Name: 616-91-1|(R)-2-Acetamido-3-mercaptopropanoic acid|98%
Brand: Ambeed
SKU: A233740
Price: 5.0 USD
Availability: InStock
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1
[ 67-56-1 ]
[ 616-91-1 ]
[ 7652-46-2 ]

Yield	Reaction Conditions	Operation in experiment
Ca. 100%	With acetyl chloride; at 20℃; for 48h;	To a solution of (R)-2-acetamido-3-mercaptopropanoic acid, N-acetyl-(z,)-cysteine (50 g, 0.30 mol) in 500 mL of methanol was added 0.5 mL of acetyl chloride. The solution was stirred at room temperature for 48 h at which time another 0.5 mL of acetyl chloride was added. The solution was stirred overnight then concentrated to a viscous liquid. Trituration with hexanes afforded the methyl ester as white solid. The product was dried under high vacuum at room temperature for 4 h to give 53.4 g (-100%) of (R)-methyl 2-acetamido-3-mercaptopropanoate. 'HNMR (CDC13) delta 6.39 (bs, 1 H), 4.90 (m, 1H), 3.79 (s, 3H), 3.01 (d, 2H), 2.06 (s, 3H).
80.5%	With thionyl chloride; at 0 - 20℃; for 3h;	Thionyl chloride (0.5 mL, 6.8 mmol) was carefully added to a stirred solution of N-acetyl-L-cysteine (1.0 g, 6.1 mmol) in 10 mL of anhydrous MeOH. The reaction mixture was stirred for 1 h at 0 C and then at room temperature for further 2 h. The solvent was removed under reduced pressure, and 5 mL of water was added to the resulting residue followed by the washing with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with ethyl acetate (3 x 5 mL), and the combined organic layers were dried with anhydrous MgSO4, filtered and concentrated in vacuo to afford N-acetyl-L-cysteine methyl ester 4 (870.3 mg, 4.9 mmol, 80.5% yield) as a light yellow solid. IR (KBr): = 3302, 2947, 2848, 2564, 1737, 1643, 1551, 1441, 1373, 1224 cm-1. 1H NMR (600.17 MHz, DMSO-d6, 25 C, TMS): delta (ppm) = 8.32 (d, 3J = 7.5 Hz, 1H), 4.44 (td, 3J = 5.1 and 7.5 Hz, 1H), 3.65 (s, 3H), 2.83 (ddd,2J = 13.7, 3J = 8.5 and 5.1 Hz, 1H), 2.74 (ddd, 2J = 13.7, 3J = 8.6 and 7.4 and Hz, 1H), 2.55 (t, 3J = 8.5 Hz, 1H), 1.88 (s, 3H). 13C NMR (150.91 MHz, DMSO-d6, 25 C, TMS): delta (ppm) = 171.34, 169.91, 54.96, 52.525.85, 22.76. HRMS (TOF-EI+): m/z [M + H]+ calculated for C6H12NO3S: 178.0532; found: 178.0543.
80.5%	With thionyl chloride; at 0 - 20℃; for 3h;	Thionyl chloride (0.50 mL, 6.80 mmol) was carefully added to a stirred solution of N-acetyl-L-cysteine (1.00 g, 6.10 mmol) in 10 mL of anhydrous CH3OH. The reaction mixture was stirred for 1 h at 0 oC and then at room temperature for further 2 h. The solvent was removed under reduced pressure, and 5 mL of water was added to the resulting residue followed by the washing with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with ethyl acetate (3 x 5.00 mL), and the combined organic layers were dried with anhydrous MgSO4, The mixture was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate =2 :1) to give the N-acetyl-L-cysteine methyl ester (870.23 mg, 4.91 mmol, 80.50% yield) as a light white solid.

69%	With thionyl chloride;	(0093) N-acetyl-L-cysteine (1 eq, 6.13 mmol, 1000 mg) (i.e., starting material) and MeOH (20 mL) were added into Rbf, and the mixture was stirred while leaving a needle placed therein, and SOCl2 was added dropwise to the stirred solution. The reaction was confirmed by anis color development (MC:MeOH=1:20). When the starting material disappeared, the solvent was evaporated, and the resultant was subjected to EA extraction with salt water, treated with MgSO4, filtered, and evaporated. The compound obtained by column chromatography (MC: MeOH solvent) separation was identified by NMR. (0094) As a result, it was confirmed that 748 mg of the product was obtained (yield: 69%), and NMR analysis confirmed the formation of the desired compound. (0095) 1H-NMR (MeOD, 400 MHz) delta4.41 (m, 1H), 3.53 (s, 3H), 2.68 (qd, 2H, J=4.9, 14.1 Hz), 1.80 (s, 3H)
68%		[0020] A suspension of N-acetyl-L-cysteine (32.6 g) in dry methanol (120 mL) under nitrogen was stirred for 15 minutes and treated dropwise with concentrated sulfuric acid (0.8 mL) at room temperature with vigorous stirring. After 22 hours of stirring, the mixture was treated with water (25 mL) and the volatiles were removed under reduced pressure. The resulting residue was diluted with ethyl acetate (200 mL), washed with aqueous saturated sodium bicarbonate (150 mL) and the layers were allowed to separate.[0021] The organic layer was separated from the aqueous layer and dried over anhydrous sodium sulfate. The aqueous layer was re-extracted with ethyl acetate (2 x 100 mL). The combined organic extract was filtered and concentrated in vacuo to yield N-AcetylL-cysteine methyl ester (24.1 g, 68%) as a white crystalline solid: 1H NMR (400 MHz DMSOd 6) 5 (ppm): 8.29 (d, 1 H), 4.39 (m, 1 H), 3.60 (s, 3H), 2.77 (dd, 1 H), 2.70 (dd, 1 H), 2.51 (s, 1H), 1.84 (s, 3H); LRMS: 178.13 (M+H).
45%	With thionyl chloride; at 20℃; for 1.5h;Inert atmosphere;	To a solution of N-acetyl-cysteine (1.00 g, 6.13 mmol, 1.0 eq.) stirring in methanol (22 mL) was added thionyl chloride (0.85 g, 0.52 mL, 7.11 mmol, 1.16 eq.) dropwise and the reaction mixture was stirred under argon at RT for 1.5 h. After this time, the reaction mixture was concentrated in vacuo and the resulting residue was partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, dried over Na2504, filtered and concentrated in vacuo. The resulting crude material was adsorbed onto Celite and purified by silica gel chromatography, eluting with methanol and chloroform (1:99 - 10:90; methanol : chloroform) to yield N-acetyl-Lcysteine methyl ester 2 as a colourless solid (0.49 g, 45%): Rf 0.6 (5:95 MeOH:chloroform); mp 79-8 1 C (MeOH: chloroform) (Lit. Value: 79-80 C (ethyl acetate))3 [ct] +75.5 (c 1.0, chloroform) (Lit. Value [ct]D +71.0 (c 1.0, chloroform))4 ?HNIVIR (400 IVIFIz; CDC13): s/ppm 6.68 (d, 1H, J5.8 Hz, NI]), 4.86-4.78 (m, 1H, Cys-ct-CI]), 3.72 (s, 3H, COOCH3), 2.93 (dd, 2H, J9.0 Hz, J4.4 Hz, Cys-f3-CH2), 2.01 (s, 3H, COCH3), 1.36 (t, 1H, J 8.8 Hz, SI]); m/z (ESj 178 ([M+H], 100%). The data are in good agreement with literature values.
	With thionyl chloride; at 0 - 20℃;Inert atmosphere;	Example 3 N-Acetyl-L-cysteine methyl ester (AcCysOMe) Thionyl chloride (SOCl2, 10.0 mL, 137.9 mmol) was added dropwise to a stirred solution of N-acetyl-L-cysteine (15.0 g, 91.9 mmol) in anhydrous methanol (140 mL) under argon at 0 C. The reaction mixture was allowed to warm slowly to room temperature and then stirred for 6 hours. The solvent was removed under reduced pressure and the resulting residue diluted with EtOAc (250 mL) and water (250 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (250 mL). The combined organic layers were washed with brine (2*150 mL) and then dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give a thick, colourless oil that solidified on standing at -20 C. overnight. This material was used without purification. 1H NMR (400 MHz, CDCl3): deltaH=1.35 (1H, t, J=9.0 Hz, SH), 2.07 (3H, s, CH3CO), 3.01 (2H, ddd, J=9.0, 4.0, 2.4 Hz, CH2SH), 3.79 (3H, s, CO2CH3), 4.89 (1H, ddd, J=7.7, 4.0, 3.9 Hz, Halpha), 6.45 (1H, br s, NH).
618 mg	With sulfuric acid; at 90℃; for 24h;	General procedure: Esters 7-8 and 10-11 were prepared according to modified literature methods [27,28].The carboxylic acid (6 or 9) was dissolved in either methanol (30 mL) or ethanol (30 mL), with 2 dropsof concentrated sulfuric acid added to the solution before refluxing at 90 C for 24 h. The reactionprogress was monitored by TLC (cyclohexane-ethyl acetate; 1:1). The reaction was concentrated underreduced pressure to yield a white solid.

Reference： [1]Patent: WO2014/11624,2014,A2 .Location in patent: Paragraph 00137; 00138
[2]European Journal of Medicinal Chemistry,1980,vol. 15,p. 495 - 497
[3]Beilstein Journal of Organic Chemistry,2017,vol. 13,p. 925 - 937
[4]Tetrahedron Letters,2020
[5]Journal of the American Chemical Society,2013,vol. 135,p. 2088 - 2091
[6]Journal of Organic Chemistry,1990,vol. 55,p. 1728 - 1735
[7]Patent: US2019/218178,2019,A1 .Location in patent: Paragraph 0092-0095
[8]Patent: WO2015/148880,2015,A1 .Location in patent: Paragraph 0019; 0020; 0021
[9]Angewandte Chemie - International Edition,2020,vol. 59,p. 3671 - 3677
Angew. Chem.,2020,vol. 132,p. 3700 - 3706,7
[10]Journal of the American Chemical Society,2019,vol. 141,p. 14931 - 14937
[11]Biomacromolecules,2019,vol. 20,p. 1412 - 1420
[12]Dalton Transactions,2006,p. 5269 - 5277
[13]Angewandte Chemie - International Edition,2008,vol. 47,p. 2244 - 2247
[14]Patent: WO2016/185200,2016,A1 .Location in patent: Page/Page column 30
[15]Journal of the Chemical Society. Perkin transactions II,1984,p. 1737 - 1744
[16]Journal of Medicinal Chemistry,1988,vol. 31,p. 1279 - 1282
[17]Journal of the American Chemical Society,2008,vol. 130,p. 9642 - 9643
[18]Patent: US2012/178913,2012,A1 .Location in patent: Page/Page column 5-6
[19]Journal of the American Chemical Society,2013,vol. 135,p. 12156 - 12159
[20]Molecules,2018,vol. 23
[21]Free radical biology and medicine,2020,vol. 152,p. 386 - 394

2
[ 50-00-0 ]
[ 616-91-1 ]
[ 1946-82-3 ]
N-acetylcysteine methylolee [ No CAS ]
(R)-2-Acetylamino-6-[((R)-2-acetylamino-2-carboxy-ethylsulfanylmethyl)-amino]-hexanoic acid [ No CAS ]

Reference： [1]Journal de Chimie Physique et de Physico-Chimie Biologique,1984,vol. 81,p. 173 - 178

3
[ 616-91-1 ]
[ 1466-82-6 ]
2-acetamido-3-(2-acetoxybenzoylthio)propionic acid [ No CAS ]
[ 50-78-2 ]

Reference： [1]Journal of Pharmaceutical Sciences,1986,vol. 75,p. 1081 - 1084

4
[ 616-91-1 ]
[ 17696-69-4 ]
N,N'-diacetylporphyrin c [ No CAS ]

Reference： [1]Australian Journal of Chemistry,1993,vol. 46,p. 1755 - 1762

5
[ 616-91-1 ]
[ 635-65-4 ]
[ 119069-25-9 ]
[ 36920-63-5 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 3507 - 3510

6
[ 616-91-1 ]
[ 95535-40-3 ]
N-Acetyl-S-<2-<(4-ethoxycarbonylphenyl)sulfonyl>ethyl>cystein [ No CAS ]

Reference： [1]Liebigs Annalen der Chemie,1985,p. 22 - 33

7
[ 616-91-1 ]
[ 5545-17-5 ]

Yield	Reaction Conditions	Operation in experiment
	With cis-diaammineplatinum(IV) tetrachloride; In aq. acetate buffer; at 25℃;pH 4.51;Kinetics;	General procedure: An Applied Photophysics SX-20 stopped-flow spectrometer( Applied Photophysics Ltd., Leatherhead, U.K.) was employed for kinetic measurements; the kinetic traces were simulated by the software provided by Applied Photophysics. Stock solutions ofNAC(20-30 mM) were prepared just before the kinetic measurements by dissolving a certain amount NAC in buffers; the stock solutions were flushed with nitrogen for 10 min and were only used for a couple of hours. Solutions of NAC and of the Pt(IV) complexes for kinetic measurements were prepared, respectively, by adding an appropriate amount of the Pt(IV) stock solution and NAC to a specific buffer. Those solutions were flushed for10 min with nitrogen before loading onto the stopped-flow machine. Reactions were started by mixing equal volumes of NACand platinum(IV) solutions directly in the stopped-flow machine. Pseudo first-order conditions were fulfilled by keeping NAC in at least ten fold excess.
	With mefenamic Acid; In aq. phosphate buffer; ethanol; water;Electrolysis;	General procedure: A mixture of a phosphate buffer (ca. 50 ml; c = 0.2 M,pH = 7.0) in water/ethanol (30:70 v/v) solution, containing mefenamic acid (1) (0.02 mmol) and glutathione (0.3 mmol) (3) orN-acetyl-L-cysteine (3?) was electrolyzed in a divided cell at 0.6 Vvs Ag/AgCl. The electrolysis was terminated when the currentdecreased by more than 95%. After having finished the electrolysis,the precipitated solid was collected by filtration and washed severaltimes with water. The products were characterized by infraredspectroscopy,7 mass spectroscopy, and melting point measurements.

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 4173 - 4177
[2]Organic Letters,2018,vol. 20,p. 6274 - 6278
[3]Journal of the American Chemical Society,1989,vol. 111,p. 4935 - 4940
[4]Journal of the American Chemical Society,1992,vol. 114,p. 9737 - 9743
[5]Canadian Journal of Chemistry,1994,vol. 72,p. 2094 - 2101
[6]Canadian Journal of Chemistry,1994,vol. 72,p. 2102 - 2107
[7]Journal de Chimie Physique et de Physico-Chimie Biologique,1997,vol. 94,p. 271 - 276
[8]Chemical Research in Toxicology,1995,vol. 8,p. 817 - 820
[9]Journal of Organic Chemistry,1999,vol. 64,p. 8161 - 8169
[10]Journal of the Chemical Society. Perkin transactions I,1999,p. 3067 - 3068
[11]Chemical Research in Toxicology,2002,vol. 15,p. 483 - 489
[12]Journal of Mass Spectrometry,2004,vol. 39,p. 1408 - 1416
[13]Journal of Mass Spectrometry,2006,vol. 41,p. 1578 - 1593
[14]Chemical Communications,2010,vol. 46,p. 409 - 411
[15]Transition Metal Chemistry,2016,vol. 41,p. 295 - 304
[16]Zeitschrift fur Physikalische Chemie,2017,vol. 231,p. 1093 - 1109
[17]Green Chemistry,2018,vol. 20,p. 118 - 124
[18]Chemistry - A European Journal,2018,vol. 24,p. 9485 - 9489
[19]Chemical Research in Toxicology,2019,vol. 32,p. 400 - 404
[20]Cell Chemical Biology,2019,vol. 26,p. 686 - 4,698
[21]Chemical Science,2019,vol. 10,p. 5308 - 5318
[22]Journal of the Electrochemical Society,2020,vol. 167

8
[ 616-91-1 ]
[ 5545-17-5 ]
[ 56577-02-7 ]

Reference： [1]Analytical Chemistry,1992,vol. 64,p. 779 - 785

9
[ 616-91-1 ]
[ 5545-17-5 ]
(R)-2-Acetylamino-3-((R)-2-acetylamino-2-carboxy-ethylsulfanyl)-propionic acid [ No CAS ]

Reference： [1]Journal de Chimie Physique et de Physico-Chimie Biologique,1993,vol. 90,p. 907 - 916

10
[ 616-91-1 ]
[ 3696-28-4 ]
[ 1121-30-8 ]
[ 136852-79-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With acetic acid In chloroform for 30h; Ambient temperature;

Reference： [1]Barton, Derek H. R.; Chen, Chen; Wall, G. Michael [Tetrahedron, 1991, vol. <32> 47, p. 6127 - 6138]

11
[ 2978-10-1 ]
[ 616-91-1 ]
[ 73908-42-6 ]
[ 73908-46-0 ]

Yield	Reaction Conditions	Operation in experiment
1: 6% 2: 44%

Reference： [1]Miller, Marvin J. [Journal of Organic Chemistry, 1980, vol. 45, # 15, p. 3131 - 3132]

12
[ 616-91-1 ]
[ 100-39-0 ]
[ 19542-77-9 ]

Reference： [1]Tetrahedron Letters,1997,vol. 38,p. 2149 - 2152
[2]European Journal of Medicinal Chemistry,1980,vol. 15,p. 495 - 497

13
[ 616-91-1 ]
[ 51264-14-3 ]
[ 57165-06-7 ]
[ 1255771-68-6 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol at 30℃; pH = 7.61 - 11.40;

Reference： [1]Khan, Niyaz M.; Malspeis, L. [Journal of Organic Chemistry, 1982, vol. 47, # 14, p. 2731 - 2740]

14
[ 616-91-1 ]
[ 540-51-2 ]
[ 15060-26-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydroxide In water at 20℃; for 12h;	2-(Acetylamino)-3-[(2-hydroxyethyl)sulfanyl]-propionic acid (1) In 50 mL of water was dissolved 5 g (30.7 mmol) of N-acetylcysteine, at cooling to the solution was added 2.48 g (62 mmol) of NaOH and 4.59 g (37 mmol) of 2-bromoethanol. The reaction mixture was stirred for 12 h at room temperature, evaporated in a vacuum, the residue was washed with acetone (100 mL). The insoluble part was acidified with 10% solution of hydrochloric acid till pH 5. Water was evaporated in a vacuum. The resinous residue contained the target compound with impurity of inorganic salts (NaCl, NaBr). For additional purification the crude product was extracted with acetone of “special purity” grade (~300 mL), the insoluble part of inorganic salts was filtered off, acetone was distilled off in a vacuum. Yield 6.34 g (90%). IR spectrum (KBr), ν, cm-1: 3285 br (NH, OH), 1722 (C=O), 1536, 1586. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.85 s(3H, CH3), 2.57 t (2H, SCH2, 3J 6.7 Hz), 2.732.90 m(2H, SCH2), 3.50 t (2H, OCH2, 3J 6.7 Hz), 4.33 m (1H,CH), 8.21 d (1H, NH, 3J 7.8 Hz). 13 NMR spectrum (DMSO-d6), δ, ppm: 22.97 (CH3), 33.89 and 35.00(SCH2CH2O), 52.95 (SCH2), 61.34 (NCH), 170.03(C=O), 172.86 [C(O)OH]. Found, %: C 39.48; H 6.39; N 6.55; S 15.31. C7H13NO4S. Calculated, %: C 40.57;H 6.32; N 6.76; S 15.47.
	With sodium methylate 1.) methanol, 10 min, room temperature, 2.) methanol; Yield given. Multistep reaction;

Reference： [1]Rozentsveig; Kondrashov; Serykh, V. Yu.; Zhurba; Alekseenko [Russian Journal of Organic Chemistry, 2016, vol. 52, # 5, p. 753 - 754][Zh. Org. Khim., 2016, vol. 52, # 5, p. 763 - 764]
[2]Van Bladeren; Buys; Breimer; Van Der Gen [European Journal of Medicinal Chemistry, 1980, vol. 15, # 6, p. 495 - 497]

15
[ 616-91-1 ]
[ 60976-49-0 ]
C₅₁H₄₄N₂O₃₂S₂ [ No CAS ]
C₄₁H₂₈O₂₇ [ No CAS ]
C₄₆H₃₇NO₃₀S [ No CAS ]
C₄₆H₃₉NO₃₁S [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1996,vol. 44,p. 34 - 40

16
[ 616-91-1 ]
[ 154226-60-5 ]
[ 133343-34-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine In dichloromethane at 23℃; for 4h;
87%	With triethylamine In dichloromethane at 20℃; for 22h; Inert atmosphere;
79%	With triethylamine In dichloromethane at 20℃; for 14h;

64%	With triethylamine In dichloromethane for 0.833333h; Ambient temperature;
58%	With triethylamine In dichloromethane at 20℃; for 24h;
47%	With triethylamine In dichloromethane at 20℃; for 18h;
880.0 mg	With triethylamine In dichloromethane at 23℃; for 4h;
	With triethylamine
2.8 mg	With triethylamine In dichloromethane at 20 - 23℃;

Reference： [1]Corey; Li, Weidong; Nagamitsu, Tohru [Angewandte Chemie - International Edition, 1998, vol. 37, # 12, p. 1676 - 1679]
[2]Yoshioka, Shun; Nagatomo, Masanori; Inoue, Masayuki [Organic Letters, 2015, vol. 17, # 1, p. 90 - 93]
[3]Ooi, Hidenori; Ishibashi, Norihisa; Iwabuchi, Yoshiharu; Ishihara, Jun; Hatakeyama, Susumi [Journal of Organic Chemistry, 2004, vol. 69, # 22, p. 7765 - 7768]
[4]Nagamitsu, Tohru; Sunazuka, Toshiaki; Tanaka, Haruo; Omura, Satoshi; Sprengeler, Paul A.; Smith III, Amos B. [Journal of the American Chemical Society, 1996, vol. 118, # 15, p. 3584 - 3590]
[5]Fukuda, Nobuhisa; Sasaki, Kazuki; Sastry; Kanai, Motomu; Shibasaki, Masakatsu [Journal of Organic Chemistry, 2006, vol. 71, # 3, p. 1220 - 1225]
[6]Hayes, Christopher J.; Sherlock, Alexandra E.; Green, Martin P.; Wilson, Claire; Blake, Alexander J.; Selby, Matthew D.; Prodger, Jeremy C. [Journal of Organic Chemistry, 2008, vol. 73, # 6, p. 2041 - 2051]
[7]Corey; Li, Weidong; Reichard, Gregory A. [Journal of the American Chemical Society, 1998, vol. 120, # 10, p. 2330 - 2336]
[8]Panek, James S.; Masse, Craig E. [Angewandte Chemie - International Edition, 1999, vol. 38, # 8, p. 1093 - 1095]
[9]Location in patent: experimental part Gu, Wenxin; Silverman, Richard B. [Journal of Organic Chemistry, 2011, vol. 76, # 20, p. 8287 - 8293]

17
[ 616-91-1 ]
[ 76-83-5 ]
[ 27486-87-9 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 20℃;	N-Acetyl-cysteine (100.0 g, 613 mmol) was dissolved in DMF (600 mL) andtriphenylmethyl chloride (179.4 g, 643 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water andextracted twice with ethyl acetate. The combined organic layers were washed withbrine, dried over sodium sulfate and filtered. The solvent was removed in vacuo to givecompound 2-1. lodoethane (144.3 g, 925 mmol) was added to a suspension of 2-1(250.0 g, 617 mmol) and K2003 (170.4 g, 1233 mmol) in DMF (1250 ml). The reaction mixture was stirred at room temperature overnight then diluted with ice-water andextracted twice with ethyl acetate. The combined organic layers were washed withwater, brine, dry over sodium sulfate and filtered. The solvent was removed from the filtrate in vacuo to give compound 2-2. TFA (480 mL) was added to a solution of 2-2 (240 g, 554 mmol) and triethylsilane (128.7 g, 1107 mmol) in dichloromethane (2.4 L) at 0 00 and the reaction mixture allowed to stir at room temperature overnight. Thesolvent was removed in vacuo and compound 2-3 isolated by column chromatography.

Reference： [1]Organic and Biomolecular Chemistry,2011,vol. 9,p. 2209 - 2218
[2]Tetrahedron Letters,1997,vol. 38,p. 2149 - 2152
[3]Liebigs Annales,1996,p. 841 - 843
[4]Patent: WO2017/60420,2017,A1 .Location in patent: Page/Page column 34; 35; 36
[5]RSC Advances,2018,vol. 8,p. 2818 - 2823

18
[ 616-91-1 ]
[ 641-49-6 ]
(R)-2-Acetylamino-3-(3-methoxy-2-nitro-phenylsulfanyl)-propionic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 133 - 138

19
[ 616-91-1 ]
[ 56577-02-7 ]
[ 5545-17-5 ]

Reference： [1]Canadian Journal of Chemistry,1998,vol. 76,p. 789 - 794

20
[ 616-91-1 ]
[ 2210-79-9 ]
o-Cresyl glycidyl ether mercapturic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine In ethanol; water at 20℃;

Reference： [1]De Rooij, Ben M.; Commandeur, Jan N. M.; Hommes, John W.; Aalbers, Tom; Groot, Ed J.; Vermeulen, Nico P. E. [Chemical Research in Toxicology, 1998, vol. 11, # 2, p. 111 - 118]

21
[ 616-91-1 ]
[ 13651-55-3 ]
N-acetyl-S-(2,3-dimethylbenzyl)-L-cysteine [ No CAS ]

Reference： [1]Chemosphere,1999,vol. 38,p. 2065 - 2070

22
[ 616-91-1 ]
[ 2257-09-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium hydrogencarbonate In water; isopropyl alcohol at 20℃;	General synthesis of diisothiocyanate-derived mercapturic acids General procedure: Diisothiocyanate (1eq) was dissolved in isopropanol and added dropwise to a solution of N-acetyl-L-cysteine (2.1 eq) and sodium hydrogen carbonate (2.1 eq) in distilled water. In the case of precipitation a small amount of isopropanol or THF (for aromatic diisothiocyanates) was added. The reaction was carried out at r.t. and the progress of the reaction was monitored by TLC. The reaction mixture was evaporated, dissolved in water and extracted 3 times with hexane. The aqueous fraction was acidified with 1M HCl and extracted 3 times with ethyl acetate. Combined organic phases were extracted with brine, dried over anhydrous MgSO4 and evaporated to dryness. The product was purified by preparative HPLC (Discovery BIO Wide Pore C8; 10 μm, 25 cm × 21.2 mm; CH3CN:H2O 0-100% in 30 min). Compound 16: N-acetyl-S-[N-(2-phenylethyl)thiocarbamoyl]-l-cysteine; phenethyl thiocarbamoylmercapturate; yield 78 %; 1HNMR (300 MHz, DMSO-d6): δ 12.87 (s, 1H), 10.14 (d, J = 4.9 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 7.31 - 7.17 (m, 5H), 4.42 - 4.35 (m, 1H), 3.78 - 3.73 (m, 3H), 3.29 (dd, J = 9.3, 13.5 Hz, 1H), 2.87 (t, J = 7.5 Hz, 2H), 1.81 (s, 3H); HRMS: observed m/z, 327.0838, calculated forC14H18N2O3S2, 327.0837 [M+ H]+.
72.8%	With sodium hydrogencarbonate In ethanol; water
	In phosphate buffer at 20℃;

Reference： [1]Grzywa, Renata; Winiarski, Łukasz; Psurski, Mateusz; Rudnicka, Agata; Wietrzyk, Joanna; Gajda, Tadeusz; Oleksyszyn, Józef [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 667 - 671]
[2]Vermeulen, Martijn; Zwanenburg, Binne; Chittenden, Gordon J.F.; Verhagen, Hans [European Journal of Medicinal Chemistry, 2003, vol. 38, # 7-8, p. 729 - 737]
[3]Adesida; Edwards; Thornalley [Food and Chemical Toxicology, 1996, vol. 34, # 4, p. 385 - 392]

23
[ 616-91-1 ]
[ 1946-82-3 ]
[ 110-13-4 ]
N^α-acetyl-6-[3-(N^α-acetylcystein-S-yl)-2,5-dimethylpyrrol-1-yl]norleucine [ No CAS ]

Reference： [1]Chemical Research in Toxicology,1995,vol. 8,p. 764 - 771

24
[ 64-17-5 ]
[ 616-91-1 ]
[ 59587-09-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	With thionyl chloride; at 0 - 20℃; for 4h;Inert atmosphere;	(R)-2-Acetylamino-3-merca to-propionic acid ethyl ester (I3)(used during synthesis of 8) (I3) N-Acetyl-L-cysteine (4.7 g, 28.8 mmol) was dissolved in ethanol (140 mL) and the reaction mixture degassed and flushed with N2 before cooling to 0C. SOCI2 (2.4 mL) was then added drop wise before allowing the reaction to warm to rt and stir at this temperature for 4 h. The solvent was removed in vacuo to give a yellow oil which was then diluted with water and EtOAc. The layers were separated and the aqueous phase extracted with EtOAc (3x). The combined organic extracts were dried over MgSC and evaporated to dryness before purifying by flash column chromatography (Biotage Isolera Four, 100g KPSil column, EtOAc) to afford the desired product as a pale yellow oil which crystallised to give a white solid (2.59g, 13.5 mmol, 47%).
650 mg	With sulfuric acid; at 90℃; for 24h;	General procedure: Esters 7-8 and 10-11 were prepared according to modified literature methods [27,28].The carboxylic acid (6 or 9) was dissolved in either methanol (30 mL) or ethanol (30 mL), with 2 dropsof concentrated sulfuric acid added to the solution before refluxing at 90 C for 24 h. The reactionprogress was monitored by TLC (cyclohexane-ethyl acetate; 1:1). The reaction was concentrated underreduced pressure to yield a white solid.

Reference： [1]Patent: WO2015/181551,2015,A1 .Location in patent: Page/Page column 36
[2]Tetrahedron Letters,2020
[3]Carbohydrate Research,2000,vol. 325,p. 72 - 80
[4]Journal of Medicinal Chemistry,2016,vol. 59,p. 4551 - 4562
[5]Molecules,2018,vol. 23
[6]Free radical biology and medicine,2020,vol. 152,p. 386 - 394

26
[ 616-91-1 ]
[ 3814-34-4 ]
(R)-2-Acetylamino-3-(2-ethyl-butylsulfanyl)-propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium ethanolate In ethanol for 4h; Heating;

Reference： [1]Perrey, David A.; Uckun, Fatih M. [Tetrahedron Letters, 2001, vol. 42, # 10, p. 1859 - 1861]

27
[ 149-29-1 ]
[ 616-91-1 ]
2-acetylamino-3-(5-carboxymethyl-4-oxo-3,4-dihydro-2<i>H</i>-pyran-3-ylsulfanyl)-propionic acid [ No CAS ]
2-((R)-2-Acetylamino-2-carboxy-ethylsulfanyl)-3-[1-((R)-2-acetylamino-2-carboxy-ethylsulfanyl)-meth-(Z)-ylidene]-6-hydroxy-4-oxo-hexanoic acid [ No CAS ]
5-((R)-2-Acetylamino-2-carboxy-ethylsulfanyl)-3-[1-((R)-2-acetylamino-2-carboxy-ethylsulfanyl)-meth-(E)-ylidene]-6-hydroxy-4-oxo-hexanoic acid [ No CAS ]
5,6-Bis-((R)-2-acetylamino-2-carboxy-ethylsulfanyl)-3-[1-((R)-2-acetylamino-2-carboxy-ethylsulfanyl)-meth-(E)-ylidene]-4-oxo-hexanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In phosphate buffer at 20℃; for 20h;

Reference： [1]Fliege, Ralph; Metzler, Manfred [Chemical Research in Toxicology, 2000, vol. 13, # 5, p. 373 - 381]

28
[ 616-91-1 ]
clofibryl-S-acyl-glutathione [ No CAS ]
[ 882-09-7 ]
clofibryl-S-acyl-N-acetylcysteine [ No CAS ]

Reference： [1]Chemical Research in Toxicology,2001,vol. 14,p. 1033 - 1040

29
[ 4478-93-7 ]
[ 616-91-1 ]
N-acetyl-S-{N-[4-(methylsulfinyl)butyl]thiocarbamoyl}-L-cysteine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.5%	With sodium hydrogencarbonate In ethanol; water
36%	With sodium hydroxide In ethanol; water at 23℃; for 2h;	N-acetyl-S-(((methylsulfinyl)butyl) carbamothioyl)-L-cysteine (27) To a solution of acetyl-L-cysteine (92 mg, 0.564 mmol) in ethanol (2 mL) and water (2 mL), wasadded 1 M aq. NaOH to adjust pH to 7-8, then 1-isothiocyanato-4-(methylsulfinyl)butane (100mg, 0.564 mmol) in Ethanol (2.000 mL) and the resulting mixture was stirred at 23 °C for 2 h,the solvent was evaporated. The crude product was purified on a Gilson HPLC (YMC C18 5mm/12 nm 50 x 20 mm preparatory column), eluting at 20 mL/min with a linear gradient runningfrom water to acetonitrile. The desired fractions were concentrated to afford N-acetyl-S-(((methylsulfinyl)butyl) carbamothioyl)-L-cysteine (27) (69 mg, 36%).

Reference： [1]Vermeulen, Martijn; Zwanenburg, Binne; Chittenden, Gordon J.F.; Verhagen, Hans [European Journal of Medicinal Chemistry, 2003, vol. 38, # 7-8, p. 729 - 737]
[2]Boehm, Jeffrey; Davis, Roderick; Murar, Claudia E.; Li, Tindy; McCleland, Brent; Dong, Shuping; Yan, Hongxing; Kerns, Jeffrey; Moody, Christopher J.; Wilson, Anthony J.; Graves, Alan P.; Mentzer, Mary; Qi, Hongwei; Yonchuk, John; Kou, Jen-Pyng; Foley, Joseph; Sanchez, Yolanda; Podolin, Patricia L.; Bolognese, Brian; Booth-Genthe, Catherine; Galop, Marc; Wolfe, Lawrence; Carr, Robin; Callahan, James F. [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 4, p. 579 - 588]

30
[ 616-91-1 ]
[ 18060-79-2 ]
N-acetyl-S-[N-(4-pentenyl)thiocarbamoyl]-L-cysteine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.6 mmol	With sodium hydrogencarbonate In ethanol; water

Reference： [1]Vermeulen, Martijn; Zwanenburg, Binne; Chittenden, Gordon J.F.; Verhagen, Hans [European Journal of Medicinal Chemistry, 2003, vol. 38, # 7-8, p. 729 - 737]

31
[ 616-91-1 ]
[ 935-92-2 ]
N-acetyl-S-(2,3,5-trimethyl-1,4-benzylquinonyl-6)cysteine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	In ethanol; water at 20℃;

Reference： [1]Li, Wen-Wu; Heinze, Juergen; Haehnel, Wolfgang [Journal of the American Chemical Society, 2005, vol. 127, # 17, p. 6140 - 6141]

32
[ 616-91-1 ]
[ 155514-79-7 ]
N-acetyl-S-(N,N-diethylcarbamoyl)cysteine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	In methanol; water at 20℃;
	In phosphate buffer

Reference： [1]Hu, Pei; Jin, Lixia; Baillie, Thomas A. [Journal of Pharmacology and Experimental Therapeutics, 1997, vol. 281, # 2, p. 611 - 617]
[2]Hu, Pei; Jin, Lixia; Baillie, Thomas A. [Journal of Pharmacology and Experimental Therapeutics, 1997, vol. 281, # 2, p. 611 - 617]

33
[ 6066-82-6 ]
[ 616-91-1 ]
[ 5786-21-0 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-acetylcystein; clozaril With sodium hypochlorite In ethanol for 0.166667h; Stage #2: 1-hydroxy-pyrrolidine-2,5-dione With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide; acetonitrile Stage #3: keyhole limpet hemocyanin In phosphate buffer; acetonitrile at 20℃; for 1h;

Reference： [1]Gardner, Iain; Leeder, J Steven; Chin, Terrence; Zahid, Nasir; Uetrecht, Jack P. [Molecular Pharmacology, 1998, vol. 53, # 6, p. 999 - 1008]

34
[ 6066-82-6 ]
[ 616-91-1 ]
[ 5786-21-0 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-acetylcystein; clozaril With sodium hypochlorite In ethanol for 0.166667h; Stage #2: 1-hydroxy-pyrrolidine-2,5-dione With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide; acetonitrile Stage #3: rabbit serum albumin In phosphate buffer; acetonitrile at 20℃; for 1h;

Reference： [1]Gardner, Iain; Leeder, J Steven; Chin, Terrence; Zahid, Nasir; Uetrecht, Jack P. [Molecular Pharmacology, 1998, vol. 53, # 6, p. 999 - 1008]

35
[ 616-91-1 ]
[ 100-44-7 ]
[ 19542-77-9 ]

Reference： [1]Biological and Pharmaceutical Bulletin,2001,vol. 24,p. 1324 - 1328

36
[ 939-18-4 ]
[ 616-91-1 ]
[ 135505-66-7 ]

Reference： [1]Toxicology,2003,vol. 190,p. 249 - 258

37
[ 25021-08-3 ]
[ 616-91-1 ]
C₁₁H₁₄N₂O₇S [ No CAS ]

Reference： [1]Bioorganic Chemistry,2006,vol. 34,p. 424 - 444

38
[ 616-91-1 ]
[ 85363-04-8 ]
NH₂CH₂CNC₅H₈O₂NH₃*C₃H₇SNO₂C₂H₂O [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2007,vol. 46,p. 2470 - 2477

39
[ 60940-34-3 ]
[ 616-91-1 ]
S-(2-phenylcarbamoyl-phenylselenyl)-N-acetyl-L-cysteine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; methanol; water;	EXAMPLE 14 S-(2-Phenylcarbamoyl-phenylselenyl)-N-acetyl-L-cysteine It is obtained similar to example 12 from: 1 g (3,65 mmol) 2-phenyl-1,2-benzoisoselenazole-3(2H)-one in 50 ml methanol and 6 ml dimethylformamide and 0,6 g (3,67 mmol) N-acetyl-L-cysteine in 20 ml water. Yield: 0,95 g (60% of the theory), Fp. 167-168 C.

Reference： [1]Patent: US4618669,1986,A

40
[ 13965-31-6 ]
[ 616-91-1 ]
Pt2(2,2'-bipyridine)2(μ-N-acetyl-L-cysteinato-S)2 [ No CAS ]

Reference： [1]Inorganic Chemistry,1993,vol. 32,p. 2608 - 2609

41
[ 616-91-1 ]
[ 124721-03-5 ]
[ 5545-17-5 ]
[ 1034767-14-0 ]

Reference： [1]Inorganic Chemistry,2000,vol. 39,p. 1728 - 1734

42
[ 616-91-1 ]
[ 1946-82-3 ]
[ 131543-46-9 ]
C₁₅H₂₅N₃O₇S [ No CAS ]

Reference： [1]Chemical Research in Toxicology,2006,vol. 19,p. 1668 - 1676

43
[ 51-61-6 ]
[ 616-91-1 ]
[ 5545-17-5 ]
2-S-(N-acetyl)-cysteinyl-dopamine [ No CAS ]
5-S-(N-acetyl)-cysteinyl-dopamine [ No CAS ]
2-S-5-S-di-(N-acetyl)-cysteinyl-dopamine [ No CAS ]

Reference： [1]Chemistry - A European Journal,2008,vol. 14,p. 8661 - 8673

44
[ 616-91-1 ]
[ 106131-61-7 ]
[ 1234326-41-0 ]

Reference： [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 3612 - 3616
[2]Journal of Physical Organic Chemistry,2014,vol. 27,p. 670 - 675

45
[ 616-91-1 ]
[ 7541-49-3 ]
N-acetyl-S-phytyl-L-cysteine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	sulfuric acid; at 120℃;	00285] N-acetyl-L-cysteine (0.5g, 3.06 mmol) and phytol (l.lg, 3.7 mmol) were mixed in a 25mL round bottomed flask. The resulting mixture was stirred at 12O0C. After ten minutes, a catalytic amount of concentrated H2SO4 was added (about 200muL). About Ih after the addition of H2SO4, TLC/HPLC showed completion of the reaction. The reaction mixture was quenched with NaOH, washed with heptanes to remove the non-polar impurities. The aqueous phase was adjusted to a pH of 2 by addition of aqueous HCl and the product was extracted from ethyl acetate (3 xlO mL). The combined organic phase (ethyl acetate) was washed with water, brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford crude product, which was further purified by preparative HPLC. 630mg of pure product was collected as a semisolid with about a 48% yield. IH-NMR (CDC13): delta 6.45 (d, IH), 5.20 (t, IH), 4.75 (q, IH), 3.22-3.14 (dd, 2H), 3.00-2.90 (dd, 2H), 2.05 (s, 3H), 1.62 (s, 3H), 1.40-1.00( m, 18H), 0.85 (s, 3H), 0.83 (s, 6H), 0.80 (s, 3H).

Reference： [1]Patent: WO2010/90845,2010,A1 .Location in patent: Page/Page column 87-88

46
[ 616-91-1 ]
[ 22494-42-4 ]
[ 96325-00-7 ]

Yield	Reaction Conditions	Operation in experiment
24%	Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With triethylamine In acetone at -10 - 9℃; for 0.416667h; Stage #2: With 2,2,2-Trichloroethyl chloroformate In acetone at -10 - 0℃; for 2h; Stage #3: N-acetylcystein With triethylamine In acetone at -12 - 15℃;	13a Example 13a Example 13aTo a solution of 2',4'-difluoro-4-hydroxy-1,1'-diphenyl-3-carboxylic acid (Diflunisal, 82.5 g, 0.329 mol) dissolved in acetone (450 mL) and cooled to -10° C. (refrigerant mixture: ice-EtOH) was added Et3N (101 mL, 0.725 mol) slowly (addition: 25 min, internal temperature: from -8° C. to 9° C.). To the resulting solution was added 2,2,2-trichloroethyl chloroformate (100 mL, 0.725 mol) slowly (addition: 60 min, internal temperature was maintained below 0° C.: from -10° C. to 0° C.). The mixture was stirred for 1 h at 0° C. (a white precipitate of triethylamine hydrochloride was gradually formed). At the end of the reaction, the mixture was filtered under vacuum, the precipitate (triethylamine hydrochloride) was washed with acetone (4×180 mL) and the filtrate was evaporated under vacuum at 30° C. The oily residue was taken with Et2O (150 mL) and the suspension was evaporated again under vacuum. The operation was repeated three times to remove excess of chlorocarbonate. The residue was dissolved in acetone (180 mL), and added to a refrigerated solution of N-acetyl-L-cysteine (N-Ac-Cys, 53.81 g, 0.329 mol) and Et3N (46 mL, 0.329 mol) in acetone (140 mL) slowly (addition: 55 min, internal temperature was maintained below 15° C.: from 0° C. to 15° C.). The reaction mixture was stirred at 15° C. for 4 h. The mixture was cooled to -12° C. (internal temperature), and Et3N (115 mL, 0.824 mol) was added. The mixture was stirred for 15 h at -12° C. (internal temperature), and at the end of the reaction, the mixture was filtered under vacuum and the precipitate was washed with acetone (3×150 mL). The oily precipitate was suspended in CH2Cl2 (400 mL), cooled to 0° C. and an aqueous HCl solution (15% v:v) was added with vigorous stirring until the pH was lowered to 3. Ethanol (80 mL) was added, and the aqueous phase was extracted with CH2Cl2 (2×400 mL). The combined organic layers were washed with a 10% HCl aqueous solution (1×500 mL) and with water (2×600 mL), were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by trituration with Et2O (100 mL), affording 44.13 g of the title compound (HPLC purity: 88.26%) To increase purity, the solid was suspended in Et2O (100 mL) and stirred at room temperature for 20 min. The solid was filtered under vacuum and was washed with Et2O (3×100 mL), to afford 31.33 g of the title compound GMC-3b (Rf=0.3 CH2Cl2/MeOH/AcOH 95:5:1), white solid, 24% yield, 96.22% HPLC purity); Purity was determined by NMR analysis and mass spectrometry to conform to the following parameters: 1H-NMR (CD3OD, 250 MHz, δ): 8.00 (m, 1H, ArH); 7.66 (dm, J=8.2 Hz, 1H, ArH); 7.50 (m, 1H, ArH); 7.06 (m, 3H, ArH); 4.74 (m, 1H, CH); 3.77 (dd, J=4.7 and 13.7 Hz, 1H, CH); 3.40 (m, 1H, CH); 1.98 (s, 3H, CH3); MS-EI+m/z: 396.00 (M+1); LC-MS: M+1: 396.00; purity: 96.52% (HPLC method: SunFire C18 3.5 um, 2.1×100 mm, flow: 0.3 mL/min, gradient: A:B 3 min 10:90+ from 10:90 to 95:5 in 17 min+10 min 95:5; A: CH3CN:MeOH 1:1; B: NH4OAc buffer 5 mM pH 7).
24%	Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With triethylamine; 2,2,2-Trichloroethyl chloroformate In acetone at -10 - 0℃; for 2h; Stage #2: N-acetylcystein In acetone at -12 - 15℃; for 20h;	A-13a Example A- 13a Example A-13a To a solution of 2'.4'-di†luoro-4-hydroxy- 1 , 1 '-diphenyl-3-carboxylie acid (Diflunisal, 82.5 g. 0.329 mol) dissolved in acetone (450 niL) and cooled to -10 °C (refrigerant mixture: ice-EtOH) was added Et3N (101 mL, 0.725 mol) slowly (addition: 25 min, internal temperature: from -8 °C to 9 °C). To the resulting solution was added 2,2,2-trichloroethyl chloro ormate (100 mL, 0.725 mol) slowly (addition: 60 min, internal temperature was maintained below 0°C: from -10 °C to 0 °C). The mixture was stirred for 1 h at 0 CC (a white precipitate of triethylamine hydrochloride was gradually formed ). At the end of the reaction, the mixture was filtered under vacuum, the precipitate (triethylamine hydrochloride) was washed with acetone (4x180 mL) and the filtrate was evaporated under vacuum at 30 °C. The oily residue was taken with Et20 (150 mL) and the suspension was evaporated again under vacuum. The operation was repeated three times to remove excess of chlorocarbonate. The residue was dissolved in acetone (180 mL), and added to a refrigerated solution of N- acetyl-Z-cysteine (N-Ac-Cys, 53.81 g, 0.329 mol) and Et3N (46 mL, 0.329 mol) in acetone (140 mL) slowly (addition: 55 min, internal temperature was maintained below 15°C: from 0 °C to 1 5 °C). The reaction mixture was stirred at 15 °C for 4 h. The mixture was cooled to - 12 °C (internal temperature), and Et3N (1 15 mL, 0.824 mol) was added. The mixture was stirred for 15 h at -12 °C (internal temperature), and at the end of the reaction, the mixture was filtered under vacuum and the precipitate was washed with acetone (3x150 mL). The oily precipitate was suspended in CH2C12 (400 mL), cooled to 0 °C and an aqueous HCl solution (15% v:v) was added with vigorous stirring until the pH was lowered to 3. Ethanol (80 mL) was added, and the aqueous phase was extracted with CTLCL (2x400 mL). The combined organic layers were washed with a 10% HCl aqueous solution (1x500 mL) and with water (2x600 mL), were dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by trituration with Et20 (100 mL), affording 44.13 g of the title compound (HPLC purity: 88.26%) To increase purity, the solid was suspended in Et20 (100 mL) and stirred at room temperature for 20 min. The solid was filtered under vacuum and was washed with Et20 (3x100 mL), to afford 31.33 g of the title compound GMC-252 (R/= 0.3 CH2Cl2/MeOH/AcOH 95:5: 1 ), white solid, 24% yield, 96.22% HPLC purity); Purity was determined by NMR analysis and mass spectrometry to conform to the following parameters: 1H-NMR (CD3OD, 250 MHz, δ): 8.00 (m, 1H, ArH); 7.66 (dm. J = 8.2 Hz, 1H, ArH); 7.50 (m, 1H, ArH); 7.06 (m, 3H, ArH); 4.74 (m, 1H, CH); 3.77 (dd, J= 4.7 and 13.7 Hz, 1H, CH); 3.40 (m, 1H, CH); 1.98 (s, 3H, CH3); MS-EI+ m/z: 396.00 (M+l); LC-MS: M+l : 396.00; purity: 96.52% (HPLC method: SunFire C18 3.5 um, 2.1x100 mm, flow: 0.3 mL/min, gradient: A:B 3 min 10:90 + from 10:90 to 95:5 in 17 min + 10 min 95:5; A: CH3CN:MeOH 1 : 1 ; B: NH4OAc buffer 5 raM pH 7).

Reference： [1]Current Patent Assignee: GENMEDICA THERAPEUTICS SL. - US2010/234452, 2010, A1 Location in patent: Page/Page column 163-164
[2]Current Patent Assignee: GENMEDICA THERAPEUTICS SL. - WO2013/37985, 2013, A1 Location in patent: Page/Page column 74; 75

47
[ 616-91-1 ]
[ 3320-83-0 ]
[ 1262526-93-1 ]