* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Gazzetta Chimica Italiana, 1892, vol. 22 II, p. 392[2] Journal fuer Praktische Chemie (Leipzig), 1892, vol. <2> 46, p. 564
2
[ 501-89-3 ]
[ 1642-81-5 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 9, p. 4258 - 4263
3
[ 501-89-3 ]
[ 876-31-3 ]
Reference：
[1] Patent: CN105001032, 2018, B,
4
[ 67-56-1 ]
[ 501-89-3 ]
[ 52787-14-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
With thionyl chloride In N,N-dimethyl-formamide at 50℃; for 4 h;
The 4-carboxymethyl-benzoic acid (5g, 27.78mmo 1) to the reaction flask, 75ml of methanol was added to dissolve the raw material, continuedWas added N, N- dimethylformamide 0.5ml and thionyl chloride (6ml, 83.33mmol). 50 ° C for 4 hours the reaction was complete. MethaneMost of thionyl chloride and an alcohol spin dry, the residual liquid was dissolved in 200ml of ethyl acetate, washed with saturated sodium carbonate solution and then(50ml X3), washed with saturated brine (50ml X3), dried over anhydrous sodium sulfate, filtered and rotary dried to give 5.5g colorless transparent liquid,Yield 95 · 2
91%
at 90℃;
A solution of 4- (carboxymethyl) benzoic acid 25, (1.00 g, 5.55 mmol) and H2SO4 (2 mL) in methanol (20 mL) was heated at 90° C. overnight. After concentrating the reaction mixture, the crude was taken into EtOAc (30 mL) and washed with sat, NaHCOj (30 mi) . Then the organic layer was dried over NazSOi and evaporated in vacuo. Crude material was purified on silica gel column (EtOAc : Hexanes - 1:6) to give the title compound 26. (1.05 mg, 91percent). *H NMR (CHC13, 400 MHz) : δ 8.00 (d, J=8.1 Hz, 1H) , 7.37 (d, J=8.1, IH) , 3.90 (3, 3H) , 3.69 (s, 3H) , 3.67 (s, 2H) ; 13C NMR (CHC13, 100 MHz): δ 167.7, 138.8, 129.8, 129.3, 128.9, 52.5, 52.3, 41.2; [M+H] * = 209.3 (APCI+S .
91.1%
for 24 h; Reflux; Autoclave
80. 0g p-carboxyphenylacetic acid was added to a 2 L autoclave,With 800 mL of anhydrous methanol stirring dissolved,8. 0 g of p-toluenesulfonic acid,Stirring heated reflux reaction 24 h,The methanol was distilled off under reduced pressure,The residue was charged with 240 mL of water,, Extracted with ethyl acetate (240 mL X 3)The organic phases were combined,The organic phase was washed with 3percent NaOH solution(80 mL of X2) and dried over anhydrous sodium sulfate.The solvent was recovered under reduced pressure and cooled to give compound B as a white solid. Weight: 84.1 g, yield: 91.1percent, HPLC content: 97. 8percent.
Reference：
[1] Patent: CN105541777, 2016, A, . Location in patent: Paragraph 0015; 0059; 0060; 0061
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 3, p. 377 - 384
[3] Patent: WO2015/100363, 2015, A1, . Location in patent: Page/Page column 52; 53
[4] Patent: CN103739604, 2016, B, . Location in patent: Paragraph 0037-0038
[5] Journal of the Indian Chemical Society, 1987, vol. 64, # 1, p. 34 - 37
[6] Chemische Berichte, 1935, vol. 68, p. 1267,1270
Reference：
[1] Journal of Chemical Research - Part S, 2000, # 6, p. 282 - 283
[2] Tetrahedron, 1997, vol. 53, # 21, p. 7335 - 7340
[3] Journal of the Indian Chemical Society, 1987, vol. 64, # 1, p. 34 - 37
7
[ 67-56-1 ]
[ 501-89-3 ]
[ 87524-66-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 20℃;
4-(2-Methoxy-2-oxoethyl)benzoic acid (12) To a solution of 4-(carboxymethyl)benzoic acid (1.00 g, 5.55 mmol, 1 equiv.) in methanol (11 mL), were added thionyl chloride (0.020 mL, 0.28 mmol, 5 molpercent). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residual material was taken up in MTBE and washed successively three times with a saturated aq. NaHC03 solution and once with water. The combined bicarbonate and aqueous extract was acidified with 1 N HCI until precipitation of the monomethyl ester. The mixture was extracted three times with MTBE. The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure in order to get 4-(2-methoxy-2-oxoethyl)benzoic acid 12 (0.985 g, 91percent) as a white solid. 1H NMR (CDCI3, 400 MHz) δ 8.08 (d, 2H, J = 8.4 Hz), 7.40 (d, 2H, J = 8.4 Hz), 3.72 (s, 5H). The data were similar to that described in WO2005/12220.
88%
at 20℃; for 5.5 h;
To a suspension of 4- (carboxymethyl) benzoic acid (2.43 g, 13.5 mmol) in methanol (30 mL) was added thionyl chloride (50 uL, 0.67 MMOL). The reaction mixture was stirred at room temperature for 5.5 h, and a clear solution was obtained. The solvent was removed under reduced pressure. The residue was taken up in ether (100 mL), washed with saturated aqueous NAHC03 (2X50 mL) and water (30 mL). The combined NAHC03 and water extract was acidfied with concentrated HCI in an ice bath. The white precipitation was collected and washed with water, dried to yield 2.30 g (88percent) compound 150 as white solid. The material was used without further purification. mp 134-136 °C.'H NMR (400 MHz, CDCI3) : 8 3.71 (s, 5H), 7.40 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.2 Hz, 2H). LCMS (ESI), m/z, 193 (M-H)-.
Reference：
[1] Patent: WO2016/199111, 2016, A1, . Location in patent: Paragraph 00146-00147
[2] Journal of Chemical Research - Part S, 1999, # 6, p. 378 - 379
[3] Patent: WO2005/12220, 2005, A2, . Location in patent: Page/Page column 113
[4] Patent: WO2013/41407, 2013, A1, . Location in patent: Page/Page column 34
[5] Patent: WO2014/125426, 2014, A1, . Location in patent: Page/Page column 40
[6] Organic Letters, 2016, vol. 18, # 21, p. 5512 - 5515
[7] Patent: WO2018/107289, 2018, A1, . Location in patent: Page/Page column 21
8
[ 67-56-1 ]
[ 501-89-3 ]
[ 52787-14-1 ]
[ 87524-66-1 ]
Reference：
[1] Journal of Chemical Research - Part S, 2000, # 6, p. 282 - 283
[2] Tetrahedron, 1997, vol. 53, # 21, p. 7335 - 7340
[3] Journal of the Indian Chemical Society, 1987, vol. 64, # 1, p. 34 - 37
9
[ 501-89-3 ]
[ 163164-47-4 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 42, p. 16901 - 16910
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;
To a solution of A-3 (5.0 g, 27.7 mol) in DCM (50 mL) was added oxalyl chloride (12.6 g, 99.2 mmol) and one drop of DMF. The mixture was stirred at room temperature for 2 h, and then concentrated to dryness. EtOH (100 mL) was added and the mixture was stirred at room temperature for 2 h, then concentrated to dryness and purified to by silica gel column chromatography (PE:EA = 5: 1) to afford A-4 as a brown oil (4.587 g, 70%).
The intermediate from Step B above (4.15 g) was added in small portions over 4 h to a mixture of fuming nitric acid (11 mL) and sulfuric acid (15 mL) at 0 C. After addition was complete, the reaction was warmed to room temperature and poured onto crushed ice. The resulting precipitate was filtered, washed with cold water and dried under vacuum to give the intermediate (4.5 g). [MNa]+=248.
EXAMPLE I Preparation of 2-(4-carboxyphenyl)-3-phenylmaleic anhydride (I) was as follows. A 500 ml flask was charged with 4-carboxyphenylacetic acid (20 g, 0.11 mole), 200 ml of acetic anhydride, and mixed sodium/potassium salt of benzoylformic acid (20.7 g, 0.11 mole). Warming resulted in a mildly exothermic reaction. The mixture was stirred at reflux for three hours, cooled to room temperature, and quenched by careful addition of 100 ml of water. The reaction mixture was poured into 1.4 l of water and the resulting precipitate was collected on a filter, washed with water, air dried to obtain 28 g (87 mole %) of (I). Recrystallization from acetone gave pure (I) as yellow crystals, mp 247-249 C., Anal. Calcd. for C17 H10 O5: C, 69.39; H, 3.42. Found: C, 68.86; H, 3.47. Molecular weight calculated 294, found 304.
To a solution of A-2 (10.0 g, 48.5 mmol) in THF/H20 (v/v=l/l, 100 mL) was added NaOH (3.88 g, 97.0 Attorney Docket: 0322.13/PCT mmol). The reaction solution was stirred at room temperature overnight. THF was removed under reduced pressure, then NaOH (17.46 g, 436.5 mmol) and water (150 mL) was added. Iodine was added portion wise at room temperature. After addition, the reaction mixture was stirred at room temperature for 30 min, then at 90 C for 2 h. Cooled to room temperature and filtered. The filtrate was adjusted to pH=8~9 with cone. HC1. NaHS03 solid was added portion wise till the color of reaction mixture changed from brown to yellow. Cone. HC1 was added to pH=2~3. The resultant precipitate was filtered, washed with water (10 mL x 2), dried in vacuo to afford A-3 as a yellow powder (4.47 g, 50%).
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