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CAS No. : | 4093-28-1 | MDL No. : | MFCD00458326 |
Formula : | C10H11NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LCXHOHRQXZMSQN-UHFFFAOYSA-N |
M.W : | 209.20 | Pubchem ID : | 77719 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 54.06 |
TPSA : | 75.63 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.19 cm/s |
Log Po/w (iLOGP) : | 1.84 |
Log Po/w (XLOGP3) : | 1.95 |
Log Po/w (WLOGP) : | 0.95 |
Log Po/w (MLOGP) : | 0.85 |
Log Po/w (SILICOS-IT) : | 0.84 |
Consensus Log Po/w : | 1.29 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.4 |
Solubility : | 0.838 mg/ml ; 0.004 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.16 |
Solubility : | 0.144 mg/ml ; 0.000687 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.29 |
Solubility : | 1.07 mg/ml ; 0.00509 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.58 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | 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 |
---|---|---|
92% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4 h; | General procedure: 2-hydroxy-4-acetyl-aminobenzoic acid methyl ester (10g, 47.8mmol) dissolved in DMF (50 ml) in, adding K2CO3(9.90g, 71 . 7mmol), benzyl chloride (9.03g, 71 . 7mmol), heating 60 °C reaction 4h. the response finishes, cooling, filtering, distilling solvent filtrate under reduced pressure, the residue with petroleum ether/ethyl acetate to obtain white solid is recrystallized (12.86g, 90percent).Iodomethane as starting material, to give the desired product according to the method of Example 58, a white solid (92percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydrogencarbonate In water; ethyl acetate at 0 - 20℃; for 2.25 h; | A solution of Methyl 4-amino-2-hydroxy benzoate (50.7 grams, 303.6 mmol, obtained in above step) in ethyl acetate (750 mL) was added to a stirred solution of water (250 mL) and sodium bicarbonate (34.9 grams, 415.5 mmol) cooled at 0 °C followed by acetyl chloride (29.7 mL, 415.5 mmol) over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. The two layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain methyl 4-acetylamino-2-hydroxy benzoate (63.5 grams).Yield: 99 percent.Ή - NMR (CDC13): δ 10.86 (bs, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.23 (s, 1H), 7.16 (bs, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.13 (bs, 1H), 3.92 (s, 3H), 2.19 (s, 3H);Mass (m/z): 208 (M-H)+. |
99% | With sodium hydrogencarbonate In water; ethyl acetate at 0 - 20℃; for 2 h; | A solution of Methyl 4-amino-2-hydroxy benzoate (50.7 grams, 303.6 mmol, obtained in above step) in ethyl acetate (750 mL) was added to a stirred solution of water (250 mL) and sodium bicarbonate (34.9 grams, 415.5 mmol) cooled at 0° C. followed by acetyl chloride (29.7 mL, 415.5 mmol) over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. The two layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain methyl 4-acetylamino-2-hydroxy benzoate (63.5 grams). Yield: 99percent. 1H-NMR (CDCl3): δ 10.86 (bs, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.23 (s, 1H), 7.16 (bs, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.13 (bs, 1H), 3.92 (s, 31-1), 2.19 (s, 3H); Mass (m/z): 208 (M-H)+. |
87.9% | With sodium hydrogencarbonate In water; ethyl acetate at 20℃; for 2 h; | Compound 77.1 (2.0 g, 12.0 mmol, 1.0 eq) in EtOAc (30 mL) was added to a cooled solution of NaHCO3 (1.38 g, 16.4 mmol, 1.37 eq) in water (15 mL). The reaction was stirred for 10 minutes. Acetyl chloride (1.28 g, 16.4 mmol, 1.37 eq) was added to the mixture over 15 minutes and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, mixture was quenched with water and extracted with EtOAc. Organic layers were combined, washed with satd. NaHCO3, dried over Na2SO4 and concentrated under reduced pressure to obtain crude material. The crude was purified by trituration with EtOAc and n-hexane to furnish 77.2 (2.2 g, 87.9percent). MS(ES): m/z 209.20 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.4% | at 40℃; for 1 h; | To a 2 L three-necked flask, 2 (108 g, 0.65 mol) and glacial acetic acid (540 mL) were added, the temperature was raised to 40 ° C after stirring,Acetic anhydride (79.2 g, 0.78 mol) was added dropwise and the reaction mixture was gradually clarified. Bi completed, TLC monitoring, the reaction was added water (1000mL) about 1h,Precipitation of a large amount of solid. After cooling to room temperature, suction filtration,Filter cake was washed with water and dried to give a white solid 125g, yield 92.4percent, purity 99.9percent |
86% | for 19 h; Cooling with ice | To a solution of compound 1b (2.46 g, 15.3 mmol) in anhydrous acetone (25 ml) was added acetic anhydride (3 ml, 31.7 mmol) in an ice bath with magnetic stirring. After being stirred for 19 h, the solvent was evaporated in vacuo, and the solid residue was washed with water and filtered to provide compound 2b (2.74 g, 86percent) as white powders.Compound 2b: Mwt: 209.20; Rf: 0.50 (ethyl acetate:hexane=1:1). 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 2.06 (3H, s, CH3), 3.85 (3H, s, OCH3), 7.04 (1H, dd, J=6.6, 2.1 Hz, Ar H-5), 7.37 (1H, d, J=1.8 Hz, Ar H-3), 7.70 (1H, d, J=8.7 Hz, Ar H-6), 10.22 (1H, s, ArNH), 10.6 (1H, s, OH). |
79% | at 1 - 20℃; for 22.9 h; | Stage 2; Methyl 4-(acetylamino)-2-hydroxybenzoate; Methyl 4-aminosalicylate (1.0 eq.) was dissolved in 9 vol dichloromethane atTOut=20°C to give a pale brown solution. The solution was cooled over 33 min. toTi=1°C. To the solution was added 1.2 eq. acetic acid anhydride in 2 vol <n="29"/>dichloromethane over 52 min. at Ti=2 to 2.10C. The solution was further stirred at Ti=2.1°C for 30 min., warmed to Ti=20°C over 32 min. and kept stirring at Ti=20°C for 3 h to give a pale brown suspension. After further stirring at Ti=20°C for 18 h the reaction was sampled to reveal 99percent conversion according to HPLC. To the suspension was added 3 vol heptane at Ti=20°C. The suspension was cooled over 49 min. to Ti=IO0C and kept stirring for 32 min. at Ti=IO0C. The suspension was filtered over a glass sinter funnel; the mother liquor was collected and washed in two portions with 2 vol water and 2 vol heptane. The filter cake was dried on the sinter funnel under N2-stream for 2.5 h. The filter cake was further dried on the rotary evaporator at Tout=40oC and 17 mbar to afford the title compound in 3.463 kg (36percent uncorr. yield; 100percent a/a HPLC). The second portion was dried on the rotary evaporator at Tout=40oC and 16 mbar to afford the title compound in 4.225 kg (43percent uncorr. yield; 100percent a/a HPLC). The overall yield was 79percent (uncorrected). |
72.4% | at 0 - 10℃; for 4 h; | Acetic anhydride (Ac20) (66.50 mL, 0.704 mole) was added drop wise to a stirred solution of methyl 4-amino-2-hydroxy benzoate (98 grams, 0.586 mole, obtained in the above step) in DCM (980 mL) at 0 °C. Then reaction mass was slowly brought to 10 °Cand stirred for 4 hours at the same temperature, while monitoring the progress of the reaction by TLC. Reaction mass was poured into chilled water (1000 mL) and stirred for 30 minutes. The solid obtained was filtered and dissolved in ethyl acetate (EtOAc) (1000 mL). The organic phase was washed with brine solution (500 mL), dried over Na2SO4 and concentrated under vacuum to obtain the title compound.Weight: 88.8 grams (Yield: 72.4 percent).1H - NMR (δ ppm): 2.03 (3H, s), 3.82 (3H, s), 7.00 - 7.03 (1H,dd, 3 8.68, 1.60 Hz), 7.33- 7.34 (1H, d, J = 1.72 Hz), 7.66 - 7.68 (1H, d, J = 8.72 Hz), 10.18 (1H, bs), 10.57 (1H, s); Mass (m/z): 210.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | at 35 - 40℃; for 2 h; Enzymatic reaction | (136.8 g, 1.0 mol) sodium acetate trihydrate was added to the reaction solution of methyl p-amino salicylate, the pH of the reaction solution was controlled at 6.5-7.5 with 10percent sodium carbonate or 10percent acetic acid, and the temperature was controlled at 35-40°C. Then, 40.0g of acetylase was added, the temperature and pH were strictly controlled, the reaction was carried out for 2 hours and the reaction was completed. The methanol was recovered under reduced pressure, and 500 g of ethyl acetate was added to the mother liquor for extraction, then carried out liquid separation, drying and concentration, followed by crystallization under reduced pressure, suction filtration, and drying at 50° C to obtain 199.2 g of Methyl p-acetaminosalicylate. The yield was 95.2percent and the purity was 99.1percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With hydrogenchloride; acetic anhydride In water | EXAMPLE 15 Synthesis of Methyl 4-acetamidosalicylate (10) To a suspension of 4.17 g (0.025 mole) methyl 4-aminosalicylate (9) in 20 mL water, was added 3 mL (0.032 mole) acetic anhydride (Aldrich 11,004-3) while stirring. The mixture was heated at 800 for 30 minutes and cooled to room temperature. The precipitate was collected and added into 100 ml of 10percent hydrochloric acid. This suspension was stirred at room temperature for 10 minutes, filtered and dried to give 4.3 g (82percent) of a crude solid, which was recrystallized from H2O/CH3OH, yielding 3 g (70percent) of 10 as white crystals, mp 153-154. Infrared (IR) and NMR analysis gave the following results: IR (potassium bromide): 3319(NH), 1680 (C=O),1604, 1157 cm-1. 1H nmr (90 MHz, CDCI3 +DMSO-d6):δ 10.80 (1H, S, OH), 9.74 (1H, br s, NH), 7.73 (1H; d, 3JH5-H6=9 Hz; H-6), 7.37 (1H; d, 4JH5-H3=1.8 Hz; H-3),7.11 (1H; dd, 3JH6-H5=9HZ, 4JH3-H5=1.8 Hz; H-5), 3.91 (3H; s; OCH3), 2.15 (3H, s, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.6% | With N-chloro-succinimide In 1,2-dichloro-ethane for 3 h; Reflux | To a stirred solution of methyl 4-acetylamino-2-hydroxy benzoate (61.4 grams, 294.0 mmol, obtained in above step) in dichloroethane (1.2 L) was added N- chlorosuccinimide (58.8 grams, 441 mmol) and the reaction mixture was refluxed for 3 hours. The volatiles were removed under reduced pressure; the solid compound thus precipitated was diluted with water (1.0 L) and filtered. The crude product was diluted with a 1 :9 mixture (methanol and dichloromethane) and washed with brine. The organic layer was dried over anhydrous sodium sulphate and the volatiles were removed under reduced pressure to obtain methyl 4-acetylamino-5-chloro-2-hydroxy benzoate (67.7 grams).Yield: 94.6 percent.Ή - NMR (DMSO-d6): δ 10.49 (bs, 1H), 9.47 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 3.85(s, 3H), 2.16 (s, 3H); Mass (m/z): 244, 246 (M+H)+. |
94.6% | With N-chloro-succinimide In 1,2-dichloro-ethane for 3 h; Reflux | To a stirred solution of methyl 4-acetylamino-2-hydroxy benzoate (61.4 grams, 294.0 mmol, obtained in above step) in dichloroethane (12 L) was added N-chlorosuccinimide (58.8 grams, 441 mmol) and the reaction mixture was refluxed for 3 hours. The volatiles were removed under reduced pressure; the solid compound thus precipitated was diluted with water (1.0 L) and filtered. The crude product was diluted with a 1:9 mixture (methanol and dichloromethane) and washed with brine. The organic layer was dried over anhydrous sodium sulphate and the volatiles were removed under reduced pressure to obtain methyl 4-acetylamino-5-chloro-2-hydroxy benzoate (67.7 grams). Yield: 94.6percent. 1H-NMR (DMSO-d6): δ 10.49 (bs, 1H), 9.47 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 3.85 (s, 3H), 2.16 (s, 3H); Mass (m/z): 244, 246 (M+H)+. |
93.9% | With N-chloro-succinimide In 1,2-dichloro-ethane at 80℃; for 4 h; | N-Chlorosuccinimide (NCS) (69 grams, 0.509 mole) was added to a stirred solution of methyl 4-acetylamino-2-hydroxy benzoate (88.8 grams, 0.424 mole, obtained in the above step) in 1 ,2-dichloroethane (2 L) at RT. Reaction mass was slowly heated to 80 °C and stirred further for 4 hours at the same temperature, while monitoring the progress of the reaction by TLC. The mass was cooled to RT and 1 ,2-dichloroethane was evaporated. The residue was diluted with water (1L) and the solid obtained was filtered.The solid obtained was dissolved in DCM (2 L) and washed with brine solution (500 mL). The organic phase was dried over Na2S0 and concentrated under vacuum to obtain the title compound. (0287) Weight: 97 grams (Yield: 93.9 percent). 1H - NMR (δ ppm): 2.15 (3H,s), 3.84 (3H,s), 7.72 (1H, s ), 7.76 (1H, s), 9.48 (1H, bs), 10.49 (1H, s); (0288) Mass (m/z): 244.1 (M+H)+, 246.0 (M+H)+. |
80% | With sulfuryl dichloride In ethyl acetate at -5 - 0℃; for 2 h; | 3 (160 g, 0.776 mol) and ethyl acetate (1100 mL) were added to a 2 L three-necked flask and sulfuryl chloride (134.5 g, 0.995 mol) was added dropwise at -5 to 0 ° C and the temperature was controlled at -5 to 0 ° C for about 1 h Within the drop completed. After the addition was completed, stirring was continued for 1 h and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into water,With 10mol / L sodium hydroxide solution to adjust the pH 4 ~ 5, suction filtration,The filtrate was extracted to separate the organic layer, the organic layer was spin-dried,A large amount of solid was obtained, which was combined with the filter cake solids, heated with 5 times ethanol hot beating 30min, suction filtered, the filter cake was dried,151.1 g of a white solid was obtained in a yield of 80percent and a purity of 98.7percent |
65% | With sulfuryl dichloride In ethyl acetate at 0.5 - 20℃; for 22 h; | Stage 3; Methyl 4-(acetylamino)-5-chloro-2-hydroxybenzoate; Methyl 4-(acetylamino)-2-hydroxybenzoate (1.0 eq.) was suspended in 12 vol ethyl acetate at Tout=20oC to give a pale brown suspension. The suspension was cooled to Ti=O.50C over 41 min. To the suspension was added 1.05 eq. sulphuryl chloride in 2 vol ethyl acetate over 82 min. at Ti=O.5°C. The suspension was stirred at Ti=O.5°C for 38 min. and heated to Ti=20°C over 90 min. then stirred for 18.5 h (91.2percent conversion according to HPLC).The suspension was cooled to Ti=10°C over 63 min. and kept stirring for 33 min. at Ti=10°C. The suspension was filtered over a glass sinter funnel; the mother liquor was collected and washed in two portions with 2 vol ethyl acetate / heptane 1 :1. The filter cake was dried on the sinter funnel under N2-stream for 16 h. The filter cake was further dried on the rotary evaporator at Tout=40oC and 17 mbar to afford the title compound in 3.163 kg (36percent uncorr. yield; 90.6percent a/a HPLC). The second portion was dried on the rotary evaporator at Tout=40oC and 15 mbar to <n="30"/>afford the title compound in 2.496 kg (29percent uncorr. yield; 90.4percent a/a HPLC). The overall yield was 65percent (uncorrected). |
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