 3-Aminophthalic acid (4 g., 0.022 mole) is refluxed with 50 ml. of acetic anhydride for 2 hours, then evaporated to a solid. Trituration with ethyl acetate gives 2.5 g. of 3-acetamidophthalic anhydride; m.p. 180°-183°.
	With acetic anhydride;	6.2.2.Preparation of 3-Acetamidophthalic AnhydrideA 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL).The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature and further to 0-5° C. for another 1 hour.The crystalline solid was collected by vacuum filtration and washed with ether.The solid product was dried in vacuo at ambient temperature to a constant weight, giving 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDCl3) delta: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).

With acetic anhydride;

Preparation of 3-acetamidophthalic anhydride A 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature and further to 0-5 °C for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacua at ambient temperature to a constant weight, giving 75 g (61percent yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDCl3) delta: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).

Reference： [1]Patent: US2003/187052,2003,A1
[2]Patent: US4456595,1984,A
[3]Patent: US2012/276087,2012,A1
[4]Patent: EP2962690,2016,A1
[5]Patent: CN105622380,2016,A

47
[ 6296-53-3 ]
[ 67865-66-1 ]
1-[N-[3-(acetylamino)-2-carboxybenzoyl]-L-alanyl]-L-proline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; ethyl acetate;	(c) 1-[N-[3-(Acetylamino)-2-carboxybenzoyl]-L-alanyl]-L-proline, phenylmethyl ester 3-Acetamidophthalic anhydride (2.5 g., 0.012 mole) and L-alanyl-L-proline, phenylmethyl ester, p-toluenesulfonic acid salt (5.46 g., 0.012 mole) is slurried in 100 ml. of methylene chloride, cooled to 0°, and treated with triethylamine (2.5 g., 0.025 mole). The mixture is allowed to come to room temperature overnight and is afterward evaporated to an oil. This oil is taken up in ethyl acetate and washed with dilute hydrochloric acid, water, and saturated sodium chloride. Drying (Na2 SO4) and evaporation gives an oil containing two components. After standing in a small volume of ethyl acetate, 2.1 g., of 1-[N-[3-(acetylamino)-2-carboxybenzoyl]-L-alanyl]-L-proline, phenylmethyl ester are obtained; m.p. 158°-160°.

Reference： [1]Patent: US4456595,1984,A

48
[ 6296-53-3 ]
[ 608141-43-1 ]
[ 608141-41-9 ]

Yield	Reaction Conditions	Operation in experiment
95.1%	With triethylamine; In ethyl acetate; at 75 - 80℃; for 18h;	The 10.0g (0.0224mol) (S) -1- (3- ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethanamine N- acetyl -L- leucine salts and 4.6g (0.0224mol) 3- acetamido-phthalic anhydride was added 250mL three-necked flask, was added 50mL of ethyl acetate and 1.81g (0.8eq) of triethylamine, heated 75 ~ 80 , incubated for 18 hours.The reaction was stopped, and then 100mL ethyl acetate was added, cooled to 20 ~ 30 .To the reaction solution was added 30g 8% sodium carbonate solution, stirred for 10 to 30 minutes, allowed to stand, and the organic layer was added 30mL of water, stirred for 10 to 30 minutes, allowed to stand, and the organic layer was added 30mL of water, stirred for 10 to 30 minutes, allowed to stand, and the organic layer was evaporated to dryness to give a pale yellow solid, was added 30mL of anhydrous ethanol, evaporated to dryness again.Hot ethanol beaten, cooled to 0 ~ 5 stirred for 1 to 2 hours, filtered and sucked dry, the filter cake was dried in vacuo to give the white powder 9.8g, yield 95.1%, HPLC: 99.9%, wherein the impurity to acetyl (4 ) 0.04% area by HPLC.
91.3%	With sodium acetate; acetic acid; at 80℃; for 5h;	(S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethylamine N- acetyl-L-leucinate (4.46 g, 10 mmol) and 3- Acetamidophthalic anhydride (2.15 g, 10.5 mmol) was added to a 100 mL three neck reaction flask, 45 mL glacial acetic acid was added, and sodium acetate (0.82 g, 10 mmol) was added.Heated to 80 C with stirring for 5 hours.The reaction was completed by TLC. The mixture was concentrated under reduced pressure to remove glacial acetic acid. The residue was added with 50 ml of ethyl acetate and washed with 20 ml of water, saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated by filtration.Concentrated residue was added ethanol 30ml, acetone 10ml mixed solvent, refluxed and stirred for 1 hour.The temperature was lowered to room temperature, and the crystal was stirred for 5 hours. The crude was filtered and dried to obtain a crude product of 4.4 kg.Put the crude product into the reaction bottle, add 25ml of absolute ethanol and 9ml of acetone, dissolve it in reflux and dissolve, stir for 1 hour, decrease to room temperature and distill the crystals for 5 hours.The solid was collected by filtration and dried under reduced pressure to give 4.2 g of white solid powder.Yield 91.3%, HPLC purity 99.9% with deacetylated impurities 0.03%.
89.2%		Example 9: Preparation of S-apremilast (I) by (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV) without isolating (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (II) In a dry 200mL glass flask was added 50g of dichloromethane, 4.5g of (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV) (prepared in Example 5), and 1.5 g of 30% sodium hydroxide at 0-5C and stirred for 2 hours. The solution was extracted with dichloromethane. 3 g of dichloromethane phase was dried over anhydrous sodium sulfate and filtered. The filtrate was transferred to another dry 250 ml glass flask. 2.5g of 3-acetamidophthalicanhydride, 25g of glacial acetic acid, and 0.2g of perchloric acid was added and heated at 40-45C for 50 minutes. The reaction was heated at 80-85C for 30 minutes then heated at reflux for 2 hours while distilling dichloromethane. 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 89.2%, e.e% to 99.8%.

85.2%	With magnesium sulfate; acetic acid; at 70℃; for 4h;	To a 2 L reaction flask was added Compound IV 100 g (0.224 mol, 98.4% ee), Anhydrous magnesium sulfate (13.5 g, 0.112 mol) and glacial acetic acid (600 mL) Mechanical stirring,Compound V 46 g (0.224 mol) was added.The reaction was stirred at 70 C for 4 h. Cooling to below 50 ,Filtration, solvent evaporation under reduced pressure, Washed with 1 L of ethyl acetate, washed with saturated sodium bicarbonate solution (2 x 800 mL), saturated sodium chloride solution (2 x 500 mL), and then dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. At room temperature, 300mL of acetone was added to the residue, and 600mL of ethanol was added after dissolving. The mixture was stirred for 30 minutes, 600mL of ethanol was added, and the mixture was stirred for 1 hour. Filtration and drying afforded 85.2 g (99.4% ee) of an off-white solid, 85.2% weight yield, 99.8% HPLC purity.
75%		A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50 C. After the solvent was removed in vacuum, the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL×2), saturated aqeous NaHCO3 (250 mL×2), and brine (250 mL×2), and then dried over anhydrous sodium sulfate. After the solvent was evaporated in vacuum, the residue was recrystallized from a binary solvent containing a mixture of ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL×2). The product was dried in vacuum at 60 C. to a constant weight, affording 19.4 g (75% yield) of (S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 (at)pH 0.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm×4.6 mm, 0.4 mL/min., (at)240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). The product in CDCl3 was characterized by a 1H NMR spectrum showing the following chemical shifts (delta in ppm): 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). The product in DMSO-d6 was characterized by a 13C NMR spectrum showing the following chemical shifts (delta in ppm): 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
75%	In acetic acid;Reflux;	A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4- methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98%ee), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g, 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <5 0C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL x 2), saturated aqeous NaHCO3 (250 mL 2), brine (250 mL 2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solventcontaining ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL 2). The product was dried in vacuo at 60C. to a constant weight, affording 19.4 g (75% yield) of Compound 3 with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 pH 3.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm x 4.6 mm, 0.4 mL/min., 240 nm): 25.4 mm (S-isomer, 98.7%), 29.5 mm (R-isomer, 1.2%). ?H-NMR (CDC13) oe:1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61(dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). ?3C-NMR(DMSO-d6) oe: 14.66, 24.92,41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02,136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
75%	In acetic acid;Reflux;	: A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (5)-2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98%> ee), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g, 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to 3(250 mL x 2), brine (250 mL x 2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL x 2). The product was dried in vacuo at 60 C to a constant weight, affording 19.4 g (75% yield) of apremilast with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2P04 pH 5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm x 4.6 mm, 0.4 mL/min, 240 nm): 25.4 min (^-isomer, 98.7%), 29.5 min (R- isomer, 1.2%). 1H-NMR (CDC13) delta: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H);13C-NMR (DMSO-d6) delta: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
75%	With acetic acid;Reflux;	6.2.4. Preparation of (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50 C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL2), saturated aqueous NaHCO3 (250 mL2), brine (250 mL2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL2). The product was dried in vacuo at 60 C. to a constant weight, affording 19.4 g (75% yield) of (S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione with 98% ee.
75%	With acetic acid;Reflux;	[0189] A 500 mL 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, (0620) 98% ee), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). (0621) The mixture was refluxed over night and then cooled to < 50 C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL x 2), saturated aqeous NaHC03 (250 mL x 2), brine (250 mL x 2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL x 2). The product was dried in vacuo at 60 (0622) C to a constant weight, affording 19.4 g (75% yield) of (0623) (S)- {2- [ 1 -(3 -ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl] -4-inoisoindoline- 1 ,3 -dione with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2P04 pH .5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm x 4.6 mm, 0.4 mL/min., 240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (i?-isomer, 1.2%). 1H-NMR (CDC13) 5: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68- 3.75 (dd, IH), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, IH), 5.84-5.90 (dd, IH), 6.82-8.77 (m, 6H), 9.46 (s, IH). 13C-NMR (DMSO-d6) delta: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
75%	With acetic acid;Reflux;	10217] A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3- ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% cc), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g, 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed overnight and then cooledto <50C. The solvent was removed invacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mLx2), saturated aqueous NaHCO3 (250 mLx2), brine (250 mLx2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solidwas isolated by vacuum filtration and washed with ethanol (100 mLx2). The product was dried in vacuo at 60C. to a constant weight, affording 19.4 g (75% yield) of S-{2-[1-(3-ethoxy-4-meth- oxyphenyl)-2-methylsulfonylethyl]-4-acetamidoisoindo- line-1,3-dione} with 98% cc. Chiral HPLC (15/85 EtOH/20mM KH2PO4 pH 5, Ultron Chiral ES-OVS from Agilent Technology, 150 mmx4.6 mm, 0.4 mL/min, 240 nm): 25.4 mm (S-isomer, 98.7%), 29.5 mm (R-isomer, 1.2%). ?H-NMR (CDC13) oe: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H); ?3C- NMR (DMSO-d6) oe: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46,169.14, 169.48.
75%	With acetic acid;Reflux;	A 500 mE 3-necked round bottom flask was equipped with amechanical stirrer, thermometer, and condenset The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine N-acetyl-E-leucine salt(25 g, 56 mmol, 98% cc), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g 58.8 mmol), and glacial acetic acid (250 mE). Themixture was refluxed over night and then cooled to <50 C. Afier the solvent was removed in vacuum, the residue was dissolved in ethyl acetate. The resulting solution was washedwith water (250 mEx2), saturated aqueous NaHCO3 (250 mEx2), andbrine (250 mEx2), and then dried over anhydroussodium sulfate. After the solvent was evaporated in vacuum, the residue was recrystallized from a binary solvent containing a mixture of ethanol (150 mE) and acetone (75 mE). The solid was isolated by vacuum filtration and washed with ethanol (100 mEx2). The product was dried in vacuum at 60 C.to a constant weight, affording 19.4 g (75% yield) of(S)-{2- [1 -(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-i,3-dione with 98% cc. Chiral HPEC (15/85 EtOH/20 mM KH2PO4 pH 0.5, Ultron Chiral ES-OVSfrom Agilent Technology, 150 mmx4.6 mm, 0.4 mE/mm.,240 nm): 25.4 mm (S-isomer, 98.7%), 29.5 mm (R-isomer,1.2%). The product in CDC13 was characterized by a ?H NMR spectrum showing the following chemical shifts (6 in ppm):1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H),3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90(dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). The product in DMSO-d5 was characterized by a ?3C NMR spectrum showing the following chemical shifis (oe in ppm): 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, ii 1.44, 112.40, 115.10,118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60,148.62 149.74 167.46 169.14 169.48.
75%	With acetic acid; at 110 - 115℃; for 1h;	To a 500 mL RBF the product of example 4, <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> and acetic acidwere charged and stirred at 110 C to 115 C for 1 hour and the solution was cooled to 60-65C. Acetic acid was distilled off completely and the residue was dissolved indichloromethane. The dichloromethane layer was washed with water followed by washing with aq. sodium bicarbonate solution. The dichloromethane layer was separated and distilled off completely. The product was isolated by recrystallization in acetone:ethanol mixture to give apremilast as a light yellow solid with chiral purity of 99.9 % and HPLC purity of 99.8%. Yield: 75 %
75%	With acetic acid;Reflux;	A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g, 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL x 2), saturated aqueous NaHCO3 (250 mL x 2), brine (250 mL x 2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL x 2). The product was dried in vacuo at 60 C to a constant weight, affording 19.4 g (75% yield) of apremilast with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 pH 5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm x 4.6 mm, 0.4 mL/min, 240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). 1H-NMR (CDCl3) delta: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H); 13C-NMR (DMSO-d6) delta: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
75%	With acetic acid;Reflux;	A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g, 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50 C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL x 2), saturated aqueous NaHCO3 (250 mL x 2), brine (250 mL x 2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL x 2). The product was dried in vacuo at 60 C to a constant weight, affording 19.4 g (75% yield) of apremilast with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 pH 5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm x 4.6 mm, 0.4 mL/min, 240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). 1H-NMR (CDCl3) delta: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H); 13C-NMR (DMSO-d6) delta: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
74%	With N-Ac-Leu; acetic acid;Reflux;	A 500ml three-neck flask was fitted with a mechanical stirrer, thermometer and cooler. 25 g (56 mmol) of the salt of (5)-2-(3-emoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine with N-acetyl-Z-leucine, 12.1 g (58.8 mmol) of 3-acetamidophtalic anhydride and 250 ml of glacial acetic acid were charged into a reaction vessel. The mixture was refluxed overnight and then cooled down to <50C. The solvent (250 ml of acetic acid) was removed in vacuo and the residue, having rich yellow colour, was dissolved in 800 ml of ethyl acetate. The obtained solution was washed with water (2 x 250), saturated aqueous NaHC03 (2 x 250 ml), brine (2 x 250 ml) and dried with sodium sulphate. The solvent (800 ml of ethyl acetate) was evaporated in vacuo and the residue was recrystallized from a binary solvent containing 150 ml of ethanol and 75 ml of acetone. The solid was isolated by filtration in vacuo and washed with 2 x 100 ml of ethanol. The product was dried in vacuo at 60C until constant weight, which provided 19.1 g of the title compound; yield 74%, HPLC purity 99.29%, XRPD confirmed Form B.
72.8%		In a 250 ml round bottom flask, 50 ml acetic acid was charged followed by 10 gms of 2-( -3-ethoxy-4-methoxyphenyl)- 1 -(methanesulfonyl)-eth-2-ylamine N-acetyl-Lleucine salt and it was stirred at room temperature for a few minutes. Then 4.82 gms of 3- acetamidophthalic anhydride was added and reaction mass was heated for 11 to 12 hours at 80 to 90 C. The solvent was removed under vacuum and ethyl acetate was addedfollowed by sodium bicarbonate solution. The layers were separated. The organic layer was washed and solvent was evaporated under vacuum. In the distilled residue, 90 ml ethanol and 30 ml acetone added and was stirred it for 2 hours at room temperature. The solid was precipitated. The solid was filtered and washed with ethanol. The material was unloaded and dried under vacuum for longer hours at 60 C. Yield: 6.41 gm. Thismaterial will be crystalized using a solvent or mixture of solvents known in the art.
70%		Charged 50 mL of 1,4-Dioxane in a flask followed by the addition of 5 g of N-acetyl L- Leucine salt of l-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (Compound (AL)), 5 mL of glacial acetic acid and 2.3 g of <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (B). The reaction mixture was heated to a temperature of 85-90 C and stirred for about 8-10 h. The reaction mixture was cooled and solvent was distilled out under vacuum. To the residue was added 50 mL of dichloromethane followed by the addition of 0.014 g of Iodine (I2) and 0.88 g of Acetyl chloride. The reaction mixture further stirred for 2-4 hr at a temperature of about 25-30 C. The reaction mixture was washed with aqueous solution of sodium bicarbonate (7- 8% solution) and sodium thiosulfate solution (10%). The organic layer was separated and evaporated under vacuum and the residue was dissolved in 40 mL of methyl isobutyl ketone. The reaction mixture was heated at temperature 80-90 C, followed with subsequent cooling to 25-30 C temperature and stirred for about 14-16 h. The reaction mixture was further cooled to 0-5 C temperature and the precipitated solid was isolated. Yield: 3.6 g (70%).
60.3%		The compound of formula VI 40. 08mmol, a compound of formula IX 42. 06mmol acetic acid and a 500 mL, added to the reaction flask and the reaction was refluxed for 15H, the solvent was distilled off under reduced pressure, the residue was added water and EA each 100mL, extract separated, and extracted with EA ( 100mLX 2), the combined organic phases were washed with 100mL 2M aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give a pale yellow solid, clear solution at reflux was added 35mL of acetone, and then adding 70mL absolute ethanol , refluxed for 15min, allowed to cool, 25 C crystallization was stirred 3h, filtered, washed with a small amount of anhydrous ethanol, the filter cake was dried in vacuo at 40 C for 5 hours to give a white solid 11. 1g, yield 60. 3%, HPLC: 99 · 7%, less than one-hybrid 0 ? 1%, : 98 · 6%
	With acetic acid; In toluene; at 120℃;	Compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindoline-1,3-dione specific preparation method: Select 480ml toluene as solvent, 48ml acetic acid as a catalyst. 24g of purified compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-ylamine N-acetyl-L-leucine and 12g compound <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> under reflux temperature is reacted for 2 ~ 3h to obtain compound 24g (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindoline-1,3-dione. The reflux temperature is 120 deg.C. Apremilast high chiral purity preparation specifically: 24g of the compound (S) -2- [1- (3- ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethyl] -4-acetyl-amino-isoindoline-1,3-dione into the solvent at 50 ~ 60 conditions recrystallization of high purity Apremilast, the solvent is a mixture of 96ml of acetone and 192ml of ethanol.
425 g	In acetonitrile; for 3h;Reflux;	A stirred solution of N-acetyl L-leucine salt of (S)-2-(3-efhoxy-4-methoxyphenyl)-l- (methylsulphonyl)eth-2-ylamine (500.0gm) and <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (229.85gm) in 4.01it acetonitrile was refluxed for 3.0 hr and then cooled to 50C. The solvent was removed under reduced pressure to obtain a semisolid residue. To the residue water was added and pH adjusted to 7-8 using saturated sodium bicarbonate solution. The product was extracted into ethyl acetate and the solvent was removed under reduced pressure to obtain apremilast. HPLC purity: 99% The apremilast thus obtained was heated at 60-65 C in a solvent mixture of acetone and ethanol to get clear solution. The reaction mixture was cooled to 25-30C and stirred for 12 hr. The precipitated product was filtered and washed with ethanol and dried at 60C under vacuum for 12.0hr to obtain 425.0gm of (5)-N-{2-(l-(3-ethoxy-4- methoxyphenyl)-2-methylsulphonyl)ethyl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yljacetamide. HPLC purity 100.0%, R isomer <0.5%, S isomer> 99.5%.
	With sodium acetate; acetic acid; at 80℃;	A reaction flask was charged with (S)-1 -(3-Ethoxy-4-methoxyphenyl)-2- Methylsulfonylethylamine-N-actyl-L-leucine salt (1 1 g), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong>(5.3g), sodium acetate anhydrous (2.0g) and glacial acetic acid (22ml). The reaction mixture was heated to 80 ± 3C till completion of the reaction. After completion of the reaction, reaction mixture was cooled to room temperature. Solvent was removed under vacuum and the residue was dissolved in ethyl acetate. The resulting organic solution was washed with water, saturated aqueous sodium bicarbonate solution and brine solution. The solvent ethyl acetate was evaporated under vacuum to give amorphous Apremilast which was stirred with cyclohexane and filtered to obtain amorphous Apremilast.
	In N,N-dimethyl acetamide; at 110 - 120℃;Inert atmosphere;	The below preparation serves as a non-limiting example for preparing APM. Any other method for preparing APM is also suitable in the context of the present invention. (0518) Reference is made to Figure 1. APM-1 (9.65g) was dissolved in dimethylacetamide (100ml) at ambient temperature. Then APM-2 (20g) was suspended and dimethylacetamide (100 ml) was charged. After warming up of the suspension to the temperature 10-120C under flow of inert gas the reaction mixture was stirred between 2-4 hours. When the reaction was finished (after 2-4h at 110-120C) the solution was cooled down to a temperature of 20-25C. Ethyl acetate (180ml) and water (180ml) were added to the reaction mixture and the reaction mass was stirred for 10 min at 20-30C. After separation, the ethyl acetate phase was left and the water phase was extracted with ethyl acetate (2x50ml). The combined ethyl acetate phases were washed with 8% aHCOs solution (2x50ml), 1N HCI (2x50ml), and water (1x50ml). The organic solvent was evaporated under reduced pressure (200-30mbar) at 35C giving compound APM (as an oil residue left after ethyl acetate distillation). (0519) 1.2 Crystallization of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1 ,3- dioxo-2,3-dihydro-1 H-isoindol-4-yl]acetamide) (APM) (0520) Crystallization - Option I (0521) Reference is made to Figure 2. For crystallization, APM in any form and prepared by any method (e.g. any known literature method), for example the method of above Example 1.1 , can be used. (0522) 10g of Apremilast were suspended in diethyl ether (200ml) and stirred for 12h at 25±5C to give a white to cream color suspension. Obtained solid was filtered under reduced pressure and dried at 85C and gave product APM Form N (as confirmed by XRPD, DSC and TGA) with purity above 99.90% (80-90% yield). (0523) Crystallization - Option II (0524) Reference is made to Figure 2. 10g of Apremilast were dissolved in dichloromethane (30ml) and stirred for 30 min at 25±5C until a clear solution was obtained. Then, methyl tert butyl ether (200m) was added under stirring and seeds of Form N were added. The mass was stirred for 12h at 25±5C to give a white to cream color suspension. Obtained solid was filtered under reduced pressure and dried at 85C gave product APM Form N (as confirmed by XRPD, DSC and TGA) with purity above 99.90% (90-95% yield). (0525) Crystallization - Option III (0526) Reference is made to Figure 2. The product 10g (APM as an oil residue left after ethyl acetate distillation) was suspended in methyl tert-butyl ether (MTBE) (1000ml) at 20±5C and 0.5g of Apremilast N seeds was charged. Crystallization mixture was vigorously stirred for 16h at 20±5C to give a white to cream color suspension. Obtained solid was filtered under reduced pressure and dried at 85C gave product APM form N (as confirmed by XRPD, DSC and TGA) with purity above 99.90% (80-90% yield)
40 g	With acetic acid; at 110 - 115℃; for 1h;	To a 500 mL RBF the product of example 5 (70 g; 0.1280 moles), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (27.6 g; 0.1345 moles) and acetic acid (350 mL) were charged and stirred at 110 C to 115 C for 1 hour and the solution was cooled to 60-65 C. Acetic acid was distilled off completely and the residue was dissolved in dichloromethane. The dichloromethane layer was washed with DM water followed by sodium bicarbonate solution and distilled off completely and the product isolated by recrystallization in acetone :ethanol mixture to give 40 g of apremilast as a light yellow solid with chiral purity of 99.9 % and HPLC purity of 99.8 %.
		(S)- N-Acetyl Leucine salt of 2- (3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine (529g, 1.183 moles) , 3- acetamidopthalic anhydride(256 g, 1.246 moles) and toluene (9051g) were refluxed under N2 atmosphere in a 20 L 4-necked RBF fitted with a Dean stark apparatus , condenser for 8 hours until HPLC shows absence of starting material. The reaction mixture was cooled to room temperature, and filtered. The wet cake was washed with sodium bicarbonate solution, water and filtered to afford 470 gm of crude APR-3 -Toluene solvate of (S) (+) Apremilast. The crude solid was dissolved in 16920 ml acetonitrile(36 volume wrt crude wt of Apremilast) at RT, treated with 25 gm Activated Carbon, and filtered through Hyflo, washed with 1880 ml acetonitrile(4 volume wrt crude wt of Apremilast) , followed by atmospheric distillation to about 4 volume. The in process residual toluene content was checked for each stripping by atmospheric distillation .When the in process residual toluene content had reached to around 100 ppm, the stripping was stopped. The reaction mass was fine filtered through Whatman filter paper , cooled to around 50 C and then poured into 37600 ml water(20 volume wrt 1880 ml ACN) , the precipitated solid was filtered, washed with water and then dried under vacuum-NLT 730 mm Hg to afford S(+) Apremilast as an amorphous solid.

Reference： [1]Patent: CN106187857,2016,A .Location in patent: Paragraph 0014; 0026; 0027; 0028; 0029; 0030-0033
[2]Patent: CN107188842,2017,A .Location in patent: Paragraph 0037-0044
[3]Patent: CN105348172,2016,A .Location in patent: Paragraph 0070; 0071; 0072
[4]Patent: CN106146384,2016,A .Location in patent: Paragraph 0039; 0040; 0041
[5]Patent: US2007/155791,2007,A1 .Location in patent: Page/Page column 14
[6]Patent: WO2014/74846,2014,A1 .Location in patent: Page/Page column 21
[7]Patent: WO2014/151180,2014,A1 .Location in patent: Paragraph 0075
[8]Patent: US9272035,2016,B2 .Location in patent: Page/Page column 23-24
[9]Patent: WO2015/175956,2015,A1 .Location in patent: Paragraph 0189
[10]Patent: US2016/128981,2016,A1 .Location in patent: Paragraph 0217
[11]Patent: US9387195,2016,B2 .Location in patent: Paragraph 27; 28
[12]Patent: WO2018/61034,2018,A1 .Location in patent: Page/Page column 12
[13]Patent: EP3096749,2019,B1 .Location in patent: Paragraph 0082
[14]Patent: EP3157520,2019,B1 .Location in patent: Paragraph 0101
[15]Patent: WO2016/169533,2016,A1 .Location in patent: Page/Page column 11; 12
[16]Patent: WO2016/189486,2016,A1 .Location in patent: Page/Page column 14; 15; 16
[17]Patent: WO2019/73431,2019,A1 .Location in patent: Page/Page column 14; 20
[18]Patent: CN105622380,2016,A .Location in patent: Paragraph 0076; 0077; 0078; 0079; 0080
[19]Patent: CN105218428,2016,A .Location in patent: Paragraph 0012; 0021; 0222
[20]Patent: WO2017/33116,2017,A1 .Location in patent: Paragraph 00116; 00118-00127
[21]Patent: WO2017/85568,2017,A1 .Location in patent: Page/Page column 21-22
[22]Patent: WO2017/196192,2017,A1 .Location in patent: Page/Page column 31-32
[23]Patent: WO2017/94031,2017,A2 .Location in patent: Page/Page column 15
[24]Patent: WO2019/21303,2019,A1 .Location in patent: Page/Page column 26; 28-34
[25]Patent: CN110467557,2019,A .Location in patent: Paragraph 0031-0039; 0044

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[ 608141-44-2 ]

Reference： [1]ChemCatChem,2019,vol. 11,p. 5808 - 5813
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 1522 - 1524

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[ 1258597-97-5 ]
[ 1258597-44-2 ]

Yield	Reaction Conditions	Operation in experiment
87%		Step 7. (S)-N-(2-(1-d-1-(3-(Ethoxy-d5)-4-(methoxy-d3)-phenyl)-2-methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (Compound 113a). (S)-11a (380 mg, 0.88 mmol) was mixed with known 12a (200 mg, 1 mmol; see US 20080234359) in acetic acid (6 mL) and heated at reflux for 24 hr to drive the reaction to completion. The mixture was concentrated and the colorless oil was re-dissolved in EtOAc (100 mL). The solution was washed with saturated aqueous NaHCO3 (20 mL), dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on an Analogix system eluding with 0-3percent MeOH/CH2Cl2 to provide 360 mg (87percent) of 113a. 1H-NMR (300 MHz, CDCl3): delta 1.58 (s, 1H), 2.27 (s, 3H), 2.87 (s, 3H). 3.72 (d, J=14.3 1H), 4.55 (d, J=14.5, 1H), 6.84 (d, J=9.8, 1H), 7.11 (d, J=9.2, 2H), 7.49 (d, J=6.5, 1H), 7.66 (s, J=7.7, 1H), 8.77 (d, J=7.7, 1H), 9.46 (s, 1H). 13C-NMR (75 MHz, CDCl3): delta 24.97, 41.67, 54.47, 111.45, 112.38, 115.14, 118.25, 120.28, 124.99, 129.18, 131.07, 136.14, 137.66, 148.70, 167.51, 169.16. HPLC (method: 50 mm 3 mum Waters Atlantis T3 2.1 column-gradient method 5-95percent ACN+0.1percent formic acid in 14 min with 4 min hold at 95percent ACN+0.1percent formic acid; wavelength: 305 nm): retention time: 5.96 min; 99.5percent purity. MS (M+H): 470.3. Elemental Analysis (C22H15D9N2O7S.H20): Calculated: C=54.20, H=5.38, N=5.75. Found: C=54.15, H=4.98, N=5.60.
87%	With acetic acid; for 24h;Reflux;	Compound (S) -11a (380 mg, 0.88 mmol) was mixed with known compound 12a (200 mg, 1 mmol; see US 20080234359) in acetic acid (6 mL) and heated at reflux for 24 hours to facilitate completion of the reaction.The mixture was concentrated and the colorless oil redissolved in EtOAc (100 mL).The solution was washed with saturated aqueous NaHCO3 (20 mL), dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on an Analogix system, eluting with 0-3percent MeOH / CH2Cl2, to yield 360 mg (87percent) of compound 113a
87%	With acetic acid; for 24h;Reflux;	(S)-11a (380 mg, 0.88 mmol) was mixed with known 12a(200 mg, 1 mmol; see US 20080234359) in acetic acid (6 mL) and heated to reflux for 24 hours to complete the reaction.The mixture was concentrated and the colorless oil was redissolved in EtOAc (100 mL). The solution was washed with saturated aqueous NaHCO3 (20 mL), dried over Na2SO4 and concentrated.The crude product was purified by column chromatography on an Analogix system eluting with 0-3percent MeOH / CH2Cl2 to give 360 mg (87percent) of 113a.

Reference： [1]Patent: US2010/324108,2010,A1 .Location in patent: Page/Page column 12-14
[2]Patent: CN102558022,2016,B .Location in patent: Paragraph 0158; 0159; 0160; 0173; 0174
[3]Patent: KR101900498,2018,B1 .Location in patent: Paragraph 0157; 0159; 0170

51
[ 6296-53-3 ]
[ 1258598-01-4 ]
[ 1258597-45-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	With acetic acid; for 24h;Reflux;	Step 5. (S)-N-(2-(1-(3-(Ethoxy-d5)-4-(methoxy-d3)-phenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (Compound 107a): (S)-11b N-acetyl-L-leucine salt (220 mg, 0.5 mmol) was mixed with known 12a (12.3 mg, 0.6 mmol) in acetic acid (5 mL) and heated at reflux for 24 hr to drive the reaction to near completion. The mixture was concentrated, the colorless oil was dissolved in EtOAc (100 mL) and the solution was washed with saturated aqueous NaHCO3 (20 mL). The organic phase was dried (Na2SO4) and concentrated. The crude product purified by column chromatography on an Analogix system eluding with 0-70percent EtOAc/heptane to afford 210 mg (89percent) of 107a. 1H-NMR (300 MHz, CDCl3): delta 1.59 (s, 1H), 2.27 (s, 3H), 2.87 (s, 3H), 3.72 (dd, J=4.6, 14.4, 1H), 3.85 (s, 3H), 4.56 (dd, J=10.8, 14.4, 1H), 5.87 (dd, J=4.4, 10.6), 6.84 (d, J=8.8, 1H), 7.10 (d, J=7.0, 2H), 7.49 (d, J=6.6, 1H), 7.65 (t, J=7.3, 1H), 8.76 (d, J=8.0, 1H), 9.46 (s, 1H). 13C-NMR (75 MHz, CDCl3): delta 24.97, 41.66, 48.60, 54.55, 55.96, 76.58, 77.01, 77.43, 111.48, 112.40, 115.14, 118.25, 120.29, 125.00, 129.26, 131.07, 136.14, 137.66, 148.70, 149.79, 167.51, 169.17, 169.53. HPLC (method: 50 mm 3 mum Waters Atlantis T3 2.1 column-gradient method 5-95percent ACN+0.1percent formic acid in 14 min with 4 min hold at 95percent ACN+0.1percent formic acid; wavelength: 305 nm): retention time: 6.02 min; >98.0percent purity. Chiral HPLC (method: Chiralpak AD 25 cm column-isocratic method 78percent hexane/22percent isopropanol/0.01percent diethylamine for 40 minutes at 1.00 mL/min; wavelength: 254 nm): retention time: 12.73 min (major enantiomer); >99percent ee purity. MS (M+Na): 488.1. Elemental Analysis (C22H21D3N2O7S): Calculated: C=56.76, H=5.20, N=6.02, S=6.89. Found: C=56.74, H=5.43, N=5.70, S=6.51.
89%	With acetic acid; for 24h;Reflux;	(S)-11b N-Acetyl-L-leucine salt (220 mg, 0.5 mmol) was mixed with known 12a (123 mg, 0.6 mmol) in acetic acid(5mL) The reaction was completed by heating at reflux for 24 hours. The mixture was concentrated and the colorless oil was dissolved in EtOAc (100 mL) and the solution was washed with saturated aqueous NaHCO3 (20 mL). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on an Analytical system eluting with 0-70percent EtOAc / heptane to give 210 mg (89percent) of 107a.

Reference： [1]Patent: US2010/324108,2010,A1 .Location in patent: Page/Page column 14-15
[2]Patent: KR101900498,2018,B1 .Location in patent: Paragraph 0171; 0174; 0180

52
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[ 1258598-05-8 ]
[ 1258597-46-4 ]

Yield	Reaction Conditions	Operation in experiment
68%	With acetic acid; for 24h;Reflux;	Step 4. (S)-N-(2-(1-(3-Ethoxy-4-(methoxy-d3)-phenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (114a). (S)-11c (0.97 g, 2.2 mmol) was mixed with known 12a (470 mg, 2.5 mmol) in acetic acid (20 mL) and heated at reflux for 24 hr to drive the reaction to near completion. The mixture was concentrated, the colorless oil was dissolved in EtOAc (200 mL) and the solution was washed with saturated NaHCO3 (40 mL). The organic phase was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on an Analogix system eluding with 0-70percent EtOAc/heptane to afford 0.7 g (68percent) of 114a. 1H-NMR (300 MHz, CDCl3): delta 1.47 (t, J=7.0, 3H), 1.61 (s, 1H), 2.26 (s, 3H), 2.87 (s, 3H), 3.72 (dd, J=4.6, 14.4, 1H), 4.11 (q, J=6.9, 14.0, 2H), 4.55 (dd, J=10.5, 1.4.4, 1H), 5.87 (dd, J=4.4, 10.6, 1H), 6.84 (d, J=8.7, 1H), 7.10 (d, J=6.5, 2H), 7.49 (d, J=7.3, 1H), 7.65 (t, J=7.7, 1H), 8.76 (d, J=8.5, 1H), 9.46 (s, 1H). 13C-NMR (75 MHz, CDCl3): delta 14:70, 24.96, 41.65, 48.59, 54.54, 64.55, 111.46, 112.44, 115.14, 118.25, 120.32, 125.00, 129.24, 131.07, 136.14, 137.66, 148.67, 149.79, 167.51, 169.17, 169.53. HPLC (method: 50 mm 3 mum Waters Atlantis T3 2.1 column-gradient method 5-95percent ACN+0.1percent formic acid in 14 min with 4 min hold at 95percent ACN+0.1percent formic acid; wavelength: 305 nm): retention time: 6.03 min; 97.4percent purity. Chiral HPLC (method: Chiralpak AD 25 cm column-isocratic method 78percent hexane/22percent isopropanol/0.01percent diethylamine for 40 minutes at 1.00 mL/min; wavelength: 254 nm): retention time: 12.69 min (major enantiomer); 39.03 min (minor enantiomer); >99percent ee purity. MS (M+Na): 486.0. Elemental Analysis (C22H21D3N2O7S): Calculated: C=57.01, H=5.22, N=6.04, S=6.92. Found: C=57.68, H=5.63, N=5.52, S=6.33.
68%	With acetic acid; for 24h;Reflux;	(S)-11c (0.97 g, 2.2 mmol) was mixed with known 12a (470 mg, 2.5 mmol) in acetic acid (20 mL) and the reaction was completed by heating at reflux for 24 hours. The mixture was concentrated and the colorless oil was dissolved in EtOAc (200 mL) and the solution was washed with saturated NaHCO3 (40 mL). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on an Analogiques system eluting with 0-70percent EtOAc / heptane to give 0.7 g (68percent) of 114a.

Reference： [1]Patent: US2010/324108,2010,A1 .Location in patent: Page/Page column 15-17
[2]Patent: KR101900498,2018,B1 .Location in patent: Paragraph 0181; 0183; 0187

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[ 1258597-47-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With acetic acid; for 24h;Reflux;	Step 4. (S)-N-(2-(1-(3-(Ethoxy-d5)-4-methoxy-phenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (110a). (S)-11d (1.4 g, 3.2 mmol) was mixed with known 12a (0.77 g, 3.84 mmol) in acetic acid (20 mL) and heated at reflux for 24 hr to drive the reaction to near completion. The mixture was concentrated, the colorless oil was dissolved in EtOAc (200 mL) and the solution was washed with saturated NaHCO3 (40 mL). The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on an Analogix system eluding with 0-70percent EtOAc/heptane (in 1 hr) to afford 1.2 g (80percent) of 110a. 1H-NMR (300 MHz, CDCl3): delta 1.59 (s, 1H), 2.27 (s, 3H), 2.87 (s, 3H), 3.72 (dd, J=4.6, 14.4, 1H), 3.85 (s, 3H), 4.56 (dd, J=10.8, 14.4, 1H), 5.87 (dd, J=4.4, 10.6), 6.84 (d, J=8.8, 1H), 7.10 (d, J=7.0, 2H), 7.49 (d, J=6.6, 1H), 7.65 (t, J=7.3, 1H), 8.76 (d, J=8.0, 1H), 9.46 (s, 1H). 13C-NMR (75 MHz, CDCl3): delta 24.97, 41.66, 48.60, 54.55, 55.96, 76.58, 77.01, 77.43, 111.48, 112.40, 115.14, 118.25, 120.29, 125.00, 129.26, 131.07, 136.14, 137.66, 148.70, 149.79, 167.51, 169.17, 169.53. HPLC (method: 50 mm 3 mum Waters Atlantis T3 2.1 column-gradient method 5-95percent ACN+0.1percent formic acid in 14 min with 4 min hold at 95percent ACN+0.1percent formic acid; wavelength: 305 nm): retention time: 6.02 min; >98.0percent purity. Chiral HPLC (method: Chiralpak AD 25 cm column-isocratic method 78percent hexane/22percent isopropanol/0.01percent diethylamine for 40 minutes at 1.00 mL/min; wavelength: 254 nm): retention time: 12.73 min (major enantiomer); >99percent ee purity. MS (M+Na): 488.1. Elemental Analysis (C22H21D3N2O7S): Calculated: C=56.76, H=5.20, N=6.02, S=6.89. Found: C=56.74, H=5.43, N=5.70, S=6.51.
80%	With acetic acid; for 24h;Reflux;	The compound (S) -11d (1.4 g, 3.2 mmol) was reacted with the known compound 12a (0.778, 3.2 mmol) in acetic acid (20 mL)3.84 mmol) and heated at reflux for 24 hours to promote the reaction to near completion. The mixture was concentrated and the colorless oil was dissolved in EtOAc (200 mL) and the solution was washed with saturated NaHCO3 (40 mL). The organic layer was dried (Na2S04) and concentrated. The crude product was purified by column chromatography on an Analogix system and eluted with 0- 70percent EtOAC / heptane (1 hour) to yield 1.2 g (80percent) of compound 110a.
80%	With acetic acid; for 24h;Reflux;	(S)-11d (1.4 g, 3.2 mmol) was mixed with known 12a (0.77 g, 3.84 mmol) in acetic acid (20 mL) and heated to reflux for 24 hours to complete the reaction. The mixture was concentrated and the colorless oil was dissolved in EtOAc (200 mL) and the solution was washed with saturated NaHCO3 (40 mL). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on an Analogix system eluting with 0-70percent EtOAc / heptane (in 1h) to give 1.2 g (80percent) of 110a.

Reference： [1]Patent: US2010/324108,2010,A1 .Location in patent: Page/Page column 17-18
[2]Patent: CN102558022,2016,B .Location in patent: Paragraph 0203; 0204; 0205; 0212; 0213
[3]Patent: KR101900498,2018,B1 .Location in patent: Paragraph 0188; 0191; 0195

54
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[ 1258598-13-8 ]
[ 1258597-49-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With deuteroacetic acid; for 24h;Reflux;	Step 2. (S)-1-(3-(Ethoxy-d5)-4-(methoxy-d3)-phenyl)-2-((methyl-d3)-sulfonyl)-2,2-d2-ethanamine N-acetyl-L-leucine salt ((S)-11e): 11e (630 mg, 2.2 mmol) was mixed with N-acetyl-L-leucine (0.23 g, 1.32 mmol) in MeOD (99 atom percent D, Cambridge Isotopes; 6 mL). This mixture was heated at 70° C. for 3 hr then stirred at room temperature overnight. The solid was collected by vacuum filtration and suspended in MeOH (6 mL). The mixture was stirred at 70° C. for 2 hr then at room temperature overnight. The solid was collected and the MeOH trituration was repeated. A 300-mg portion (29percent) of (S)-11e N-acetyl-L-leucine salt was obtained with >99percent ee.
84%	With acetic acid; for 24h;Reflux;	The compound (S) -11e N-acetyl-L-leucine salt (280 mg, 0.62 mmol) was mixed with acetic acid-d (99atpercentAldrich; 5 mL) was mixed and heated at reflux for 24 hours to promote the reaction to near completion. The mixture was concentrated and the colorless oil was dissolved in EtOAc (100 mL). The solution was washed with NaHCO3 (20 mL), dried (Na2S04) and concentrated. The crude product was purified by column chromatography on an Analogix system, eluting with 0-3percent MeOH / CH2Cl2, to yield 245 mg (84percent) of compound 116a.
84%	With acetic acid; for 24h;Reflux;	(S)-11e N-acetyl-L-leucine salt (280 mg, 0.62 mmol) was mixed with known 12a in acetic acid-d (99 atom percent D, Aldrich; 5 mL) and the reaction was refluxed for 24 hours and heated to near completion. The mixture was concentrated and the colorless oil was dissolved in EtOAc (100 mL). The solution was washed with NaHCO3 (20 mL), dried over Na2SO4 and concentrated.The crude product was purified by column chromatography on an Analogy system eluting with 0-3percent MeOH / CH2Cl2 to give 245 mg (84percent) of 116a.

Reference： [1]Patent: US2010/324108,2010,A1 .Location in patent: Page/Page column 19-20
[2]Patent: CN102558022,2016,B .Location in patent: Paragraph 0224; 0225; 0226; 0233; 0234
[3]Patent: KR101900498,2018,B1 .Location in patent: Paragraph 0204; 0206; 0211

55
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[ 608141-43-1 ]
[ 253168-86-4 ]
(S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In ethanol; acetic acid; ethyl acetate; acetone;	6.2.4.Preparation of (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dioneA 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser.The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98percent ee), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g 58.8 mmol), and glacial acetic acid (250 mL).The mixture was refluxed over night and then cooled to <50° C.The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate.The resulting solution was washed with water (250 mL2), saturated aqueous NaHCO3 (250 mL2), brine (250 mL2), and dried over sodium sulphate.The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL).The solid was isolated by vacuum filtration and washed with ethanol (100 mL2).The product was dried in vacuo at 60° C. to a constant weight, affording 19.4 g (75percent yield) of (S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione with 98percent ee.

Reference： [1]Patent: US2012/276087,2012,A1

56
[ 6296-53-3 ]
1-(3-ethoxy-4-methoxyphenyl)-methylsulfonylethylamine [ No CAS ]
[ 253168-86-4 ]

Yield	Reaction Conditions	Operation in experiment
59%	In acetic acid;	Example 1Synthesis of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dioneA stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-methylsulfonylethylamine (1.0 g, 3.7 mmol) and <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (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, 59percent 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.

Reference： [1]Patent: US2012/276087,2012,A1

57
[ 6296-53-3 ]
(S)-1-(3-(ethoxy)-4-(methoxy-d3)phenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine [ No CAS ]
C₂₂H₂₁⁽²⁾H₃N₂O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		To a slurry of d3-aminosulfone leucine salt (2.2 g, 4.89 mmol) in dichloromethane (20 mL) was charged 17percent aqueous NaOH (2.2 mL). The mixture was stirred for 5 minutes at room temperature, and then the organic layer was dried (MgSO4) and evaporated. To the residue was added THF (13.2 mL), acetic acid (3.27 g, 57.3 mmol) and <strong>[6296-53-3]N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide</strong> (1.00 g, 4.89 mmol). The resulting mixture was heated at 70° C. for 24 hours. The batch was cooled to 35° C., THF (12 mL) and iPrOAc (24 mL) were added, the reaction mixture was washed with 10percent NaH2PO4 solution (3×7 mL), and water (3×7 mL), and was evaporated to dryness. To the residue was added iPrOAc (3×20 mL), and the mixture was evaporated to dryness. The residue was dissolved in iPrOAc (9 mL) and the product was precipitated by adding MTBE (13 mL) slowly. The precipitate was filtered, washed with MTBE (4.4 mL) and dried under vacuum. The crude product was recrystallized in acetone-EtOH (7 mL:22 mL), providing 1.7 g of the product, in 79percent yield; UPLC (BEH C18, 1.7 mum, 2.1×50 mm, 0.6 mL/min, 230 nm, 95/5 gradient to 15/85 0.06percent aqueous TFA/Acetonitrile (0.06percent TFA) over 5 min): 2.60 (99.9percent); chiral HPLC (Chiralpak AD-H 5.0 mum Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30 heptane-EtOH): 13.32 (0.51percent), 15.30 (99.49percent); 1H NMR (d6-DMSO) delta 1.32 (t, J=6.9 Hz, 3H), 2.19 (s, 3H), 3.02 (s, 3H), 4.02 (q, J=7.0 Hz, 2H), 4.09-4.23 (m, 1H), 4.35 (dd, J=10.7, 14.3 Hz, 1H), 5.78 (dd, J=4.2, 10.4 Hz, 1H), 6.88-7.03 (m, 2H), 7.07 (d, J=1.7 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 8.44 (d, J=8.3 Hz, 1H), 9.72 (s, 1H); 13C NMR (d6-DMSO) delta 14.63, 24.15, 41.03, 47.16, 52.87, 63.87, 111.79, 112.42, 116.66, 118.18, 119.71, 126.10, 129.42, 131.33, 135.89, 136.48, 147.86, 148.91, 166.89, 167.80, 169.21; Anal. (C22H21D3N2O7S) C, H, N. Calcd C, 57.00; H, 5.22; N, 6.04. Found C, 57.15; H, 5.51; N, 6.04.

Reference： [1]Patent: US2014/81032,2014,A1 .Location in patent: Paragraph 0399; 0400

58
[ 6296-53-3 ]
C₁₂H₁₁⁽²⁾H₈NO₄S*C₈H₁₅NO₃ [ No CAS ]
C₂₂H₁₅⁽²⁾H₉N₂O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		To a slurry of aminosulfone leucine salt (2.5 g, 5.44 mmol) in dichloromethane (25 mL) was added 17percent aqueous NaOH (2.5 mL). The mixture was stirred for 5 minutes and the organic layer was dried (MgSO4) and evaporated under vacuum. To the residue was added THF (15 mL), d6-acetic acid (4.1 g, 63.6 mmol) and <strong>[6296-53-3]N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide</strong> (1.12 g, 5.44 mmol). The resulting mixture was heated at 70° C. for 24 hours, and then the mixture was cooled to 35° C. THF (15 mL) and iPrOAc (30 mL) were added, and the mixture was washed with 10percent NaH2PO4 solution (3×7.5 mL), and water (3×7.5 mL), and the organic phase was evaporated to dryness. To the residue was added i-PrOAc (3×20 mL), and the mixture was evaporated to dryness. The residue was dissolved in i-PrOAc (10 mL) and the product was precipitated by adding MTBE (15 mL) slowly. The precipitate was filtered, washed with MTBE (5 mL) and dried under vacuum. The crude product was recrystallized in acetone-EtOH (7.6 mL:24 mL), providing 1.85 g of the product, in 76percent yield; UPLC (BEH C18, 1.7 mum, 2.1×50 mm, 0.6 mL/min, 230 nm, 95/5 gradient to 15/85 0.06percent aqueous TFA/Acetonitrile (0.06percent TFA) over 5 min): 2.55 (99.7percent); chiral HPLC (Chiralpak AD-H 5.0 mum Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30 heptane-EtOH): 13.04 (0.43percent), 14.90 (99.57percent); 1H NMR (d6-DMSO) delta 1.32 (t, J=6.9 Hz, 3H), 2.19 (s, 3H), 4.02 (q, J=6.9 Hz, 2H), 6.86-7.03 (m, 2H), 7.03-7.19 (m, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 8.44 (d, J=8.3 Hz, 1H), 9.71 (s, 1H); 13C NMR (d6-DMSO) delta 14.63, 24.15, 63.87, 111.69, 111.79, 112.43, 116.66, 118.16, 119.72, 126.08, 129.26, 129.35, 131.33, 135.88, 136.49, 147.86, 148.93, 166.89, 167.80, 169.20; Anal. (C22H15D9N2O7S) C, H, N. Calcd C, 56.27; H, 5.15; N, 5.97. Found C, 56.58; H, 5.12; N, 5.95.

Reference： [1]Patent: US2014/81032,2014,A1 .Location in patent: Paragraph 0405; 0406

59
[ 6296-53-3 ]
[ 608141-43-1 ]
(R)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With acetic acid;Reflux;	[0114j A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4- methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to < 500 C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL x 2), saturated aqeous NaHCO3 (250 mL x 2), brine (250 mL x 2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL x 2). The product was dried in vacuo at 60C to a constant weight, affording 19.4 g (75% yield) of(5)- {2- [1 -(3 -ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl] -4-inoisoindoline- 1,3 -dione with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 pH .5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm x 4.6 mm, 0.4 mL/min., 240 nm): 25.4 mm (S-isomer, 98.7%), 29.5 mm (R-isomer, 1.2%). ?H-NMR (CDC13) oe:1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.5 1-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). ?3C-NMR(DMSO-d6) oe: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74,167.46, 169.14, 169.48.

Reference： [1]Patent: WO2015/175773,2015,A1 .Location in patent: Paragraph 0114

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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

[ CAS No. 6296-53-3 ]

Quality Control of [ 6296-53-3 ]

Related Doc. of [ 6296-53-3 ]

Product Details of [ 6296-53-3 ]

Calculated chemistry of [ 6296-53-3 ]

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 1~8

[ 6296-53-3 ] Synthesis Path-Downstream 1~59

Pharmaceutical Intermediates of [ 6296-53-3 ]

Apremilast Intermediates

Related Functional Groups of [ 6296-53-3 ]

Anhydrides

Amides

Esters

Amines

Related Parent Nucleus of [ 6296-53-3 ]

Benzofurans

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Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Pharmaceutical Intermediates of
[ 6296-53-3 ]

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[ 6296-53-3 ]

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[ 6296-53-3 ]