* 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.
With water; sodium hydroxide In ethanol at 15 - 30℃; for 4 h;
To a solution of Methyl 5-chloro-2- methoxybenzoate (2.0g, 0.01 mol) [Alfa Aesar] in ethanol (60 mL) was added in one portion 1M aqueous sodium hydroxide (60 mL, 0,06 mol) and the mixture was stirred at ambient temperature for 4 hr. Thin layer chromatography indicated that the reaction was complete. Concentrated the mixture in vacuo to remove the ethanol and extracted the aqueous residue with ethyl acetate. Chilled the aqueous phase in an ice bath and adjusted the pH to 2 with concentrated aqueous hydrogen chloride. After stirring in an ice bath for 1 hr., the resulting solid was filtered, washed with water and air dried to give 1.4g (74.9percent) of 3-chloro- 2-methoxy benzoic acid as a white solid MS: m/z 185.1 (MH~). 1H NMR (500 MHz, DMSO-d6): δ 3.818 (s, 3H), 7.162 (d, 1H), 7.551 (dd,lH)5 7.607 (d, 1H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 21, p. 6819 - 6829
[2] Patent: WO2014/165816, 2014, A1, . Location in patent: Page/Page column 98-99
[3] Journal of the American Chemical Society, 1988, vol. 110, p. 7178
[4] Patent: US4895860, 1990, A,
2
[ 321-14-2 ]
[ 77-78-1 ]
[ 3438-16-2 ]
Reference：
[1] Journal of Organic Chemistry, 1959, vol. 24, p. 1759,1762
[2] Patent: CN105461549, 2016, A, . Location in patent: Paragraph 0012; 0013
[3] Patent: CN106699717, 2017, A, . Location in patent: Paragraph 0032-0034
[4] RSC Advances, 2017, vol. 7, # 61, p. 38171 - 38178
Stage #1: With potassium carbonate In methanol at 20℃; for 0.333333 h; Stage #2: With dicobalt octacarbonyl In methanol for 0.0833333 h;
General procedure: K2CO3 (2.5 g, 18 mmol), methanol (10 mL), and appropriate amount of substrate (see below) were placed in a jacketed glass reactor. The intensively stirred mixture was subjected to flow of carbon monoxide, preliminary passed through methanol, at room temperature for 20 min followed by thei nsertion of 2()8 (0.050 g, 0.15 mmol) under CO atmosphere. The orange colour of the mixture disappeared after 5 min. The reaction mixture was heated to 62 °C, and methyl oxirane (0.35 g, 6 mmol) was added by a syringe. The conversion was controlled by measurement of the absorbed carbon monoxide volume. After reaching of the desired conversion (see below) the reaction mixture was cooled to room temperature and an excess of thionyl chloride (about 0.6 g, 5 mmol) was carefully added into the reaction mixture to pH < 2. The mixture was kept at room temperature for 24 h. A small sample was taken, dissolved with DCM and H2O, and the organic layer was analysed by GC to check the conversion. Then the solvent and excess of thionyl chloride were removed from the reaction mixture under reduced pressure. The rest was dissolved with DCM and H2O, the organic layer was divided, washed with brine, and dried with Na2SO4. The solvent was removed under reduced pressure, the resulting mixture was analysed by TLC and 1H-NMR methods, and then the methoxycarbonylation products were isolated by column chromatography (eluent—ethyl acetate-hexane, 1:5). The regioselectivity of methoxycarbonylation for compounds 2, 3, 5, 8, 9 and 11 has been reported by us previously [36,38].
Reference：
[1] Chemistry - An Asian Journal, 2015, vol. 10, # 4, p. 1010 - 1016
6
[ 321-14-2 ]
[ 74-88-4 ]
[ 3438-16-2 ]
Reference：
[1] Patent: US4474792, 1984, A,
7
[ 623-12-1 ]
[ 3438-16-2 ]
Reference：
[1] Journal of the American Chemical Society, 1941, vol. 63, p. 545,548
[2] Journal of the American Chemical Society, 1940, vol. 62, p. 2327,2333
[3] Journal of the American Chemical Society, 1941, vol. 63, p. 545,548
[4] Journal of the American Chemical Society, 1940, vol. 62, p. 2327,2333
[5] Journal of Organic Chemistry, 1959, vol. 24, p. 1759,1762
8
[ 60633-25-2 ]
[ 3438-16-2 ]
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 830
9
[ 63213-94-5 ]
[ 3438-16-2 ]
Reference：
[1] Journal of Organic Chemistry, 1959, vol. 24, p. 1759,1762
10
[ 6342-64-9 ]
[ 3438-16-2 ]
Reference：
[1] Journal of Organic Chemistry, 1960, vol. 25, p. 1016 - 1020
11
[ 1450-74-4 ]
[ 3438-16-2 ]
Reference：
[1] Journal of Organic Chemistry, 1960, vol. 25, p. 1016 - 1020
12
[ 3260-85-3 ]
[ 3438-16-2 ]
Reference：
[1] Gazzetta Chimica Italiana, 1898, vol. 28 I, p. 211
13
[ 579-75-9 ]
[ 3438-16-2 ]
Reference：
[1] Proceedings - Indian Academy of Sciences, Section A, 1938, vol. <A> 8, p. 208,212, 213
14
[ 1570-64-5 ]
[ 3438-16-2 ]
Reference：
[1] Gazzetta Chimica Italiana, 1898, vol. 28 I, p. 211
15
[ 95-48-7 ]
[ 3438-16-2 ]
Reference：
[1] Gazzetta Chimica Italiana, 1898, vol. 28 I, p. 211
With potassium hydroxide; In ethylene glycol; at 170℃; for 7h;
General procedure: 2-Ethylbenzonitrile (7.6mmol) and KOH (24.8mmol) were suspended in ethane-1,2-diol (10mL) and stirred at 170C for 7h. Then, the reaction mixture was cooled down to rt, H2O (50mL) was added and the resulting mixture was extracted three times with ether (30mL). pH of the aqueous layer was adjusted to 1 by diluted HCl and the aqueous phase was extracted three times with ether (40mL). Organic phases were collected, extracted three times with H2O (40mL) and dried over Na2SO4. The solvent was removed and obtained compound was directly used in the next step. Yield: 89.0%, white solid; mp: 64-65C; IR: 3400-2300 (b, OH), 2977 (as CH3), 2955 (as CH2), 2869 (s CH3), 1681 ( CO), 1601, 1575, 1488, 1447 ( CC aromatic) cm-1; 1H NMR (DMSO-d6, 300MHz): delta 12.79 (1H, br s, COOH), 7.76 (1H, d, J=7.0Hz), 7.43 (1H, t, J=7.5Hz), 7.33-7.21 (2H, m), 2.90 (2H, q, J=7.4Hz, CH2), 1.14 (3H, t, J=7.4Hz, CH3); 13C NMR (DMSO-d6, 75MHz): delta 169.14, 145.12, 131.96, 130.54, 130.35, 130.34, 126.04, 27.03, 16.32.
II
Reaction tank successively added 35% sodium hydroxide solution 300kg, 5-chlorosalicylic acid 30kg, stir 71/92 dimethyl sulfate 85kg, 35°C incubated 3 hours, heated to reflux for 98°C 4 hours with 30% hydrochloric acid to pH = 6, was stirred for one hour, added 30% hydrochloric acid was continued acidified to pH = 2, 42kg total consumption of hydrochloric acid, stirred for two hours after the rejection filter, to give 5-chloro-2-methoxybenzene acid wet goods, wet goods placed in an oven dried (35 °C) to give 5-chloro-2-methoxy benzoic acid crude 28.2kg, a yield of 86.94 percent.
Stage #1: 5-chloro-2-hydroxybenzoic acid With sodium hydroxide In water at 37℃; for 0.5h;
Stage #2: dimethyl sulfate With sodium hydroxide In water at 80℃; for 2.25h;
5
5-chlorosalicylic acid (5 mmol) was dissolved in 15 mL of distilled water, heated in a 37 ° C water bath, and the solution was adjusted with 30% NaOH, PH 10, stirring 30min, slowly add 2 mL of dimethyl sulfate, the reaction to the solution pH becomes 7, and then 30%NaOH solution solution pH 10, after 1 h reaction, again slowly dropping dimethyl sulfate 1 mL, the reaction to the solution pH becomes 7, and then 30% NaOH to adjust the pH of the solution 10, the reaction 1 h, at 80 ° C Water bath under the conditions of hydrolysis 15 min,TLC to monitor the reaction process (developing agent for the ethyl acetate: petroleum ether = 1: 1 ~ 1: 4), cooled to room temperature, adjusted with 10% HCl pH 5, a white precipitate generated, distilled water, precipitation, precipitation vacuum drying ; The dried precipitate was dissolved in 10 mL of dichloromethane, two drops of DMF and 0.5 mL of thionyl chloride were added, heated to reflux at 40 ° C for 0.5 h, The methylene chloride and thionyl chloride were distilled off under reduced pressure, dissolved in 10 mL of acetone, and 80 mg of 5,6,7-trimethoxy-4 '- hydroxyflavone obtained in Example 1 was added, and lmL of triethylamine was added dropwise, 3 h, the filtrate was recovered by filtration, and the acetone was recovered by silica gel column chromatography. The eluent was ethyl acetate: petroleum ether = 1: 1 ~ 1: 4 to give 4- (5,6,7-trimethoxy Oxo-4H-chromen-2-yl) phenyl 5-chloro-2-methoxybenzoate. Light yellow powder in a yield of 41%.
Stage #1: 5-chloro-2-hydroxybenzoic acid With sodium hydroxide In water at 37℃; for 0.5h;
Stage #2: dimethyl sulfate In water at 37℃; for 2h;
With water; sodium hydroxide In ethanol at 15 - 30℃; for 4h;
67.1 5-Chloro-2-methoxybenzoic acid
To a solution of Methyl 5-chloro-2- methoxybenzoate (2.0g, 0.01 mol) [Alfa Aesar] in ethanol (60 mL) was added in one portion 1M aqueous sodium hydroxide (60 mL, 0,06 mol) and the mixture was stirred at ambient temperature for 4 hr. Thin layer chromatography indicated that the reaction was complete. Concentrated the mixture in vacuo to remove the ethanol and extracted the aqueous residue with ethyl acetate. Chilled the aqueous phase in an ice bath and adjusted the pH to 2 with concentrated aqueous hydrogen chloride. After stirring in an ice bath for 1 hr., the resulting solid was filtered, washed with water and air dried to give 1.4g (74.9%) of 3-chloro- 2-methoxy benzoic acid as a white solid MS: m/z 185.1 (MH~). 1H NMR (500 MHz, DMSO-d6): δ 3.818 (s, 3H), 7.162 (d, 1H), 7.551 (dd,lH)5 7.607 (d, 1H).
With sodium hydroxide for 16h; Ambient temperature; Yield given;
With sodium hydroxide In 1,4-dioxane
2 Step (2)
Step (2) Preparation of 5-Chloro-2-methoxybenzoic Acid To a stirred solution of methyl 5-chloro-2-methoxybenzoate (23.1 g, 0.115 mol) in dioxane (300 mL) was added 2.5N NaOH (230 mL). The resulting mixture was stirred at room temperature for 4 hours, concentrated, diluted with H2 O, and acidified with 2N HCl. 19.70 g (91%) of the desired product was collected by filtration as a white solid. NMR (CDCl3, 200 MHz): δ 4.08 (s, 3H), 7.00 (d, J=8.9, 1H), 7.53 (dd, J=8.9, 2.6, 1H), 8.15 (d, J=2.6, 1H).
4-([(2-methoxy-5-chlorobenzoyl)amino]sulfonyl)benzoyl chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91 - 95%
With thionyl chloride; In chlorobenzene; at 120℃; for 7 - 9h;
Example 1 4-[(2-Methoxy-5-chlorobenzoyl)amino]sulfonyl)benzoyl chloride A mixture of 4-aminosulfonylbenzoic acid (1 mol), 2-methoxy-5-chlorobenzoic acid (1 mol) and thionyl chloride (2.5 mol) in chlorobenzene (700 ml) was heated at 120C for 7-9 hours. After the reaction was complete 200 ml of the solvent was removed in vacuo. The mixture was cooled and the precipitate filtered off and washed with heptane to give the title compound, mp. 138-140C, yield 93 % of theory. 4-[(Benzoyl)amino]sulfonyl)benzoyl chloride was prepared in a similar manner from 4-aminosulfonylbenzoic acid and benzoic acid, mp. 180-182C, yield 96 % of theory. 4-[(2-Chlorobenzoyl)amino]sulfonyl)benzoyl chloride was prepared in a similar manner from 4-aminosulfonylbenzoic acid and 2-chlorobenzoic acid, mp. 198-200C, yield 95 % of theory.
With hydrogenchloride; triethylamine; In tetrahydrofuran;
a 5-Chloro-2-methoxy-N-(2-(4-nitrophenyl)ethyl)benzamide A solution of 8.8 g (47.2 mmol) of 5-chloro-2-methoxybenzoic acid and 8.5 g (51.9 mmol) of carbonylbisimidazole in 180 ml of absolute THF was stirred at room temperature for 2 h. 10 g (49.7 mmol) of 2-(4-nitrophenyl)ethylamine hydrochloride and 9.4 ml of triethylamine were added and the resulting solution was then stirred overnight at room temperature. The reaction solution was then slowly poured onto 1.2 l of 1N hydrochloric acid, and the deposited precipitate was filtered off and washed with water. Drying of the precipitate in a high vacuum yielded 13.8 g of the title compound as a white solid. M.p.: 159-160 C. Rf (silica gel, EA/heptane 4:1)=0.46. MS (ESI): m/z=334 (M+H)+.
3,5'-dichloro-2'-methoxy-[1,1'-biphenyl]-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate In 1,4-dioxane; methanol for 16h; Heating / reflux;
21.a
4-bromo-2-chlorobenzoic acid (0.4 g), 5-chloro-2-methoxybenzoic acid (0.4 g),Pd(dppf)Cl2 (0.12 g), sodium carbonate (0.9 g), dioxan (15 ml) and methanol (5 ml) werecharged to a flask and heated at reflux for 16 h. Cooled to room temp and filtered (hyflo).The filtrate was concentrated in vacua, then dissolved in ethyl actetate. The suspension wasmade basic by addition of dilute NaOH. The aqueous layer was separated and acidified using2M HC1, extracted with EtOAc, dried (MgSO4) and evaporated in vacua to give the sub-titlecompound Yield 0.4 g'HNMRDMSO-De: 5 13.37 (1H, s), 7.86 (1H, m), 7.64 (1H, s), 7.41-7.38 (3H, m), 7.2 (1H,d) and 3.8 (3H, s).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 60℃; for 16h;
Example 21A (Z)-5-chloro-N-(6,7-dihydro-1H-pyrano[4,3-d]thiazol-2(4H)-ylidene)-2-methoxybenzamide To a solution of commercially available <strong>[259810-12-3]6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-amine</strong> (1.73 g, 11.1 mmol, JW-Pharmalab) in tetrahydrofuran/N,N-dimethylformamide (5:1, 60 mL) were added 5-chloro-2-methoxybenzoic acid (2.27 g, 12.2 mmol, Aldrich), 1-hydroxybenzotriazole (1.9 g, 12.2 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (2.3 g, 12.2 mmol, Aldrich) and triethylamine (4.6 ml, 33.2 mmol). After stirring at 60 C. for 16 h, the reaction mixture was cooled, diluted with EtOAc (50 mL) and quenched with saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2*50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 0-5% methanol in methylene chloride). MS (ESI+) m/z 325 (M+H)+.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; ethyl acetate; at 20℃; for 14h;
Example 4A N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-5-chloro-2-methoxybenzamide To a solution of 2-amino-5-tert-butyl-1,3,4-thiadiazole (Aldrich) (2.5 g, 16.3 mmol) in tetrahydrofuran (30 mL) were added 5-chloro-2-methoxybenzoic acid (Aldrich) (3.65 g, 19.6 mmol), triethylamine (5.5 mL, 39.5 mmol), and 1-propanephosphonic acid cyclic anhydride 50% solution in ethyl acetate (Aldrich) (11.6 mL, 19.6 mmol). The reaction mixture was stirred at about room temperature for 14 hours, cooled with external ice bath while quenching with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2*40 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 0-100% ethyl acetate in hexanes) to afford 4.65 g of the title compound. 1H NMR (300 MHz, DMSO-d6) delta ppm 1.43 (s, 9H), 3.88 (s, 3H), 7.22 (d, J=8.7 Hz, 1H), 7.55-7.64 (m, 2H), 12.41 (s, 1H); MS (ESI+) m/z 326 (M+H)+.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; ethyl acetate; at 20℃; for 14h;
Example 4; N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide; Example 4A; N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-5-chloro-2-methoxybenzamide; To a solution of 2-amino-5-tert-butyl-1,3,4-thiadiazole (Aldrich) (2.5 g, 16.3 mmol) in tetrahydrofuran (30 mL) were added 5-chloro-2-methoxybenzoic acid (Aldrich) (3.65 g, 19.6 mmol), triethylamine (5.5 mL, 39.5 mmol), and 1-propanephosphonic acid cyclic anhydride 50% solution in ethyl acetate (Aldrich) (11.6 mL, 19.6 mmol). The reaction mixture was stirred at about room temperature for 14 hours, cooled with external ice bath while quenching with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 0-100% ethyl acetate in hexanes) to afford 4.65 g of the title compound. 1H NMR (300 MHz, DMSO-d6) delta ppm 1.43 (s, 9H), 3.88 (s, 3H), 7.22 (d, J=8.7 Hz, 1H), 7.55-7.64 (m, 2H), 12.41 (s, 1H); MS (ESI+) m/z 326 (M+H)+.
General procedure: A solution of 2,3-dimethoxybenzoic acid (3.64 g, 21 mmol) and thionyl chloride (5 mL, 69 mmol) in anhydrous benzene was refluxed for 3 h. The mixture was evaporated in vacuo and traces of thionyl chloride were coevaporated with benzene (2 × 20 mL). The residue was dissolved in anhydrous CHCl3 (50 mL) and added dropwise to a stirred, cooled (?0 C) solution of 8-methyl-8-azabicyclo[3.2.1]oct-3alpha-ylamine 11 (2.8 g, 20 mmol) and triethylamine (3.0 mL, 20 mmol) in anhydrous CHCl3 (75 mL). The mixture was stirred at room temperature for 24 h, washed with a 5% aqueous solution of Na2CO3 (2 × 30 mL), dried with magnesium sulphate and evaporated in vacuo.
General procedure: K2CO3 (2.5 g, 18 mmol), methanol (10 mL), and appropriate amount of substrate (see below) were placed in a jacketed glass reactor. The intensively stirred mixture was subjected to flow of carbon monoxide, preliminary passed through methanol, at room temperature for 20 min followed by thei nsertion of 2()8 (0.050 g, 0.15 mmol) under CO atmosphere. The orange colour of the mixture disappeared after 5 min. The reaction mixture was heated to 62 C, and methyl oxirane (0.35 g, 6 mmol) was added by a syringe. The conversion was controlled by measurement of the absorbed carbon monoxide volume. After reaching of the desired conversion (see below) the reaction mixture was cooled to room temperature and an excess of thionyl chloride (about 0.6 g, 5 mmol) was carefully added into the reaction mixture to pH < 2. The mixture was kept at room temperature for 24 h. A small sample was taken, dissolved with DCM and H2O, and the organic layer was analysed by GC to check the conversion. Then the solvent and excess of thionyl chloride were removed from the reaction mixture under reduced pressure. The rest was dissolved with DCM and H2O, the organic layer was divided, washed with brine, and dried with Na2SO4. The solvent was removed under reduced pressure, the resulting mixture was analysed by TLC and 1H-NMR methods, and then the methoxycarbonylation products were isolated by column chromatography (eluent-ethyl acetate-hexane, 1:5). The regioselectivity of methoxycarbonylation for compounds 2, 3, 5, 8, 9 and 11 has been reported by us previously [36,38].
5-chloro-2-methoxy-N-(4-(piperidin-1-ylmethyl)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 0.25h;Microwave irradiation;
With dmap; triethylamine; In acetonitrile; at 20℃;
General procedure: 2-Methoxybenzoic acid (1a, 761 mg, 5.0 mmol), triethylamine (725 μL, 5.2 mmol), and 4-DMAP (61 mg, 0.5 mmol) was added to a solution of N-methoxy-N-methyl carbamoyl chloride (619 mg, 5.0 mmol) in acetonitrile at room temperature and stirred for 1.5 h. After evaporation of acetonitrile, the mixture was poured into saturated NaHCO3 solution (40 mL) and extracted with methylene chloride (3 × 25 mL). The condensed residue was purified with short pathway silica gel column chromatography using 50% EtOAc/n-hexane to give 2a (820 mg, 84%).
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