* 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.
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 15, p. 5146 - 5154
2
[ 52-89-1 ]
[ 106-96-7 ]
[ 3262-64-4 ]
Reference：
[1] Bioorganic Chemistry, 1996, vol. 24, # 4, p. 401 - 416
[2] Journal of Organic Chemistry, 1965, vol. 30, p. 895 - 896
[3] Patent: US2009/36534, 2009, A1, . Location in patent: Page/Page column 7
[4] Patent: EP2186512, 2010, A1, . Location in patent: Page/Page column 12
[5] Journal of Organometallic Chemistry, 2016, vol. 806, p. 12 - 21
3
[ 52-89-1 ]
[ 106-95-6 ]
[ 21593-77-1 ]
Reference：
[1] Journal of Physical Chemistry B, 2011, vol. 115, # 45, p. 13408 - 13417
[2] Die Pharmazie, 1968, vol. 23, # 8, p. 462 - 467
[3] Journal of Agricultural and Food Chemistry, 2000, vol. 48, # 12, p. 6254 - 6260
[4] Journal of Organic Chemistry, 2004, vol. 69, # 19, p. 6185 - 6201
[5] Patent: US2009/36534, 2009, A1, . Location in patent: Page/Page column 9
[6] Tetrahedron, 2014, vol. 70, # 42, p. 7621 - 7626
4
[ 52-89-1 ]
[ 100-39-0 ]
[ 3054-01-1 ]
Yield
Reaction Conditions
Operation in experiment
92%
With sodium hydroxide In ethanol at 20℃; for 1 h;
To a rapidly stirring solution of 2N sodium hydroxide (15 mL) and ethanol (35 mL) was added L-cysteine hydrochloride (1.3 g, 8.2 mmol) and benzyl bromide (0.98 mL, 8.2 mmol). The reaction mixture was neutralized after 1 h to pH 6-7 by careful addition of concentrated hydrochloric acid. The precipitate was filtered and washed successively with water, ethanol and ether to give S-benzylcysteine (7) as a white powder (1.87 g, 92percent), mp 210-212 °C (lit [36].: 215-216 °C).
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 176 - 187,12
[2] Journal of Pharmaceutical Sciences, 1984, vol. 73, # 4, p. 559 - 561
[3] Organic Preparations and Procedures International, 1991, vol. 23, # 1, p. 93 - 102
5
[ 52-89-1 ]
[ 100-44-7 ]
[ 3054-01-1 ]
Reference：
[1] Tetrahedron Letters, 2010, vol. 51, # 46, p. 5977 - 5979
[2] Journal of Physical Chemistry B, 2011, vol. 115, # 45, p. 13408 - 13417
[3] Helvetica Chimica Acta, 1948, vol. 31, p. 737,743
[4] Journal of the Chemical Society, 1960, p. 1390 - 1393
[5] Carbohydrate Polymers, 2014, vol. 117, p. 211 - 214
6
[ 52-89-1 ]
[ 3054-01-1 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1996, vol. 69, # 4, p. 1099 - 1106
7
[ 76-84-6 ]
[ 58632-95-4 ]
[ 52-89-1 ]
[ 21947-98-8 ]
Reference：
[1] Canadian Journal of Chemistry, 1979, vol. 57, p. 1388 - 1396
8
[ 76-84-6 ]
[ 52-89-1 ]
[ 2799-07-7 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: for 2 h; Stage #2: With sodium acetate; sodium hydroxide In diethyl ether; water at 0℃;
Triphenylmethanol (3.3 g, 12.7 mmol) was added to a solution of Cysteine chlorydrate (2 g, 12.7 mmol) in TFA (25 mL) and the mixture was stirred for 2 h. After cooling to 0 °C, NaOH 4N and diethyl ether (40 mL) were added until pH 4-5 and then 10percent sodium acetate aqueous solution was added until pH 5-6. The precipitated obtained was filtered, washed with fresh Et2O and finally dried to obtain the desired product (5 g, 98percent yield).1H NMR (DMSO): δ (ppm) 2.35-2.61 (m, 2H, CH2); 2.85-2.98 (m, 1H, CH); 7.2-7.45 (m, 15H, trityl-H).MALDI-TOF MS: m/z364.7 Da [M + H]+, C22H21NO2S, Mol. Wt.: 363.47.
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 383 - 392
[2] Chemical Communications, 2013, vol. 49, # 92, p. 10808 - 10810
[3] Journal of the Chemical Society [Section] C: Organic, 1970, p. 2687
[4] Journal of Medicinal Chemistry, 1970, vol. 13, p. 414 - 418
[5] Canadian Journal of Chemistry, 1981, vol. 59, # 2, p. 406 - 421
9
[ 52-89-1 ]
[ 76-83-5 ]
[ 2799-07-7 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 20℃; for 48 h;
L-Cysteine hydrochloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10percent sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50° C. for 30 min after which it was cooled to 0° C. and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine 1b (205 g, 89percent) was obtained as a white powder. 1b: m.p. 192° C. (decomp). 1H NMR (DMSO-d6) δ 2.45 (dd, 1H, J=9 Hz, 12 Hz), 2.58 (dd, 1H, J=4.4 Hz, 12 Hz), 2.91 (m, 1H), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO-d6): δ 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
89%
With sodium acetate In N,N-dimethyl-formamide at 20℃; for 48 h;
L-Cysteine hydro-chloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10percent sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50 0C for 30 min after which it was cooled to 00C and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine Ic (205 g, 89percent) was obtained as a white powder. Ic: m.p. 192 °C (decomp) ; 1H NMR (300 MHz, DMSCW5) δ 2.45 (dd, IH, J= 9 Hz, 12 Hz), 2.58 (dd, IH, J= 4.4 Hz, 12 Hz), 2.91 (m, IH), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO- d6): δ 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
78%
at 20℃; for 48 h;
Preparation 75: Synthesis of (R)-3-amino-4-tritylsulfanyl-butyric acid methyl ester hydrochloride; (Step 1); L-cysteine hydrochloride (5Og, 284.7mmol) was dissolved in N,N- dimethylformamide (200ml). Trityl chloride (119g, 427.0mmol) was added thereto, and the mixture was stirred for 48 h at room temperature. After completion of the reaction, 10percent sodium acetate (1.5L) was added. The mixture was filtered to give a solid, which was then added to acetone (1.5L), and stirred for 30 min at 50 °C . The insoluble solid was filtered, and dried to give a trityl compound (80g, Yield 78percent).
77%
at 20℃; for 48 h;
Synthetic Example 1; (R)-3-Mercapto-2-(5-methyl-4-phenyl-thiazoI-2-yIamino)-propionic acid; Step 1 : S-Trityl-L-cysteine falso known as (R)-2-amino-3- (tritylsulfanyl)propanoic acid); L-Cysteine hydrochloride (5.0 g, 31.7 mmol) and trityl chloride (13.5 g, 48.4 mmol) were stirred in DMF (20 ml) for 48 h at room temperature. A 10percent NaOAc solution (175 mL) was then added, and the precipitate was filtered and washed with water. Afterward, the residue was suspended in acetone and stirred at 50 °C for 30 min, then cooled and filtered. The residue was washed with acetone (cold) and diethyl ether. After drying 8.86 g (77percent) S-trityl-L-cysteine was obtained.
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 4, p. 619 - 626
[2] Organic Letters, 2005, vol. 7, # 13, p. 2615 - 2618
[3] Patent: US7829709, 2010, B1, . Location in patent: Page/Page column 19-20
[4] Patent: WO2009/100431, 2009, A1, . Location in patent: Page/Page column 28
[5] Patent: WO2009/82152, 2009, A2, . Location in patent: Page/Page column 214
[6] Patent: WO2009/151744, 2009, A1, . Location in patent: Page/Page column 93
[7] Chemical Communications, 2009, # 4, p. 407 - 409
[8] Acta Chemica Scandinavica (1947-1973), 1959, vol. 13, p. 383
[9] Journal of the American Chemical Society, 1962, vol. 84, p. 3887 - 3897
10
[ 52-89-1 ]
[ 76-83-5 ]
[ 2799-07-7 ]
[ 27686-50-6 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1956, p. 698
11
[ 52-89-1 ]
[ 1625-72-5 ]
Reference：
[1] Journal of the American Chemical Society, 1956, vol. 78, p. 4482,4486
12
[ 24424-99-5 ]
[ 52-89-1 ]
[ 20887-95-0 ]
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10206 - 10210[2] Angew. Chem., 2015, vol. 127, # 35, p. 10344 - 10348,5
Stage #1: at 20℃; for 1 h; Cooling with ice; Inert atmosphere Stage #2: at 20℃; for 4 h; Reflux
Under ice-bath condition, 3 ml SOCl2 was added dropwise to 35 ml methanol in the presence of nitrogen atmosphere. Afterward, the solution was stirred at room temperature for 1 h, then 1 g Cys·HCl·H2O was added in batches to the solution. And the mixture solution reacted at room temperature for 3 h, and then refluxed for 1 h. Removing the volatile component and solvent, the residue was recrystallized with CH3OH-CH2Cl2, and 0.84 g white solid was obtained with 85.9percent yield. IR (KBr, cm-1): 3040.4 (s, NH2), 1709.7 (s, C=O), 2580 (w, SH). 1H NMR (D2O, TMS, ppm); δ 4.453 (t, 1H, CH, J = 5.2 Hz), 3.871 (s, 3H, CH3), 3.164 (t, 2H, CH2, J = 6.4 Hz). Elemental Anal. Calcd for C4H10NO2SCl: C, 27.99; H, 5.87; N, 8.16percent. Found: C, 28.11; H, 6.01; N, 8.08percent.
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 74, p. 199 - 215
[2] Journal of Organic Chemistry, 2013, vol. 78, # 9, p. 4270 - 4277
[3] Tetrahedron Asymmetry, 2000, vol. 11, # 21, p. 4255 - 4261
[4] Journal of the American Chemical Society, 2008, vol. 130, # 15, p. 5052 - 5053
[5] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 176 - 187,12
19
[ 52-89-1 ]
[ 1885-14-9 ]
[ 19771-63-2 ]
Reference：
[1] Chemistry - A European Journal, 2004, vol. 10, # 23, p. 6102 - 6110
[2] Patent: EP1462444, 2004, A1, . Location in patent: Page 23
[3] European Journal of Pharmaceutics and Biopharmaceutics, 2016, vol. 103, p. 62 - 70
20
[ 52-89-1 ]
[ 75-65-0 ]
[ 2481-09-6 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 9, p. 1868 - 1873
21
[ 877674-77-6 ]
[ 52-89-1 ]
[ 82009-34-5 ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: With sodium hydroxide In water at 5℃; for 0.166667 h; Stage #2: at 45 - 50℃; for 0.166667 h;
At 5° C ,10.5 g of sodium hydroxide was added to 65 g of water,Stirring for 10min,10 g of the compound (Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropylcarboxamido) -2-heptenoic acid represented by the formula (V)Stirring for 10 min;At 45° C ,8 g of cysteine hydrochloride monohydrate was added, stirred for 10 min,The reaction begins at 50 ° C,(Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropylcarboxamido) -2-heptenoic acid in the resulting reaction solution by HPLC was less than 5 percent To complete the reaction;After cooling to 20° C ,To the solution was added 223 g of water,Stir,To the solution was slowly added 6M hydrochloric acid solution,Adjust the pH to 2. The obtained solution was added to the Φ45 * 4.0m macroporous adsorption resin column HZ-816, eluted with water, and the conductivity of the collected liquid was less than 100us / cm, and then the aqueous solution was eluted with an aqueous solution of ethanol. The ethanol and water The mass ratio was 15:85 and the elution temperature was 25 ° C. (Z) -7-chloro-2 - ((S) -2,2-dimethylcyclopropylcarboxyl) was added to the above raw material under reduced pressure to collect the material liquid having a conductivity of 100 μ / cm or more 2-heptenoic acid) to obtain the compound of formula (VI). After the addition of 200 g of acetone in the cilastatin, the seeds were incubated at -30 ° C for 6 h, filtered and dried The water content in the obtained cilastatin was less than 3percent, and 7.8 g of the pale yellow cilastatin was obtained. The purity was 99.4percent by HPLC and the yield was 78percent.
Reference：
[1] Patent: CN106518741, 2017, A, . Location in patent: Paragraph 0087; 0088; 0092; 0093; 0097; 0098; 0102-0163
[2] Patent: US7371897, 2008, B1, . Location in patent: Page/Page column 7
[3] Patent: US2009/143614, 2009, A1, . Location in patent: Page/Page column 4
[4] Patent: US2009/143614, 2009, A1, . Location in patent: Page/Page column 4
[5] Patent: WO2011/80648, 2011, A1, . Location in patent: Page/Page column 11
[6] Patent: EP2402312, 2012, A1, . Location in patent: Page/Page column 6
[7] Patent: CN107522642, 2017, A, . Location in patent: Paragraph 0036; 0041
22
[ 52-89-1 ]
[ 84348-37-8 ]
[ 401564-36-1 ]
Reference：
[1] Patent: CN106349237, 2017, A, . Location in patent: Paragraph 0043; 0044; 0052
23
[ 52-89-1 ]
[ 57617-09-1 ]
[ 75498-96-3 ]
Yield
Reaction Conditions
Operation in experiment
97.9%
With ethylenediaminetetraacetic acid; sodium thiosulfate In water at 50℃;
433.1 g of 7β-chloroacetamido-7a-methoxy-3- (1-methyl-1H-tetrazole-5-thiomethyl) -3-cephem-4- Cysteine hydrochloride was added to 2 L of water, and then 30 g of EDTA and 412 g of sodium thiosulfate were added thereto. The mixture was reacted at 50 ° C and the reaction was complete by TLC. After cooling to room temperature, a mixed solution of 1500 ml of ethanol and 500 ml of acetone was added, Filtration and drying gave 530 g of cefminox sodium in a yield of 97.9percent. The purity was found to be 99.5percent by HPLC.
Reference：
[1] Patent: CN105924456, 2016, A, . Location in patent: Paragraph 0033; 0035
With sodium hydrogencarbonate; In ethanol; water; for 6h;
General procedure: To the solution of <strong>[52-89-1]l-cysteine hydrochloride</strong> hydrate and NaHCO3 (1.1 equiv) in water (200 mL), benzaldehyde (1.1 equiv) in 95% ethanol (200 mL) was added in one portion. The reaction mixture was stirred for 6 h. The product was filtered, washed with ethanol, and dried to afford as a white solid.
5 g (0.14 mol) of L-cysteine hydrochloride, 25 mol of water was added to a 150 mL one-neck flask, and stirred for 5 min.18.3 mL (0.21 mol) of a formaldehyde solution was added thereto, and reacted at 10 C for 10 hours.15 mL (0.18 mol) of pyridine was added to the solution, and the mixture was stirred to precipitate a white solid.After cooling, filtration, filter cake V (water): V (ethanol) = 1: 1.1 recrystallized, dried,The white needle crystal thiazolidine-4-carboxylic acid 17.31 was obtained in a yield of 90.9%.
80%
With sodium hydroxide; In water; at 20℃; for 24h;
To a solution of L-cysteine hydrochloride (95 mmol, 16.0 g) in water (10 mL) and 1M NaOH solution (10 mL) was added formaldehyde 37 % in water (11 mL). The mixture was stirred for 24 h at r.t. Next, ethanol (25 mL) and pyridine (12 mL) were added at 0 C. A white solid precipitated and it was filtered and washed with cold ethanol. The white solid product was utilized without further purification. Yield: 80%. M.P. = 195-198 C. [alpha]D 20 = -13 (c 1, H2O). 1H NMR (300 MHz, D2O): 4.51 (d, 1H, J = 10.5 Hz); 4.41 (dd, 1H, J = 3.9 Hz; 13.0 Hz); 4.27 (d, 1H, J = 10.2 Hz); 3.25 (dd, 1H, J = 7.5 Hz; 12.3 Hz); 3.25 (dd, 1H, J = 6.0 Hz; 12.0 Hz).
Triphenylmethanol (3.3 g, 12.7 mmol) was added to a solution of Cysteine chlorydrate (2 g, 12.7 mmol) in TFA (25 mL) and the mixture was stirred for 2 h. After cooling to 0 °C, NaOH 4N and diethyl ether (40 mL) were added until pH 4-5 and then 10percent sodium acetate aqueous solution was added until pH 5-6. The precipitated obtained was filtered, washed with fresh Et2O and finally dried to obtain the desired product (5 g, 98percent yield).1H NMR (DMSO): delta (ppm) 2.35-2.61 (m, 2H, CH2); 2.85-2.98 (m, 1H, CH); 7.2-7.45 (m, 15H, trityl-H).MALDI-TOF MS: m/z364.7 Da [M + H]+, C22H21NO2S, Mol. Wt.: 363.47.
L-Cysteine hydrochloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10percent sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50° C. for 30 min after which it was cooled to 0° C. and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine 1b (205 g, 89percent) was obtained as a white powder. 1b: m.p. 192° C. (decomp). 1H NMR (DMSO-d6) delta 2.45 (dd, 1H, J=9 Hz, 12 Hz), 2.58 (dd, 1H, J=4.4 Hz, 12 Hz), 2.91 (m, 1H), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO-d6): delta 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
89%
With sodium acetate; In N,N-dimethyl-formamide; at 20℃; for 48h;
L-Cysteine hydro-chloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10percent sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50 0C for 30 min after which it was cooled to 00C and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine Ic (205 g, 89percent) was obtained as a white powder. Ic: m.p. 192 °C (decomp) ; 1H NMR (300 MHz, DMSCW5) delta 2.45 (dd, IH, J= 9 Hz, 12 Hz), 2.58 (dd, IH, J= 4.4 Hz, 12 Hz), 2.91 (m, IH), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO- d6): delta 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
78%
In N,N-dimethyl-formamide; at 20℃; for 48h;
Preparation 75: Synthesis of (R)-3-amino-4-tritylsulfanyl-butyric acid methyl ester hydrochloride; (Step 1); L-cysteine hydrochloride (5Og, 284.7mmol) was dissolved in N,N- dimethylformamide (200ml). Trityl chloride (119g, 427.0mmol) was added thereto, and the mixture was stirred for 48 h at room temperature. After completion of the reaction, 10percent sodium acetate (1.5L) was added. The mixture was filtered to give a solid, which was then added to acetone (1.5L), and stirred for 30 min at 50 °C . The insoluble solid was filtered, and dried to give a trityl compound (80g, Yield 78percent).
77%
In N,N-dimethyl-formamide; at 20℃; for 48h;
Synthetic Example 1; (R)-3-Mercapto-2-(5-methyl-4-phenyl-thiazoI-2-yIamino)-propionic acid; Step 1 : S-Trityl-L-cysteine falso known as (R)-2-amino-3- (tritylsulfanyl)propanoic acid); L-Cysteine hydrochloride (5.0 g, 31.7 mmol) and trityl chloride (13.5 g, 48.4 mmol) were stirred in DMF (20 ml) for 48 h at room temperature. A 10percent NaOAc solution (175 mL) was then added, and the precipitate was filtered and washed with water. Afterward, the residue was suspended in acetone and stirred at 50 °C for 30 min, then cooled and filtered. The residue was washed with acetone (cold) and diethyl ether. After drying 8.86 g (77percent) S-trityl-L-cysteine was obtained.
Sodium hydroxide pellets (2.28 g, 56 .9 mmol) were added to a solution of l-cystein hydrochlorate monohydrate (10.0 g, 56.9 mmol) in water (37 mL). After complete dissolution, successively, ethanol (11 mL), benzaldehyde (5.78 ml, 56.9 mmol), and ethanol (30 mL) were added and the mixture was stirred for 3 h at room temperature. The resulting precipitate was filtered and washed with water before being dried under vacuo to lead to the expected compound quantitatively (11.9 g).1H NMR (DMSO-d6) delta 3.07-3.16 (m, 1H), 3.26-3.39 (m, 1H), 3.86 (dd, J = 9.0, 7.8 Hz, 0.4H), 4.22 (dd, J = 7.2, 4.5 Hz, 0.6H), 5.49 (s, 0.4H), 5.66 (s, 0.6H), 7.26-7.52 (m, 5H). 13C NMR (DMSO-d6) delta 35.7, 36.2, 65.9, 66.2, 71.8, 72.2, 126.9, 128.1, 128.8, 140.1.
98%
Example 1 to 4 (Chavan et al , J. Org. Chem. 2005, 70, 1901) Example 1 (4R)-2-phenylthiazolidine-4-carboxylic acid (13) To a solution of <strong>[52-89-1]L-cysteine hydrochloride hydrate</strong> (60 g, 0.34 mol), in water (525 mL) was added potassium acetate (36 g, 0.37 mol) was added and allowed to stir till a solution was obtained. To this solution 95% of methanol (525 mL) was added followed by immediate addition of benzaldehyde (44.2 g, 0.42 mol) in one portion. The reaction mixture was kept at 25 C for 3 h and an additional 3 h at 0 C. The product formed as a solid was filtered, washed with methanol, and dried to afford 3 as a white solid. Yield: 72.0 g (98%).
95%
With sodium hydrogencarbonate; In ethanol; water; for 6h;
To the solution of <strong>[52-89-1]l-cysteine hydrochloride</strong> hydrate and NaHCO3 (1.1 equiv) in water (200 mL), benzaldehyde (1.1 equiv) in 95% ethanol (200 mL) was added in one portion. The reaction mixture was stirred for 6 h. The product was filtered, washed with ethanol, and dried to afford as a white solid. Yield: 95%. Mp 159-160 C (lit. 159-160 C). 1H NMR (DMSO-d6, 300 MHz): 3.049-3.166 (m, 0.9H, 5-H), 3.294-3.406 (m, 1.1H, 5-H), 3.902 (q, J = 7.2 Hz, J = 1.5 Hz, 0.45H, 4-H), 4.234 (t, J = 4.8 Hz, J = 2.4 Hz, 0.55H, 4-H), 5.504 (s, 0.45H, 2-H), 5.669 (s, 0.55H, 2-H), 7.242-7.533 (m, 5H).HRMS: m/z calcd for C12H14N2O3S [M+H]+ 210.0588; found: 210.0587.
With potassium acetate; In ethanol; water; at 20℃;
General procedure: To a stirred solution of L-cysteine hydrochloride (4.73g; 0.033M) in water (47.3 mL), potassium acetate (0.036M) was added and dissolved. To this reaction mixture an equal volume of absolute ethanol (47.3 mL) was added. An appropriate aldehyde (0.017M) was then added slowly in a drop-wise manner. As soon as the aldehyde addition was completed, precipitation of the product was observed immediately. The solution was kept stirring for 4-5 h at RT. The precipitate was filtered using vacuum and washed thrice with cold ethanol then kept in vacuum desiccator for drying
With sodium hydroxide; In ethanol; water; at 0℃; for 0.5h;
L-cysteine hydrochloride (15.7 g, 0.1mol) was dissolved in 2N sodium hydroxide (100 mL) and ethanol (100 mL) at 0C. Benzyl chloride (12.6 g, 0.1 mol) was added in dropwise with stirring. In a few minutes anexothermic reaction started with precipitation of S-benzyl-L-cysteine. Aftercontinuous stirring for another 30 min, the mixture was transferred into ice water andadjusted to neutralpH usinghydrochloric acid, and then the precipitate was filtered and recrystallized from ethanol.1H NMR (400 MHz, DMSO-d6,delta): 3.38 (d, 1H),3.57 (s, 1H), 3.77 (s, 2H), 4.36 (brm, 1H), 7.24-7.35 (s, 5H). MS(ESI, m/z): [M+Na]+ calcd for C10H13NO2S, 211.28; found, 234.02
With sodium hydrogencarbonate; In ethanol; water; for 6h;
General procedure: To the solution of <strong>[52-89-1]l-cysteine hydrochloride</strong> hydrate and NaHCO3 (1.1 equiv) in water (200 mL), benzaldehyde (1.1 equiv) in 95% ethanol (200 mL) was added in one portion. The reaction mixture was stirred for 6 h. The product was filtered, washed with ethanol, and dried to afford as a white solid.
With acetic acid; In acetic acid; dimethyl sulfoxide; at 70℃; for 3.5h;
To a suspension of 5.86 g (37.18 mmol) cysteine hydrochloride in 150 mL acetic acid 10 g (52.74 mmol) (commercial) 2-nitrobenzenesulfenyl chloride was added. The suspension was stirred until it got solid, then 100 mL acetic acid was added and the mixture was heated to 70 C for 3.5 h. The solvent was removed in vacuo, the residue was dissolved in 20 mL DMSO and precipitated with 250 mL CHCl3. After filtration the precipitate was suspended in 200 mL CHCl3, stirred for 30 min, and collected by filtration twice. The product was dried in vacuo yielding 8.63 g (31.45 mmol, 85%) of a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta [ppm] = 8.85 (s, 3H, NH3+), 8.28 (dd, J = 9.6, 8.2 Hz, 2H, HAr), 7.89 (dd, J = 8.3, 7.2 Hz, 1H, HAr), 7.55 (dd, J = 8.3, 7.2 Hz, 1H, HAr), 4.20 (t, J = 5.8 Hz, 1H, CHNH3), 3.43-3.26 (m, 2H, CHCH2S). 13C{1H} NMR (101 MHz, DMSO-d6) delta [ppm] = 169.09 (COO-), 145.26 (CarNO2), 135.31 (CarS, Car), 127.42 (Car), 127.36 (Car), 126.44 (Car), 51.22 (Calpha), 37.14 (Cbeta). FD-MS: 274.3 (M+H+).
With sodium hydrogencarbonate; In ethanol; at 0 - 20℃;
To a solution of <strong>[52-89-1]L-cysteine hydrochloride monohydrate</strong> (47 g, 0.3 mol) in absolute ethanol (900 mL) was added powdered sodium bicarbonate (30 g, 0.36 mol) at 0 C. in one portion. Phenylsulfenyl chloride (50 g, 0.345 mol) was added dropwise with stirring to the mixture. After the complete addition of the reagent, the reaction mixture was allowed to stand at room temperature and the sodium chloride which was produced during the reaction was removed by filtration. After basifying the mixture by the addition of pyridine (38 mL) into the filtrate, the fine precipitate which formed was allowed to stand for a couple of hours, then filtrated and washed well with ethanol and dried to provide the crude product as a white solid. After recrystallization from aqueous HCl (0.5 N, 4000 mL), the final product S-thiol-phenyl-L-cysteine 1a was obtained (52 g) in 76% yield as colorless plates. m.p. 192 C. (decomp). 1H NMR (CD3CO2D): delta 3.53-3.76 (m, 2H), 4.89 (t, 1H), 7.26-7.88 (m, 5H); 13C NMR (75.5 MHz, CD3CO2D): delta 35.5, 52.5, 127.6, 128.5, 129.1, 129.3, 133.5, 171.6. This material was employed directly in the next step.
76%
With sodium hydrogencarbonate; In ethanol; at 0 - 20℃;
To a solution of L-cysteine hydrochloride mono-hydrate (47 g, 0.3 mol) in absolute ethanol (900 mL) was added powdered sodium bicarbonate (30 g, 0.36 mol) at 0 0C in one portion. Phenylsulfenyl chloride (50 g, 0.345 mol) was added dropwise with stirring to the mixture. After the complete addition of the reagent, the reaction mixture was allowed to stand at room temperature and the sodium chloride which was produced during the reaction was removed by filtration. After basifying the mixture by the addition of pyridine (38 mL) into the filtrate, the fine precipitate which formed was allowed to stand for a couple of hours, then filtrated and washed well with ethanol and dried to provide the crude product as a white solid. After recrystallization from aqueous HCl (0.5 N, 4000 mL), the final product S-thiol-phenyl-L-cysteine (Ib) was obtained (52 g) in 76% yield as colorless plates. Ib: m.p. 192 0C (decomp). 1H NMR (300 MHz, CD3CO2D): delta 3.53-3.76 (m, 2H), 4.89 (t, IH), 7.26-7.88 (m, 5H); 13C NMR (75.5MHz, CD3CO2D): delta 35.5, 52.5, 127.6, 128.5, 129.1, 129.3, 133.5, 171.6. This material was employed directly in the next step.
(2Ξ,4<i>R</i>)-2-(Dr-3<i>c</i>F-β-D-galactopyranosyloxy-1<i>c</i>F,2<i>t</i>F,4<i>r</i>F,5-tetrahydroxy-pent-<i>cat</i>F-yl)-thiazolidine-4-carboxylic acid[ No CAS ]
With sodium hydrogencarbonate; In methanol; at 70℃;pH 7;aq. phosphate buffer; Inert atmosphere;
Modified from Bergeron R.J., et. al. J. Med. Chem. 1999, 42, 95-108.Benzonitrile (2.46 g, 23.9 mmol) and L-cysteine hydrochloric salt (5.6 g, 35.8 mmol) were added to a solution of 60 ml methanol and 40 ml phosphate buffer (pH 7.0) then solution was degassed with argon for 10 min. Sodium bicarbonate (3.0 g, 35.8 mmol) was carefully added portion wise. The resulting solution was heated to 70oC overnight. The reaction was concentrated in vacuo to near dryness and the pH was adjusted to 2 with slow addition of 1N HCl while cooling in an ice bath. The reaction mixture was extracted with EtOAc (4x) and the organic phase was collected, dried over Na2SO4, filtered and then concentrated in vacuo to give 4.91 g (99%) of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxylic acid as a pale solid. 1H NMR (300 MHz, CD3OD) 7.80 - 7.72 (2 H, m), 7.47 - 7.31 (3 H, m), 5.25 - 5.18 (1 H, m), 3.69 - 3.56 (2 H, m).(R)-2-Phenyl-4,5-dihydrothiazole-4-carboxylic acid (219 mg, 1.04 mmol) and benzyl alcohol (133 mL, 1.24 mmol) were dissolved in 5 mL of acetonitrile and treated with EDC (321 mg, 2.07 mmol) and DMAP (380 mg, 3.09 mmol). The resulting solution was stirred for 12 h at room temperature. The reaction mixture was diluted with CH2Cl2, washed with 10% aqueous NaHCO3 solution (2x), water and 5% acetic acid solution (2x). The organic phase was collected, dried over Na2SO4, filtered and then concentrated in vacuo. Crude material obtained was purified by silica gel column chromatography with 20% - 50% ethyl acetate : hexane gradient solvent system to give 187 mg (61%) of 4 as an light yellow solid. Mp 63-64oC; 1H NMR (300 MHz, CDCl3) 7.89-7.86 (2 H, m), 7.51-7.33 (8 H, m), 5.33 (2 H, t, J = 9.1, 9.1 Hz), 5.28 (2 H, d, J = 1.8 Hz), 3.67 (2 H, ddd, J = 31.3, 11.2. 9.1 Hz).; 13C NMR (126 MHz, CDCl3) d 171.27, 170.85, 135.65, 132.87, 131.90, 129.18, 128.86, 128.81, 128.70, 128.61, 128.49, 78.75, 67.51, 35.64. HRMS (EI), M+1 calcd. for C17H16NO2S, 298.0896; found 298.0909. HPLC tR = 5.1 min.
73%
With sodium hydrogencarbonate; In methanol; aq. phosphate buffer; for 72h;pH 6;Reflux;
General procedure: A mixture of a nitrile (2 mmol), L-cysteine hydrochloride (378 mg, 2.4 mmol) and sodium bicarbonate (302 mg, 3.6 mmol) in methanol and phosphate buffer (pH = 6) (12 mL, 1:1) were refluxed for 72 h. After cooling, the mixture was concentrated, basified with 1 N NaOH to pH 10, then washed with ethyl acetate (5 mL x 2). The water phase was acidified with 1 N HCl to pH 2 and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over sodium sulfate and evaporated to give a 2-substituted 4,5-dihydrothiazole-4-carboxylic acid as a white solid or colorless oil.
Example 15Synthesis of S-Allyl-Cysteine (SAC)SAC is synthesized from L-cysteine hydrochloride and 3-bromopropene with the following steps. L-cysteine hydrochloride (13 g, 0.083 mol) in NH4OH (2M, 240 ml) is prepared and pre-cooled to 0 degree C. Then 3-bromopropene (15 g, 0.124 mol) is added to the ice-cooled solution of L-cysteine hydrochloride in NH4OH. The mixture was stirred vigorously at 0 degree C. for 2 h and filtered, and the filtrate was concentrated in vacuum at the temperature less than 40 degree C. to a small volume, and filtered again. The solid was washed repeatedly with ethanol, dried in vacuum, and re-crystallized from 2:3 H2O/C2H5OH to yield purified SAC in white needle crystal appearance. The chemical structure of SAC is determined by Proton Nuclear Magnetic Resonance Spectroscopy.
With ammonia; In ethanol; water; at 20℃; for 20h;
General procedure: L-Cysteine hydrochloride (2.90 g, 16 mmol) was mixed with allyl bromide (3.0 g, 2.2 mL, 25 mmol) in 50 mL 2 M NH4OH/EtOH (5:4) and stirred at room temperature for 20 h. The reaction mixture was concentrated and S-allyl-C precipitated out as white solid. The solid was filtered, washed with ethanol (50 mL twice), dried under reduced pressure, and used without further purification.
Example 6Synthesis of S-propargyl-cysteine (SPRC)SPRC is synthesized from L-cysteine hydrochloride and 3-bromopropene with the following steps. L-cysteine hydrochloride in NH4OH (2M, 240 ml) is prepared and pre-cooled to 0 degree C. Then propargyl bromide (14.5 g, 0.124 mol) is added to the ice-cooled solution of L-cysteine hydrochloride in NH4OH. The mixture is stirred vigorously at 0 degree C. for 2 h and filtered, and the filtrate was concentrated in vacuum at the temperature less than 40 degree C. to a small volume, and filtered again. The solid is washed repeatedly with ethanol, dried in vacuum, and re-crystallized from 2:3 H2O/C2H5OH to yield purified SPRC in white needle crystal appearance. The chemical structure of SPRC is determined by Proton Nuclear Magnetic Resonance Spectroscopy (FIG. 11).
With ammonium hydroxide; In water; for 2.0h;
Example 6: synthesis of SPRC; This example is shown in Figure 11. L-cysteine hydrochlorate was dissolved in a pre-cooled NH4OH solution (2M, 240ml), and 3-propargyl bromide (14.5g, 0.124mol) was added to said solution; the mixed solution was stirred thoroughly at 0C for 2 hours and filtered, then the filtrate was distilled in reduced pressure ( <40) and concentrated to a smaller volume, and then filtered again. The solid separated out was washed repeatedly with ethanol, dried in vacuum and re-crystallized from water/ethanol with a 2:3 volume ratio to yield white needle crystals. The NMR structure was detected by Proton Nuclear Magnetic Spectroscopy (Figure 11).
With ethanol; sodium; for 2.0h;Inert atmosphere;
To 60 mL of absolute EtOH under N2 was added 1.030 g (44.8 mmol, 4.0 equiv.) of Na metal. Once all the Na had reacted, 1.956 g (11.1 mmol, 1.0 equiv.) of L-cysteine hydrochloride hydrate and 4.90 mL (44.8 mmol, 4.0 equiv.) of propargyl bromide were added to the solution. After stirring for 2 h, the solvent was evaporated. The remaining residue was redissolved in 15 mL THF. To this solution was added a solution of 4.865 g (22.3 mmol, 2.0 equiv.) of Boc2O dissolved in 12.5 mL THF, followed by 5.0 mL (55 mmol, 5 equiv.) of Et3N and 25 mL of H2O. After stirring for 18 h the THF was evaporated, and the remaining aqueous layer was brought to pH > 11 by the addition of 1 M NaOH. The alkaline aqueous layer was washed 3 x 25 mL EtOAc, then acidified to pH 2 using concentrated HCl. The resulting acidic aqueous layer was extracted 3 x 25 mL EtOAc. The combined EtOAc extracts were dried (MgSO4), filtered and evaporated to yield 1.96 g of 11 [16-18] as a tan oil: TLC (1:1 EtOAc/MeOH), Rf 0.67; 1H NMR (400 MHz, CDCl3): 6.36 (1H, br s, OH), 5.39 (1H, d, J = 7.7 Hz, NH), 4.62 (1H, q, J = 5.9 Hz, CalphaH), 3.33 (2H, dd, J = 8.8 and 2.7 Hz, SCH2), 3.27 (2H, dd, J = 13.3 and 4.8 Hz, beta-CH2), 2.32 (1H, s, CCH), 1.49 (9H, s, OtBu).
3 g (17.08 mmol) cysteine hydrochloride monohydrate was dissolved in 17 mL 2 M hydrochloric acid and cooled to 5 C in an ice bath. 1.18 g (17.08 mmol) Sodium nitrite was dissolved in 10 mL milli-Q water, cooled and added to the cysteine solution via a dropping funnel. The solution turned red. After stirring for 80 min at 5 C, 5.61 g (34.16 mmol) sodium benzylsulfinate was added. After 2 h discoloration of the solution was observed and a precipitate formed. Another 1.40 g (8.54 mmol) sodium benzylsulfinate was added and the mixture was stirred for 2 more hours and stored at 4 C overnight. The solid was collected by filtration and washed two times with ice-cold milli-Q water. The brown solid was recrystallized from water, washed with ethanol and diethyl ether and dried in vacuo to yield 2.14 g (8.20 mmol, 48%) of a slightly yellowish solid. 1H NMR (400 MHz, D2O + TFA-d) delta [ppm] = 7.90-7.81 (m, 2H, HAr), 7.69-7.61 (m, 1H), 7.58-7.48 (m, 2H, HAr), 4.27 (dd, J = 7.3, 4.6 Hz, 1H, CalphaH), 3.48 (dd, J = 15.8, 4.6 Hz, 1H, CH2), 3.39 (dd, J = 15.8, 7.3 Hz, 1H, CH2). 13C{1H} NMR (101 MHz, D2O) delta [ppm] = 171.52 (COOH), 144.52 (CArS), 137.88 (CAr), 132.51 (CAr), 129.69 (CAr), 54.71 (CH2), 36.97 (Calpha).
With sodium hydroxide; In ethanol; at 20℃; for 1h;
To a rapidly stirring solution of 2N sodium hydroxide (15 mL) and ethanol (35 mL) was added L-cysteine hydrochloride (1.3 g, 8.2 mmol) and benzyl bromide (0.98 mL, 8.2 mmol). The reaction mixture was neutralized after 1 h to pH 6-7 by careful addition of concentrated hydrochloric acid. The precipitate was filtered and washed successively with water, ethanol and ether to give S-benzylcysteine (7) as a white powder (1.87 g, 92%), mp 210-212 C (lit [36].: 215-216 C).
L-Cysteine hydrochloride hydrate (21.08g, 0.12mol) was suspended in absolute alcohol (350ml), and cuts of sodium (11g, 0.48mol) were added in 15-min intervals to the solution. After all the sodium had dissolved, methyl iodide (8.3ml, 0.13mol) was added and the mixture was stirred at room temperature for 15min. Water was added to dissolve precipitate, the solution was acidified by 48% aqueous hydroiodic acid to pH 5.0. Diethyl ether (600ml) was added to solubilize a precipitate and the solution was cooled in a refrigerator (8h). Crystalline precipitate was collected by filtration, washed with cold absolute ethanol, then with diethyl ether, and dried. The yield of S-methyl-l-cysteine was 88%. M.p. 219-220C dec., [a]D25=-32 (c 0.8, H2O). 1H NMR (400MHz, D2O, ppm) delta: 2.13 (s, 3H, CH3); 2.97 (dd, 1H, CH2, J=14.9, 7.7Hz); 3.08 (dd, 1H, CH2, J=14.9, 4.3Hz); 3.92 (dd, 1H, CH, J=7.7, 4.3Hz). ESI-MS (m/z)=136 [M+H]+.
The L-cysteine hydrochloride monohydrate (3.1g, 17 . 5mmol) dissolved in MeOH (45 ml) in, under the ice-bath adds by drops 30% of the methanol solution of sodium methoxide (11.2g, 62mmol), reaction 1h rear, methane instillment iodine (0.9 ml, 13. mmol), the reaction temperature-raised to room temperature, TLC detection reaction, 2h end of the reaction, using 10NHCl adjusting the pH value to 5, by adding 40 ml ethyl ether stirring 10 min, filtering, with 60 ml ethyl ether washing, vacuum drying, obtain crude product 4.715 g.
L-cysteine hydrochloride monohydrate (3.1 g, 17.5 mmol) was dissolved in MeOH (45 mL), and a 30% solution of sodium methoxide in methanol (11.2 g, 62 mmol) was added dropwise under an ice bath,After 1 hour of reaction, methyl iodide (0.9 mL, 13.mmol) was added dropwise, and the temperature was raised to room temperature for reaction.The reaction was detected by TLC. After 2h, the pH was adjusted to 5 with 10N HCl.Add 40 mL of ether and stir for 10 min, filter, and wash the filter cake with 60 mL of ether.Vacuum drying gave 4.715 g of crude product.
With sodium acetate; In ethanol; water; at 30℃; for 1.5h;
Example 1 (4R)-2-(4-Methoxyphenyl)thiazolidine-4-carboxylic Acid A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with <strong>[52-89-1]L-cysteine hydrochloride monohydrate</strong> (500.0 g, 2.85 mol), sodium acetate (260.0 g, 3.17 mol) and water (4 L). The mixture was stirred until all of the L-cysteine dissolved. A solution of 4-methoxybenzaldehyde (426.0 g, 3.13 mol) in ethanol (3.5 L) was prepared and added to the reaction dropwise such that the internal reaction temperature was kept below 30 C. The reaction went from a clear solution to a thick white slurry during the addition of the 4-methoxybenzaldehyde solution. After 30 minutes, ethanol (3.5 L) was added to the reaction and the slurry thickened. Stirring was continued for 1 hour and then the solid was isolated by filtration, and the solid was washed with additional ethanol. The solid was dried in a vacuum oven at 50 C. over 48 hours to afford the title compound (610 g, 90%). 1H NMR (DMSO, 300 MHz): delta3.16-3.00 (m, 2H), 3.37-3.23 (m, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 3.84 (dd, J=7.6, 7.1 Hz, 1H), 4.23 (dd, J=6.7, 4.4 Hz, 1H), 5.42 (s, 1H), 5.56 (s, 1H), 6.93-6.83 (m, 4H), 7.41-7.31 (m, 4H).
90%
Example 1; Preparation of (R)-2-(4-methoxy-phenyl)-thiazolidine-4-carboxylic acid (A compound of Formula IIIa): A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with <strong>[52-89-1]L-cysteine hydrochloride monohydrate</strong> (500.0 g, 2.85 mol), sodium acetate (260.0 g, 3.17 mol) and 4.00 L of water. The mixture was stirred until all of the L-cysteine dissolved. A solution of p-methoxybenzaldehyde (426.0 g, 3.13 mol) in 3.50 L of ethanol was prepared and added to the reaction such that the internal reaction temperature was kept below 30 C. The reaction becomes a thick white slurry during the addition of the p-methoxybenzaldehyde solution. After 30 minutes, 3.50 L of ethanol was added to the reaction. Stirring was continued for 1 hour and then the solid was isolated by filtration. A 1.50 L portion of ethanol was used to wash the solid. The solid was dried in a vacuum oven at 50 C. for 48 hours. Approximately 610 g of 2-(4-methoxy-phenyl)thiazolidine-4-carboxylic acid was obtained (90% yield). 1H NMR (300 MHz, DMSO) delta 7.41-7.31 (m, 4H), 6.93-6.83 (m, 4H), 5.56 (s, 1H), 5.42 (s, 1H), 4.23 (dd, J=6.7, 4.4 Hz, 1H), 3.84 (dd, J=7.6, 7.1 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.37-3.23 (m, 2H), 3.16-3.00 (m, 2H).
With potassium acetate; In methanol; water; at 20℃;
(R)-2-(4-Methoxy-phenyl)-thiazolidine-4-carboxylic acidTo a solution of L-cysteine hydrochloride (400 mg, 2.54 mmol) in distilled water (4 mL), potassium acetate (274 mg, 2.79 mmol) was added. Once the solids went into solution, methanol (4 mL) was added followed by 4-methoxy-benzaldehyde (370 muL, 3.04 mmol). The reaction was stirred at ambient temperature overnight. The solvent was removed, and no further purification steps were taken.
To a solution of L-cysteine hydrochloride (16 g, 95 mmol) in water (10 mL) and 1M NaOH (10 mL) were added formaldehyde 37% in water (11 mL). The mixture was stirred for 24 h at r.t. The following step, at 0 C was added ethanol (25 mL) and pyridine (12 mL). A white solid precipitates and it was filtered and washed utilizing cold ethanol. The white solid product was utilized without further purifications. Yield: 80%.
Under ice-bath condition, 3 ml SOCl2 was added dropwise to 35 ml methanol in the presence of nitrogen atmosphere. Afterward, the solution was stirred at room temperature for 1 h, then 1 g Cys·HCl·H2O was added in batches to the solution. And the mixture solution reacted at room temperature for 3 h, and then refluxed for 1 h. Removing the volatile component and solvent, the residue was recrystallized with CH3OH-CH2Cl2, and 0.84 g white solid was obtained with 85.9% yield. IR (KBr, cm-1): 3040.4 (s, NH2), 1709.7 (s, C=O), 2580 (w, SH). 1H NMR (D2O, TMS, ppm); delta 4.453 (t, 1H, CH, J = 5.2 Hz), 3.871 (s, 3H, CH3), 3.164 (t, 2H, CH2, J = 6.4 Hz). Elemental Anal. Calcd for C4H10NO2SCl: C, 27.99; H, 5.87; N, 8.16%. Found: C, 28.11; H, 6.01; N, 8.08%.
With thionyl chloride; at 0 - 20℃; for 24h;
To a solution of L-cysteine hydrochloride (2 g, 12.6 mmol) in methanol (40 mL) at 0 C was dropped SOCl2 (1.5 mL, 7 mmol) and then the mixture was reacted at room temperature for 24 h. Methanol was evaporated to give 9 as a colorless oil which was directly used in the next process.
With sodium hydroxide; In water; toluene; at 0 - 30℃; for 2h;
(1) A aqueous solution comprising 0.88 liter of water and 184.0 g of sodium hydroxide was dissolved 175.6 g of L-cysteine monohydrochloride·monohydrate under ice-cooling, 0.35 liter of a toluene solution containing 313.2 g of phenyl chloroformate was added to the above solution within a range not exceeding 30C. After stirring the mixture at room temperature for 2 hours, it was allowed to stand and the liquids were separated. The aqueous layer was washed with 0.35 liter of toluene, the layers were separated, and the aqueous layer was concentrated to give 139.84 g of (4R)-2-oxothiazolidin-4-carboxylic acid as colorless crystal. Melting point: 168-170C MS ·APCI (m/z): 148 [(M+H)+] [alpha]D25: -62.8 (C=1.0, H2O).
I
I. Synthesis of S-(2,3-Dihydroxypropyl)cysteine:Triethylamine; (6 g, 8.2 ml, 58 mmoles) was added to L-cysteine hydrochloride (3 g, 19 mmole) and 3-bromo-propan-l,2-diol (4.2 g, 2.36 ml, 27 mmole) in water and the homogeneous solution kept at room temperature for 3 days. The solution was reduced in vacuo at 400C to a white residue which was boiled with methanol (100ml), centrifuged and the residue dissolved in water (5ml). This aqueous solution was added to acetone (300ml) and the precipitate isolated by centrifugation. The precipitate was purified by several precipitations from water with acetone to give S-(2,3-dihydroxypropyl)cysteine as a white amorphous powder (2.4 g, 12.3 mmol, 64.7%).
EXAMPLE 11 A homogeneous solution was prepared by adding 175.64 g (1.0 mmole) of L-cysteine monohydrochloride powder to 1 liter of ice-cooled 2 N sodium hydroxide solution (2 mole as NaOH). To the solution was added 2 l of methyl alcohol and 70 ml (1.10 mole) of methyl iodide was then added dropwise under ice cooling. After white crystals were formed, the mixture was stirred for several hours and then allowed to stand overnight at room temperature. Enough 5% hydrochloric acid was added to adjust to pH 6.5 and the mixture was then ice-cooled and filtered. The collected crystals were washed with aqueous 60% methyl alcohol to give an yield of 62.9 g. The filtrate was concentrated in vacuo to recover a second crop of 69.7 g. Thus, S-methyl-L-cysteine was obtained in a yield of 132.6 g (98% of the theoretical).
At 5 C ,10.5 g of sodium hydroxide was added to 65 g of water,Stirring for 10min,10 g of the compound (Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropylcarboxamido) -2-heptenoic acid represented by the formula (V)Stirring for 10 min;At 45 C ,8 g of cysteine hydrochloride monohydrate was added, stirred for 10 min,The reaction begins at 50 C,(Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropylcarboxamido) -2-heptenoic acid in the resulting reaction solution by HPLC was less than 5 % To complete the reaction;After cooling to 20 C ,To the solution was added 223 g of water,Stir,To the solution was slowly added 6M hydrochloric acid solution,Adjust the pH to 2. The obtained solution was added to the Phi45 * 4.0m macroporous adsorption resin column HZ-816, eluted with water, and the conductivity of the collected liquid was less than 100us / cm, and then the aqueous solution was eluted with an aqueous solution of ethanol. The ethanol and water The mass ratio was 15:85 and the elution temperature was 25 C. (Z) -7-chloro-2 - ((S) -2,2-dimethylcyclopropylcarboxyl) was added to the above raw material under reduced pressure to collect the material liquid having a conductivity of 100 mu / cm or more 2-heptenoic acid) to obtain the compound of formula (VI). After the addition of 200 g of acetone in the cilastatin, the seeds were incubated at -30 C for 6 h, filtered and dried The water content in the obtained cilastatin was less than 3%, and 7.8 g of the pale yellow cilastatin was obtained. The purity was 99.4% by HPLC and the yield was 78%.
With sodium hydroxide; In water; at 20℃;
Ex. 3; Preparation of Aqueous Cilastatin Solution; 34.4 g of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (1) obtained from Ex. 1 was dissolved in mixed aqueous solution of L-cystein hydrochloric acid salt (20 g) and caustic soda solution (116 ml) and stirred at room temperature. The reaction was continued until (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (2) was fully consumed according to high speed liquid chromatograph assay. In result, high purity aqueous cilastatin solution showing only a faint trace of E isomers was obtained.
With sodium hydroxide; In water; at 25 - 30℃;Product distribution / selectivity;
EXAMPLE 3 Preparation of Cilastatin Acid (I) To the solution of sodium hydroxide (90 gm) in water (1 lt) was added L-Cysteine hydrochloride monohydrate (96 gm) and Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid and stirred at 25-30 C. till the disappearance of Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid. After completion of reaction, the reaction mass was washed with dichloromethane (500 ml. To the aqueous layer was added carbon (10 gm) and stirred and filtered. To the filtrate was added water (1 lt) and the pH of the solution was adjusted to 3.0 and stirred for 24 hrs. The precipitated mass was filtered, washed with water (200 ml) and with acetone (500 ml) and dried to obtain 10 gm white solid with 97% purity. The solid was dissolved in water (700 ml) and added MDC (700 ml) and ethyl acetate (100 ml) and stirred for 10 hrs. The precipitated mass was filtered and washed with water (100 ml) and acetone (200 ml) and dried to obtain 100 gm white Cilastatin acid with 99.5% purity.
With sodium hydroxide; In methanol; at 60 - 65℃;Product distribution / selectivity;
EXAMPLE 5 Preparation of Cilastatin Acid To the solution of sodium hydroxide (88 gm) in methanol (1500 ml) was added Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid and stirred to dissolve. To the resulted clear solution was added L-Cysteine hydrochloride monohydrate (97 gm) and stirred the resulted suspension at 60 to 65 C. till the disappearance of Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid. After completion of reaction, the pH insoluble salts were filtered. The filtrate was distilled out under vacuum. The residue was dissolved in water (500 ml) and washed with dichloromethane (500 ml). The pH of aqueous layer was adjusted to 3 to 4 from the original pH in the range of 5.5, and with n-butanol (500 ml). The butanol layer was washed with water and distilled. The residue was dissolved in water (100 ml) and added acetonitrile (1500 ml) at 50 C. and further refluxed at 80 C. for one hr. The precipitated cilastatin acid was filtered and washed with acetonitrile (100 ml). The crude wet cake (60 gm) was refluxed with acetonitrile water mixture (9:1,1500 ml), and cooled to yield 60 gm pure cilastatin acid with 99.5% purity. EXAMPLE 6 Preparation of Cilastatin Acid To the solution of sodium hydroxide (88 gm) in methanol (1500 ml) was added Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid and stirred to dissolve. To the resulted clear solution was added L-Cysteine hydrochloride monohydrate (97 gm) and stirred the resulted suspension at 60 to 65 C. till the disappearance of Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid. The pH of the reaction mass was adjusted to 7.0 with conc.HCl and filtered the insoluble salts. The filtrated was distilled out under vacuum. The residue was dissolved in water (500 ml) and washed with dichloromethane (500 ml). The pH of aqueous layer was adjusted to 3 to 4 from the original pH in the range of 5.5, and with n-butanol (500 ml). The butanol layer was washed with water and distilled up to 50% of original volume and stirred at 25 C. The precipitated cilastatin acid was filtered and washed with n-butanol (100 ml) followed by acetone to yield 60 gm pure cilastatin acid with 99.7% purity.
Reference Example 1: Preparation of Cilastatin Acid:To the solution of sodium hydroxide in Methanol, Chloro amido acid (50 gm) was charged followed by L-Cysteine hydrochloride (48.5 gm) and reaction mixture was refluxed for 3-4 hrs. After completion of reaction, pH was adjusted to 7-7.5 and filtered. The clear filtrate was distilled completely under vacuum. The residue obtained was dissolved in water and washed with MDC. To the aqueous layer n- butanol (7.0 vol.) was charged followed by the adjusting the pH to 3-3.5 at 25-30 C. The product was extracted into n-butanol. The n-butanol layer was washed with brine solution followed by water and distilled completely. The residue was dissolved in water. To the clear solution acetone (13 vol.) was added for precipitation and it was refluxed to 54- 56C for 2.0 hrs. The obtained product was filtered and washed with acetone. The solid was again purified with aqueous acetone to yield pure Cilastatin acid in crystalline form.
Example 6 Preparation of Cilastatin Acid: To the solution of sodium hydroxide (88gm) in methanol (1500ml) was added Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid and stirred to dissolve. To the resulted clear solution was added L-Cysteine hydrochloride monohydrate (97gm) and stirred the resulted suspension at 60 to 65C till the disappearance of Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid. The pH of the reaction mass was adjusted to 7.0 with conc.HCl and filterd the insoluble salts. The filtrated was distilled out under vacuum. The residue was dissolved in water (500ml) and washed with dichloromethane (500ml). The pH of aqueous layer was adjusted to 3 to 4 from the original pH in the range of 5.5, and with n-butanol (500ml). The butanol layer was washed with water and distilled up to 50% of original volume and stirred at 25C. The precipitated cilastatin acid was filtered and washed with n-butanol (100ml) followed by acetone to yield 60gm pure cilastatin acid with 99.7% purity.
at 55 - 60℃; for 8.5h;Inert atmosphere;
247.8 g of ethyl 7-chloro-2-oxoheptanoate,135.6 g of S - (+) 2,2-dimethylcyclopropylcarboxamidewith1.6 g of p-toluenesulfonic acid at 130 C1200ml toluene refluxed for 10 hours;After the reaction is completed, the toluene is concentrated and recovered;To the concentrate is added 600 ml of ethanol and 720 g of 10% sodium hydroxide solution,HPLC monitoring of the reaction process,At 45 ~ 50 for 10 hours;Then add t-butyl ether three times,Each 1000ml, discard the organic layer,Add concentrated hydrochloric acid,Adjust the pH to 3 ~ 3.5, add ethyl acetate three times,Each time 1000ml,Discard the water layer,Add anhydrous sodium sulfate drying,Concentration under reduced pressure gave (Z) -7-chloro-2- [(S) -2,2-dimethylcyclopropylcarboxamido] -2-heptenoic acid viscous liquid. Under reflux, 200 g of the above concentrate was added to 600 ml of dioxane,Then add 1260ml cyclohexane, stir,Let stand for 12 hours at room temperature, filtered,Drying in vacuo gave (Z) -7-chloro-2- [(S) -2,2-dimethylcyclopropylcarboxamido] -2-heptenoic acid as a solid; After controlling the temperature to be less than or equal to 10 DEG C, purging with nitrogen, 105.3 g of L-cysteine hydrochloride monohydrate was added, the mixture was stirred for 0.5 hours, warmed to 55-60 DEG C, the reaction was monitored by HPLC, the reaction was completed in 8 hours, Cooled to room temperature, washed three times with dichloromethane,Each 600ml, discard the organic layer,One volume of water was added to the reaction solution,Concentrated hydrochloric acid to adjust the pH to 2.5 to 3.0,Four times with dichloromethane,Each 800ml, discard the organic layer,That is included[R- [R *, S * (Z)]] - 7 - [(2-Amino-2- carboxyethyl) thio]2 - [[(2,2-dimethylcyclopropyl) carbonyl] amino] -2-heptenoic acid.
With sodium hydrogencarbonate; In ethanol; water; for 6h;
General procedure: To the solution of <strong>[52-89-1]l-cysteine hydrochloride</strong> hydrate and NaHCO3 (1.1 equiv) in water (200 mL), benzaldehyde (1.1 equiv) in 95% ethanol (200 mL) was added in one portion. The reaction mixture was stirred for 6 h. The product was filtered, washed with ethanol, and dried to afford as a white solid.
With potassium acetate; In methanol; water; at 20℃;
(R)-2-(4-Cyano-phenyl)-thiazolidine-4-carboxylic acidTo a solution of L-cysteine hydrochloride (400 mg, 2.54 mmol) in distilled water (4 mL), potassium acetate (274 mg, 2.79 mmol) was added. Once the solids went into solution, methanol (4 mL) was added followed by 4-formyl-benzonitrile (399 muL, 3.04 mmol). The reaction was stirred at ambient temperature overnight. The solvent was removed, and no further purification steps were taken.
With potassium acetate; In methanol; water; at 20℃; for 4h;
(R)-2,3,4,5-Tetrahydro-[2,5']bithiazolyl-4-carboxylic acidTo a solution of L-cysteine hydrochloride (428 mg, 2.72 mmol) in distilled water (4.3 mL), potassium acetate (293 mg, 2.99 mmol) was added. Once the solids went into solution, methanol (4.3 mL) was added followed by thiazole-5-carbaldehyde (370 mg, 3.27 mmol). The reaction was stirred at ambient temperature for 4 hours. The solvent was removed, and no further purification steps were taken.
With potassium acetate; In methanol; water; at 20℃; for 1h;
R)-2-Pyrimidin-5-yl-thiazolidine-4-carboxylic acidTo a solution of L-cysteine hydrochloride (400 mg, 2.54 mmol) in distilled water (4 mL), potassium acetate (275 mg, 2.80 mmol) was added. Once the solids went into solution, methanol (4 mL) was added followed by <strong>[10070-92-5]pyrimidine-5-carbaldehyde</strong> (328.3 mg, 3.04 mmol). The reaction was allowed to stir at ambient temperature for one hour. The solvent was removed, and no further purification steps were taken.
With potassium acetate; In methanol; water; at 20℃;
(R)-2-(2-Chloro-pyridin-4-yl)-thiazolidine-4-carboxylic acidTo a solution of L-cysteine hydrochloride (403.7 mg, 2.56 mmol) in distilled water (4 mL), potassium acetate (306.2 mg, 3.12 mmol) was added. Once the solids went into solution, methanol (4 mL) was added followed by 2-chloro-pyridine-4-carbaldehyde (432.2 mg, 3.06 mmol). Precipitate crashed out of solution within one hour, and the reaction was stirred at ambient temperature overnight. The solvent was removed, and no further purification steps were taken.
With potassium acetate; In methanol; water; at 20℃;
(R)-2-(2-Fluoro-phenyl)-thiazolidine-4-carboxylic acid To a solution of L-cysteine hydrochloride (400 mg, 2.54 mmol) in distilled water (4 mL), potassium acetate (274 mg, 2.79 mmol) was added. Once the solids went into solution, methanol (4 mL) was added followed by 2-fluoro-benzaldehyde (325 muL, 3.06 mmol). The reaction was stirred at ambient temperature overnight. The solvent was removed, and no further purification steps were taken. (R)-2-(2-Fluoro-phenyl)-thiazolidine-3,4-dicarboxylic acid 3-benzyl ester
With potassium acetate; In methanol; water; at 20℃; for 4h;
(R)-2-Oxazol-5-yl-thiazolidine-4-carboxylic acidTo a solution of L-cysteine hydrochloride (446.9 mg, 2.84 mmol) in distilled water (4.3 mL), potassium acetate (319.8 mg, 3.26 mmol) was added. Once the solids went into solution, methanol (4.3 mL) was added followed by <strong>[118994-86-8]oxazole-5-carbaldehyde</strong> (339.0 mg, 3.49 mmol). The reaction was stirred at ambient temperature for 4 hours. The solvent was removed, and no further purification steps were taken. (R)-2-Oxazol-5-yl-thiazolidine-3,4-dicarboxylic acid 3-benzyl ester
With potassium acetate; In methanol; water; at 20℃;
(R)-2-(3-Fluoro-pyridin-4-yl)-thiazolidine-4-carboxylic acidTo a solution of L-cysteine hydrochloride (400 mg, 2.54 mmol) in distilled water (4 mL), potassium acetate (275 mg, 2.80 mmol) was added. Once the solids went into solution, methanol (4 mL) was added followed by <strong>[40273-47-0]3-fluoro-pyridine-4-carbaldehyde</strong> (305 muL, 3.06 mmol). Precipitate crashed out of solution within one hour, and the reaction was <n="76"/>stirred at ambient temperature overnight. The solvent was removed, and no further purification steps were taken.
With potassium acetate; In methanol; water; at 20℃;
(R)-2-(2-Hydroxy-pyridin-4-yl)-thiazolidine-4-carboxylic acidTo a solution of L-cysteine hydrochloride (402.9 mg, 2.56 mmol) in distilled water (4 mL), potassium acetate (281.7 mg, 2.87 mmol) was added. Once the solids went into solution, methanol (4 mL) was added followed by <strong>[188554-13-4]2-hydroxy-pyridine-4-carbaldehyde</strong> (376.4 mg, 3.06 mmol). Precipitate crashed out of solution within one hour, and the reaction was stirred at ambient temperature overnight. The solvent was removed to give the crude product.
0-methyl-S-trityl-Z-cysteine hydrochloride (Compound 1-Ci'): L-Cysteine hydrochloride monohydrate was dehydrated azeotropically. To the anhydrous L-cysteine hydrochloride (7.0 g) were added successively trityl alcohol (10.4 g, 40 mmol), freshly distilled acetic acid (40 mL), and boron trifluoride etherate (5.6 mL). The orange mixture was then placed in a preheated oil bath (40C) and heated with stirring to 100 C over a period of 25 min. During this time most of the trityl alcohol dissolved and, after a further 15 min at 100 C a clear amber-coloured solution resulted. Heating was discontinued and the solution was allowed to cool to room temperature (45 min), during which time a white precipitate formed. The reaction was quenched by addition of ethanol (60 mL), which discharged the amber colour, and the solid dissolved. Water (40 mL) was added, followed by anhydrous sodium acetate (12 g). The mixture was stirred until all of the solid had dissolved and was then diluted with water (140 mL). The product precipitated as colourless oil, which rapidly crystallized as a fluffy white solid. This was collected the next day, washed well with water and acetone, and dried, finally under high vacuum to give a white amorphous solid, 13.06g (90% yield) which was characterized by ESI MS C22H2iN02S (MW = 362.472 g/mol) M+H = 363.18.
With sodium hydrogencarbonate; In ethanol; water; at -20℃; for 48h;
[Synthetic Example 38] N-acetyl-2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylic acid L-Cysteine hydrochloride (8.00 g, 45.6 mmol), <strong>[58-56-0]pyridoxal hydrochloride</strong> (8.80 g, 43.25 mmol) and sodium hydrogen carbonate (7.60 g, 90.5 mmol) were added to a mixed solvent of water (60 ml) and ethanol (120 ml), and the mixture was at stored -20C for 2 days. The precipitated solid was collected by filtration, and dried under reduced pressure to give 2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylic acid as a pale-yellow solid (10.73 g).
General procedure: A solution of L-cysteine hidrochloride (60 mmol;10.8 g), NaHCO3 (60 mmol; 5.3g), the appropriate nitrile(20 mmol) in 85 mL of ethanol was refluxed for 30 min. After, the pH was adjusted to 8.0 by adding a few drops of morpholine, and the reflux was continued for additional 12 h. The ethanol was removed, the residue dissolved in distilled water and acidified to pH 1.5 by adding concentrated HCl. The product was extracted with CH2Cl2 (3 × 50 mL), the organic layers where combined, dried over MgSO4 and the solvent removed under vacuum. The products were obtained with satisfactory purity and were used in the next step without further purification.
c) (Ethylsulfonylsulfanyl)cysteine[2-am ino-3-ethylsu Ifonylsulfanyl-propanoic acid]An ice-cold solution of 5.93 g sodiumnitrite in 45 ml water was slowly added at 000 to astirred solution of 13.57 g cysteine hydrochloride in 90 ml 2 M HOl. Stirring was continued for 1 h at 000. Then, 20 g <strong>[20035-08-9]sodium ethanesulfinate</strong> was added to the obtained deep red solution and stirring was continued for 2 h at 000. Then, additional 5 g <strong>[20035-08-9]sodium ethanesulfinate</strong> wasadded, and stirring of the reaction mixture was continued overnight at 000. The resulting pale pink precipitate was filtered off and washed with ice-cold water (2x 10 ml) and diethyl ether (2x 10 ml). The crude product was redissolved in water and neutralized with 2 M NaOH. The product precipitated at a pH in the range of 3-4 and, after complete precipitation, was washed with ice-cold water (2x 10 ml) and diethyl ether (2x 10 ml). Drying in vacuo at 21C yielded 5.03 g pure (ethylsulfonylsulfanyl)cysteine.
S-(pentafluorophenylsulfanyl)-L-cysteine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With acetic acid; In acetic acid; at 70℃; for 3.5h;
To a suspension of 1.35 g (8.59 mmol) cysteine hydrochloride in 35 mL acetic acid, 3.02 g (13 mmol) pentafluorophenylsulfenyl chloride was added. The suspension solidified after 5 min and another 23 mL of acetic acid was added, yielding a yellow solution, which was stirred at 70 C for 3.5 h. During the reaction the yellow color of the solution got weaker. The solvent was removed in vacuo and the slightly yellow residue was extracted twice with 58 mL CHCl3, yielding 2.7 g (8.46 mmol, 98%) of a colorless solid. 1H NMR (400 MHz, CD3CN + TFA-d) delta [ppm] = 4.43 (dd, J = 8.5, 4.3 Hz, 1H, CalphaH), 3.51 (dd, J = 15.3, 4.3 Hz, 1H,CH2), 3.35 (dd, J = 15.3, 8.6 Hz, 1H, CH2). 19F NMR (400 MHz, CD3CN + TFA-d) delta [ppm] = -134.66 (m, 2F, o-F), -153.01 (tt, J = 20.0, 3.9 Hz, 1F, p-F), -163.35 (m, 2F, m-F). 13C{1H} NMR (101 MHz, CD3CN + TFA-d) delta [ppm] = 168.95 (COO), 147.61 (ddd, J = 246.4, 11.6, 4.4 Hz, o-CAr), 144.73-140.78 (m, p-CAr), 139.72-135.61 (m, m-CAr), 110.06 (t, J = 20.6 Hz, CArS), 53.23 (CH2), 39.31 (Calpha). FD-MS: 319.1 (M+H+).
(2R,4R)-2-(2-cyanophenyl)-1,3-thiazolidine-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With sodium hydroxide In ethanol; water at 20℃; for 3h;
5 5.1. General procedure for the synthesis of compounds 1 to 13:
General procedure: L-cysteine hydrochloride monohydrate (1.0 eq) and sodium hydroxide (1.0 eq) were dissolved in water. Then aldehyde (1.0 eq) in ethanol was added and the mixture was stirred at room temperature (RT) for three hours. Solid crystals of the expected product were filtered and washed with dichloromethane. The crystals were dried under vacuo.
8 Synthesis of S-(2.3-dihvdroxyorooyl)cvsteine:
Triethvlamine (6 g, 8.2 ml, 58 mmoles) is added to L-cysteine hydrochloride (3 g, 19 mmole) and 3-bromo-propan-1 ,2-diol (4.2 g, 2.36 ml, 27 mmole) in water and the homogeneous solution kept at room temperature for 3 days. The solution is reduced in vacuo at 40°C to a white residue which is then precipitated with acetone (300ml) and the precipitate isolated by centrifugation. The precipitate is washed with acetone twice more and dried to yield S-(2,3- dihydroxypropyl)cysteine as a white amorphous powder.
1.2 Synthesis of S-(2,3-dihydroxypropyl) Cysteine
1. Triethylamine (6 g, 8.2 mL, 58 mmol) was added to 1-cysteine hydrochloride (3 g, 19 mmol) and 3-bromo-propan-1,2-diol (4.2 g, 2.36 mL, 27 mmol) in water. This homogeneous solution was kept at room temperature for 3 d. 2. The solution was reduced in vacuum at 4 degree C to a white residue which was washed three times with acetone and dried to give S-(2,3-dihydroxypropyl) cysteine as a white amorphous powder (2.4 g, 12.3 mmol, 64.7%). This product was used for the next step without further purification.
2-methylthiazolidine-2,4-dicarboxylic acid 2-methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.5%
Stage #1: l-cysteine hydrochloride With sodium hydroxide In water
Stage #2: pyruvic acid methyl ester at 20℃; for 4h;
2-Methylthiazolidine-2,4-dicarboxylic Acid 2-Ethyl Ester(CP2Et, 2a, b)
General procedure: Under an argon atmosphere, L-Cys hydrochloride(60.0 g, 381 mmol) was added to ion-exchanged water(500 mL), and the pH of the solution was adjusted to 5.05by adding aqueous sodium hydroxide (4 N, ca. 88 mL). Ethylpyruvate (63.0 mL, 567 mmol) was added to the solution andthe mixture was stirred for 4 h at r.t. The mixture was concentratedunder reduced pressure to ca. 150 mL. Water (100 mL)was added, and the mixture was extracted with ethyl acetate(500, 200 mL). The organic layer was washed with saturatedsodium chloride solution (50 mL), dried over anhydrousMgSO4, and concentrated to ca. 200 mL. To the residue wasadded n-heptane (220 mL) at 45°C and the mixture was storedovernight at r.t. The precipitate was collected and dried underreduced pressure to give 2a and b (ca. 1 : 1 diastereomer mixture,65.6 g, 299 mmol, 79% yield).
With ethylenediaminetetraacetic acid; sodium thiosulfate; In water; at 50℃;
433.1 g of 7beta-chloroacetamido-7a-methoxy-3- (1-methyl-1H-tetrazole-5-thiomethyl) -3-cephem-4- Cysteine hydrochloride was added to 2 L of water, and then 30 g of EDTA and 412 g of sodium thiosulfate were added thereto. The mixture was reacted at 50 C and the reaction was complete by TLC. After cooling to room temperature, a mixed solution of 1500 ml of ethanol and 500 ml of acetone was added, Filtration and drying gave 530 g of cefminox sodium in a yield of 97.9%. The purity was found to be 99.5% by HPLC.
With ammonia; ammonium bicarbonate; In water; at 20 - 50℃; for 0.5h;pH 7.5;Large scale;
The preparation process of carboxymethamer of this embodiment is achieved by the following steps:(A) taking L-cysteine hydrochloride monohydrate and solid chloroacetic acid, wherein L-cysteine hydrochloride monohydrate is 150 Kg, chloroacetic acid is L-cysteine hydrochloride A water quality of 60% of the volume, that is 90KG; (B) the reaction of L-cysteine hydrochloride monohydrate and chloroacetic acid into the reactor, add water, 600KG stirring dissolved, dissolved in the process of heating to control the system temperature is about 20 ; (C) using liquid ammonia,While adding ammonium bicarbonate,To adjust the pH of the system to 7.5, the amount of ammonium bicarbonate added to 200KG, while the control system temperature of 45-50 , 30 minutes in the stirring state reaction; (D) After the reaction was completed, the pH of the system was adjusted to 6.0 with hydrochloric acid, and 20 kg of activated carbon was added to decolorize, adsorb impurity treatment, decolorize and adsorb impurities. The temperature of the system was 75 and the treating time was 30 minutes. (E) filtration, adjust the pH of the filtrate to 2.8 with hydrochloric acid, the whole regulation process is controlled at about 20 minutes, cooling to get carboxymethyl stearate crystal. The purity of the product was 99.2%. The yield of Carbocisteine was 96% on the basis of L-cysteine hydrochloride monohydrate.
(1) L-cysteine hydrochloride (1 mol) was uniformly dispersed in 3 L of absolute ethanol, then at room temperature, 3.5 mol of sodium hydroxide solution (20 mol / L) was added dropwise with magnetic stirring and stirring was continued for 5 min. Then add 1.1mol of methyl bromide, to maintain a constant temperature reaction for 6h, to form a deoxythiomethyl cysteine sulfoxide (MCS) crude solution. The solution was transferred to a clean container and the pH was adjusted to 5.2 with an acid at 30 C. then paced at 4 C for 12 h to form white deoxidized MCS crystals. [0047] (2 ) The MCS crystals obtained in step (1) were filtered, dried at 40 C, and then redissolved in 10 mL of distilled water containing 1% glacial acetic acid and heated to boiling. The solution was poured into 150 mL of boiling anhydrous ethanol to recrystallize, and the MCS crystals were inverted in the solvent to make the solution cloudy. The solution was allowed to stand at 4 C for 12 h and recrystallized. The crystals were filtered and dried at 40 C to give about 58 g of pure deoxythiomethyl cysteine sulfoxide (MCS) crystals.
L-Cysteine hydrochloride-hydrate (5.07 g, 20 mmol) was suspendedin the mixture of THF/H2O (9:1, 10 mL) and NaOAc 3H2O(5.44 g, 40 mmol) was added with stirring. Through the next 1 h, asolution of Ac2O (2 mL) in THF/H2O (9:1, 3 mL) was added. Theresulting solution was stirred 16 h at rt under inert atmosphere(N2), and after that 4 h at the reflux. To the cooled reaction mixtureconc. HCl (2 mL) was added, followed by the addition of THF(50 mL), wherein NaCl precipitates. The resulting suspension wasfiltered and the filtrate was evaporated to dryness to give yellowishoil. Methanol (40 mL) was added, followed by the addition of sat.HCl in MeOH (5 mL). The resulting clear solution was refluxed for1 h. After removal of the solvent on a rotary evaporator the crudeproduct was obtained in the form of yellowish oil. Product waspurified by chromatography on silica gel using CH2Cl2/EtOAc (1:1)as an eluent to give pure product 13 (2.13 g, 60%) in the form ofcolorless oil, which solidifies upon standing in refrigerator. Characterisationis in accordance with previously reported. (R)-Methyl-N-acetamidocysteinate (13): 2.13 g (60%); 1H NMR(300 MHz, CDCl3) delta/ppm: 6.38 (br, s, 1H), 4.88-4.71 (m, 1H), 3.80 (s,3H), 3.02 (ddd, 2H, J 8.9, 4.0 and 1.0 Hz), 2.07 (s, 3H), 1.34 (t, 1H,J 8.9 Hz).
With formaldehyd; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; at -10 - 20℃;
The tert-butoxycarbonyl-N-4-oxo-proline obtained in step S7 and the cysteine hydrochloride were dissolved in a polar proton solvent. Then, carried out reaction again with formaldehyde aqueous solution at -10 ~ 20 C under the action of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and triethylamine , followed by post-treatment to give (2S) - tert-butyl - 4-oxo-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate , standby
With sodium hydrogencarbonate In ethanol at 90℃; for 12h;
1 Pyridine-hydrosothiazole carboxylic acid synthesis reaction of the general formula:
3 - cyanopyridine(10mmol, 1.04 g), L-cysteine hydrochloride (15 mmol), sodium bicarbonate(60 mmol) was added to a 100 mL round bottom flask and 30 mL of absolute ethanol was added and heated at 90 ° C for 12 hours until the reaction was completed.Cooled to room temperature, spin to anhydrous ethanol to milky white solid. Dissolved in water, in the ice bath conditions, slowly add hydrochloric acid solution (thickDegree of 2mol / L), to the determination of solution ρH- = 3-4, the reaction system precipitated a large number of white solid, filter, and then washed with ice water2-3 times, after drying to give the compound pyridine dihydrothiazole carboxylic acid A1, white solid in 87% yield
With sodium hydrogencarbonate In ethanol at 90℃; for 12h;
1 Pyridine-hydrosothiazole carboxylic acid synthesis reaction of the general formula
Weigh 2-chloro-3-cyano-pyridine (lOmmol, 1.04 g), L-cysteine hydrochloride (25 mmol), sodium bicarbonate(60 mmol) was added to a 100 mL round bottom flask and 30 mL of absolute ethanol was added and heated at 90 ° C for 12 hours until the reaction was completed.Cooled to room temperature, spin to anhydrous ethanol to milky white solid. Dissolved in water, in the ice bath conditions, slowly add hydrochloric acid solution (thickDegree of 2mol / L), to the determination of solution ρH- = 3-4, the reaction system precipitated a large number of white solid, filter, and then washed with ice water2-3 times, after drying to give the compound pyridine dihydrolthiazole carboxylic acid A3, light orange powder as a solid, the yield of 88%.
In aq. phosphate buffer; isopropyl alcohol at 50℃; for 16h; Inert atmosphere;
2-(2-Chloropyridin-3-yl)thiazole-4-carboxylic Acid (11)
2-Chloronicotinonitrile (10; 50 g, 361 mmol, 1 equiv) was dissolved in 1.5:1 i-PrOH/pH 7 phosphate buffer (722 mL, 0.5 M) and solid L-cysteine hydrochloride (65.6 g, 542 mmol, 1.5 equiv) was added in one portion. The reaction mixture was heated to 50 °C and stirred for 16 h. The reaction was then terminated by removing i-PrOH under reduced pressure and diluting with EtOAc (500 mL) and aq 2 M HCl until the solution was acidic (pH >2). The mixture was extracted with EtOAc (3 × 400 mL), the combined extracts were dried (Na2SO4), and concentrated to give the intermediate thiazoline as a yellow solid (76.9 g, 317 mmol, 88%); mp 156-158 °C. The crude material was of sufficient purity to be used directly in the next reaction without further purification. 1H NMR (600 MHz, MeOD): δ = 8.49 (dd, J = 4.9, 1.8 Hz, 1 H), 8.10 (dd, J = 7.7, 1.8 Hz, 1 H), 7.49 (dd, J = 7.7, 4.9 Hz, 1 H), 5.36 (t, J = 9.2 Hz, 1H), 3.87-3.80 (m, 2 H). Crude thiazoline (76.9 g, 317 mmol, 1 equiv) and BrCCl3 (46.9 mL, 476 mmol, 1.5 equiv) were dissolved in DMF (317 mL, 1 M) in a flask and the flask was immersed in an ice bath. DBU (99 mL, 666 mmol, 2.1 equiv) was added dropwise via an addition funnel over 20 min. On large scale this addition was significantly exothermic. After addition, the reaction mixture was then brought to 50 °C and stirred for 3 h. After completion, the mixture was slowly introduced dropwise into a vigorously stirring aq 1 M HCl (2 L) at 0 °C to ensure a uniform precipitate. The mixture was stirred for 10 min and the fine brown precipitate was filtered and dried under vacuum at 50 °C for 18 h to give 76.0 g (99%, 87% over 2 steps) of crude thiazole product 11 as a grey-brown solid; mp > 200 °C. The crude material was of sufficient purity to be used directly in the next reaction without further purification. 1H NMR (600 MHz, MeOD): δ = 8.76 (dd, J = 7.9, 1.8 Hz, 1 H), 8.58 (s, 1H), 8.50 (dd, J = 4.7, 1.9 Hz, 1 H), 7.58 (dd, J = 7.9, 4.7 Hz, 1 H). 13C NMR (150 MHz, DMSO-d6): δ = 162.4, 161.6, 151.3, 148.0, 147.6, 140.2, 131.1, 128.3, 124.4. HRMS (ESI): m/z calcd for C9H5ClN2O2S [M - H]-: 238.9687; found: 238.9689.
potassium (S)-2-(6-aminobenzo[d]thiazol-2-yl) -4,5-dihydrothiazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
D-Cysteine hydrochloride monohydrate (81.2 mg, 0.462 mmol, 1.1 eq) and 6-amino-cyano- benzothiazole (71 .0 mg, 0.405 mmol, 1 eq) were dissolved in 2:1 MeOH:H20 (1 mL). The resulting solution was allowed to stir at room temperature for 5 mm under a nitrogen atmosphere, after which potassium carbonate (56.5 mg, 0.409 mmol, 1.01 eq) was added. The resulting brightyellow-green solution was allowed to stir for an additional 40 mm, while maintaining an inert atmosphere. Upon consumption of 6-amino-cyanobenzothiazole, as evidenced by TLC analysis, the reaction mixture was diluted with water (4 mL) and washed with EtOAc (1 x 4 mL). The aqueous was then reduced and the resulting precipitate was filtered and washed with cold MeOH (2 x 1 mL). The precipitate was then further purified using reverse phase chromatography elutingwith a gradient of 0-90percent MeOH in water to afford D-aminoluciferin postassium salt as a paleyellow solid (0.123 g, 96percent). [c]ObS: -14° (H20, c = 1). Mp: 111-123°C. 1H-NMR (400 MHz, D20)68.32 (1H, d, J= 8.8 Hz, H-7), 7.79 (1H, s, H-b), 7.55 (1 H, d, J= 8.0 Hz, H-8), 5.72 (1H, m, H-2), 3.8-4.2 (2H, m, H-3). HRMS (ESI+): m/zCalculated for C11H9N302S2K [M+H] 317.9773, found317.9768.
D-Cysteine hydrochloride monohydrate (30.0 mg, 0.171 mmcl, 1.04 eq) and 2-cyano-6-hydroxy- benzothiazole (29.0 mg, 0.163 mmol, 1 eq) were dissolved in 2:1 MeOH:H20 (1 mL). The resultingsolution was allowed to stir at room temperature for 5 mm under a nitrogen atmosphere, after which potassium carbonate (23.0 mg, 0.164 mmol 1.01 eq) was added. The resulting bright yellow-green solution was allowed to stir for an additional 20 mm, at room temperature, while maintaining the inert atmosphere. Upon consumption of <strong>[939-69-5]2-cyano-6-hydroxybenzothiazole</strong>, as evidenced by TLC analysis, the methanol was removed in vacuo and the remaining aqueoussolution cooled to 0 °C and acidified to pH 3 with 3 M HCI. The aqueous layer was then extracted with EtOAc (5 x 10 mL) and the combined organ ics were dried over Na2SO4, filtered, concentrated in vacuo and purified with column chromatography 3:6:1 DCM:EtOAc:MeOH to provide D-luciferin as a pale yellow solid (39.0 mg, 86 percent). [c]ObS = 290, DMF, c = 1 ([a]1. = -34°, DMF, c = 1). Mp:197-199°C (lit. 196 °C).3 1H-NMR (400 MHz, MeOD) (57.93 (1H, d, J= 8.9 Hz, H-7), 7.35 (iH, d,J= 2.3 Hz, H-b), 7.10 (1H, dd, J= 8.9, 2.3 Hz, H-8), 5.40 (iH, appt, J= 9.0 Hz, H-2), 3.79 (2H, m, H-3) ppm. 13C-NMR (100.6 MHz, CDCI3) oe 172.1 (C-i), 166.2 (C-4), 157.6 (C-9), 157.1 (C-5), 146.8 (C-6), 137.7 (C-il), 124.5 (C-7), 116.8 (C-b), 105.9 (C-8), 78.2 (C-2), 34.5 (C-3) ppm. HAMS (ESI+): m/zCalculated for C11H8N20352 [M+Na] 302.9874, found 302.9868.
80%
With potassium carbonate; In methanol; dichloromethane; water; for 0.166667h;Cooling with ice;
<strong>[939-69-5]2-cyano-6-hydroxybenzothiazole</strong> (100 mg, 0.57 mmol) was dissolved in DCM:MeOH = 2:3 (10 mL: 15 mL).And pass N2 to the solution.D-cysteine hydrochloride (136 mg, 0.86 mmol) and K2CO3 (119 mg, 0.86 mmol) were dissolved in DI H2O:MeOH = 1:1 (3 mL).The solution was added dropwise to the above <strong>[939-69-5]2-cyano-6-hydroxybenzothiazole</strong>, and the reaction was carried out in the ice bath for 10 min.After the reaction was completed, DCM and MeOH were distilled off under reduced pressure.The pH was then adjusted to 2-3 with a solution of hydrochloric acid (1M) and a yellow precipitate precipitated.The precipitate was filtered and washed with DI H 2 O until the pH became neutral to give D-luciferin crude product.By column chromatography (silica, DCM: MeOH: AcOH, 10:1:1 v/v/v)Purification gave 128 mg of a pale yellow solid.The yield was 80percent.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
