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CAS No. : | 32443-99-5 | MDL No. : | MFCD00012632 |
Formula : | C3H8ClNO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IFQSXNOEEPCSLW-HSHFZTNMSA-N |
M.W : | 157.62 | Pubchem ID : | 147419 |
Synonyms : |
D-Cysteine hydrochloride
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P321-P332+P313-P337+P313-P362-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With hydrogenchloride In water for 24h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydroxide In ethanol Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.76g | With potassium carbonate; In methanol; for 8h;Inert atmosphere; | Under an inert gas atmosphere, the 100 ml methanol is added to the above-mentioned product 1 in, stirring to dissolve, weighing D-cysteine hydrochloride monohydrate 23g (130.93mmol) is added to the above-mentioned system, lucifugous conditions adding anhydrous potassium carbonate 36.2g (261.86mmol), stirring 8 hours. After the reaction, the methanol is removed under reduced pressure, the concentration of 10percent aqueous solution of hydrochloric acid for pH adjustment system 2, a solid precipitated, filtered, the filter cake is washed with water 200 ml water back-washing 3 times, filtering the white solid obtained, the final product is obtained by freezing and drying 22.76g (93percent, m.p.187-188 °C, nuclear magnetism hydrogen spectrogram see Figure 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With phosphate buffer; sodium hydrogencarbonate In <i>tert</i>-butyl alcohol at 60℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydroxide In ethanol Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium hydrogencarbonate In methanol for 48h; Heating; | |
55% | With sodium hydrogencarbonate In methanol for 48h; Aqueous phosphate buffer; Heating / reflux; | 4 D-Cysteine hydrochloride monohydrate (1.23 g, 7.02 mmol) was added to 11 (1.00 g, 2.34 mmol) in degassed CH3OH (20 mL) and 0.1 M phosphate buffer at pH 6.0 (15 mL). Sodium bicarbonate (0.590 g, 7.02 mmol) was carefully added, and the mixture was stirred at reflux for 2 days. The reaction mixture was concentrated under reduced pressure, H2O was added, and the pH was adjusted to 2 by addition of 10% citric acid solution. Solid was filtered and recrystallized from aqueous ethanol to furmish 2 (0.81 g, 55%) as a beige powder: 1H NMR (d6-DMSO-2.49) δ 1.72 (m, 6 H), 2.48 (t, 4 H, J=7.2), 3.32 (t, 4 H, J=6.3), 3.41 (t, 4 H, j=6.3) 3.54(dd, 1 H, J=7.2, 11.1),3.61 (dd, 1 H, J=9.3, 11.1)5.34(dd,2H, J=7.2, 9.3), 6.36 (s, 2 H), 7.03 (s, 2 H), 10.24 (br s, 2 H), 12.45 (br s, 2 H), 13.04 (br s, 2 H); 13C NMR (d6-DMSO-39.50) δ 25.50, 29.19, 29.78, 33.15, 67.17, 69.25, 75.91, 102.00, 107.64, 120.11, 131.49, 158.55, 160.17, 171.57, 171.95; HRMS m/z calculated for C29H35N2O10S2 635.1733 (M+H), found 635.1696. Elemental analysis of C29H34N2O10S2: C: calculated 54.88, found 54.17; H: calculated 5.40, found 5.45; N: calculated 4.41, found 4.40. Optical rotation: α24D+3.1 (c 1.06, DMF). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydroxide In ethanol; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydrogencarbonate In methanol; phosphate buffer at 60℃; for 89h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydrogencarbonate In methanol; phosphate buffer at 65℃; for 67h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With zinc In water at 85℃; for 2.25h; Heating / reflux; | 2 EXAMPLE 2 L-cysteine hydrochloride (50g) was dissolved in water (200 ml; a 100 mmol solution) and zinc metal (130 g; 2 mol) was added. The reaction mixture was slowly heated to 85 degrees C. over 15 minutes and stirred on a heated mixing plate for an additional 2 hours. The mixture was filtered and the solid residue discarded (136.87 g). The mixture was then placed in an ethanol dry ice bath and evaporated to solid residue (41.65g; 84% recovery). This method produces a zinc-monocysteine complex. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In water at 20 - 70℃; for 2.5h; | 81 To a suspension of D-cysteine 1.5 hydrate hydrochloride (Q-1, Scheme Q where RQ-1 and RQ-1 are equal to hydrogen, RQ-3 is hydrogen and stereochemistry is (S)) (5 g, 27.1 mmol) in absolute ethyl alcohol (50 mL) was added triethylorthoformate (13.5 mL, 81.2 mmol) at ambient temperature. A stream of anhydrous HCl gas was bubbled through the solution for 30 min. The stream of anhydrous HCl gas was maintained as the mixture heated to 70° C. for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue triturated with diethyl ether to afford D-cysteine ethyl ester (4.43 g) as a white solid which was used without further purification. Physical data as follows: 1H NMR (300 MHz, D2O) 4.36 (1H), 4.27 (2H), 3.12 (2H), 1.25 (3H); MS (ESI+) for C5H11NO2S m/z 150.0 (M+H)+. [00685] To a solution of D-cysteine ethyl ester (1.89 g, 10.2 mmol) in H2O (46 mL) was added potassium acetate (1.22 g, 12.4 mmol) and t-butyl N-(2-oxoethyl)carbamate (Aldrich, 2.38 g, 12.0 mmol based on 80% purity as determined by 1H NMR) in ethyl alcohol (46 mL) at ambient temperature. After 8 h, the reaction mixture was concentrated in vacuo and the residue purified by flash chromatography using methylene chloride/methanol (1%) as eluant to afford the title compound (1.9 g) as an oil: 1H NMR (300 MHz, CDCl3) δ 5.01 (1H), 4.75 (1H), 4.26 (2H), 3.93 (1H), 3.37 (2H), 3.12 (1H), 2.91 (1H), 1.47 (9H), 1.32 (3H); MS (ESI+) for C12H22N2O4S m/z 291.1 (M+H)+, MS (ESI-) for C12H22N2O4S m/z 288.9 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: formaldehyd; D-cysteine hydrochloride In water at 20℃; for 18h; Stage #2: With pyridine In ethanol; water at 0 - 5℃; for 1h; | 1 D-Cysteine hydrochloride monohydrate (A-1, where RA-1 and RA-2 are the same and equal to H and stereochemistry is (S)) (35.04 g, 0.19 mol) was dissolved in formaldehyde (40 wt % solution in water, 38 mL) and the reaction mixture allowed to stir for 18 h at ambient temperature. The mixture was cooled (0-5° C.) and absolute ethanol (93 mL) and pyridine (57 mL) were added. After one hour, the precipitate was collected by filtration, washed with cold absolute ethanol followed by diethyl ether and dried in vacuo to afford the title compound (24.6 g) as a white crystalline solid: mp 181-184° C. (Lit. 194-196° C.; Lewis, N. J.; Inoles, R. L.; Hes, J. J. Med. Chem. 1978, 21, 1070.); 1H NMR (DMSO-d6) δ 4.22 (1H), 4.04 (1H), 3.86 (1H), 3.09 (1H), 2.24 (1H); MS (ESI+) for C4H7NO2S m/z 134.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium In ammonia; water; isopropyl alcohol | 16.A (2S)-2-((tert-butoxycarbonyl)amino)-3-((cyclohexylmethyl)sulfanyl)propanoic acid EXAMPLE 16A (2S)-2-((tert-butoxycarbonyl)amino)-3-((cyclohexylmethyl)sulfanyl)propanoic acid A solution of D-cysteine hydrochloride (4.78 g, 39.4 mmol) in liquid ammonia (250 mL) at -70° C. was slowly treated with sodium (3.78 g, 161 mmol), stirred for 30 minutes, treated with (bromomethyl)cyclohexane (6.33 mL, 45.4 mmol), warmed to room temperature, and stirred until the ammonia evaporated. The residue was treated with water(75 mL), isopropanol (50 mL) and di-tert-butyl dicarbonate (9.97 mL, 43.3 mmol), stirred for 24 hours, and concentrated. The concentrate was dissolved in water (150 mL), cooled to 0° C., adjusted to pH<7 with 3N HCl, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS(APCI) m/e 318 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In sodium hydroxide; aqueous-acetonitrile | 6 [Reference Example 6] [Reference Example 6] (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-(4-(2-((2S)-2-(p-nitrobenzyloxycarbonyl) -2-(p-nitrobenzyloxycarbonylamino) ethylthio)acetyl)piperazine-1-yl)carbonyl-4-mercaptopyrrolidine STR13 1) To 5.05 g of D-cysteine hydrochloride dissolved in 4N sodium hydroxide and cooled on an ice bath was added dropwise 9.39 ml of p-methoxybenzyl chloride, followed by 2 hours of stirring at room temperature. The resulting reaction solution was washed with ether and acidified with concentrated hydrochloric acid, and a crystal was collected by filtration to yield 7.78 g of S-p-methoxybenzyl-D-cysteine in the form of pale yellow crystals. A 7.025 g portion of the thus obtained S-p-methoxybenzyl compound was dissolved in an aqueous-acetonitrile, and, with cooling on an ice bath, to this were added 12.75 g of sodium bicarbonate and 7.09 g of p-nitrobenzyloxycarbonyl chloride, and the mixture was stirred for 1.5 hours at room temperature. The reaction solution was washed with ether, acidified with concentrated sulfuric acid and extracted with ethyl acetate, the resulting organic layer was washed with water and dried over sodium sulfate and then the solvent was removed by evaporation under a reduced pressure, thereby yielding 6.47 g of S-p-methoxybenzyl-N-p-nitrobenzyloxycarbonylcysteine as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: D-cysteine hydrochloride With potassium carbonate In water Reflux; Inert atmosphere; Stage #2: 6-(dimethylamino)benzo[d]thiazole-2-carbonitrile In methanol; water at 20℃; Inert atmosphere; Darkness; Stage #3: With hydrogenchloride In methanol; water | |
In methanol; water at 20℃; for 2h; Potassium phosphate buffer; | 1 D-2-(6'-dimethylamino-2'-benzothiazolyl)-Δ2-thiazoline-4-carboxylic acid (1a)D-cysteine-HCl (2.5 mg) was dissolved in 0.6 ml of deoxygenated 50 mM potassium phosphate buffer, pH 8.1 and added to 2 mg (10 μmol) of (44) in 0.6 ml of deoxygenated methanol and stirred under argon at room temperature. After 2 h, the methanol was removed by rotary evaporation, and the remaining aqueous solution was extracted with ethyl acetate twice and dried with sodium sulfate. Removal of the solvent by rotary evaporation yielded 3 mg of an orange-red solid. 1H-NMR (d6-DMSO): d 7.89 (d, 1H, J=9.2 Hz), 7.29 (d, 1H, J=2.4 Hz), 7.05 (dd, 1H, J=2.4, 9.2 Hz), 5.35 (app t, 1H, X of ABX, J=8-10 Hz), 3.74-3.59 (m, 2H, AB of ABX), 3.01 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: D-cysteine hydrochloride With potassium carbonate In water Reflux; Inert atmosphere; Stage #2: 6-(ethylamino)benzo[d]thiazole-2-carbonitrile In methanol; water at 20℃; Inert atmosphere; Darkness; Stage #3: With hydrogenchloride In methanol; water | |
In methanol; water at 20℃; for 2h; Potassium phosphate buffer; | 2 D-2-(6'-ethylamino-2'-benzothiazolyl)-Δ2-thiazoline-4-carboxylic acidD-cysteine-HCl (7 mg, 40 μmol) was dissolved in 1 ml of deoxygenated 50 mM potassium phosphate buffer, pH 8 and added to 6.3 mg (31 μmol) of 2-cyano-6-ethylaminobenzothiazole in 1 ml of deoxygenated methanol and stirred under argon at room temperature. After 2 h, the solution was acidified to pH 5 with 0.1M HCl and the methanol was removed by rotary evaporation. The precipitated solid and the remaining aqueous solution was extracted with ethyl acetate three times and dried with sodium sulfate. Removal of the solvent by rotary evaporation yielded 8.8 mg of an orange-red solid. 1H-NMR (d6-DMSO): δ 7.76 (d, 1H, J=8.8 Hz), 7.03 (s, 1H), 6.86 (d, 1H, J=9.2 Hz), 6.35 (m, 1H), 5.32 (app t, 1H, X of ABX), 3.75-3.55 (m, 2H, AB of ABX), 3.09 (m, 2H), 1.18 (t, 3H, J=7.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water at 20℃; for 2h; Potassium phosphate buffer; | 3 D-2-(6'-isopropylamino-2'-benzothiazolyl)-Δ2-thiazoline-4-carboxylic acidD-cysteine-HCl (8.8 mg, 50 μmol) was dissolved in 1.25 ml of deoxygenated 50 mM potassium phosphate buffer, pH 8 and added to 9.1 mg (42 μmol) of 2-cyano-6-isopropylaminobenzothiazole in 1.25 ml of deoxygenated methanol and stirred under argon at room temperature. After 2 h, the solution was acidified to pH 5 with 0.1M HCl and the methanol was removed by rotary evaporation. The precipitated solid and the remaining aqueous solution was extracted with ethyl acetate three times and dried with sodium sulfate. Removal of the solvent by rotary evaporation yielded 15 mg of an orange-red solid. 1H-NMR (d6-DMSO): δ 7.75 (d, 1H, J=9.2 Hz), 7.05 (d, 1H, J=2.4 Hz), 6.85 (dd, 1H, J=2.4, 8.8 Hz), 6.22 (bd, 1H, J=7.2 Hz), 5.32 (app t, 1H, X of ABX, J=8-10 Hz), 3.61 (m, 1H), 3.55-3.72 (m, 2H, AB of ABX), 1.14 (d, 6H, J=6.4 Hz).. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water at 20℃; for 2h; Potassium phosphate buffer; | 4 D-2-(6'-butylamino-2'-benzothiazolyl)-Δ2-thiazoline-4-carboxylic acidD-cysteine-HCl (7 mg, 40 μmol) was dissolved in 1 ml of deoxygenated 50 mM potassium phosphate buffer, pH 8 and added to 6.6 mg (29 μmol) of 2-cyano-6-butylaminobenzothiazole in 1 ml of deoxygenated methanol and stirred under argon at room temperature. After 2 h, the solution was acidified to pH 5 with 0.1M HCl and the methanol was removed by rotary evaporation. The precipitated solid and the remaining aqueous solution was extracted with ethyl acetate three times and dried with sodium sulfate. Removal of the solvent by rotary evaporation yielded 8.5 mg of an orange-red solid. 1H-NMR (d6-DMSO): δ 7.75 (d, 1H, J=9.2 Hz), 7.03 (s, 1H), 6.87 (d, 1H, J=9.2 Hz), 6.36 (m, 1H), 5.32 (app t, 1H, X of ABX), 3.75-3.55 (m, 2H, AB of ABX), 3.04 (m, 2H), 1.54 (m, 2H), 1.37 (m, 2H), 0.90 (t, 3H, J=7.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.8% | Stage #1: 2-cyano-6-(1-(2-nitrophenyl)ethoxy)benzothiazole; D-cysteine hydrochloride In methanol; dichloromethane Stage #2: With sodium hydrogencarbonate In methanol; dichloromethane; water Stage #3: With hydrogenchloride In methanol; dichloromethane; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.4% | Stage #1: 2-cyano-6-(2-nitrobenzyloxy)benzothiazole; D-cysteine hydrochloride In methanol; dichloromethane Stage #2: With sodium hydrogencarbonate In methanol; dichloromethane; water for 0.25h; Stage #3: With hydrogenchloride In methanol; dichloromethane; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.6% | Stage #1: 2-cyano-6-(4,5-dimethoxy-2-nitrobenzyloxy)benzothiazole; D-cysteine hydrochloride In methanol; dichloromethane Stage #2: With sodium hydrogencarbonate In methanol; dichloromethane; water Stage #3: With hydrogenchloride In methanol; dichloromethane; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium acetate In methanol; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate at 60℃; for 12h; Inert atmosphere; aq. phosphate buffer; | |
85% | With potassium carbonate; citric acid In methanol; aq. phosphate buffer at 60℃; | |
60% | With potassium carbonate In methanol; aq. phosphate buffer at 60℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: D-cysteine hydrochloride With potassium carbonate In water Reflux; Inert atmosphere; Stage #2: 6-(methylamino)benzo[d]-thiazole-2-carbonitrile In methanol; water at 20℃; Inert atmosphere; Darkness; Stage #3: With hydrogenchloride In methanol; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: D-cysteine hydrochloride With potassium carbonate In water Reflux; Inert atmosphere; Stage #2: 2-cyano-6-[2-(1,3-dicarboxypropylamino)-2-oxoethylamino]benzothiazole In methanol; water at 20℃; Inert atmosphere; Darkness; Stage #3: With hydrogenchloride In methanol; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: D-cysteine hydrochloride With potassium carbonate In water Reflux; Inert atmosphere; Stage #2: 2-cyano-6-diethylaminobenzothiazole In methanol; water at 20℃; Inert atmosphere; Darkness; Stage #3: With hydrogenchloride In methanol; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: D-cysteine hydrochloride With potassium carbonate In water Reflux; Inert atmosphere; Stage #2: 6-phenethylamino-2-cyanobenzothiazole In methanol; water at 20℃; Inert atmosphere; Darkness; Stage #3: With hydrogenchloride In methanol; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: D-cysteine hydrochloride With potassium carbonate In water Reflux; Inert atmosphere; Stage #2: 6-(4-phenylbutylamino)-2-cyanobenzothiazole In methanol; water at 20℃; Inert atmosphere; Darkness; Stage #3: With hydrogenchloride In methanol; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In 1,4-dioxane; water at 0℃; for 1h; Inert atmosphere; | 5.1.20. Methyl (4S)-2-oxo-1,3-thiazolidine-4-carboxylate (37) To a stirred solution of d-cysteine hydrochloride (5.26 g, 30.0 mmol) in 1 N sodium hydroxide (90 mL) was added a solution of triphosgene (8.88 g, 30.0 mmol) in 1,4-dioxane (60 mL) at 0 °C under argon atmosphere. After being stirred at the same temperature for 1 h, the reaction mixture was evaporated. To the resulting residue was added warm acetonitrile. The resulting precipitates were removed by filtration and the filtrate was evaporated. A solution of the resulting residue in EtOAc was treated with diazomethane to give 37 (4.49 g, 93%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 3.64 (dd, J = 11.4, 5.3 Hz, 1H), 3.68-3.81 (m, 1H), 3.83 (s, 3H), 4.45 (dd, J = 7.9, 5.3 Hz, 1H), 6.05 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium hydrogencarbonate In methanol; aq. phosphate buffer for 72h; Reflux; | General Method A. 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sodium hydroxide In ethanol at 20 - 80℃; for 10h; | 4.2.1 (S)-2-(4-Hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid (1a) To a solution of 4-cyanophenol (4a) (120mg, 1.01mmol) and d-cysteine hydrochloride monohydrate (d-Cys·HCl) (211mg, 1.20mmol) in EtOH (5mL) was added 1M NaOH (5mL). After the reaction mixture was stirred at 80°C for 6h, additional d-Cys·HCl (422mg, 2.40mmol) and 1M NaOH (1mL) were added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was filtered and the filtration residue was washed with 50% aqueous EtOH (20mL). The filtrate and washings were combined and the pH of the mixture was adjusted to pH 2 with 2M HCl. The precipitates were collected by suction filtration, washed by distilled water, and dried under reduced pressure to give anaolg 1a (111mg, 50%) as a white powder. Mp 200-204°C dec; 90% ee from chiral HPLC (retention time of l-isomer: 8.0min, d-isomer: 8.7min); 1H NMR (270MHz, CD3OD) δ 3.70 (dd, J=7.9, 11.5Hz, 1H, ABX system), 3.76 (dd, J=8.9, 11.5Hz, 1H, ABX system), 5.23 (dd, J=7.9, 8.9Hz, 1H, ABX system), 6.85 (d, J=8.9Hz, 2H, AA′BB′ system), 7.74 (d, J=8.9Hz, 2H, AA′BB′ system); 13C NMR (67.8MHz, CDCl3) δ 36.0 (t), 78.0 (d), 116.5 (d)×2, 124.5 (s), 131.8 (d)×2, 163.0 (s), 173.9 (s), 174.6 (s); FT-IR νmax (cm-1): 2680, 1610, 1580, 1510; EI-MS m/z: 223 (M+, 44%), 178 (100). HR-ESI-MS: m/z: [M+Na]+ calcd for C10H9NNaO3S, 246.0201; found, 246.0157. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With sodium hydroxide In ethanol at 80℃; for 5h; | 4.2.2 (S)-2-(4-(Dimethylamino)phenyl)-4,5-dihydrothiazole-4-carboxylic acid (1b) General procedure: To a solution of 4-(dimethylamino)benzonitrile (4b) (103mg, 0.71mmol) and d-Cys·HCl (371mg, 2.12mmol) in EtOH (4mL) was added 1M NaOH (5mL). After the reaction mixture was stirred at 80°C for 5h, 1M HCl (5mL) was added, and the mixture was concentrated under reduced pressure. The residue was washed with distilled water to give analog 1b (50.9mg, 29%) as a yellow solid. 92% ee from chiral HPLC (retention time of l-isomer: 11.1min, d-isomer: 11.5min); 1H NMR (270MHz, CDCl3) δ 3.01 (s, 6H), 3.50 (dd, J=9.2, 11Hz, 1H, ABX system), 3.61 (dd, J=9.2, 11Hz, 1H, ABX system), 5.00 (dd, J=9.2, 9.2Hz, 1H, ABX system), 6.71 (d, J=7.0Hz, 2H, AA′BB′ system), 7.71 (d, J=7.0Hz, 2H, AA′BB′ system); FT-IR νmax (cm-1): 3392, 1608; ESI-MS m/z: 251 [(M+H)+]. HR-ESI-MS: m/z: [M+Na]+ calcd for C12H14N2NaO2S, 273.0674; found, 273.0649. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide; In ethanol; at 80℃; for 5h; | General procedure: To a solution of 4-(dimethylamino)benzonitrile (4b) (103mg, 0.71mmol) and d-Cys·HCl (371mg, 2.12mmol) in EtOH (4mL) was added 1M NaOH (5mL). After the reaction mixture was stirred at 80C for 5h, 1M HCl (5mL) was added, and the mixture was concentrated under reduced pressure. The residue was washed with distilled water to give analog 1b (50.9mg, 29%) as a yellow solid. 92% ee from chiral HPLC (retention time of l-isomer: 11.1min, d-isomer: 11.5min); 1H NMR (270MHz, CDCl3) delta 3.01 (s, 6H), 3.50 (dd, J=9.2, 11Hz, 1H, ABX system), 3.61 (dd, J=9.2, 11Hz, 1H, ABX system), 5.00 (dd, J=9.2, 9.2Hz, 1H, ABX system), 6.71 (d, J=7.0Hz, 2H, AA?BB? system), 7.71 (d, J=7.0Hz, 2H, AA?BB? system); FT-IR numax (cm-1): 3392, 1608; ESI-MS m/z: 251 [(M+H)+]. HR-ESI-MS: m/z: [M+Na]+ calcd for C12H14N2NaO2S, 273.0674; found, 273.0649. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With sodium hydroxide In methanol at 80℃; for 6h; | 4.2.4 (S,E)-2-(4-Hydroxystyryl)-4,5-dihydrothiazole-4-carboxylic acid (2a) Following the literature,36 to a solution of 4-iodophenol (5) (1100mg, 5.0mmol) in water (10mL) were added CH3CO2K (491mg, 5.0mmol), K2CO3 (865mg, 6.3mmol), acrylonitrile (495μL, 7.5mmol), and Pd(OAc)2 (11mg, 0.05mmol), and the mixture was heated under reflux for 30min. After the reaction mixture was cooled to room temperature, precipitates were filtered off through a pad of Celite and the filter cake was washed with water (50mL). The filtrate and washings were combined, adjusted to pH 7 with 2M HCl, and the products were extracted with EtOAc (40mL). The organic layers were combined, dried over Na2SO4, and concentrated to leave a white solid. Recrystallization from EtOAc/i-Pr2O gave nitrile 6 (417mg, 58%) as colorless needles being a mixture of stereoisomers (cis/trans=1:3 by 1H NMR). 1H NMR (500MHz, CDCl3) δ 5.30 (d, J=12.5Hz, 0.25H cis), 5.85 (d, J=16Hz, 0.75H trans), 6.75 (d, J=8Hz, 1.5H trans, AA′BB′ system), 6.77 (d, J=9.0Hz, 0.5H cis, AA′BB′ system), 7.08 (d, J=12.5Hz, 0.25H cis), 7.33 (d, J=16Hz, 0.75H trans), 7.35 (d, J=8Hz, 1.5H trans, AA′BB′ system), 7.66 (d, J=9.0Hz, 0.5H cis, AA′BB′ system). To a solution of d-Cys·HCl (106mg, 0.60mmol) and nitrile 6 (65.0mg, 0.45mmol) in MeOH (2mL) was added 1M NaOH (2mL) and the mixture was stirred at 80°C for 6h. The reaction mixture was neutralized with 1M HCl and was directly purified using a Sep-Pak cartridge (Waters, C18, water to 60% MeOH stepwise gradient) to give anaolg 2a (9.2mg, 8%) as a pale-yellow solid. Mp 138-140°C dec; 98% ee; from chiral HPLC (retention time of l-isomer: 12.3min, d-isomer: 12.9min); 1H NMR (270MHz, CD3OD) δ 3.52 (dd, J=8.9, 10.9Hz, 1H, ABX system), 3.61 (dd, J=8.9, 10.9Hz, 1H, ABX system), 5.01 (dd, J=8.9, 8.9Hz, 1H, ABX system), 6.80 (d, J=8.9Hz, 2H, AA′BB′ system), 6.91 (d, J=16.0Hz, 1H), 7.10 (d, J=16.0Hz, 1H), 7.42 (d, J=8.9Hz, 2H, AA′BB′ system); 13C NMR (67.8MHz, CDCl3) δ 36.5 (t), 81.2 (d), 116.9 (d)×2, 119.7 (d), 128.0 (s), 130.5 (d)×2, 143.7 (d), 160.7 (s), 172.0 (s), 177.5 (s); FT-IR νmax (cm-1): 3151, 1626, 1568; ESI-MS m/z: 250 [(M+H)+]. HR-ESI-MS: m/z: [M+H]+ calcd for C12H12NO3S, 250.0538; found, 250.0516. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In water at 40℃; for 4.5h; | S.11 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester [Synthetic Example 11] N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester D-Cysteine hydrochloride monohydrate (10 g, 57 mmol) was dissolved in water (20 ml), and the pH of the solution was adjusted to 5.13 with 6N aqueous sodium hydroxide solution. The reaction mixture was heated to 40°C, ethyl pyruvate (7.6 ml, 68 mmol) was gradually added thereto, and the mixture was stirred at 40°C for 4.5 hr to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by NMR to find about 55:45). After completion of the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With hydrogenchloride; potassium carbonate In methanol; dichloromethane; water Inert atmosphere; | 1 (S)-2-(6-(4-Boronobenzyloxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (1) (S)-2-(6-(4-Boronobenzyloxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (1) D-cysteine hydrochloride (58.7 mg, 0.334 mmol) and potassium carbonate (50.36 mg, 0.364 mmol) were dissolved in 2 mL N2-sparged DI H2O under an N2 atmosphere. 5 mL N2-sparged dichloromethane was added to the flask, followed by 5 (100 mg, 0.304 mmol). After 5 dissolved, the flask was charged with 7.6 mL N2-sparged methanol. The flask was monitored to ensure that no precipitate formed while the methanol was added. The reaction was stirred vigorously for ten minutes before 3 mL N2-sparged DI H2O were added to the flask. The DCM and MeOH were removed from the flask under low pressure prior to the addition of 25 mL of a N2-sparged 20% aqueous HCl solution. A yellow precipitate formed immediately upon addition of the HCl solution. The mixture was stirred for 15-20 minutes and the precipitate was filtered and washed with DI H2O until the pH became neutral. The crude material was purified using HPLC (H2O:MeOH, 40-100% MeOH over 45 minutes) to give 58.9 mg (47%) pure product. 1H NMR (400 MHz, CD3OD): δ 3.78 (2H, dd, J=9.2, 2.8 Hz), 5.22 (2H, s), 5.40 (1H, t, J=9.2), 7.26 (1H, dd, J=9.2, 2.6 Hz), 7.48 (2H, d, J=6.4 Hz), 7.63 (1H, d, J=2.4 Hz), 7.67 (1H, br), 7.78 (1H, br), 7.98 (1H, d, J=9.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In methanol; water at 20℃; for 1h; Inert atmosphere; | |
84% | With potassium carbonate In methanol; water at 20℃; for 0.666667h; Inert atmosphere; | 1 Synthesis of 7-Allyl-Firefly Luciferin 35 2-cyano-7-allyl-6-hydroxybenzothiazole 34 (50 mg, 0.23 mmol) and D-cysteine hydrochloride monohydrate (45 mg, 0.25mmol) were dissolved in methanol : distilled water (2:1.6 ml). Potassium carbonate (50 mg, 0.36 mmol) was added in an argon atmosphere, and the result was stirred at room temperature for 40 minutes. The resulting solid was filtered and cleaned with distilled water, yielding 7-allyl-firefly luciferin 35 (64 mg, 84%) as a yellow solid. [0099] 1H NMR (270 MHz, CD3OD) δ 7.78 (1H, d, J = 8.9 Hz), 7.10 (1H, dd, J = 8.9 Hz), 5.92 (1H, m), 5.42 (1H, t, J = 8.9 Hz), 5.15-5.03 (comp. 2 H), 3.75 (2 H, d, J = 8.1 Hz), 3.59 (2 H, J = 6.2 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.0833333h; | 1 (S)-2-(6-((3-((15-carboxypentadecyl)disulfanyl)propoxy)carbonyloxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (FFA-luc) (S)-2-(6-((3-((15-carboxypentadecyl)disulfanyl)propoxy)carbonyloxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (FFA-luc) D -cysteine hydrochloride (13.5 mg, 0.09 mmol) was placed in a flask which contained 6 (49.90 mg, 0.09 mmol). To this flask was added methanol (5 mL) and dichloromethane (5 mL). A solution of potassium carbonate (11.8 mg, 0.09 mmol) in water (2 mL) and methanol (5 mL) was added to the reaction. The reaction was allowed to stir for 5 min at room temperature (RT) at which time it was quenched by acidification to a pH of 3-4 with 1M HCl. The organic solvent was removed in vacuo and the remaining water removed via lyophilization. The crude material was purified by RP-HPLC (40% methanol/60% water to 100% methanol over 45 min then 100% methanol for 20 min, maximum peak elution at 54.4 min). The methanol was removed from fractions containing product to afford a white solid. 1H NMR (CD3OD, 500 MHz): δH 1.33 (m), 1.58 (m, 2H), 1.70 (q, 2H), 2.27 (t, 2H), 2.70 (t, 2H), 2.83 (t, 2H), 3.21 (q, 2H), 3.79 (dd, 2H), 4.39 (t, 2H), 5.33 (t, 1H), 7.30 (dd, 1H), 7.95 (d, 1H), 8.13 (d, 1H) Calcd for C31H45N2O7S4 [M+H]+ 685.2. found 685.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.5h; | 1 (S)-2-(6-((3-((16-methoxy-16-oxohexadecyl)disulfanyl)propoxy)carbonyloxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (Me-FFA-luc) (S)-2-(6-((3-((16-methoxy-16-oxohexadecyl)disulfanyl)propoxy)carbonyloxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (Me-FFA-luc) D-cysteine hydrochloride (10.7 mg, 0.07 mmol) was placed in a flask which contained 7 (37.2 mg, 0.06 mmol). To this flask was added methanol (3.4 mL) and dichloromethane (3.4 mL). A solution of potassium carbonate (8.7 mg, 0.06 mmol) in water (1.4 mL) and methanol (3.4 mL) was added to the reaction. The reaction was allowed to stir for 30 min at room temperature at which time it was quenched by acidification to a pH of 3-4 with 1M HCl. The organic solvent was removed in vacuo and diluted further with methanol and DMF. The crude material was purified by RP-HPLC (40% methanol/60% water to 100% methanol over 45 min then 100% methanol for 30 min, maximum peak elution at 56.0 min). The methanol was removed from fractions containing product to afford a white solid. This was further purified by RP-HPLC (80% methanol/20% water to 100% methanol over 45 min then 100% methanol for 30 min, maximum peak elution at 47.6 min) followed by extraction (acetonitrile/hexanes) to yield a white solid (15.0 mg, 34%). 1H NMR (CD3OD, 500 MHz): δH 1.24-1.32 (m, 20H), 1.36-1.45 (m, 2H), 1.59 (q, 2H, J=7.5 Hz), 1.69 (q, 2H, J=7.5 Hz), 2.15 (q, 2H, J=6.5 Hz), 2.30 (t, 2H, J=7.5 Hz), 2.72 (t, 2H, J=7.5 Hz), 2.83 (t, 2H, J=7.5 Hz), 3.65 (s, 3H), 3.78 (dd, 2H, J=2.0 Hz, 9.5 Hz), 4.39 (t, 2H, J=6.5 Hz), 5.36 (t, 1H, J=9.5 Hz), 7.43 (dd, 1H, J=2.0 Hz, 9.0 Hz), 7.95 (d, 1H, J=2.0 Hz), 8.11 (d, 1H, J=9.0 Hz). 13C NMR ((CD3)2CO, 150 MHz): δc 25.67, 28.98, 29.11, 30.36, 30.38, 30.46, 34.34, 35.15, 35.53, 35.64, 39.29, 51.44, 68.10, 79.46, 115.76, 122.21, 125.73, 137.49, 151.13, 152.00, 154.09, 162.48, 171.24, 174.13. Calcd for C32H47N2O7S4 [M+H]+ 699.2272. found 699.2268 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.5h; | 1 (S)-2-(6-((3-(15-carboxypentadecylthio)propoxy)carbonyloxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (FFA-S-luc) (3). D-cysteine hydrochloride (3.1 mg, 0.02 mmol) was placed in a flask which contained 11 (10.1 mg, 0.02 mmol). To this flask was added methanol (1 mL) and dichloromethane (1 mL). A solution of potassium carbonate (2.6 mg, 0.02 mmol) in water (0.4 mL) and methanol (1 mL) was added to the reaction. The reaction was allowed to stir for 30 min at room temperature at which time it was quenched by acidification to a pH of 3-4 with 1M HCl. The organic solvent was removed in vacuo and diluted further with methanol and DMF. The crude material was purified by RP-HPLC (40% methanol/60% water to 100% methanol over 45 min then 100% methanol for 20 min, maximum peak elution at 51.8 min). The methanol was removed from fractions containing product which was further purified by extraction (acetonitrile/hexanes) to afford a white solid (5.0 mg, 31%). 1H NMR (CD3OD, 500 MHz): δH 1.24-1.37 (m, 20H), 1.37-1.45 (m, 2H), 1.59 (q, 4H, J=7.5 Hz), 2.02 (q, 2H, J=6.5 Hz), 2.27 (t, 2H, J=7.5 Hz), 2.54 (t, 2H, J=7.5 Hz), 2.65 (t, 2H, J=7.5 Hz), 3.78 (dd, 2H, J=3.0 Hz, 9.5 Hz), 4.38 (t, 2H, J=6.5 Hz), 5.37 (t, 1H, J=9.5 Hz), 7.43 (dd, 1H, J=2.5 Hz, 8.5 Hz), 7.96 (d, 1H, J=2.5 Hz), 8.11 (d, 1H, J=8.5 Hz). HRMS (ESI): Calcd for C31H43N2O7S3 [M-H]- 651.2238. found 651.2233. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | Stage #1: 6-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzo[d]thiazole-2-carbonitrile; D-cysteine hydrochloride With potassium carbonate In methanol; dichloromethane; water Inert atmosphere; Stage #2: With hydrogenchloride; water Inert atmosphere; | 2C Example 2C: (S)-2-( 6-(4-borono-3-fluorobenzyloxy)benzo[d]thiazol-2-yl)-4, 5-dihydrothiazole- 4-carboxylic acid (also referred to herein as PCL-F) Example 2C: (S)-2-( 6-(4-borono-3-fluorobenzyloxy)benzo[d]thiazol-2-yl)-4, 5-dihydrothiazole- 4-carboxylic acid (also referred to herein as PCL-F)(PCL-F)[0088] D-cysteine hydrochloride (58.7 mg, 0.334 mmol) and potassium carbonate (50.4 mg, 0.364 mmol) were dissolved in 2.0 ml. N2-sparged deionized H20 under an N2atmosphere. 5.0 ml. N2-sparged dichloromethane was added to the flask, followed by the compound of Example 2B (125.0 mg, 0.304 mmol). After the compound of Example 2B dissolved, the flask was charged with 8.0 ml. N2-sparged methanol. The flask was monitored to ensure that no precipitate formed while the methanol was added. The reaction was stirred vigorously for ten minutes before 3.0 ml. N2-sparged deionized H20 was added to the flask. The dichloromethane and methanol were removed from the flask under low pressure prior to the addition of 25 mL of a N2-sparged 20% aqueous HCI solution. A yellow precipitate formed immediately upon addition of the HCI solution. The mixture was stirred for 15-20 minutes and the precipitate was filtered and washed with deionized H20 until the pH became neutral. The crude material was purified using HPLC (H20:MeOH, 40-100% MeOH over 45 minutes) to give 35.0 mg (27 %) pure product of Example 2C (i.e., PCL-F).1H NMR (CD3OD): δ 3.35 (s, 1 H), 3.77 (br, 2H), 5.22 (s, 2H), 5.37 (br, 1 H), 7.21 (d, J = 9.5 Hz, 1 H), 7.28 (dd, J = 9.8 Hz, J = 2.4 Hz, 2H), 7.31 (s, 1 H), 7.44 (t, J = 7.0 Hz, 1 H), 7.64 (m, 1 H), 7.99 (d, J = 9.0 Hz, 1 H).13C NMR (CD3OD): δ 159.7, 135.6, 125.9, 124.0, 1 18.7, 1 14.8, 1 14.5, 106.4, 85.7, 79.8, 70.6, 36.0, 2.3. Electrospray ion mass spectroscopy (positive ion mode) for the compound of Example 2C yielded a m/z of 433.0478 (calculated: 433.2659) for PCL-F, and a m/z of 415.0563 (calculated: 415.2748) for the non-fluorinated peroxy-caged-luciferin (PCL-1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In methanol; water at 20℃; Inert atmosphere; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In methanol; water at 20℃; Inert atmosphere; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine In methanol; water at 20℃; for 1h; | 5 Method 2: Synthesis of 5651 [00248j Method 2: Synthesis of 5651. Dissolved 12mg of d-cysteine (0.077 mmol) in 1 mL of water and adjusted pH to 8-8.5 with TEA and then added 30 mg (0.025 mmol) of 5648 in 1 mL methanol and stirred for an hour at room temperature. The product was acidified with acetic acid and then extracted into methylene chloride. The solvent was removed, and the product was purified by flash column chromatography using a gradient of heptaneTHF followed by methylene chloridemethanol to give the product in a yield of 70 % (22.8 mg). MS-ESI (mle):1276.93 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 % de | Stage #1: D-cysteine hydrochloride With sodium hydroxide In water Stage #2: 2-oxo-propionic acid ethyl ester In water at 40℃; for 4.5h; | 11 D-Cysteine hydrochloride monohydrate (10 g, 57 mmol) was dissolved in water (20 ml), and the pH of the solution was adjusted to 5.13 with 6N aqueous sodium hydroxide solution. The reaction mixture was heated to 40° C., ethyl pyruvate (7.6 ml, 68 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 4.5 hours to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by NMR to find about 55:45). After completion of the reaction, the reaction mixture was extracted with ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.0833333h; | Synthesis of FMO-1 General procedure: To the solution of dimethylamine (0.235 g, 0.90 mmol) and D-cystine (0.158g, 0.90 mmol)in methanol (5ml), CH2Cl2 (1 ml) and H2O (1 ml) was added K2CO3 (0.125 g, 0.90 mol). The mixture was stirred at roomtemperature for 5 min and then neutralized to slightly acidic condition. After removal of organic solvent, the product waspurified by HPLC using 0.1 %TFA water/acetonitrile as eleuent.1H NMR (CD2Cl2): 7.90 (d, 1H), 7.23 (s, 1H), 7.04 (d, 1H), 5.37 (t, 1H, CHCOO), 4.10 (t, 2H, OCH2), 3.79 (m, 2H, CH2),3.32 (t, 2H, CH2N), 2.97 (s, 6H, CH3), 2.30 (m, 2H, CH2). MS (ES): m/e (M+), 365. The compound was synthesized by employing the similar method for the preparation ofMAO-1 and purified by flash chromatography using methylene chloride/methanol (95:5) as eluent in a yield of 50%.1H NMR (d6-DMSO): 8.0 (d, 1H), 7.71 (s, 1H), 7.40 (d, 2H), 7.32 (t, 2H), 7.20 (t, 1H), 7.12 (d, 1H), 5.39 (t, 1H, CHCOO),4.24 (t, 2H, OCH2), 3.6-3.8 (m, 2H, CH2), 3.40 (t, 2H, SCH2). MS (ES) m/e (M+1): 417. λmax 328 nm, εmax 19,900 cm-1M-1in water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 80% 2: 20% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.0833333h; | Synthesis of 6-(3,3-Dichloro-propoxy)-luciferin. General procedure: To the solution of dimethylamine (0.235 g, 0.90 mmol) and D-cystine (0.158g, 0.90 mmol)in methanol (5ml), CH2Cl2 (1 ml) and H2O (1 ml) was added K2CO3 (0.125 g, 0.90 mol). The mixture was stirred at roomtemperature for 5 min and then neutralized to slightly acidic condition. After removal of organic solvent, the product waspurified by HPLC using 0.1 %TFA water/acetonitrile as eleuent.1H NMR (CD2Cl2): 7.90 (d, 1H), 7.23 (s, 1H), 7.04 (d, 1H), 5.37 (t, 1H, CHCOO), 4.10 (t, 2H, OCH2), 3.79 (m, 2H, CH2),3.32 (t, 2H, CH2N), 2.97 (s, 6H, CH3), 2.30 (m, 2H, CH2). MS (ES): m/e (M+), 365. The compound was synthesized by employing the similar method for the preparation ofMAO-1 and purified by flash chromatography using methylene chloride/methanol (95:5) as eluent in a yield of 50%.1H NMR (d6-DMSO): 8.0 (d, 1H), 7.71 (s, 1H), 7.40 (d, 2H), 7.32 (t, 2H), 7.20 (t, 1H), 7.12 (d, 1H), 5.39 (t, 1H, CHCOO),4.24 (t, 2H, OCH2), 3.6-3.8 (m, 2H, CH2), 3.40 (t, 2H, SCH2). MS (ES) m/e (M+1): 417. λmax 328 nm, εmax 19,900 cm-1M-1in water. The compound was made by employing the similar procedureused for the synthesis of GST-3. 1H NMR (d6-DMSO): 8.02 (d, 1H), 7.80 (d, 1H), 7.19 (dd, 1H), 6.46 (t, 1H, CHCl2),5.35 (t, 1H, CHCOO), 4.24 (t, 2 H, OCH2), 3.6-3.8 (m, 2H, SCH2), 2.69 (q, 2H, CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.0833333h; | Synthesis of 6-(3-t-BOC-3-methylaminopropoxy)quinolinyl-luciferin General procedure: The compound was made by employing the similar method used for the preparation of MAO-3.1H NMR (d6-DMSO): 8.33 (d, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.4-7.5 (m, 2H), 5.51 (dd, 1H, CHCOO), 4.12 (t, 2H, OCH2),3.6-3.9 (m, SCH2), 3.37 (t, 2H, NCH2),1.99 (m, 2H, CHO2), 1.30 (s, br, 9H, CH3). MS (ES): m/e (M+1), 446 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 6-acetoxy-4-methyl-1,3-benzothiazole-2-carbonitrile With potassium carbonate In methanol; water; acetonitrile at 20℃; Stage #2: D-cysteine hydrochloride In methanol; water; acetonitrile at 20℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | Stage #1: 2-Bromoacetyl bromide; 7-amino-7-methoxy-3-[(1-methyl-1H-1,2,3,4-tetrazol-5-yl)sulfanyl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbonyloxidanyl derivatives With <i>N</i>,<i>N</i>-dimethyl-aniline In dichloromethane at -20℃; for 1.5h; Stage #2: With hydrogenchloride; trimethylsilyl iodide In dichloromethane at -35℃; for 2h; Stage #3: D-cysteine hydrochloride | 2 Providing a method for synthesizing cefmino sodium, comprising the steps of : (1) 50 g of 7-AMCA and 800 mL of dichloromethane were added to a dry 1000 mL reaction flask, cooled to -20 ± 2 ° C, 14 g of N, N-dimethylaniline was added and 20 g of bromoacetyl bromide was added dropwise to maintain this temperature Reaction for 1.5 hours. (2) the end of the reaction, adding trimethyl iodosilane and anisole, cooling to -35 ° C, through the measurement of hydrogen chloride gas for 2 hours. (3) raise the temperature to 0 ~ 5 ° C drop K2CO33 solution, Control the pH to 7.0 ± 0.2, Layered, The aqueous phase was transferred to another 1000 mL three-necked flask, 1000 mL of ethyl acetate was added, Dropping the hydrochloric acid solution with the mass fraction of 15%, adjusting the pH value to 0.8, stirring, Static stratification, A solution of ethyl acetate in ethyl acetate was added dropwise 14.5 g D-cysteine hydrochloride aqueous solution, Diethylamine was added dropwise, the pH was controlled, the reaction was stirred for 3 hours, After completion of the reaction, ethyl acetate was separated, The water phase by adding 2g activated carbon decolorization 1 hour, Filtered, the aqueous phase transferred to 1 OOOrnL three bottles. (4) temperature control 25 ± 2 ° C, add 8g sodium acetate formed by stirring the reaction 30min, add isopropyl alcohol 300ml, add seed crystal stirring 2 hours, down to -5 ~ 0 °C, crystallization 2 hours , Filtered, ethanol washed, 40 ° C vacuum drying to moisture qualified, the product 58g cefmino sodium, the yield was 91.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In methanol; water at 20℃; for 0.166667h; | (4S)-2-(6-(5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanamido)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (1b) To a solution of 1a (92 mg, 0.2 mmol) in MeOH 2ml was added the mixture of D-cysteine hydrochloride (46 mg, 0.15 mmol) and potassium carbonate (40 mg, 0.3 mmol) dissolved in 2 mL H2O. The mixture was stirred at room temperature for 10 min. Then the organic solvents were removed under reduced pressure. 20 mL water was added to the solution and acidified with 1 M HCl solution to afford the crude product as yellow solid. The crude product was used for the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1,4-diaza-bicyclo[2.2.2]octane In methanol; dichloromethane at 20℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 1,4-diaza-bicyclo[2.2.2]octane In methanol; dichloromethane; water at 20℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 30h; Inert atmosphere; | 2.2.i (ferf-Butoxycarbonyl)-L-cysteine (8): A mixture of L-cysteine hydrochloride (1.23 g, 8.25 mmol), (Boc)2Ο (1.801g, 8.25 mmol) and NaHCO3 (2.5 g, 29.8 mmol) in THF (7mL) and water (18mL) was stirred under argon at room temperature for 30 hours under nitrogen atmosphere. After completion of the reaction pH was adjusted to 3 and extracted with ethyl acetate and evaporated in vacuo to give an oil of (tert-butoxycarbonyl)-L-cysteine (1.54 g, 84%). 1H NMR (CDC13) δ 9.05 (brs, 1H, -COOH), 5.51 (brs, 1H, -NHCO), 4.64-4.61 (m, 1H, -CHNHCO), 3.07-3.02 (m, 1, -CH2S), 2.99-2.93 (m, 1 H, , -CH2S), 1.44 (s, 9H, C- (CH3)3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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74.2% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate In methanol Inert atmosphere; Darkness; | 1.S6 Synthesis of 4,7-Dimethoxy-8,9-diacetoxy-N-acetylneuraminate-Fluorescein S61: Taken separately2-cyano-6-hydroxybenzothiazole18.9 mg (0.1072 mmol),K2CO3 20.7mg (0.1500mmol) was placed in a glass bottle,Add 1mL anhydrous CH3CN, N2 protection, stirring for 30min,form2-cyano-6-hydroxybenzothiazolesuspension.S62:Take the compound shown in Formula 64,7-dimethoxy-8,9-diacetoxy-2-chloro-N-acetylneuraminic acid methyl ester0.1022mmol,Dissolved in 0.7mL anhydrous CH3CN,An organic solution of the compound shown in Formula 6 is obtained; S63:The 2-cyano-6-hydroxy group obtained by adding the organic solution of the compound represented by Formula 6 obtained in S62 dropwise to S61In benzothiazole suspension, react for 2h,TCL: CH2Cl2: MeOH = 96:4 monitoring, suction filtration, rotary evaporation at 30 °C, cryopreservation;Column chromatography mobile phase separation conditions: CH2Cl2:CH3OH=98:2,37.4 mg intermediate obtained after separation4,7-Dimethoxy-8,9-diacetoxy-2-(2-cyano-6-oxobenzothiazole)-N-acetylneuraminic acid methyl ester,The yield is 75%. S64:Take 37.4g (0.08mmol) of intermediates4,7-Dimethoxy-8,9-diacetoxy-2-(2-cyano-6-oxobenzothiazole)-N-acetylneuraminic acid methyl ester,D-Cysteine Hydrochloride Hydrate18.92 mg (0.12 mmol),K2CO311.04mg (0.08mmol), add 0.6mL anhydrous methanol,Nitrogen protection, 5 min light stirring reaction, filtration, spin-drying, TLC detection and verification reaction; column chromatography mobile phase separation conditions:1. Acetone: n-hexane = 2:1;2.DCM:MeOH:TEA=20:1:0.1The 7,7-dimethoxy-8,9-diacetoxy-N-acetylneuraminic acid methyl ester-fluorescein represented by Formula 7 was obtained in a yield of 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.9% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.333333h; Inert atmosphere; | 3 Preparation of compound (3) Under argon protection,Compound 2 (0.42 mmol, 240 mg)Dissolved in 5 ml of a mixed solvent of methanol and dichloromethane (v/v = 1:1),Add a mixed solvent of 5 ml of methanol and deionized water (v/v = 1:1)Dissolved D-cysteine hydrochloride (0.45 mmol, 55 mg)And a solution of potassium carbonate (0.45 mmol, 62 mg).The reaction was carried out at room temperature for 20 min.After the reaction is over,Spin the organic solvent,Add equal volume of water,The pH was adjusted to about 2-3 with a 1 M hydrochloric acid solution.The crude product obtained was a yellow solid. The crude product was recrystallized from methanol to give a pale yellow product (100 mg, 53.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.14% | Stage #1: 7β-amino-7α-methoxy-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid With triethylamine In dichloromethane at -5℃; Inert atmosphere; Stage #2: 2-Bromoacetyl bromide In dichloromethane at -65 - -25℃; Inert atmosphere; Stage #3: D-cysteine hydrochloride With ammonium chloride In water at 20℃; for 4h; | 7; 8 Example 8 150 ml of dichloromethane was placed in a dry 250 ml three-necked flask.15 g of the methoxycephalosporin intermediate represented by Formula I, and the reaction vessel was stirred under a nitrogen atmosphere.Cool to -5 °C. 7.5 g of triethylamine was added, and the dropwise addition time was about 5 to 10 minutes. At the end of the dropwise addition, the temperature of the feed liquid was cooled to -30 to -25 °C. Cool to -65 ° C,Slowly add 10 g of bromoacetyl bromide solution at a temperature of -65 ° C.The dropping time is about 5 to 10 minutes. At the end of the addition, the temperature of the feed liquid was slowly raised to -40 to -25 °C. The reaction was stirred at a temperature of -40 to -25 ° C for 90 minutes. Sampling analysis, TLC detection (benzene: acetone = 8:3), the spot of the methoxycephalosporin intermediate shown in Formula I disappeared as the end of the reaction.After the reaction, 10% Na2CO3 was added to adjust the pH to 6-6.5, and the layer was allowed to stand.A solution of 18.6 g of D-cysteine hydrochloride and 120 g of purified water was added with stirring of the aqueous layer.Add 2.5g of ammonium chloride, react at room temperature for 4 hours, the reaction is completed, add sodium isooctanoate 6g(dissolved in 20 ml of acetone) 0.5 g of activated carbon, decolorized for 30 min, filtered,The mother liquor is added with 8 times the amount of the mother liquor in acetone to precipitate white crystalline particles.The crystal was raised at 0 to 5 ° C for 30 minutes, filtered, and dried under vacuum to obtain 22.4 g of cefminox sodium.The yield was 80.14%, and the purity by HPLC was 99.56% (normalized method). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Fmoc‑Gly‑Pro‑6‑amino‑2‑cyanobenzothiazole; D-cysteine hydrochloride In methanol; water at 20℃; for 0.333333h; Inert atmosphere; Stage #2: With sodium hydrogencarbonate In methanol; water at 20℃; for 2h; Inert atmosphere; | Synthesis of Fmoc-Gly-Pro-6-Amino-d-Luciferin (3) 5.512 g (0.010 mol, 1 equiv.) Fmoc-Gly-Pro-6-amino-2-cyanobenzothiazole (2) was dissolved in 25 mL MeOH. 2.634 g (0.015 mol, 1.5 equiv.) d-cysteine*HCl*H2O, solved in 19 mL distilled water, was added to the solution at room temperature, under argon atmosphere, then the mixture was stirred continuously under pH control (starting pH: 2.27). After 20 min’ stirring at room temperature, 30 mL, 5%(m/m) NaHCO3 was added dropwise over a period of 1 h to the mixture in order to release cysteine from its salt, while checking pH continuously. Reaching pH 2.6, a fine, yellow solid material, Fmoc-Gly-Pro-6-amino-d-luciferin free carboxylic acid, started to precipitate. At pH 6.3, this material started to dissolve, and at pH 7.40, it dissolved completely. Here the Fmoc-Gly-Pro-6-amino-d-luciferin formed Na-salt, which dissolved under these conditions. After another 20 min’ stirring at room temperature, the organic solvent was evaporated. From the remaining aqueous solution, a pale yellow solid material, Fmoc-Gly-Pro-6-amino-d-luciferin Na-salt precipitated partly. This aqueous mixture was extracted with 3 × 15 mL ethyl acetate, in order to get rid of possible impurities. The combined organic layers were extracted with saturated NaCl solution. Having dropped the resulting solution on a mixture of ice and cc HCl, a fine yellow precipitate, Fmoc-Gly-Pro-6-aminod-luciferin free carboxylic acid, formed. It was allowed to settle for 10 min, filtered and washed with 2 × 5 mL water, then air-dried to constant weight, which was 5.115 g (7.80 mmol), yield corresponding to the crude product: 78%. 1H NMR (500 MHz, [D6]DMSO) δ 10.39 (s, 1H),8.59 (t, J = 15.85 Hz, 1H), 8.09 (d, J = 8.98 Hz, 1H), 7.88(d, J = 7.43 Hz, 2H), 7.71 (d, J = 7.48 Hz, 2H), 7.66-7.60(m, 1H), 7.48 (t, J = 5.65 Hz, 1H), 7.39 (q, J1 = 7.60 Hz,J2 = 15.29 Hz, 2H), 7.30 (q, J1 = 6.78 Hz, J2 = 13.76 Hz,2H), 5.43 (t, J = 8.98 Hz, 1H), 4.47 (dd, J1 = 2.92 Hz,J2 = 5.21 Hz, 1H), 4.29-4.25 (m, 1H), 4.21 (q, J1 = 6.68 Hz,J2 = 14.87 Hz, 1H), 3.95-3.67 (m, 4H), 3.65-3.48 (m, 4H),2.20-2.11 (m, 1H), 2.06-1.99 (m, 1H), 1.97-1.88 (m, 2H)(Fig. S14). 13C NMR (125 MHz, [D6]DMSO) δ 171.15,171.05, 167.43, 164.43, 159.04, 156.55, 148.58, 143.86,140.70, 138.38, 136.28, 127.61, 127.08, 125.27, 124.20,120.10, 119.64, 111.52, 78.11, 65.70, 60.47, 46.62, 45.92,42.72, 34.78, 29.28, 24.52 (Figure S15). m/z [M + H]+ calcdfor C33H29N5O6S2655.74 found 656.0 (Figure S16). RPHPLC:70-100% B in 15 min, tR=12.608 min. TLC: toluene/EtOH 50:30 saturated with water, Rf: 0.44. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In methanol; water for 0.5h; Inert atmosphere; | D-Thioluciferin (S-luc, 7) D-Cysteine hydrochloride monohydrate (19.2 mg,0.110 mmol) and 2-cyano-6-mercaptobenzothiazole (19.1 mg, 0.100 mmol) weresuspended in 2:1 MeOH:H2O (1 mL). K2CO3 (13.8 mg, 0.100 mmol) was added. Theresulting yellow-green solution was stirred under N2 for 30 min. The methanol wasremoved under reduced pressure and the remaining solution was acidified to pH 3with 1 M aq HCl. The resulting pale yellow precipitate was filtered and washedwith H2O. The solid was dissolved in DCM and recrystallized upon addition ofhexanes, affording D-thioluciferin (26 mg, 87%) as a pale yellow solid. HRMS calcd.for C11H8N2O2S3 [M+H]+ 296.9826, found 296.9807. mp 156-158 (dec). 1H NMR (300MHz, CD3OD): δ 7.97 (d, J=8.7 Hz, 1H), 7.90 (s, 1H), 7.47 (d, J=8.7 Hz, 1H), 5.41 (t, J=8.4Hz, 1H), 3.78 (d, J=8.4 Hz, 2H). 13C NMR (400 MHz, CDCl3) δ 176.9, 161.4, 157.3,151.2, 136.6, 131.9, 130.2, 125.0, 122.1, 78.8, 34.2. IR (thin film): 3355, 2922, 2853, 1733, 1462, 1103, 900, 804 cm-1. [a]D23 -30 (c 0.9, MeOH). UV (H2O) lmax (log e) 300 nm (3.5).Fluorescence (H2O) lex 300 nm, lem 500 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 0.333333h; Inert atmosphere; | 2 Preparation of compound (2): TYR-LH2 Under the protection of argon, the compound (1) (1.06 mmol, 300 mg) prepared in Example 1 was dissolved in 5 ml of a mixed solvent of methanol and dichloromethane (v / v = 1: 1). A solution of D-cysteine hydrochloride (1.06 mmol, 160 mg) and potassium carbonate (1.32 mmol, 183 mg) in a mixed solvent of ionized water (v / v = 1: 1). The reaction was carried out at room temperature for 20 min. After the reaction, the organic solvent was spin-dried, an equal volume of water was added, and the pH was adjusted to about 2-3 with a 1M hydrochloric acid solution. The resulting crude product was a yellow solid. The crude product was recrystallized from methanol to give a slightly yellow product (268 mg, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.9% | With sodium hydrogencarbonate In methanol; dichloromethane; water | 1 Compound 2 (122 mg, 0.5 mmol) was dissolved with 8 mL of a mixture of dichloromethane and methanol.D-cysteine hydrochloride (88 mg, 0.5 mmol) dissolved in 2 mL of a mixture of methanol and water (1: 1) was addedAnd anhydrous sodium bicarbonate (42 mg, 0.5 mmol) solution.It was adjusted with dilute hydrochloric acid to give a solid compound I in a yield of 91.9%. |
41.9% | With sodium hydrogencarbonate In methanol; dichloromethane; water at 0℃; for 0.0833333h; | (S)-2-(6-(but-2-enoyloxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (CBP) To a solution of compound 2 (122 mg, 0.5 mmol) in the mixture of MeOH and DCM (9 mL, v/v = 4/5) was added D-Cysteine hydrochloride (88 mg, 0.5 mmol) and NaHCO3 (42 mg, 0.5 mmol) in the mixture of MeOH and water (2 mL, v/v = 1/1). The reaction mixture was stirred at 0 °C for 5 min. After 3 was consumed (monitored by TLC), the reaction mixture was adjusted to pH = 3 and filtered. The crude product was then purified by silica gel column chromatography (DCM : MeOH = 100 : 5 as eluent) to afford compound CBP as a white solid (85 mg, 41.9% yield). mp: 163.9-164.5 oC. ESI-HRMS C15H12N2O4S2 [M-H]- m/z: calcd. 347.0160, Found 347.0165. 1H NMR (400 MHz, DMSO-d6) δ 13.3 (s, 1H), 8.2 (d, J = 8.9 Hz, 1H), 8.1 (d, J = 2.3 Hz, 1H), 7.4 (dd, J = 8.9, 2.4 Hz, 1H), 7.2 (dd, J = 13.8, 6.9 Hz, 1H), 6.2 (dd, J = 13.8, 1.7 Hz, 1H), 5.5 (t, J = 9.1 Hz, 1H), 3.8 (d, J = 9.2 Hz, 2H), 2.0 (dd, J = 6.9, 1.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 171.0, 164.4, 164.1, 161.0, 150.4, 149.2, 148.5, 136.0, 124.6, 122.1, 121.2, 115.8, 78.2, 34.8, 18.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.7% | With sodium hydrogencarbonate In methanol; dichloromethane; water | 2 Compound 3 (115 mg, 0.5 mmol) was dissolved with 8 mL of a mixture of dichloromethane and methanol.A solution of D-cysteine hydrochloride (88 mg, 0.5 mmol) and anhydrous sodium bicarbonate (42 mg, 0.5 mmol) dissolved in 2 mL of a mixed solution of methanol and water (1: 1) was added.It was adjusted with dilute hydrochloric acid until a solid compound II appeared, with a yield of 87.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 1h; Inert atmosphere; | 1 (S)-2-(6,7-dihydro-5H-thiazolo[4,5-f]indol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (end product cycluc) Intermediate 6 (40mg, 0.199mmol) was dissolved in 10mL of dichloromethane and 10mL of anhydrous methanol, and potassium carbonate (70mg) dissolved in 2mL of anhydrous methanol and 2mL of distilled water was added dropwise under the protection of nitrogen.D-cysteine hydrochloride (41mg, 0.238mmol), react at room temperature, the reaction time is 1h, spin dry, adjust the pH to 7 with 1mol hydrochloric acid to precipitate a solid, filter, the filtrate is the final product, the crude product is used Dichloromethane and ethyl acetate were slurried and filtered to obtain a solid powder of 50 mg of the final product 7 with a yield of 48%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.1% | With potassium carbonate In methanol; dichloromethane; water at 20℃; for 1h; Inert atmosphere; | 2 (4R)-2-(6,7-dihydro-5H-thiazolo[4,5-f]indol-2-yl-6,7-d2)-4,5-dihydrothiazole-4-carboxylic acid (final product d2 -cycluc) Intermediate 15 (500mg, 1.0mmol) was dissolved in 10mL of dichloromethane and 10mL of anhydrous methanol. Under nitrogen protection, potassium carbonate (370mg) dissolved in 2mL of anhydrous methanol and 2mL of distilled water was added dropwise, D-cysteine hydrochloride (450 mg, 2.0 mmol) was reacted at room temperature, the reaction time was 1 h, spin-dried, the pH was adjusted to 7 with 1 mol hydrochloric acid to precipitate a solid, and the filtrate was the final product. The crude product was slurried with dichloromethane and ethyl acetate, filtered to obtain 544.4 mg of the target yellow solid powder, with a yield of 78.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.8% | With sodium hydrogencarbonate In methanol; dichloromethane; water at 20℃; for 0.5h; Inert atmosphere; | 4.5. Synthesis of (S)-2-(6-((5-oxohexanoyl)oxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (SBP-2) Compound S-2b (100 mg, 0.347 mmol) was dissolved in the mixture of MeOH and CH2Cl2 (5 mL, v/v 2:3), then D-Cysteine hydrochloride (60.8 mg, 0.347 mmol) and NaHCO3 (29 mg,0.347 mmol) in the mixture of MeOH and water (2 mL, v/v 1:1)was added slowly at 0 °C. Then, the mixture was stirred at room temperature under N2 protection for 30 min. After the completion,the above mixture was adjusted to pH 5 with 1 M HClaq. and the organic solvent was removed under reduced pressure. The precipitate was then purified by silica column chromatography (elute MeOH/DCM from 0 to 8%) to afford compound SBP-2 as a white solid (106 mg, 77.8% yield). mp:148.5-150.5 °C. 1H NMR (400 MHz,DMSO-d6) δ 13.21 (s, 1H), 8.20 (d, J 8.8 Hz, 1H), 8.05 (d, J 2.4 Hz,1H), 7.41 (dd, J 8.8, 2.4 Hz, 1H), 5.46 (dd, J 9.8, 8.4 Hz, 1H), 3.81(dd, J 11.2, 9.8 Hz, 1H), 3.72 (dd, J 11.2, 8.4 Hz, 1H), 2.62 (dt,J 14.8, 7.2 Hz, 4H), 2.12 (s, 3H), 1.84 (m, 2H). 13C NMR (101 MHz,DMSO-d6) δ 207.89, 171.56, 171.01, 164.35, 160.97, 150.37, 149.28,135.94,124.61,122.09,115.81, 78.13, 41.49, 34.81, 32.64, 29.74,18.43.ESI-MS calcd. for C17H16N2O5S2 (M H) 393.0501, found 393.0577. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.7% | With sodium hydrogencarbonate In methanol; dichloromethane; water at 20℃; for 0.5h; Inert atmosphere; | 4.7. Synthesis of (S)-2-(6-((6-oxoheptanoyl)oxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (SBP-3) Compound S-3b (120 mg, 0.4 mmol) was added into a round bottom flask containing a mixture of MeOH and CH2Cl2 (5 mL, v/v 2:3). Then D-Cysteine hydrochloride (70 mg, 0.4 mmol) and NaHCO3 (33 mg, 0.4 mmol) with a mixture of MeOH and water (2 mL, v/v 1:1) was added into the flask under stirring. The system was stirred for 30 min at room temperature under nitrogen atmosphere. After completion, diluted hydrochloric acid (1 mol/L)was added to tune the pH value to ~5 and distilled in a rotary evaporator to obtain a crude precipitate. Pure product was finallyobtained by silica column chromatography as a white solid SBP-3(92 mg, 56.7% yield), eluting MeOH/DCM from 0 to 8%. mp:137.9-138.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 8.21(d, J 8.8 Hz, 1H), 8.04 (d, J 2.4 Hz, 1H), 7.40 (dd, J 8.8, 2.4 Hz,1H), 5.48 (dd, J 9.8, 8.4 Hz, 1H), 3.78 (ddd, J 33.6, 11.2, 9.0 Hz,2H), 2.65 (t, J 7.0 Hz, 2H), 2.51 (t, J 6.8 Hz, 2H), 2.11 (s, 3H),1.79e1.41 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 208.20, 171.68,171.01, 164.34, 160.99, 150.36, 149.29, 135.97, 124.63, 122.06, 115.80,78.14, 42.23, 34.82, 33.25, 29.67, 23.77, 22.46. ESI-MS calcd. for C18H18N2O5S2 (M Na) 429.0657, found 429.0557. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.7% | With sodium hydrogencarbonate In methanol; dichloromethane; water at 20℃; for 0.5h; Inert atmosphere; | 4.3. Synthesis of (S)-2-(6-((4-oxopentanoyl)oxy)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid(SBP-1) To a solution of compound S-1b (100 mg, 0.364 mmol) in the mixture of MeOH and CH2Cl2 (5 mL, v/v 2:3) was added D-Cysteinehydrochloride (64 mg, 0.364 mmol) and NaHCO3 (30 mg,0.364 mmol) in the mixture of MeOH and water (2 mL, v/v 1:1).The reaction mixture was stirred at room temperature under nitrogen atmosphere for 30 min, then the above mixture was adjusted to pH 5 using diluted HClaq. (1 M) and the organic solvent was evaporated. The crude precipitate was purified by silica column chromatography using MeOH/DCM (1/12, v/v) to afford compound SBP-1 as a white solid (96 mg, 69.7% yield).mp:140.6-142.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 1H),8.20 (d, J 8.8 Hz, 1H), 8.00 (d, J 2.4 Hz, 1H), 7.36 (dd, J 8.8,2.4 Hz, 1H), 5.47 (dd, J 9.8, 8.4 Hz, 1H), 3.89-3.67 (m, 2H), 2.89 (t,J 6.4 Hz, 2H), 2.83-2.72 (m, 2H), 2.17 (s, 3H). 13C NMR (101 MHz,DMSO-d6) δ 206.80, 171.34, 171.00, 164.36, 161.04, 150.36, 149.30,135.99, 124.65, 121.93, 115.69, 78.13, 37.52, 34.81, 29.48, 27.85. ESI-MS calcd. for C16H14N2O5S2 (M+H) 379.0344, found 379.0420. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: benzyl (Z)-3-((2-cyanobenzo[d]thiazol-6-yl)thio)acrylate; D-cysteine hydrochloride In water; dimethyl sulfoxide at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: With potassium carbonate In water; dimethyl sulfoxide at 0℃; for 0.166667h; Inert atmosphere; regioselective reaction; | (S,Z)-2-(6-((3-(benzyloxy)-3-oxoprop-1-en-1-yl)thio)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (IX). (S,Z)-2-(6-((3-(benzyloxy)-3-oxoprop-1-en-1-yl)thio)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (IX). To a stirring solution of benzyl (Z)-3-((2-cyanobenzo[d]thiazol-6-yl)thio)acrylate (IVd) (40.0 mg, 0.110 mmol, 1 eq) in DMSO (4 mL) at room temperature under a nitrogen atmosphere was added D-cysteine (20.0 mg, 0.110 mmol, 1 eq) in H2O (6 mL). The solution was left to stir for 5 min, cooled to 0 oC, and then potassium carbonate (150.0 mg, 0.110, 1 eq) was added. The reaction mixture was then left to stir a further 10 min after which the pH was adjusted to pH 3 using 3 M HCl, all whilst maintaining a reaction temperature of 0 oC. The solution was then allowed to warm to room temperature and diluted with ethyl acetate (10 mL) and washed with H2O (4 x 10mL). The organic layer was then dried over MgSO4, filtered and evaporated under reduced pressure at 35 oC to afford a red oil. The crude material was further purified using silica column chromatography, eluting with 1:9 methanol:dichloromethane to afford the title compound as a red oil (50.0 mg, 99%). 1H-NMR (300 MHz, DMSO) δ 8.47 (1H, d, J 1.9 Hz), 8.20 (1H, d, J 8.6 Hz), 7.76 (2H, m), 7.40 (5H, m), 6.13 (1H, d, J 10.1 Hz), 5.47 (1H, dd, J 9.7, 8.5 Hz), 5.22 (2H, s), 3.77 (2H, m). MS (ESI+): m/z Calculated for C21H16N2O4S3 [M+H] 457.0350, found 457.0341. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In methanol; water at 20℃; for 0.5h; Inert atmosphere; Darkness; | (4S)-2-(6-(5-oxopyrrolidine-2-carboxamido)benzo[d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (3) To a solution of intermediate (2) (35 mg, 0.12 mmol) in 2 mL of MeOH was added the mixture of D-cysteine hydrochloride (64.41 mg, 0.36 mmol) and potassium carbonate (50.68 mg, 0.36 mmol) dissolved in 2 mL of H2O. The mixture was stirred at room temperature for 30 min. Then, the organic solvents were removed under reduced pressure. 20 mL water was added to the solution and acidified with 1 M HCl solution to afford the product as a yellow solid (43 mg, yield 90%). M.p.:170.2~171.2°C. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.68 - 8.60 (m, 1H), 8.11 (d, J = 8.9 Hz, 1H), 7.95 (s, 1H), 7.70 (ddd, J = 7.1, 5.0, 2.1 Hz, 1H), 5.44 (dd, J = 9.8, 8.3 Hz, 1H), 4.29 (dd, J = 8.6, 4.1 Hz, 1H), 3.74 (ddd, J = 19.5, 11.3, 9.1 Hz, 2H), 2.43 - 2.32 (m, 1H), 2.28 - 2.11 (m, 2H), 2.07 - 1.99 (m, 1H).13C NMR (101 MHz, DMSO-d6) δ 177.97, 172.31, 171.58, 164.89, 159.69, 149.20, 138.67, 136.74, 124.72, 120.23, 112.21, 78.58, 56.90, 35.23, 29.68, 25.82. HRMS m/z calcd. for C16H14N4O4S2 [M+H] + 391.0490, found 391.0530. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate In methanol; dichloromethane; water-d2 for 0.5h; Inert atmosphere; Darkness; | 1 Preparation of BL-FAP: Dissolve BL-NH2-Ac (212 mg, 0.57 mmol) in a mixed solution of dichloromethane: methanol = 2:3 (10:15 mL), and under the protection of nitrogen, D-cysteine hydrochloride(136mg, 0.86mmol) and K2CO3 (119mg, 0.86mmol) were dissolved in a mixed solution of DIH2O:MeOH=1:1 (5:5mL) and added dropwise to the BL-NH2-Ac solution. Light reaction for 30min; after the reaction, DCM and MeOH were removed by distillation under reduced pressure, and then the pH was adjusted to 3 with hydrochloric acid (1M) solution, and a yellow precipitate was deposited. The precipitate was filtered and washed with DI H2O until pH = 7. The crude product was purified by column chromatography (silica, DCM:MeOH, 15:1 v/v), and then recrystallized three times with ethyl acetate to obtain a pale yellow pure product. The yield is 56%. The spectra are shown in Figure 1, Figure 2 and Figure 3. TLC (silica, DCM: MeOH: HOAc, 30:1:1v/v/v): Rf =0.36 |
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[ 921-01-7 ]
(S)-2-Amino-3-mercaptopropanoic acid
Similarity: 1.00
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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