[ CAS No. 608141-43-1 ] {[proInfo.proName]}

Name: 608141-43-1|(S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (S)-2-acetamido-4-methylpentanoate|97%
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SKU: A142160
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Quality Control of [ 608141-43-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 608141-43-1 ]

SDS Specification

Alternatived Products of [ 608141-43-1 ]

Product Details of [ 608141-43-1 ]

CAS No. :	608141-43-1	MDL No. :	MFCD28167941
Formula :	C₂₀H₃₄N₂O₇S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KJZXYHPZWRDLAR-JIJBYVMQSA-N
M.W :	446.56	Pubchem ID :	66648136
Synonyms :

Calculated chemistry of [ 608141-43-1 ]

Physicochemical Properties

Num. heavy atoms :	30
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.6
Num. rotatable bonds :	11
Num. H-bond acceptors :	8.0
Num. H-bond donors :	3.0
Molar Refractivity :	115.83
TPSA :	153.4 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-9.68 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.53
Log Po/w (XLOGP3) :	-0.92
Log Po/w (WLOGP) :	2.52
Log Po/w (MLOGP) :	0.61
Log Po/w (SILICOS-IT) :	1.28
Consensus Log Po/w :	1.4

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	2.0
Egan :	1.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.45
Solubility :	15.8 mg/ml ; 0.0354 mol/l
Class :	Very soluble
Log S (Ali) :	-1.82
Solubility :	6.79 mg/ml ; 0.0152 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.46
Solubility :	0.153 mg/ml ; 0.000344 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	3.94

Safety of [ 608141-43-1 ]

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

Application In Synthesis of [ 608141-43-1 ]

* 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 [ 608141-43-1 ]
Downstream synthetic route of [ 608141-43-1 ]

[ 608141-43-1 ] Synthesis Path-Upstream 1~15

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Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: With bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate; (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene; hydrogen In 2,2,2-trifluoroethanol at 50℃; for 18 h; Inert atmosphere Stage #2: at 55℃; for 2 h;	A solution of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (17 mg, 0.037 mmol) and (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (20 mg, 0.037 mmol) in 10 mL of 2,2,2-trifluoroethanol was prepared under nitrogen. To this solution was then charged 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol). The resulting mixture was heated to 50° C. and hydrogenated under 90 psig hydrogen pressure. After 18 h, the mixture was cooled to ambient temperature and removed from the hydrogenator. Ecosorb C-941 (200 mg) was added and the mixture was stirred at ambient temperature for 3 h. The mixture was filtered through Celite, and the filter was washed with additional trifluoroethanol (2 mL). Then, the mixture was heated to 55° C., and a solution of N-acetyl-L-leucine (1.3 g, 7.5 mmol) was added dropwise over the course of 1 h. Stirring proceeded at the same temperature for 1 h following completion of the addition, and then the mixture was cooled to 22° C. over 2 h and stirred at this temperature for 16 h. The crystalline product was filtered, rinsed with methanol (2×5 mL), and dried under vacuum at 45° C. to provide the product as a white solid (2.6 g, 80percent yield); achiral HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1percent aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1percent aqueous TFA/MeOH over the next 15 min): 8.57 (99.8percent); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-i-PrOH-diethylamine): 8.35 (99.6percent); ¹H NMR (DMSO-d₆) δ 0.84 (d, 3H), 0.89 (d, J=6.6 Hz, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.41-1.52 (m, 2H), 1.62 (dt, J=6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94 (s, 3H), 3.28 (dd, J=4.0, 14.4 Hz, 1H), 3.44 (dd, J=9.1, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J=6.9 Hz, 2H), 4.18 (q, J=7.7 Hz, 1H), 4.29 (dd, J=4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s, 1H), 8.04 (d, J=7.9 Hz, 1H); Anal. (C₂₀H₃₄N₂O₇S) C, H, N. Calcd C, 53.79; H, 7.67; N, 6.27. Found C, 53.78; H, 7.57; N, 6.18.

Reference： [1] Patent: US2013/217919, 2013, A1, . Location in patent: Paragraph 0278-0279

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Yield	Reaction Conditions	Operation in experiment
90%	at 20℃; for 8 h; Reflux; Resolution of racemate	A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3 -ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered andwashed with methanol (250 mL). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98percent yield) of the crude product (85.8percent ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried invacuo at 30°C. to a constant weight, yielding 49.6 g (90percent recovery) of(S)-2-(3-ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine-N-acety l-L-leucine salt (98.4percent ee). ChiralHPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies,150 mm4.6 mm, 0.5 mL/min., 240 nm): 18.4 mm (S-isomer, 99.2percent), 25.5 mm (R-isomer,0.8percent)
90%	Stage #1: for 1 h; Reflux Stage #2: at 20℃; for 4 h; Reflux	General procedure: [0188] A 3 L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-l - (methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98percent yield) of the crude product (85.8percent ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 °C to a constant weight, yielding 49.6 g
90%	at 20℃; for 4 h; Reflux	A mixture of 2-(3-ethoxy-4-meth- oxyphenyl)-i -(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), andmethanol (1.0 L) was charged into a 3-L 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser. Afier the reaction mixture was refluxed for 1 hour, the mixture was allowed to cool to ambient temperature and then stirred for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuum at ambient temperature to a constant weight, giving 109.5 g (98percent yield) of the crude product (85.8percent cc). The crude solid (55.0 g) and methanol (440 mE) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mE). The solid was air-dried and then dried in vacuum at 30° C. to a constant weight, yielding 49.6 g (90percent recovery) of (S)-2-(3-ethoxy- 4-methoxyphenyl)-i -(methylsulphonyl)-eth-2-ylamine-N- acetyl-L-leucine salt (98.4percent cc). Chiral HPLC (1/99 EtOH/ 20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mmx4.6 mm, 0.5 mE/mm., 240 nm): 18.4 mm (S-isomer, 99.2percent), 25.5 mm (R-isomer, 0.8percent).

73.5%	at 60 - 70℃; for 2 h;	In a 500 ml round bottom flask, 200 ml of methanol was added followed by 20 gms of 2-(3-ethoxy-4-methoxyphenyl)-l-(methanesulfonyl)-eth-2-ylamine. The reaction mass was stirred and 76 gms of N-Acetyl-L-Leucine added and reaction mass was stirred. The reaction mass was heated for 2 hours at 60 to 65°C, After heating, the reaction masswas cooled at room temperature and it was stirred at room temperature for 3 to 4 hours. The slurry was filtered. Washed with 30 ml methanol, material was unloaded and dried under vacuum for 2 hours at 45°C. Yield: 14.36 gm. Further, this material is purified with methanol.
41%	for 2 h; Reflux	A mixture of 27.3 g (100 mmol) of 1- (3-ethoxy-4-methoxy) phenyl-2-methanesulfonyl ethylamine (4), 10.4 g(60 mmol) of N-acetyl-L-leucine was dissolved in 200 mL of methanol, heated under reflux for 2 h, and then cooled to room temperature to a large amountThe slurry was precipitated, filtered and washed with methanol to give the crude product. The crude product was again dissolved in 80 mL of methanol, heated to reflux for 2 h, and cooled againTo a large amount of slurry to the slurry, filter, and wash the filter cake with methanol. The solid was dried in vacuo to give 9.1 g (41percent recovery)(S) -1- (3-ethoxy-4-methoxy) phenyl-2-methanesulfonylethylamine N-acetyl-L-leucine salt (97.9percent ee).
35%	for 1 h; Inert atmosphere; Reflux	Example 5: Preparation of (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV) A dry 1,000mL glass flask equipped with a mechanical stirrer, a thermometer, and a condenser was added 500g of methanol, 136 g (0.5mol) (R,S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (E.g. racemate III prepared in Example 1), and 86.5 g (0.5mol) N-acetyl-L-leucine under nitrogen protection. The solution was heated to reflux for 1 hour. The solution was then cooled to 10°C and filtered. The resultant filtrate will be used as mother liquor in Example 6. The resulting filter cake was washed with 55g of cold methanol 10°C and dried under vacuum to give 78.1 g of white solid (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV). Yield 35.0percent, optical purity 99.8percent.
98.4 % ee	at 20℃; for 8 h; Heating / reflux	A mixture of 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L) was charged into a 3-L 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser. After the reaction mixture was refluxed for 1 hour, the mixture was allowed to cool to ambient temperature and then stirred for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuum at ambient temperature to a constant weight, giving 109.5 g (98percent yield) of the crude product (85.8percent ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuum at 30° C. to a constant weight, yielding 49.6 g (90percent recovery) of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine-N-acetyl-L-leucine salt (98.4percent ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 (at)pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm.x.4.6 mm, 0.5 mL/min., (at)240 nm): 18.4 min (S-isomer, 99.2percent), 25.5 min (R-isomer, 0.8percent).
49.6 g	for 1 h; Reflux	6.2.3. Resolution of 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98percent yield) of the crude product (85.8percent ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30° C. to a constant weight, yielding 49.6 g (90percent recovery) of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine-N-acetyl-L-leucine salt (98.4percent ee).
18 g	at 25℃; for 4 h; Reflux	The compound of formula V 0. 1mol 200mL of methanol was added and the reaction flask was refluxed clear solution was added portionwise N- acetyl-L- leucine (0.06mol ), a large number of the resulting solid was refluxed 1h, cooled to 25 ° C, stirred 1h, filtered and the filter cake was dried in vacuo at 40 ° C 5h, to give a white solid 22. 6g; The solid was added to the reaction flask and 180mL of methanol, refluxed for 1h, cooled to 25 ° C, stirred for 1h, filtered and the filter cake in and dried in vacuo 40 ° C 5h, to give a white solid 18g, 40 ° C and dried in vacuo 5h, ee: 98 · 6percent
68 g	at 25℃; for 2 h; Reflux	To a reaction mixture of 700 ml methanol and 100 grams (gm) (0.366 moles) of 1-(3-ethoxy-4- methoxy phenyl)-2-(methylsulfonyl) ethanamine, 38gm (0.2196 moles) of N-acetyl-L-leucine was charged. The reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to 25°C to 30°C and stirred for 1 hour. The product was filtered and washed with 100 ml methanol.The obtained solid material was dried under vacuum at 30°C to obtain (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine N-acetyl-L-leucine salt.(Yield = 68.Ogms)R-isomer: 0.5percent
35 g	at 60 - 65℃; for 1 h;	To 1 liter RBF the product of example 3 or 4 (75 g; 0.2743 moles), N- acetyl-L-leucine (47.5 g ; 0.2743) and methanol (545 mL) were charged and the suspension was stirred at 60 °C to 65 °C for 1 hour, the suspension was cooled to room temperature and stirred for another 3 hours. The solid was filtered and dried under reduced pressure to obtain 60 g of title compound with chiral purity of 85percent desired isomer. It was further purified by methanol to give 35 g of pure title compound having chiral purity 99.5percent.

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

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Yield	Reaction Conditions	Operation in experiment
41%	Stage #1: With ammonium acetate; ammonia In 2,2,2-trifluoroethanol for 24.75 h; Reflux Stage #2: With bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate; (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene; hydrogen In 2,2,2-trifluoroethanol at 50℃; for 18 h; Stage #3: at 55℃; for 2 h;	A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2 g, 7.34 mmol) and ammonium acetate (0.90 g, 11.7 mmol) in TFE (75 mL) was heated to reflux, and anhydrous ammonia was bubbled through the solution for 45 min while distilling off solvent until the total volume was reduced to 20 mL. Then, the distillation was discontinued and the batch was held at reflux for 24 h. The batch was cooled and evaporated to dryness. Methanol (10 mL) was then added to the residue and the resultant slurry was stirred for 30 min. Then, the solids were filtered, washed with MeOH (5 mL), and dried under vacuum. The solids were then transferred to a hydrogenation reaction vessel. To this vessel was also charged a solution of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (12.6 mg, 0.027 mmol), (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (14.4 mg, 0.027 mmol), and TFE (7.2 mL). The mixture was warmed to 50° C. and hydrogenated under 90 psig hydrogen gas for 18 h. Then Ecosorb C-941 (150 mg) was added and the mixture was stirred at 20° C. for 4 h. The mixture was filtered through Celite and the filtrate was transferred into a clean vessel. The mixture was warmed to 55° C. with stirring, and a solution of N-acetyl-L-leucine (0.79 g, 3.7 mmol) in methanol (7.25 mL) was added over 1 h, resulting in precipitation of the product as the N-acetyl-L-leucine salt. The mixture was stirred at 55° C. for 1 h and then a mixture 1:1 TFE-MeOH (5 mL) was added. The mixture was cooled to 25° C. over 2 h, and stirring proceeded at this temperature for 16 h. The mixture was filtered and washed 1:1 TFE-MeOH (10 mL) and with MeOH (10 mL), and was dried under vacuum. The product was obtained as a white solid (1.35 g, 41percent yield); achiral HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1percent aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1percent aqueous TFA/MeOH over the next 15 min): 8.89 (98.8percent); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-i-PrOH-diethylamine): 6.94 (0.81percent), 8.21 (99.34percent); ¹H NMR (DMSO-d₆) δ 0.84 (d, 3H), 0.89 (d, J=6.6 Hz, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.41-1.52 (m, 2H), 1.62 (dt, J=6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94 (s, 3H), 3.28 (dd, J=4.0, 14.4 Hz, 1H), 3.44 (dd, J=9.1, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J=6.9 Hz, 2H), 4.18 (q, J=7.7 Hz, 1H), 4.29 (dd, J=4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s, 1H), 8.04 (d, J=7.9 Hz, 1H); Anal. (C₂₀H₃₄N₂O₇S)C, H, N. Calcd C, 53.79; H, 7.67; N, 6.27. Found C, 53.86; H, 7.97; N, 6.36.

Reference： [1] Patent: US2013/217919, 2013, A1, . Location in patent: Paragraph 0292-0293

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Yield	Reaction Conditions	Operation in experiment
44%	Stage #1: With palladium 10% on activated carbon; hydrogen In 2,2,2-trifluoroethanol at 20℃; for 9 h; Stage #2: at 55℃; for 3 h;	The product from Step 1 (0.5 g, 1.670 mmol) was dissolved in TFE, and then 10percent Pd—C (0.05 g) was added. The resulting mixture was hydrogenated at ambient temp under 40 psig hydrogen for 9 h, and then the mixture was filtered through Celite. The filtrate was warmed to 55° C. with stirring, and a solution of N-Acetyl-L-Leu (0.29 g, 1.67 mmol) in MeOH (10 mL) was added to the mixture in dropwise fashion over 1 h. The mixture was stirred at the same temperature for 2 h and was then cooled to 21° C. over 2 h and stirred at this temperature for 16 h. The mixture was filtered and rinsed with 1:1 (v/v) TFE-MeOH (10 mL), and the solids were dried under vacuum to provide (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt as a white solid (0.33 g, 44percent yield); achiral HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1percent aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1percent aqueous TFA/MeOH over the next 15 min): 7.26 (99.8percent); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-i-PrOH-diethylamine): 7.10 (2.8percent), 8.02 (97.2percent); ¹H NMR (DMSO-d₆) δ 0.84 (d, 3H), 0.89 (d, J=6.6 Hz, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.41-1.52 (m, 2H), 1.62 (dt, J=6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94 (s, 3H), 3.28 (dd, J=4.0, 14.4 Hz, 1H), 3.44 (dd, J=9.1, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J=6.9 Hz, 2H), 4.18 (q, J=7.7 Hz, 1H), 4.29 (dd, J=4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s, 1H), 8.04 (d, J=7.9 Hz, 1H).

Reference： [1] Patent: US2013/217919, 2013, A1, . Location in patent: Paragraph 0301-0302

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Yield	Reaction Conditions	Operation in experiment
98.3%	for 1 h; Reflux	Under a nitrogen atmosphere, a dry 1000 ml glass flask equipped with a mechanical stirrer, a thermometer and a condenser was added (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine (110 g), N-acetylleucine 69.3 g (0.4 mol) and 500g of methanol, Heated to reflux for 1 hour with stirring and then cooled to ambient temperature in a stirred state and stirred at room temperature for 3 hours, filtered and the filter cake was washed with methanol, then the cake was dried under vacuum to constant weight. To give 176.3 g of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-1-leucine (Optical purity 99.6percent) yield 98.3percent. Chiral HPLC (ethanol: 20 mM KH2PO4 = 1:99, pH = 7.0, Agilent's ES-OVM chiral column, 150 mm x 4.6 mm, flow rate 0.5 ml/min, detection wavelength 240 nm): 18.1 min (S-isomer, 99.6percent), 25.0 min (R-isomer, 0.4percent).
1670 g	for 1 h; Reflux	To a stirred solution l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (2500gm) in methanol (20.01it) was added N-acetyl-L-Leucine (950.0gm) slowly at 25°C and then the reaction mixture was heated to reflux temperature and maintained for 1.Ohr. The reaction mass was cooled to 25-30°C and stirred for 4.0 hr at 25-30°C. The product was filtered and washed with methanol and dried under vacuum at 60°C for 4.0 hr to obtain 2000.0gm of crude product. The crude product was subjected to methanol purification to obtain 1670gm of N-acetyl L-leucine salt of (5)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl) eth-2-ylamine. chiral purity >99.5percent.

Reference： [1] Patent: CN104447445, 2016, B, . Location in patent: Paragraph 0083; 0084
[2] Patent: CN105218428, 2016, A, . Location in patent: Paragraph 0012; 0019; 0020
[3] Patent: WO2017/33116, 2017, A1, . Location in patent: Paragraph 00115

6
[ 253168-94-4 ]
[ 1188-21-2 ]
[ 608141-43-1 ]
[ 1382429-55-1 ]

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

7
[ 1450657-28-9 ]
[ 608141-43-1 ]

Reference： [1] Patent: US2013/217919, 2013, A1,
[2] Patent: US2013/217919, 2013, A1,
[3] Patent: CN104447445, 2016, B,
[4] Patent: CN104447445, 2016, B,
[5] Patent: CN104447445, 2016, B,

8
[ 60758-86-3 ]
[ 608141-43-1 ]

Reference： [1] Patent: US2013/217919, 2013, A1,
[2] Patent: WO2016/189486, 2016, A1,

9
[ 97966-31-9 ]
[ 608141-43-1 ]

Reference： [1] Patent: CN104447445, 2016, B,
[2] Patent: CN104447445, 2016, B,
[3] Patent: CN104447445, 2016, B,

10
[ 1131-52-8 ]
[ 608141-43-1 ]

Reference： [1] Patent: WO2018/61034, 2018, A1,
[2] Patent: WO2017/94031, 2017, A2,

11
[ 1450657-24-5 ]
[ 608141-43-1 ]

Reference： [1] Patent: US2013/217919, 2013, A1,

12
[ 52849-52-2 ]
[ 608141-43-1 ]

Reference： [1] Patent: CN105348172, 2016, A,

13
[ 6100-74-9 ]
[ 608141-43-1 ]

Reference： [1] Patent: CN105622380, 2016, A,

14
[ 31526-71-3 ]
[ 608141-43-1 ]

Reference： [1] Patent: CN105622380, 2016, A,

15
[ 608141-43-1 ]
[ 608141-42-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide In dichloromethane; water at 15 - 25℃; for 0.25 h;	Example 3 Preparation of (1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine After a mixture of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionized water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionized water was charged into the reaction vessel over about 5 minutes at 15-25° C. The resulting mixture was stirred for at least 10 minutes at 15-25° C. and then the aqueous and organic phases were allowed to separate. The pH of the upper aqueous phase was maintained or adjusted at pH 13-14. The phases were separated and the upper aqueous phase was extracted with DCM (2*4.4 L). The pH of the aqueous phase was maintained at 13-14 throughout the extractions. The DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less. DCM was removed under vacuum below 35° C. The water content of the residual solid should be <0.1percent w/w as measured by Karl Fisher titration. The residual solid was dried azeotropically with more DCM. The solid was dried to a constant weight in vacuo at 30-35° C. to give (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100percent yield).
100%	With sodium hydroxide In dichloromethane; water at 15 - 25℃; for 0.25 h;	[011 8j After a mixture of (1 S)- 1 -(3 -ethoxy-4-methoxyphenyl)-2-methanesulfonyl- ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionized water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionized water was charged into the reaction vessel over about 5 minutes at 15-25°C. The resulting mixture was stirred for at least 10 minutes at 15-25°C and then the aqueous and organic phases were allowed to separate. The pH of the upper aqueous phase was maintained or adjusted at pH 13-14. The phases were separated and the upper aqueous phase was extracted with DCM (2x4.4 L). The pH of the aqueous phase was maintained at 13-14 throughout the extractions. The DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less. DCM was removed under vacuum below 35°C. The water content of the residual solid should be <0.1percent w/w as measured by Karl Fisher titration. The residual solid was dried azeotropically with more DCM. The solid was dried to a constant weight in vacuo at 30-35°C to give (1S)-1-(3-ethoxy-4- methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100percent yield).
100%	With sodium hydroxide In dichloromethane; water at 15 - 25℃; for 0.25 h;	6.5.3. Preparation of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine After a mixture of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionizer water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionizer water was charged into the reaction vessel over about 5 minutes at 15-25° C. The resulting mixture was stirred for at least 10 minutes at 15-25° C. and then the aqueous and organic phases were allowed to separate. The pH of the upper aqueous phase was maintained or adjusted at pH 13-14. The phases were separated and the upper aqueous phase was extracted with DCM (2*4.4 L). The pH of the aqueous phase was maintained at 13-14 throughout the extractions. The DCM extracts were combined and washed with deionizer water (3.3 L) until the pH of the aqueous phase reached 11 or less. DCM was removed under vacuum below 35° C. The water content of the residual solid should be <0.1percent w/was measured by Karl Fisher titration. The residual solid was dried azeotropically with more DCM. The solid was dried to a constant weight in vacuo at 30-35° C. to give (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100percent yield).

99.3%	With sodium hydroxide In dichloromethane at 0 - 5℃; for 2 h;	Example 7: Preaparation of (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (II) Into a 200 ml glass flask was added sequentially 500g of dichloromethane, 44.5g (0.1mol) (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV) (prepared as described in Example 5), and 11g of 40percent sodium hydroxide. The reaction was stirred at 0-5°C for 2 hours. The solution was extracted with dichloromethane. 3g of dichloromethane phase was dried over anhydrous sodium sulfate and filtered. After distilling off the dichloromethane, 27.1g (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (II) was obtained. Optical purity 99.9percent, Yield 99.3percent.
95%	With sodium hydroxide In dichloromethane; water	6.5.3. Preparation of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine After a mixture of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionized water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionized water was charged into the reaction vessel over about 5 minutes at 15-25° C. The resulting mixture was stirred for at least 10 minutes at 15-25° C. and then the aqueous and organic phases were allowed to separate. The pH of the upper aqueous phase was maintained or adjusted at pH 13-14. The phases were separated and the upper aqueous phase was extracted with DCM (2*4.4 L). The pH of the aqueous phase was maintained at 13-14 throughout the extractions. The DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less. DCM was removed under vacuum below 35° C. The water content of the residual solid should be <0.1percent w/was measured by Karl Fisher titration. The residual solid was dried azeotropically with more DCM. The solid was dried to a constant weight in vacuo at 30-35° C. to give (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100percent yield).

Reference： [1] Patent: US2011/87033, 2011, A1, . Location in patent: Page/Page column 11
[2] Patent: WO2015/175773, 2015, A1, . Location in patent: Paragraph 0118
[3] Patent: US9272035, 2016, B2, . Location in patent: Page/Page column 29
[4] Patent: CN105348172, 2016, A, . Location in patent: Paragraph 0066; 0067
[5] Patent: US2012/276087, 2012, A1,
[6] Patent: WO2015/175956, 2015, A1, . Location in patent: Paragraph 0193

[ 608141-43-1 ] Synthesis Path-Downstream 1~43

Yield	Reaction Conditions	Operation in experiment
		Resolution of 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 mL). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ec). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine-N-acetyl-L-leucine salt (98.4% ee).

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

Yield	Reaction Conditions	Operation in experiment
90%	In methanol; at 20℃; for 8h;Reflux; Resolution of racemate;	A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3 -ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered andwashed with methanol (250 mL). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried invacuo at 30C. to a constant weight, yielding 49.6 g (90% recovery) of(S)-2-(3-ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine-N-acety l-L-leucine salt (98.4% ee). ChiralHPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies,150 mm 4.6 mm, 0.5 mL/min., 240 nm): 18.4 mm (S-isomer, 99.2%), 25.5 mm (R-isomer,0.8%)
90%		General procedure: [0188] A 3 L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-l - (methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C to a constant weight, yielding 49.6 g
90%	In methanol; at 20℃; for 4h;Reflux;	A mixture of 2-(3-ethoxy-4-meth- oxyphenyl)-i -(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), andmethanol (1.0 L) was charged into a 3-L 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser. Afier the reaction mixture was refluxed for 1 hour, the mixture was allowed to cool to ambient temperature and then stirred for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuum at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% cc). The crude solid (55.0 g) and methanol (440 mE) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mE). The solid was air-dried and then dried in vacuum at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-2-(3-ethoxy- 4-methoxyphenyl)-i -(methylsulphonyl)-eth-2-ylamine-N- acetyl-L-leucine salt (98.4% cc). Chiral HPLC (1/99 EtOH/ 20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mmx4.6 mm, 0.5 mE/mm., 240 nm): 18.4 mm (S-isomer, 99.2%), 25.5 mm (R-isomer, 0.8%).

73.5%	at 60 - 70℃; for 2h;	In a 500 ml round bottom flask, 200 ml of methanol was added followed by 20 gms of 2-(3-ethoxy-4-methoxyphenyl)-l-(methanesulfonyl)-eth-2-ylamine. The reaction mass was stirred and 76 gms of N-Acetyl-L-Leucine added and reaction mass was stirred. The reaction mass was heated for 2 hours at 60 to 65C, After heating, the reaction masswas cooled at room temperature and it was stirred at room temperature for 3 to 4 hours. The slurry was filtered. Washed with 30 ml methanol, material was unloaded and dried under vacuum for 2 hours at 45C. Yield: 14.36 gm. Further, this material is purified with methanol.
41%	In methanol; for 2h;Reflux;	A mixture of 27.3 g (100 mmol) of 1- (3-ethoxy-4-methoxy) phenyl-2-methanesulfonyl ethylamine (4), 10.4 g(60 mmol) of N-acetyl-L-leucine was dissolved in 200 mL of methanol, heated under reflux for 2 h, and then cooled to room temperature to a large amountThe slurry was precipitated, filtered and washed with methanol to give the crude product. The crude product was again dissolved in 80 mL of methanol, heated to reflux for 2 h, and cooled againTo a large amount of slurry to the slurry, filter, and wash the filter cake with methanol. The solid was dried in vacuo to give 9.1 g (41% recovery)(S) -1- (3-ethoxy-4-methoxy) phenyl-2-methanesulfonylethylamine N-acetyl-L-leucine salt (97.9% ee).
35%	In methanol; for 1h;Inert atmosphere; Reflux;	Example 5: Preparation of (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV) A dry 1,000mL glass flask equipped with a mechanical stirrer, a thermometer, and a condenser was added 500g of methanol, 136 g (0.5mol) <strong>[253168-94-4](R,S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine</strong> (E.g. racemate III prepared in Example 1), and 86.5 g (0.5mol) N-acetyl-L-leucine under nitrogen protection. The solution was heated to reflux for 1 hour. The solution was then cooled to 10C and filtered. The resultant filtrate will be used as mother liquor in Example 6. The resulting filter cake was washed with 55g of cold methanol 10C and dried under vacuum to give 78.1 g of white solid (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV). Yield 35.0%, optical purity 99.8%.
	In methanol; at 20℃; for 8h;Heating / reflux;	A mixture of <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L) was charged into a 3-L 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser. After the reaction mixture was refluxed for 1 hour, the mixture was allowed to cool to ambient temperature and then stirred for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuum at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuum at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 (at)pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm×4.6 mm, 0.5 mL/min., (at)240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).
	In methanol;	6.2.3. Resolution of <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm*4.6 mm, 0.5 mL/min., 240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).
	In methanol; at 20℃; for 4h;Reflux;	[0113j A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-1 - (methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C to a constant weight, yielding 49.6 g (90% recovery) of (S)-2-(3 -ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine -Nacetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150mm x 4.6 mm, 0.5 mL/min., 240 nm): 18.4 mm (S-isomer, 99.2%), 25.5 mm (R-isomer, 0.8%).
49.6 g	In methanol; for 1h;Reflux;	6.2.3. Resolution of <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee).
	In methanol; for 1h;Reflux;	Resolution of 2-(3-ethoxy-4-methoxyphenyl-1-(methylsulphonyl)-eth-2-ylamine A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee).
18 g	In methanol; at 25℃; for 4h;Reflux;	The compound of formula V 0. 1mol 200mL of methanol was added and the reaction flask was refluxed clear solution was added portionwise N- acetyl-L- leucine (0.06mol ), a large number of the resulting solid was refluxed 1h, cooled to 25 C, stirred 1h, filtered and the filter cake was dried in vacuo at 40 C 5h, to give a white solid 22. 6g; The solid was added to the reaction flask and 180mL of methanol, refluxed for 1h, cooled to 25 C, stirred for 1h, filtered and the filter cake in and dried in vacuo 40 C 5h, to give a white solid 18g, 40 C and dried in vacuo 5h, ee: 98 · 6%
68 g	In methanol; at 25℃; for 2h;Reflux;	To a reaction mixture of 700 ml methanol and 100 grams (gm) (0.366 moles) of 1-(3-ethoxy-4- methoxy phenyl)-2-(methylsulfonyl) ethanamine, 38gm (0.2196 moles) of N-acetyl-L-leucine was charged. The reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to 25C to 30C and stirred for 1 hour. The product was filtered and washed with 100 ml methanol.The obtained solid material was dried under vacuum at 30C to obtain (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine N-acetyl-L-leucine salt.(Yield = 68.Ogms)R-isomer: 0.5%
35 g	In methanol; at 60 - 65℃; for 1h;	To 1 liter RBF the product of example 3 or 4 (75 g; 0.2743 moles), N- acetyl-L-leucine (47.5 g ; 0.2743) and methanol (545 mL) were charged and the suspension was stirred at 60 C to 65 C for 1 hour, the suspension was cooled to room temperature and stirred for another 3 hours. The solid was filtered and dried under reduced pressure to obtain 60 g of title compound with chiral purity of 85% desired isomer. It was further purified by methanol to give 35 g of pure title compound having chiral purity 99.5%.
	In methanol; at 60 - 65℃; for 1h;	To 1 liter round bottom flask, 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine,N-acetyl-L-leucine and methanol were charged and the suspension was stirred at 60 C to 65C for 1 hour, the suspension was cooled to room temperature and stirred for another 3 hours.The solid was filtered and dried under reduced pressure to obtain the title compound withchiral purity of 85 % desired isomer. Yield: 40 %.It was further purified by methanol to give pure title compound having chiral purity 99.5%
49.6 g	In methanol; for 1h;Reflux;	A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm x 4.6 mm, 0.5 mL/min., 240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).
49.6 g	In methanol; for 1h;Reflux;	A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with <strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong> (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C to a constant weight, yielding 49.6 g (90% recovery) of (S)-<strong>[253168-94-4]2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine</strong>-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm x 4.6 mm, 0.5 mL/min., 240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).

Reference： [1]Patent: WO2014/74846,2014,A1 .Location in patent: Page/Page column 21
[2]Patent: WO2015/175956,2015,A1 .Location in patent: Paragraph 0188
[3]Patent: US9387195,2016,B2 .Location in patent: Page/Page column 27
[4]Patent: WO2016/189486,2016,A1 .Location in patent: Page/Page column 14; 15; 16
[5]Patent: CN106543050,2017,A .Location in patent: Paragraph 0046; 0047; 0053; 0054
[6]Patent: CN105348172,2016,A .Location in patent: Paragraph 0061; 0062
[7]Patent: US2007/155791,2007,A1 .Location in patent: Page/Page column 14
[8]Patent: US2012/276087,2012,A1
[9]Patent: WO2015/175773,2015,A1 .Location in patent: Paragraph 0113
[10]Patent: US9272035,2016,B2 .Location in patent: Page/Page column 23
[11]Patent: US2016/128981,2016,A1 .Location in patent: Paragraph 0216
[12]Patent: CN105622380,2016,A .Location in patent: Paragraph 0072; 0073; 0074; 0075
[13]Patent: WO2016/146990,2016,A1 .Location in patent: Page/Page column 17; 18
[14]Patent: WO2017/94031,2017,A2 .Location in patent: Page/Page column 15
[15]Patent: WO2018/61034,2018,A1 .Location in patent: Page/Page column 12
[16]Patent: EP3096749,2019,B1 .Location in patent: Paragraph 0081
[17]Patent: EP3157520,2019,B1 .Location in patent: Paragraph 0100

3
[ 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

4
[ 608141-43-1 ]
[ 635705-76-9 ]

Reference： [1]Patent: US2011/87033,2011,A1
[2]Patent: US9272035,2016,B2

5
[ 608141-43-1 ]
cyclopropanecarboxylic acid {2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide [ No CAS ]

Reference： [1]Patent: US2011/87033,2011,A1
[2]Patent: WO2015/175773,2015,A1
[3]Patent: US9272035,2016,B2
[4]Patent: WO2015/175956,2015,A1

6
[ 608141-43-1 ]
[ 608141-42-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; In dichloromethane; water; at 15 - 25℃; for 0.25h;pH 13 - 14;	Example 3 Preparation of (1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine After a mixture of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionized water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionized water was charged into the reaction vessel over about 5 minutes at 15-25 C. The resulting mixture was stirred for at least 10 minutes at 15-25 C. and then the aqueous and organic phases were allowed to separate. The pH of the upper aqueous phase was maintained or adjusted at pH 13-14. The phases were separated and the upper aqueous phase was extracted with DCM (2*4.4 L). The pH of the aqueous phase was maintained at 13-14 throughout the extractions. The DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less. DCM was removed under vacuum below 35 C. The water content of the residual solid should be <0.1% w/w as measured by Karl Fisher titration. The residual solid was dried azeotropically with more DCM. The solid was dried to a constant weight in vacuo at 30-35 C. to give (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100% yield).
100%	With sodium hydroxide; In dichloromethane; water; at 15 - 25℃; for 0.25h;	[011 8j After a mixture of (1 S)- 1 -(3 -ethoxy-4-methoxyphenyl)-2-methanesulfonyl- ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionized water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionized water was charged into the reaction vessel over about 5 minutes at 15-25C. The resulting mixture was stirred for at least 10 minutes at 15-25C and then the aqueous and organic phases were allowed to separate. The pH of the upper aqueous phase was maintained or adjusted at pH 13-14. The phases were separated and the upper aqueous phase was extracted with DCM (2x4.4 L). The pH of the aqueous phase was maintained at 13-14 throughout the extractions. The DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less. DCM was removed under vacuum below 35C. The water content of the residual solid should be <0.1% w/w as measured by Karl Fisher titration. The residual solid was dried azeotropically with more DCM. The solid was dried to a constant weight in vacuo at 30-35C to give (1S)-1-(3-ethoxy-4- methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100% yield).
100%	With sodium hydroxide; In dichloromethane; water; at 15 - 25℃; for 0.25h;	6.5.3. Preparation of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine After a mixture of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionizer water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionizer water was charged into the reaction vessel over about 5 minutes at 15-25 C. The resulting mixture was stirred for at least 10 minutes at 15-25 C. and then the aqueous and organic phases were allowed to separate. The pH of the upper aqueous phase was maintained or adjusted at pH 13-14. The phases were separated and the upper aqueous phase was extracted with DCM (2*4.4 L). The pH of the aqueous phase was maintained at 13-14 throughout the extractions. The DCM extracts were combined and washed with deionizer water (3.3 L) until the pH of the aqueous phase reached 11 or less. DCM was removed under vacuum below 35 C. The water content of the residual solid should be <0.1% w/was measured by Karl Fisher titration. The residual solid was dried azeotropically with more DCM. The solid was dried to a constant weight in vacuo at 30-35 C. to give (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100% yield).

99.3%	With sodium hydroxide; In dichloromethane; at 0 - 5℃; for 2h;	Example 7: Preaparation of (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (II) Into a 200 ml glass flask was added sequentially 500g of dichloromethane, 44.5g (0.1mol) (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV) (prepared as described in Example 5), and 11g of 40% sodium hydroxide. The reaction was stirred at 0-5C for 2 hours. The solution was extracted with dichloromethane. 3g of dichloromethane phase was dried over anhydrous sodium sulfate and filtered. After distilling off the dichloromethane, 27.1g (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (II) was obtained. Optical purity 99.9%, Yield 99.3%.
95-100%	With sodium hydroxide; In dichloromethane; water;	6.5.3. Preparation of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine After a mixture of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionized water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionized water was charged into the reaction vessel over about 5 minutes at 15-25 C. The resulting mixture was stirred for at least 10 minutes at 15-25 C. and then the aqueous and organic phases were allowed to separate. The pH of the upper aqueous phase was maintained or adjusted at pH 13-14. The phases were separated and the upper aqueous phase was extracted with DCM (2*4.4 L). The pH of the aqueous phase was maintained at 13-14 throughout the extractions. The DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less. DCM was removed under vacuum below 35 C. The water content of the residual solid should be <0.1% w/was measured by Karl Fisher titration. The residual solid was dried azeotropically with more DCM. The solid was dried to a constant weight in vacuo at 30-35 C. to give (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100% yield).
94%	With sodium carbonate; In water;pH 10;	To a solution of 102-A ((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine (S)-2-acetamido-4-methylpentanoate, 800 mg, 1.79 mmol) in H2O (10 mL) was added saturated aqueous solution of Na2CO3 to pH = 10,then the mixture was extracted with EtOAc (30 mL2). The combined EtOAc solution was dried, filtered and concentratedto give compound 102-B ((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine, 460 mg, yield: 94%) asyellow solid.1H NMR (300 MHz, DMSO-d6) delta 7.02 (s, 1H), 6.89 (s, 2H), 4.27 (dd, J = 9.3, 3.6 Hz, 1H), 3.99-4.06 (m, 2H), 3.73 (s,3H), 3.20-3.45 (m, 2H), 2.95 (s, 3H), 2.16 (s, 2H), 1.27-1.35 (m, 3H).
	With sodium hydroxide; In dichloromethane; water; at 15 - 25℃; for 0.25h;	[0193] After a mixture of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl- ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionized water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionized water was charged into the reaction vessel over about 5 minutes at 15-25C. The resulting mixture was stirred for at least 10 minutes at 15-25C and then the aqueous and organic phases were allowed to separate. The pH of the upper aqueous phase was maintained or adjusted at pH 13-14. The phases were separated and the upper aqueous phase was extracted with DCM (2x4.4 L). The pH of the aqueous phase was maintained at 13-14 throughout the extractions. The DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less. DCM was removed under vacuum below 35C. The water content of the residual solid should be <0.1% w/w as measured by Karl Fisher titration. The residual solid was dried azeotropically with more DCM. The solid was dried to a constant weight in vacuo at 30-35C to give (lS)-l-(3-ethoxy-4- methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100% yield).

Reference： [1]Patent: US2011/87033,2011,A1 .Location in patent: Page/Page column 11
[2]Patent: WO2015/175773,2015,A1 .Location in patent: Paragraph 0118
[3]Patent: US9272035,2016,B2 .Location in patent: Page/Page column 29
[4]Patent: CN105348172,2016,A .Location in patent: Paragraph 0066; 0067
[5]Patent: US2012/276087,2012,A1
[6]Patent: EP3590924,2020,A1 .Location in patent: Paragraph 0142-0143
[7]Patent: WO2015/175956,2015,A1 .Location in patent: Paragraph 0193

7
[ 608141-43-1 ]
[ 1227368-31-1 ]

Reference： [1]Patent: US2011/87033,2011,A1
[2]Patent: WO2015/175773,2015,A1
[3]Patent: US9272035,2016,B2
[4]Patent: WO2015/175956,2015,A1

8
[ 6296-53-3 ]
[ 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

9
[ 1188-21-2 ]
[ 1450657-28-9 ]
[ 608141-43-1 ]

Yield	Reaction Conditions	Operation in experiment
41%		A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2 g, 7.34 mmol) and ammonium acetate (0.90 g, 11.7 mmol) in TFE (75 mL) was heated to reflux, and anhydrous ammonia was bubbled through the solution for 45 min while distilling off solvent until the total volume was reduced to 20 mL. Then, the distillation was discontinued and the batch was held at reflux for 24 h. The batch was cooled and evaporated to dryness. Methanol (10 mL) was then added to the residue and the resultant slurry was stirred for 30 min. Then, the solids were filtered, washed with MeOH (5 mL), and dried under vacuum. The solids were then transferred to a hydrogenation reaction vessel. To this vessel was also charged a solution of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (12.6 mg, 0.027 mmol), (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (14.4 mg, 0.027 mmol), and TFE (7.2 mL). The mixture was warmed to 50 C. and hydrogenated under 90 psig hydrogen gas for 18 h. Then Ecosorb C-941 (150 mg) was added and the mixture was stirred at 20 C. for 4 h. The mixture was filtered through Celite and the filtrate was transferred into a clean vessel. The mixture was warmed to 55 C. with stirring, and a solution of N-acetyl-L-leucine (0.79 g, 3.7 mmol) in methanol (7.25 mL) was added over 1 h, resulting in precipitation of the product as the N-acetyl-L-leucine salt. The mixture was stirred at 55 C. for 1 h and then a mixture 1:1 TFE-MeOH (5 mL) was added. The mixture was cooled to 25 C. over 2 h, and stirring proceeded at this temperature for 16 h. The mixture was filtered and washed 1:1 TFE-MeOH (10 mL) and with MeOH (10 mL), and was dried under vacuum. The product was obtained as a white solid (1.35 g, 41% yield); achiral HPLC (Hypersil BDS C8, 5.0 mum, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 8.89 (98.8%); chiral HPLC (Chiralpak AD-H 5.0 mum Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-i-PrOH-diethylamine): 6.94 (0.81%), 8.21 (99.34%); 1H NMR (DMSO-d6) delta 0.84 (d, 3H), 0.89 (d, J=6.6 Hz, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.41-1.52 (m, 2H), 1.62 (dt, J=6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94 (s, 3H), 3.28 (dd, J=4.0, 14.4 Hz, 1H), 3.44 (dd, J=9.1, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J=6.9 Hz, 2H), 4.18 (q, J=7.7 Hz, 1H), 4.29 (dd, J=4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s, 1H), 8.04 (d, J=7.9 Hz, 1H); Anal. (C20H34N2O7S)C, H, N. Calcd C, 53.79; H, 7.67; N, 6.27. Found C, 53.86; H, 7.97; N, 6.36.

Reference： [1]Patent: US2013/217919,2013,A1 .Location in patent: Paragraph 0292-0293

10
[ 1188-21-2 ]
[ 1450657-43-8 ]
[ 608141-43-1 ]

Yield	Reaction Conditions	Operation in experiment
44%		The product from Step 1 (0.5 g, 1.670 mmol) was dissolved in TFE, and then 10% Pd-C (0.05 g) was added. The resulting mixture was hydrogenated at ambient temp under 40 psig hydrogen for 9 h, and then the mixture was filtered through Celite. The filtrate was warmed to 55 C. with stirring, and a solution of N-Acetyl-L-Leu (0.29 g, 1.67 mmol) in MeOH (10 mL) was added to the mixture in dropwise fashion over 1 h. The mixture was stirred at the same temperature for 2 h and was then cooled to 21 C. over 2 h and stirred at this temperature for 16 h. The mixture was filtered and rinsed with 1:1 (v/v) TFE-MeOH (10 mL), and the solids were dried under vacuum to provide (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt as a white solid (0.33 g, 44% yield); achiral HPLC (Hypersil BDS C8, 5.0 mum, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 7.26 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 mum Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-i-PrOH-diethylamine): 7.10 (2.8%), 8.02 (97.2%); 1H NMR (DMSO-d6) delta 0.84 (d, 3H), 0.89 (d, J=6.6 Hz, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.41-1.52 (m, 2H), 1.62 (dt, J=6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94 (s, 3H), 3.28 (dd, J=4.0, 14.4 Hz, 1H), 3.44 (dd, J=9.1, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J=6.9 Hz, 2H), 4.18 (q, J=7.7 Hz, 1H), 4.29 (dd, J=4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s, 1H), 8.04 (d, J=7.9 Hz, 1H).

Reference： [1]Patent: US2013/217919,2013,A1 .Location in patent: Paragraph 0301-0302

11
[ 1188-21-2 ]
[ 1450657-31-4 ]
[ 608141-43-1 ]

Yield	Reaction Conditions	Operation in experiment
80%		A solution of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (17 mg, 0.037 mmol) and (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (20 mg, 0.037 mmol) in 10 mL of 2,2,2-trifluoroethanol was prepared under nitrogen. To this solution was then charged 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol). The resulting mixture was heated to 50 C. and hydrogenated under 90 psig hydrogen pressure. After 18 h, the mixture was cooled to ambient temperature and removed from the hydrogenator. Ecosorb C-941 (200 mg) was added and the mixture was stirred at ambient temperature for 3 h. The mixture was filtered through Celite, and the filter was washed with additional trifluoroethanol (2 mL). Then, the mixture was heated to 55 C., and a solution of N-acetyl-L-leucine (1.3 g, 7.5 mmol) was added dropwise over the course of 1 h. Stirring proceeded at the same temperature for 1 h following completion of the addition, and then the mixture was cooled to 22 C. over 2 h and stirred at this temperature for 16 h. The crystalline product was filtered, rinsed with methanol (2×5 mL), and dried under vacuum at 45 C. to provide the product as a white solid (2.6 g, 80% yield); achiral HPLC (Hypersil BDS C8, 5.0 mum, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 8.57 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 mum Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-i-PrOH-diethylamine): 8.35 (99.6%); 1H NMR (DMSO-d6) delta 0.84 (d, 3H), 0.89 (d, J=6.6 Hz, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.41-1.52 (m, 2H), 1.62 (dt, J=6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94 (s, 3H), 3.28 (dd, J=4.0, 14.4 Hz, 1H), 3.44 (dd, J=9.1, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J=6.9 Hz, 2H), 4.18 (q, J=7.7 Hz, 1H), 4.29 (dd, J=4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s, 1H), 8.04 (d, J=7.9 Hz, 1H); Anal. (C20H34N2O7S) C, H, N. Calcd C, 53.79; H, 7.67; N, 6.27. Found C, 53.78; H, 7.57; N, 6.18.

Reference： [1]Patent: US2013/217919,2013,A1 .Location in patent: Paragraph 0278-0279

12
[ 1450657-28-9 ]
[ 608141-43-1 ]

Reference： [1]Patent: US2013/217919,2013,A1
[2]Patent: US2013/217919,2013,A1
[3]Patent: CN104447445,2016,B
[4]Patent: CN104447445,2016,B
[5]Patent: CN104447445,2016,B

13
[ 1450657-24-5 ]
[ 608141-43-1 ]

Reference： [1]Patent: US2013/217919,2013,A1

14
[ 60758-86-3 ]
[ 608141-43-1 ]

Reference： [1]Patent: US2013/217919,2013,A1
[2]Patent: WO2016/189486,2016,A1

15
[ 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

16
[ 253168-94-4 ]
[ 1188-21-2 ]
[ 608141-43-1 ]
[ 1382429-55-1 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; for 1h;Reflux;	[0188] A 3 L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-l - (methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 C to a constant weight, yielding 49.6 g

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

17
[ 52849-52-2 ]
[ 608141-43-1 ]

Reference： [1]Patent: CN105348172,2016,A

18
2-chloro-1-(3-ethoxy-4-methoxyphenyl)ethanone [ No CAS ]
[ 608141-43-1 ]

Reference： [1]Patent: CN105622380,2016,A

19
[ 6100-74-9 ]
[ 608141-43-1 ]

Reference： [1]Patent: CN105622380,2016,A

20
[ 31526-71-3 ]
[ 608141-43-1 ]

Reference： [1]Patent: CN105622380,2016,A

21
[ 608141-42-0 ]
[ 1188-21-2 ]
[ 608141-43-1 ]

Yield	Reaction Conditions	Operation in experiment
98.3%	In methanol; for 1h;Reflux;	Under a nitrogen atmosphere, a dry 1000 ml glass flask equipped with a mechanical stirrer, a thermometer and a condenser was added (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine (110 g), N-acetylleucine 69.3 g (0.4 mol) and 500g of methanol, Heated to reflux for 1 hour with stirring and then cooled to ambient temperature in a stirred state and stirred at room temperature for 3 hours, filtered and the filter cake was washed with methanol, then the cake was dried under vacuum to constant weight. To give 176.3 g of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-1-leucine (Optical purity 99.6%) yield 98.3%. Chiral HPLC (ethanol: 20 mM KH2PO4 = 1:99, pH = 7.0, Agilent's ES-OVM chiral column, 150 mm x 4.6 mm, flow rate 0.5 ml/min, detection wavelength 240 nm): 18.1 min (S-isomer, 99.6%), 25.0 min (R-isomer, 0.4%).
	In methanol; at 65 - 70℃;	Compound <strong>[608141-42-0](S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-ylamine</strong> N-acetyl-L-leucine salt specific preparation methods are: Reaction temperature 65 ~ 70 deg.C. Under 420ml methanol selected as a solvent condition, 60g of the compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-ylamine and 22g compound N-acetyl-L-leucine salt formation reaction to give the compound 60g <strong>[608141-42-0](S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-ylamine</strong> N-acetyl-L-leucine salt. Compound (S) -2- (3- ethoxy-4-methoxyphenyl) -1- (methylsulfonyl) - ethyl 2-acetyl-amine -N- -L- leucine salt specific purification methods are: reaction temperature 65 ~ 70 , 420ml methanol as the choice of solvent, at the reflux temperature of the purified purified (S) -2- (3- ethoxy-4-methoxyphenyl) -1 - (methylsulfonyl) - ethyl 2-acetyl-amine -N- -L- leucine salts, reflux temperature was 70 deg.C .
1670 g	In methanol; for 1h;Reflux;	To a stirred solution l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (2500gm) in methanol (20.01it) was added N-acetyl-L-Leucine (950.0gm) slowly at 25C and then the reaction mixture was heated to reflux temperature and maintained for 1.Ohr. The reaction mass was cooled to 25-30C and stirred for 4.0 hr at 25-30C. The product was filtered and washed with methanol and dried under vacuum at 60C for 4.0 hr to obtain 2000.0gm of crude product. The crude product was subjected to methanol purification to obtain 1670gm of N-acetyl L-leucine salt of (5)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl) eth-2-ylamine. chiral purity >99.5%.

Reference： [1]Patent: CN104447445,2016,B .Location in patent: Paragraph 0083; 0084
[2]Patent: CN105218428,2016,A .Location in patent: Paragraph 0012; 0019; 0020
[3]Patent: WO2017/33116,2017,A1 .Location in patent: Paragraph 00115

22
[ 608141-43-1 ]
[ 5434-20-8 ]
[ 635705-72-5 ]

Yield	Reaction Conditions	Operation in experiment
13 g		Reaction mixture of 100 ml acetonitrile, 10 grams (gms) (0.OSS4moles) of 3-amino phthalic acid, 15gms (0.0336 moles) of (S)-1 -(3-ethoxy-4-methoxyphenyl)-2-(methyl sulfonyl) ethanami ne N-acetylL-leucine salt , 13.26gms (0.22lmoles) of acetic acid were stirred at 25C for 10 minutes. 11.16gms (0.11 moles) of triethylamine was slowly added to the reaction mixture. The mixture was heated to reflux temperature (approximately 80C) and maintained for 3 hours. Solvent was completely distilled under vacuum at 45C. Water (150 ml) was charged and stirred for 3 hour at 25C to 30C. Solid was filtered and washed with water. The obtained solid material was dried under vacuum at 50C to obtain (S)-4-amino-2-(1 -(3-ethoxy-4-methoxyphenyl)-2-(methyl sulfonyl)ethyl) isoindoline-1, 3-dione.Yield = 13.0 grams

Reference： [1]Patent: WO2016/146990,2016,A1 .Location in patent: Page/Page column 18

23
[ 6296-53-3 ]
[ 608141-43-1 ]
[ 616-38-6 ]
(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)acetamide dimethylcarbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3 g		A stirred solution of N-acetyl -L-leucine salt of (S)-2-(3- ethoxy-4-methoxyphenyl)- 1 -(methylsulfonyl) ethanamine. (5gm) and 3- acetamidophthalic anhydride (2.34 gm) in 50ml acetonitrile was refluxed for 2.0hr and then cooled to 50°C and the solvent was removed under reduced pressure to obtain semisolid residue and to the residue was added water and saturated aqueous sodium bicarbonate solution. This was extracted with ethyl acetate and again washed with water and brine. The ethyl acetate was distilled under vacuum to obtain oily residue. To the residue was charged 25ml of dimethyl carbonate and heated to 85-90°C to get clear solution then slowly cooled the reaction mixture to 25-30°C and stirred for 2 hr. The precipitated product was filtered and dried at 70°C under vacuum for 6 hr to obtain 3.0 gm of (S)-N-{2-(l-(3-ethoxy-4-methoxyphenyl)-2-methylsulphonyl)ethyl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl}acetamide dimethyl carbonate solvate. H1 NMR Data delta DMSO 1.32, 2.19, 3.02, 3.69, 3.73, 3.98-4.05, 4.13-4.18, 4.31-4. 34 , 5.77-5.80, 6.92-8.45, 9.71. DSC endotherm: 121°C±3°C, TGA Loss- 9.2percent up to 150°C.

Reference： [1]Patent: WO2017/33116,2017,A1 .Location in patent: Paragraph 00130

24
[ 6296-53-3 ]
[ 608141-43-1 ]
[ 635705-72-5 ]

Reference： [1]Patent: WO2017/33116,2017,A1

25
(1S)-Ν-(1-methyl-1-phenylmethyl)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-vinylamine [ No CAS ]
[ 608141-43-1 ]

Reference： [1]Patent: CN104447445,2016,B

26
(1S)-Ν-(1-methyl-1-hydroxymethylmethyl)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-vinylamine [ No CAS ]
[ 608141-43-1 ]

Reference： [1]Patent: CN104447445,2016,B

27
(1S)-N-1-(naphthyl)ethyl-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-vinylamine [ No CAS ]
[ 608141-43-1 ]

Reference： [1]Patent: CN104447445,2016,B

28
[ 97966-31-9 ]
[ 608141-43-1 ]

Reference： [1]Patent: CN104447445,2016,B
[2]Patent: CN104447445,2016,B
[3]Patent: CN104447445,2016,B

29
[ 6296-53-3 ]
[ 608141-43-1 ]
[ 108-88-3 ]
apremilast hemitoluene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With acetic acid; sodium hydroxide; In dichloromethane; water; at 90℃; for 3h;	Example 1 Preparation of Form I of Apremilast A mixture containing (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-Ac-L-Leu 1 (37.4 g, 83.8 mmole, >99.9percent ee) and DCM (374 mL) was neutralized with NaOH(aq) (17percent, 37 mL). The separated organic portion was subjected to solvent chase with toluene (747 mL). After HOAc (112 mL) and <strong>[6296-53-3]3-acetamidophthalic anhydride</strong> 2 (18 g, 87.7 mmole, 1.05 equiv) were added, the mixture was heated at 90° C. for 3 hr completing the reaction. Apremilast solids precipitated along with cooling to 20-30° C. The mixture was cooled to 0-10° C. and stirred for 1 hr. The mixture was filtered to give apremilast hemitoluene solvate in 91percent yield with 99.94percent purity and >99.9percent ee.

Reference： [1]Patent: US2017/57916,2017,A1 .Location in patent: Paragraph 0118

30
2-ethoxy-1-methoxy-4-vinylbenzene [ No CAS ]
[ 608141-43-1 ]

Reference： [1]Patent: CN106543050,2017,A

31
[ 608141-43-1 ]
[ 15371-06-9 ]
[ 608141-41-9 ]

Yield	Reaction Conditions	Operation in experiment
86.7%	With acetic acid; at 100 - 120℃; for 2h;	Add to 250ml three-neck bottle(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine. N-acetyl-L-leucine salt (compound of formula II) 45 g 36.4 g of 3-acetylaminophthalic acid and 135 g of glacial acetic acid.After heating, the temperature was raised to 100-120 C, the reaction was kept for 2 hours, and then 10.2 g of acetic anhydride was added.The reaction was continued for 0.5 h. After the reaction is completed, the solvent is removed under reduced pressure.The residue was dissolved in ethyl acetate, washed with brine, dried and concentrated.Acetone and ethanol were recrystallized to obtain Aprster 40 g, the yield was 86.7%, and the purity was 99.7%.
3.4 g	With acetic acid; at 110 - 115℃; for 1h;	To a 500 mL RBF the product of example 5 (5 g; 0.01119 moles), 3-acetamidophthalic acid(2.62 g; 0.01 1756 moles) and acetic acid (50 mL) were charged and stirred at 110 C to 115C 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 washing with aq. sodium bicarbonate solution. The dichloromethane layer was separated and distilled off completely. The product was isolatedby recrystallization in acetone:ethanol mixture to give 3.4 g of apremilast as a light yellow solid with HPLC purity of 99.9 %.

Reference： [1]Patent: CN109384704,2019,A .Location in patent: Paragraph 0033; 0034; 0035; 0036
[2]Patent: WO2017/94031,2017,A2 .Location in patent: Page/Page column 16

32
[ 1131-52-8 ]
[ 608141-43-1 ]

Reference： [1]Patent: WO2018/61034,2018,A1
[2]Patent: WO2017/94031,2017,A2

33
tert-butyl N-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]carbamate [ No CAS ]
[ 608141-43-1 ]

Reference： [1]Patent: WO2018/61034,2018,A1

34
tert-butyl N-[(3-ethoxy-4-methoxyphenyl)-p-tolylsulfonylmethyl]carbamate [ No CAS ]
[ 608141-43-1 ]

Reference： [1]Patent: WO2018/61034,2018,A1

35
[ 608141-43-1 ]
N-(7-fluoro-1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide [ No CAS ]
((S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-7-fluoro-1,3-dioxoisoindolin-4-yl)acetamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; at 120℃;	To a solution of 102-A ((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine (S)-2-acetamido-4-methylpentanoate) (CAS No. 608141-43-1) (300 mg, 0.67 mmol) in AcOH (15 mL) was added 101-E (N-(7-fluoro-1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide) (157 mg, 0.7 mmol) and reacted at 120 C for overnight. The reactionmixture was evaporated to dryness via rotary evaporation, purified by prep-HPLC and freeze-dried to get compound102((S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-7-fluoro-1,3-dioxoisoindolin-4-yl)acetamide))(197 mg, yield: 61%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) delta 9.73 (s, 1H), 8.41-8.44 (m, 1H), 7.65 (t, J = 9.2 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H),6.93-7.01 (m, 2H), 5.76 (dd, J = 10.4, 4.4 Hz, 1H), 4.31 (dd, J = 14.4, 10.4 Hz, 1H), 4.16 (dd, J = 14.4, 4.4 Hz, 1H), 4.02(q, J = 7.2 Hz, 2H), 3.74 (s, 3H), 3.02 (s, 3H), 2.17 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). LC-MS: 496 ([M+18]+).

Reference： [1]Patent: EP3590924,2020,A1 .Location in patent: Paragraph 0111

36
[ 608141-43-1 ]
(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-fluoro-1,3-dioxoisoindolin-4-yl)acetamide [ No CAS ]