608141-42-0|(S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine| Ambeed

Structure of 608141-42-0

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Quality Control of [ 608141-42-0 ] Purity: 98% SDS Specification

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Product Details of [ 608141-42-0 ]

CAS No. :	608141-42-0
Formula :	C₁₂H₁₉NO₄S
M.W :	273.35
SMILES Code :	O=S(C[C@@H](N)C1=CC=C(OC)C(OCC)=C1)(C)=O
MDL No. :	MFCD22677268
InChI Key :	BXUJVINGXQGNFD-SNVBAGLBSA-N
Pubchem ID :	11282264

Safety of [ 608141-42-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 608141-42-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	6
Fraction Csp3	0.5
Num. rotatable bonds	6
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	70.48
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	87.0 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.23
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.5
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.89
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.75
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.28
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.33

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.7
Solubility	5.45 mg/ml ; 0.0199 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.9
Solubility	3.46 mg/ml ; 0.0127 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.46
Solubility	0.0939 mg/ml ; 0.000344 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.61 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.83

Application In Synthesis of [ 608141-42-0 ]

* 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.

Downstream synthetic route of [ 608141-42-0 ]

[ 608141-42-0 ] Synthesis Path-Downstream 1~35

1
[ 253168-94-4 ]
[ 608141-42-0 ]

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

2
[ 6296-53-3 ]
[ 608141-42-0 ]
[ 608141-41-9 ]

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

91.5%	In toluene; at 90℃; for 5h;	148.7 g of N-acetyl-L-leucinate (0.4% isomer content) of chiral amine intermediate II, 71.38 g of anhydride intermediate III, 1487 ml of toluene were charged into the reaction flask;Heated to 90 ± 5 , incubated for 5 hours, concentrated under reduced pressure to remove toluene; added to 3000ml of ethanol, heating; steamed out of ethanol until evaporated to dryness;Add 1000mL of ethanol, 500mL acetone, heated to reflux, dissolved until clear, add 1.5g activated carbon decolorization, slowly cooled to 15 ; incubated at 10 ± 5 for 6 hours;Filter and wash the filter cake with 200 mL of ethanol. Drying in vacuo at 50 ± 5 C for 4 hours afforded 139.1 g of aphthous (I) in 91.5% yield.After testing, Purcert purity of 99.94%, 0.05% isomer content, crystal form B (see Figure 1).
89%	With perchloric acid; acetic acid; at 85℃; for 2.5h;Reflux;	Example 8: Preparation of S-apremilast (I) In a dry 250mL glass flask was added 2.5g of 3-acetamidophthalicanhydride, 25g of glacial acetic acid, 0.2g of perchloric acid, and 2.7g of (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (II) (prepared in Example 7). The reaction was heated at 80-85C for 30 minutes then heated at reflux for 2 hours. Glacial acetic acid was recovered through vacuum distillation. The remaining material was then cooled to room temperature 20C. 10g of saturated brine and 20g of ethyl acetate were added and allowed to seperate under stirring. The organic phase was separated. The aqueous phase was extracted once with 20 g of ethyl acetate. The combined organic phases, recovered by distillation of ethyl acetate, gave 4.1g of solid S-apremilast (I). Yield 89.0%, e.e% to 99.8%.
89%	With acetic acid; for 3h;Reflux;	3.17 g (11,6 mmol; 99.4 % ee) of (S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethylamine of formula (S)-2a (see Example 9), 2.50 g (12.2 mmol) of 3- acetamidopbtalic anhydride of formula S and 52 ml of glacial acetic acid were placed into a250 ml flask. The mixture was refluxed for 3 h and cooled down to 20C. After that, 4 x 25 ml of water were gradually added, under continuous stirring the mixture was inoculated with crystals of Apremilast of formula 1 and stirred at 20 C. The separated crystals were aspirated, washed with a mixture of acetic acid - water (volume ratio 2:5) and dried at a reduced pressure. The amount of 4.75 g of yellowish crystals of the product of formula 1 was obtained(yield 89%, >99% ee, HPLC 99.1%).
84%	With acetic acid; at 120℃;	1 Anhydride (4.16 g, 20.26 mmol), chiral amine (19.3 mmol) were added to a 250 mL reaction flask, glacial acetic acid (65 mL) was added, refluxed at 120 C., and thin layer chromatography (TLC) detection reaction ( Methanol: Dichloromethane volume fraction ratio = 1:10). The chiral amine material was completely reacted (about 5-6 h). Acetic anhydride (60 mmol) was added. The reaction was continued for 1 h. The glacial acetic acid was distilled off, and the residue was poured into 100 mL. Intensely stirred water forms a suspension. After suction filtration, the filter cake was washed with 4×50 mL of water, and the filter cake was dried in a drying oven at 50 C. for approximately 4-5 h to obtain 8.0 g of crude yellow appress. The purity was 98.8 by HPLC. %, the deacetylated by-product content is about 0.05%.The above crude product was added to ethanol (70 mL), heated to reflux for 2 h, and then slowly lowered to room temperature with stirring. The solid precipitated and was filtered under suction. The filter cake was washed with ethanol (2×10 mL) and dried (60 C., dried for 3 h). ,getApstThe product is 7.5g, and the total yield is 84%.
81.5%	With acetic acid; for 6h;Reflux;	The reaction flask was charged with 350 mL of glacial acetic acid,(0.22 mol) of (1S) -1- (3-ethoxy-4-methoxybenzene) Yl) -2- (methylsulfonyl) ethylamine (formula V)57.4 g (0.28 mol) of 3-acetylaminophthalic anhydride,Stir well, reflux reaction for 6 hours,The reaction was stopped and the residue after dissolution was dissolved in 400 ml of ethyl acetate,Washed with saturated aqueous sodium carbonate (300 mL x 2 times)Washed with brine (150 mL x 1 time).After further desolvation, a mixed solvent of 400 mL of absolute ethanol and 150 mL of acetone was added and stirred for 5 hours,Filter, filter cake with 100mL anhydrous ethanol washing, drying was 82.6g products,The molar yield was 81.5%, the HPLC purity was 98.3%Ee value of 97.9%.
73.1%	With acetic acid; at 115 - 125℃;	(1S)-i -(3 -ethoxy-4-methoxy-phenyl)-2-methanesulfonyl- ethyl amine (Formula-V) (125gm) and N-(1, 3-dioxo-1, 3dihyro-2-benzofuran-4-yl) acetamide (Formula-IV) (98.5gm) in to methyl isobutyl ketone (lSOOml) and acetic acid (SSOml) mixture of solvent at ambient temperature. Raise temperature up to 115-120C (115-125C). Remove the water formed during the reaction. After completion of reactiondistill out reaction mass completely. Charge ethyl acetate for extraction and wash with sodium bicarbonate solution and sodium chloride solution. Distill out reaction mass completely and charge acetone followed by ethanol. Raise temperature up to reflux and maintain 1 hr. Reaction gradually cool to ambient temperature and maintain reaction mass and stir for 7-8 hr. Filter the product and wash with ethanol. Charge wet cake into acetone followed by ethanol. Raise temperature up to reflux and maintain 1 hr. Reaction gradually cool to ambient temperature and maintain reaction mass and stir for 7-8 hr. Filter the product and wash with ethanol resulting Formula I with 73.1%yield and 99.98% HPLC purity and 99.99 Chiral purity. The titled product having XRPD values as, 10.1, 12.4, 13.5, 20.8, 22.5, 24.7, and 27.0 ±0.2 (Form-B).
64%	With acetic acid;Reflux;	Example 8: Preparation of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl)-4-amino- isoindoline-1 ,3-dione (apremilast) from the compound of formula VII Into a reaction vessel equipped with magnetic stirrer and condenser was placed (S)-1 -(3- ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (2.24 mmol, 1 g) and was dissolved in 10 mL of glacial acetic acid. Afterwards 3-acetamidophthalic anhydride was added (2.35 mmol, 0.48 g) and reaction mixture was vigorously stirred at reflux overnight. Reaction system was cooled down to room temperature and acetic acid was evaporated under reduced pressure. The organic residue was extracted with dichloromethane, organic phases were washed with water, dried over Na2S04 and solvent was evaporated. The residue was recrystallized from acetone/ethanol mixture, solid material was filtered off and dried in vacuo at 60 C affording 0.66 g (64% Yield) of final product with > 99% ee. 1 H NMR analysis was in agreement with known data.
64%	With acetic acid;Reflux;	Example 11 : Preparation of (S)-1 -(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl)-4-amino- isoindoline-1 ,3-dione (apremilast) from the compound of formula 5S Into a reaction vessel equipped with magnetic stirrer and condenser was placed (S)-1 -(3- ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (2.24 mmol, 1 g) and was dissolved in 10 mL of glacial acetic acid. Afterwards 3-acetamidophthalic anhydride was added (2.35 mmol, 0.48 g) and reaction mixture was vigorously stirred at reflux overnight. Reaction system was cooled down to room temperature and acetic acid was evaporated under reduced pressure. The organic residue was extracted with dichloromethane, organic phases were washed with water, dried over Na2S04 and solvent was evaporated. The residue was recrystallized from acetone/ethanol mixture, solid material was filtered off and dried in vacuo at 60 C affording 0.66 g (64% Yield) of final product with > 99% ee. 1 H NMR analysis was in agreement with known data.
59%	With acetic acid; for 15h;Reflux;	A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144 C; 1H NMR (CDCl3) delta: 1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J= 7 Hz, 1H, Ar), 7.64 (t, J= 8 Hz, 1H, Ar), 8.74 (d, J= 8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) delta: 14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
	With acetic acid;Reflux;	N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide, which may be obtained via techniques known in the art, (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine, and glacial acetic acid is refluxed overnight and then cooled to <50 C. The solvent is then removed in vacuo, and the residue is dissolved in ethyl acetate. The resulting solution is washed with water, saturated aqueous NaHCO3, brine, and dried over sodium sulphate. The solvent is evaporated in vacuo, and the residue is recrystallized from a binary solvent containing ethanol and acetone. The solid is isolated by vacuum filtration and washed with ethanol. The product is then dried to afford H-CH2-CH3-Compound A.
8.5 g	With acetic acid; In toluene; at 100 - 105℃;	(S)- 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine (6.5 g, 0.023 moles) were added to toluene (120 ml) and stirred at room temperature. Acetic acid (30 ml) and N-acetylphthalic anhydride (5.12 g, 0.024 moles) was added to the reaction mixture at room temperature. The temperature of reaction mixture was raised to 100-105C and maintained for 8-10 hours. Distilled the solvent at below 60C under vacuum and cooled the reaction mixture to room temperature. Methyl ethyl ketone (150 ml) was added to the reaction mixture at room temperature. The temperature of reaction mixture was raised to 50-60C and 10% sodium bicarbonate solution (150 ml) was added followed by water (50 ml). The layers were separated and the organic layer was distilled upto one-fourth of its initial volume under vacuum and cooled to 0-5C. The reaction mixture was maintained at 0-5C for 1-2 hours. The solid was filtered, washed with methyl ethyl ketone (15 ml) and dried in oven to provide apremilast as product.Yield: 8.5 g
		A reaction vessel was charged with glacial acetic acid (300 ml_), Tri ethyl amine (40.72 g), (S) - 1 -(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (100 g) and 3-Acetamido phthalic anhydride (75.05g). Reaction mass was heated for 1.0 hour at 90±3C. After completion of the reaction; reaction mass was cooled to 27 ± 3C. Process water (500 ml_) and dichloromethane (300 ml_) were added in to the reaction mass. Reaction mass was stirred and settled. Layers were separated. Acetyl chloride (17.23 g) was charged in to the organic layer and was heated for 15-20 min at 40 ± 3C. The organic layer was cooled to 27 ± 3C and washed with sodium bicarbonate solution in water. Benzyl alcohol (1 18.68 g) was charged into the organic layer and solvent was distilled out completely under reduced pressure at 42 ± 3C. Methanol (200 ml_) was charged into reaction mass at below 40C. Reaction mass was stirred for 15-20 min. at 52 ± 3C and 1 hour at 27 ± 3C. The solid was filtered and washed with methanol.
	With acetic acid; at 85℃; for 5h;	In a three-neck flask, 500 g of chiral amine and 412 g of anhydride were added.Glacial acetic acid 4L, heated at 85 C under reflux for 5 h.The system was cooled to room temperature and extracted and washed.The solvent was evaporated to dryness to obtain 750 g of crude Apstar.Purity (HPLC) 96%;_(2)Crude refiningThe crude product (200 g) was added to 2-butanone (3L) and water (1L).Heat to 50-60C to dissolve the solids.Cool to 0 ~ 10 C crystallized 1h, suction filtration,175g of refined white crystals are dried at 50C.Yield 87.5%, purity (HPLC) 99.8%,The largest single miscellaneous 0.02%.

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

3
[ 608141-42-0 ]
[ 61940-21-4 ]
[ 1227368-31-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In acetonitrile; at 81 - 83℃; for 2h;Product distribution / selectivity;	Example 4B Alternative Preparation of Compound (1)Compound (1) was also prepared by the following procedure. A mixture of methyl 2-bromomethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 2), <strong>[608141-42-0](1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine</strong> (104.7 g, 383 mmol, prepared previously in Example 3), and potassium carbonate powder (100.8 g, 730 mmol, from Aldrich Chemicals) was suspended in acetonitrile (500 mL) at room temperature. The reaction mixture was refluxed at 81-83 C. for about two hours until there was less than 2% of unreacted methyl 2-bromomethyl-6-nitrobenzoate. After the reaction mixture was cooled to 45-50 C., methanol (200 mL) was charged over 5-10 minutes. After the mixture was allowed to cool to 20-25 C. and stirred for 2 hours, deionized water (1.40 L) was charged over 0.5-1 hour and stirred at 20-25 C. for 30 minutes and at 0-5 C. for 1-2 hours. The solid was filtered, washed with deionized water (3×300 mL), and dried to <10% of water content as measured by Karl Fisher titration. The solid was suspended in methanol (750 mL) and refluxed for 1-1.5 hours. The suspension was cooled to 0-5 C. over 1.5-2 hours and kept at 0-5 C. for 1-1.5 hours. The solid was filtered, washed with 0-5 C. methanol (2×200 mL) and heptane (200 mL), and then dried at 40-45 C. under vacuum to a constant weight. The yield of Compound (1) was 148.0 g (93%), based on 100.0 g input of methyl 2-bromomethyl-6-nitrobenzoate. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of <1.0% measured by Karl Fisher titration.
93%	With potassium carbonate; In acetonitrile; at 81 - 83℃; for 0.2h;	(1 S)-7-nitro-2-[ 1 -(3 -ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl]isoindolin-1-one was prepared by the following procedure. A mixture of methyl 2-bromomethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 6.5.2.), (iS)1 -(3 -ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (104.7 g, 383 mmol, preparedpreviously in Example 6.5.3.), sodium hydrogen carbonate (67.5 g, 8.03 moles, from Aldrich Chemicals) and dimethyl formamide (500 mL) was charged into a 1-L 3-necked flask at room temperature under nitrogen. The reaction mixture was gradually heated to an internal temperature of 70-75C for two hours until there was less than 99% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration.
93%	With potassium carbonate; In acetonitrile; at 81 - 83℃; for 2h;Inert atmosphere;	6.5.5. Alternative Preparation of (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (0178) (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl] isoindolin-1-one was also prepared by the following procedure. A mixture of methyl 2-bromomethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 6.5.2.), <strong>[608141-42-0](1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine</strong> (104.7 g, 383 mmol, prepared previously in Example 6.5.3.), and potassium carbonate powder (100.8 g, 730 mmol, from Aldrich Chemicals) was suspended in acetonitrile (500 mL) at room temperature. The reaction mixture was refluxed at 81-83 C. for about two hours until there was less than 2% of unreacted methyl 2-bromomethyl-6-nitrobenzoate. After the reaction mixture was cooled to 45-50 C., methanol (200 mL) was charged over 5-10 minutes. After the mixture was allowed to cool to 20-25 C. and stirred for 2 hours, deionizer water (1.40 L) was charged over 0.5-1 hour and stirred at 20-25 C. for 30 minutes and at 0-5 C. for 1-2 hours. The solid was filtered, washed with deionizer water (3×300 mL), and dried to <10% of water content as measured by Karl Fisher titration. The solid was suspended in methanol (750 mL) and refluxed for 1-1.5 hours. The suspension was cooled to 0-5 C. over 1.5-2 hours and kept at 0-5 C. for 1-1.5 hours. The solid was filtered, washed with 0-5 C. methanol (2×200 mL) and heptane (200 mL), and then dried at 40-45 C. under vacuum to a constant weight. The yield of (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one was 148.0 g (93%), based on 100.0 g input of methyl 2-bromomethyl-6-nitrobenzoate. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of <1.0% measured by Karl Fisher titration.

93%	With potassium carbonate; In acetonitrile; at 81 - 83℃; for 20h;Reflux;	10223] (1 S)-7-nitro-2-[1 -(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]isoindolin-1 -one was also prepared by the following procedure. A mixture of methyl 2-bromom- ethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 5.7.2), (1S)-1-(3-ethoxy-4-methoxyphe- nyl)-2-methanesulfonyl-ethylamine (104.7 g, 383 mmol, prepared previously in Example 5.7.3), and potassium carbonate powder (100.8 g, 730 mmol, fromAldrich Chemicals) was suspended in acetonitrile (500 mE) at room temperature. The reaction mixture was refluxed at 81-83 C. for about two hours until there was less than 2% of unreacted methyl 2-bro- momethyl-6-nitrobenzoate. Afier the reaction mixture was cooled to 45-50 C., methanol (200 mE) was charged over 5-10 minutes. Afier the mixture was allowed to cool to 20-25 C. and stirred for 2 hours, deionized water (1.40 L) was charged over 0.5-1 hour and stirred at 20-25 C. for 30 minutes and at 0-5 C. for 1-2 hours. The solid was filtered, washed with deionized water (3 x3 00 mE), and dried to 99% measured by HPLC based on area percentage, and a water content of <1.0% measured by Karl Fisher titration
54%	With triethylamine; In N,N-dimethyl-formamide; at 80 - 90℃; for 24h;	Step 1 :; A solution of 2-bromomethyl-6-nitro-benzoic acid methyl ester (4.0g, 14.6 mmol), (l S)- l-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (4.0g, 14.6 mmol) and triethylamine (4.4 mL, 31.6 mmol) in DMF (40 mL) was heated at 80C-90C for 1 day. The solvent was removed in vacuo to give an oil. The oil was extracted with ethyl acetate (150 mL) and HC1 (2N, 50 mL). The organic layer was washed with HC1 (2N, 2X50 mL), water (2X50 mL), brine (2X50 mL) and dried over MgS04. The solvent was removed in vacuo to give a yellow oil. The oil was slurried in ether (50 mL) to give a suspension. The suspension was filtered and washed with ether to give 2-[(l S)- 1 -(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-nitro-2,3-dihydro- isoindol- l -one as a yellow solid (3.43 g, 54% yield): lH NMR (CDC13) delta 1.5 (t, J= 7 Hz, 3H, CH3), 2.99 (s, 3Eta, CH3), 3.69 (dd, J= 5, 15 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J = 7 Hz, 2H, G¾), 4.27 (dd, J = 1 1 , 15 Hz, 1H, CHH), 4.30 (d, J = 17 Hz, 1H, NCHH), 4.54 (d, J = 17 Hz, 1H, NCHH), 5.70 (dd, J = 5, 10 Hz, 1H, NCH), 6.85 (d, J= 8 Hz, 1H, Ar), 6.94-7.00 (m, 2H, Ar), 7.58- 7.76 (m, 3H, Ar).

References: [1]Patent: US2011/87033,2011,A1 .Location in patent: Page/Page column 11.
[2]Patent: WO2015/175773,2015,A1 .Location in patent: Paragraph 0119.
[3]Patent: US9272035,2016,B2 .Location in patent: Page/Page column 30.
[4]Patent: US2016/128981,2016,A1 .Location in patent: Paragraph 0223.
[5]Patent: WO2011/79091,2011,A1 .Location in patent: Page/Page column 39.

4
[ 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).

References: [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.

5
[ 608141-42-0 ]
[ 635705-76-9 ]

References: [1]Patent: US2011/87033,2011,A1 .
[2]Patent: WO2011/79091,2011,A1 .
[3]Patent: US2014/81032,2014,A1 .
[4]Patent: US9272035,2016,B2 .

6
[ 608141-42-0 ]
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 ]

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

7
[ 608141-42-0 ]
[ 1312952-61-6 ]