* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the Chemical Society, 1912, vol. 101, p. 548
2
[ 99-06-9 ]
[ 618-49-5 ]
Yield
Reaction Conditions
Operation in experiment
64%
With thionyl chloride; ammonia In tetrahydrofuran; benzene
EXAMPLE 1 Preparation of 3-Hydroxybenzamide Ten g (72.4 mmol) of 3-hydroxybenzoic acid and 10 ml SOCl2 were mixed and allowed to stand for 1 hr, heated on a steam bath for 2 hr, and then cooled and diluted with 25 ml of benzene. The benzene was then evaporated in vacuo to dryness and the residue extracted with 2*50 ml benzene. The extracted residue was dissolved in 25 ml tetrahydrofuran (THF) and this solution added dropwise over a period of 15 min to a stirred, cold (-10° C.) 50 ml solution of concentrated ammonia. The mixture was stirred with cooling for an hour and then at room temperature overnight. The mixture was poured into an open dish and allowed to evaporate to a solid mass. The solid was triturated with 50 ml ice water, collected, and air dried to yield 6.4 g (64percent) of the desired product 3-hydroxybenzamide, mp 160°-162° C. The identity of the product with the desired 3-hydroxybenzamide was further confirmed using thin layer chromatography (TLC).
Reference：
[1] Journal of the Indian Chemical Society, 2005, vol. 82, # 7, p. 675 - 676
[2] Phosphorus and Sulfur and the Related Elements, 1980, vol. 9, p. 155 - 164
[3] Naunyn-Schmiedebergs Archiv fuer Experimentelle Pathologie und Pharmakologie, 1938, vol. 191, p. 55,57
[4] Patent: US5032617, 1991, A,
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 14, p. 4076 - 4079
[6] Letters in Drug Design and Discovery, 2013, vol. 10, # 4, p. 320 - 326
[7] Chemical Biology and Drug Design, 2016, vol. 87, # 2, p. 257 - 264
[8] Angewandte Chemie - International Edition, 2017, vol. 56, # 46, p. 14498 - 14501[9] Angew. Chem., 2017, vol. 129, p. 14690 - 14693,4
[10] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 5, p. 884 - 891
[11] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 667 - 672
[12] Patent: WO2007/107758, 2007, A1,
3
[ 100-39-0 ]
[ 99-06-9 ]
[ 1700-37-4 ]
Yield
Reaction Conditions
Operation in experiment
85.7%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3 h;
The 3 - hydroxybenzaldehyde (1.0 g, 8.2 mmol) dissolved in 15 ml DMF in, adding [...] (1.52 g, 9.0 mmol), potassium carbonate (1.35 g, 9.8 mmol), 80 °C reaction 3 hours, adding 15 ml distilled water, extracted with ethyl acetate twice (2 × 20 ml), then saturated sodium chloride solution for washing 1 time, dried with anhydrous sodium sulfate. Concentrated, column chromatography, eluting agent is petroleum ether: ethyl acetate=3:1, to obtain white solid 1.5 g, yield 85.7percent
Reference：
[1] Patent: CN107151220, 2017, A, . Location in patent: Paragraph 0246; 0247; 0248; 0249; 0250
4
[ 99-06-9 ]
[ 1700-37-4 ]
Reference：
[1] Archiv der Pharmazie, 2007, vol. 340, # 5, p. 244 - 250
5
[ 917-54-4 ]
[ 99-06-9 ]
[ 121-71-1 ]
[ 7765-97-1 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 9, p. 1550 - 1552
[2] Journal of Organic Chemistry, 1983, vol. 48, # 9, p. 1550 - 1552
6
[ 99-06-9 ]
[ 121-71-1 ]
Reference：
[1] Patent: CN108530277, 2018, A,
7
[ 99-06-9 ]
[ 75-05-8 ]
[ 873-62-1 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 20, p. 10567 - 10571
Reference：
[1] Justus Liebigs Annalen der Chemie, 1894, vol. 280, p. 17
[2] Justus Liebigs Annalen der Chemie, 1873, vol. 170, p. 101
[3] Bulletin de la Societe Chimique de France, 1878, vol. <2>29, p. 401,434[4] Chemische Berichte, 1876, vol. 9, p. 946
[5] Chemische Berichte, 1877, vol. 10, p. 1225[6] Chemische Berichte, 1878, vol. 11, p. 969,1176
10
[ 99-06-9 ]
[ 84-60-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1913, vol. 398, p. 171
11
[ 99-06-9 ]
[ 117-12-4 ]
[ 84-60-6 ]
[ 569-08-4 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 21, p. 1033
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 21, p. 1033
12
[ 7647-01-0 ]
[ 7664-93-9 ]
[ 84-60-6 ]
[ 99-06-9 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1894, vol. 280, p. 17
13
[ 99-06-9 ]
[ 58123-77-6 ]
Yield
Reaction Conditions
Operation in experiment
92%
With sodium hydroxide; sodium hypochlorite; sodium iodide In methanol; water at 0 - 20℃;
21.0 g (0.52 mol, 1.05 eq.) of sodium hydroxide and then 78.7 g (0.52 mol, 1.05 eq.) of sodium iodide are added to a solution of 69.1 g (0.5 mol, 1 eq.) of 3-hydroxybenzoic acid in 700 ml of methanol. The reaction mixture is cooled to 0°C and then aqueous sodium hypochlorite solution (0.52 mol, 1.05 eq.) is added dropwise. The reaction medium is stirred at 0-5°C for 2 hours and then at ambient temperature overnight. The methanol is evaporated and then the reaction medium is acidified with a concentrated hydrochloric acid solution. The precipitated product is filtered off, washed with water and dried. 121 g of 3-hydroxy-4-iodobenzoic acid are obtained in the form of an off-white solid. Yield = 92percent
92%
Stage #1: With sodium hydroxide; potassium hypochlorite; sodium iodide In methanol; water at 0 - 20℃; Stage #2: With hydrogenchloride In water
21.0 g (0.52 mol, 1.05 eq) of sodium hydroxide and then 78.7 g (0.52 mol, 1.05 eq) of sodium iodide are added to a solution of 69.1 g (0.5 mol, 1 eq) of 3-hydroxybenzoic acid in 700 ml of methanol. The reaction mixture is cooled to 0°C and potassium hypochlorite solution (0.52 mol, 1.05 eq) is then added dropwise. The reaction medium is stirred at 0-5°C for 2 hours and then at room temperature overnight. The methanol is evaporated off and the reaction medium is then acidified with concentrated hydrochloric acid solution. The precipitated product is filtered off, washed with water and dried. 121 g of 3-hydroxy-4-iodobenzoic acid are obtained in the form of an off-white solid. Yield = 92percent
56%
Stage #1: With sodium hypochlorite solution; sodium iodide; sodium hydroxide In methanol; water at 0 - 5℃; Stage #2: With hydrogenchloride In water
21 g (520 mmol) of sodium hydroxide and then 79 g (520 mmol) of sodium iodide are added to a solution of 69 g (500 mmol) of 3-hydroxybenzoic acid in 700 ml of methanol. The reaction mixture is cooled to 0° C. and then Javel water (520 mmol) is added dropwise. The reaction mixture is stirred at 0-5° C. for 2 hours and then at room temperature for 15 h. After evaporating the methanol, the reaction mixture is acidified with a concentrated solution of hydrochloric acid. The precipitate is filtered, washed with water and dried. 41.9 g of 3-hydroxy-4-iodobenzoic acid is obtained in the form of a white solid with melting point of 218° C. The aqueous phase is extracted with ethyl acetate, the organic phase obtained is dried over magnesium sulfate, filtered, and evaporated. The residue obtained is taken up in heptane and the precipitate obtained is filtered.Analysis showed that 61.3 g (56percent) of 3-hydroxy-4-iodobenzoic acid is obtained.
54%
Stage #1: With iodine; ammonium hydroxide; potassium iodide In water at 20℃; for 1 h; Stage #2: With hydrogenchloride In water
3-Hydroxybenzoic acid (13.8 g, 100 mmol) is dissolved in concentrated NH4OH (200 mL) using an overhead stirrer and is treated slowly drop-wise with a solution of iodine (23.4 g, 92 mmol) and KI (18.26 g, 110 mmol) in water (100 mL). The solution is stirred for 1 h at RT and then treated rapidly drop-wise with concentrated HCl (180 mL). The solid is collected via filtration, rinsed with water and dried overnight by pulling air through the solid to afford 13.1 g (54percent) of 3-hydroxy-4-iodobenzoic acid as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ7.13, 7.43, 7.80, 10.71, 12.98 ppm.
51%
at 45℃; for 70 h; Large scale
To a solution of 3-hydroxybenzoic acid (18; 1.90 kg, 13.8 mol) in acetic acid (9.0 L) was added iodine monochloride (3.32 kg, 20.6 mol). The resultant dark mixture was stirred and heated at 45 °C for 70 h. The mixture was then concentrated under vacuum to a thick slurry, and aqueous Na2S2O3 (1.5percent, 10 L). The mixture was stirred for 1 h, filtered, and rinsed with water (3 × 2.5 L). The resultant solid was treated with Na2S2O3 twice more, filtered, and rinsed. The solid was dried to give 1.85 kg (51percent) of product as a tan solid: HPLC analysis showed a purity of 95percent with a retention time of 3.7 min.
54%
With hydrogenchloride; Ki; iodine In ammonium hydroxide; water
EXAMPLE 13 N-[(1S,2R,4R)-7-Azabicyclo[2.2.1]hept-2-yl]-1-benzofuran-6-carboxamide hydrochloride 3-Hydroxybenzoic acid (13.8 g, 100 mmol) is dissolved in concentrated NH4OH (200 mL) using an overhead stirrer and is treated slowly dropwise with a solution of iodine (23.4 g, 92 mmol) and KI (18.26 g, 110 mmol) in water (100 mL). The solution is stirred for 1 h at RT and then treated rapidly dropwise with concentrated HCl (180 mL). The white solid is collected via filtration, rinsed with water and dried overnight by pulling air through the solid to afford 13.05 g (54percent) of 3-hydroxy-4-iodobenzoic acid as a tan solid.
280 g
With sodium hypochlorite; sodium iodide; sodium hydroxide In methanol; water at -10 - -5℃; for 2 h;
(a) Add 2L of methanol, 200g of m-hydroxybenzoic acid, 61g of NaOH and 226g of NaI to a 5L three-necked bottle.1.43L NaClO aqueous solution (mass content 9percent, drop rate 2L / h) and control temperature is -10 ° C ~ -5 ° C, reaction 2h; concentrated at 50 ° C under reduced pressure to remove methanol, followed by 1N (ie equivalent concentration) Hydrochloric acid adjusts the pH to about 1, at which time a large amount of white solid precipitates, is filtered, and dried to obtain 280 g of compound II; the nuclear magnetic spectrum of compound II is resolved as:
Reference：
[1] Patent: WO2006/18325, 2006, A1, . Location in patent: Page/Page column 25-26
[2] Patent: WO2006/18326, 2006, A1, . Location in patent: Page/Page column 78
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 9, p. 1103 - 1114
[4] Beilstein Journal of Organic Chemistry, 2009, vol. 5,
[5] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 15, p. 2077 - 2086
[6] Dalton Transactions, 2015, vol. 44, # 19, p. 9281 - 9288
[7] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 83, p. 10328 - 10330,3
[8] Patent: US2010/144884, 2010, A1, . Location in patent: Page/Page column 9
[9] Chemical Communications, 2017, vol. 53, # 53, p. 7222 - 7225
[10] Patent: US2003/232853, 2003, A1, . Location in patent: Page 38
[11] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 15, p. 3366 - 3372
[12] Journal of Medicinal Chemistry, 2003, vol. 46, # 10, p. 1845 - 1857
[13] Justus Liebigs Annalen der Chemie, 1874, vol. 174, p. 100
[14] Recueil des Travaux Chimiques des Pays-Bas, 1922, vol. 41, p. 701
[15] Journal of the American Chemical Society, 1948, vol. 70, p. 2314,2317
[16] Synthesis, 2002, # 17, p. 2503 - 2512
[17] Synlett, 2007, # 9, p. 1383 - 1386
[18] Patent: US2003/105089, 2003, A1,
[19] Patent: US2002/198195, 2002, A1,
[20] Patent: US2009/12129, 2009, A1, . Location in patent: Page/Page column 21
[21] Patent: EP1217000, 2002, A1, . Location in patent: Page 60
[22] Journal of Medicinal Chemistry, 2009, vol. 52, # 8, p. 2289 - 2310
[23] Patent: US2015/284405, 2015, A1, . Location in patent: Paragraph 0398
[24] Patent: WO2016/112088, 2016, A1, . Location in patent: Paragraph 0646
[25] Patent: CN108467375, 2018, A, . Location in patent: Paragraph 0011; 0013; 0014; 0015
14
[ 99-06-9 ]
[ 58123-77-6 ]
Yield
Reaction Conditions
Operation in experiment
30%
With Iodine monochloride In water; acetic acid
Step 3 Synthesis of 3-hydroxy-4-iodobenzoic acid 30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the obtained solution at room temperature. After stirring at 45° C. for 15 hours, the solvent was evaporated under reduced pressure. The residue was washed with 500 ml of 1percent aqueous sodium thiosulfate solution twice and with 500 ml of water twice and then dried to solid at 80° C. under reduced pressure to obtain the title compound. Yield: 17.2 g (65.2 mmol) (yield: 30percent) MS (FAB, m/z) 265 (MH+) H-NMR (DMSO-d6) δ7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)
Reference：
[1] Journal of the American Chemical Society, 1961, vol. 83, p. 4678
19
[ 99-06-9 ]
[ 106291-80-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3540 - 3560
[2] Gazzetta Chimica Italiana, 1902, vol. 32 II, p. 335
[3] Indian Journal of Chemistry, 1973, vol. 11, p. 1081 - 1083
[4] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273
20
[ 99-06-9 ]
[ 17100-63-9 ]
Reference：
[1] Indian Journal of Chemistry, 1973, vol. 11, p. 1081 - 1083
[2] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273
[3] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273
21
[ 99-06-9 ]
[ 610-37-7 ]
Yield
Reaction Conditions
Operation in experiment
70%
With copper(II) nitrate trihydrate In tetrahydrofuran for 3 h; Reflux
General procedure: A suspension of 2-methylphenol(18.5 mmol, 1.0 eq) and Cu(NO3)2.3H2O (27.7 mmol, 1.5 eq) in THF was stirred magnetically at 60°C or reflux for several hours. Then after the solvent was removed under vacuum, the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (5mL), dried over anhydrous MgSO4 and concentrated under vacuum. The crude residue was purified by column chromatography to afford the product (67-90percent).
Reference：
[1] Arkivoc, 2014, vol. 2014, # 5, p. 64 - 71
[2] Journal of the Chemical Society, 1921, vol. 119, p. 1431
[3] Recueil des Travaux Chimiques des Pays-Bas, 1921, vol. 40, p. 621
22
[ 99-06-9 ]
[ 610-37-7 ]
[ 619-14-7 ]
[ 54797-73-8 ]
[ 67175-28-4 ]
Reference：
[1] Journal of the Chinese Chemical Society, 2005, vol. 52, # 3, p. 581 - 588
23
[ 99-06-9 ]
[ 610-37-7 ]
[ 619-14-7 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1431
24
[ 7697-37-2 ]
[ 98-95-3 ]
[ 99-06-9 ]
[ 610-37-7 ]
[ 619-14-7 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1425
25
[ 7732-18-5 ]
[ 7697-37-2 ]
[ 99-06-9 ]
[ 610-37-7 ]
[ 619-14-7 ]
[ 602-00-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1921, vol. 40, p. 624
[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1924, vol. 178, p. 1286
[3] Chemische Berichte, 1887, vol. 20, p. 408
26
[ 7697-37-2 ]
[ 99-06-9 ]
[ 610-37-7 ]
[ 619-14-7 ]
[ 602-00-6 ]
[ 116779-73-8 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1425
[2] Recueil des Travaux Chimiques des Pays-Bas, 1921, vol. 40, p. 623
[5-(4-Bromo-3-methoxy-phenyl)-3-methyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-cyclohexyl-amine To a mixture of 3-hydroxybenzoic acid (14.480 mmol, 2 g) in acetic acid (14.5 mL) and sulfuric acid (1.5 mL) at 50° C., a solution of bromine (15.204 mmol, 0.780 mL) in acetic acid (7.2 mL) was added and stirred 30 minutes at 100° C. The reaction was allowed to cool to RT and diluted with water. The aqueous layer was extracted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give the 4-bromo-2-hydroxy-benzoic acid. Yield: 100percent.
Reference：
[1] Patent: US2003/45557, 2003, A1,
29
[ 586-38-9 ]
[ 121-34-6 ]
[ 877-22-5 ]
[ 99-06-9 ]
Reference：
[1] Canadian Journal of Chemistry, 2001, vol. 79, # 4, p. 394 - 404
30
[ 586-38-9 ]
[ 99-50-3 ]
[ 121-34-6 ]
[ 877-22-5 ]
[ 99-06-9 ]
Reference：
[1] Canadian Journal of Chemistry, 2001, vol. 79, # 4, p. 394 - 404
31
[ 586-38-9 ]
[ 121-34-6 ]
[ 877-22-5 ]
[ 2612-02-4 ]
[ 99-06-9 ]
Reference：
[1] Canadian Journal of Chemistry, 2001, vol. 79, # 4, p. 394 - 404
32
[ 586-38-9 ]
[ 121-34-6 ]
[ 877-22-5 ]
[ 2612-02-4 ]
[ 99-06-9 ]
Reference：
[1] Canadian Journal of Chemistry, 2001, vol. 79, # 4, p. 394 - 404
33
[ 99-06-9 ]
[ 4920-80-3 ]
Reference：
[1] Journal of the Chemical Society, 1912, vol. 101, p. 548
34
[ 917-54-4 ]
[ 99-06-9 ]
[ 121-71-1 ]
[ 7765-97-1 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 9, p. 1550 - 1552
[2] Journal of Organic Chemistry, 1983, vol. 48, # 9, p. 1550 - 1552
35
[ 99-06-9 ]
[ 17100-64-0 ]
Reference：
[1] Chemical Communications, 2014, vol. 50, # 100, p. 15905 - 15908
36
[ 99-06-9 ]
[ 602-00-6 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1431
[2] Recueil des Travaux Chimiques des Pays-Bas, 1921, vol. 40, p. 621
[3] Recueil des Travaux Chimiques des Pays-Bas, 1921, vol. 40, p. 624
[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1924, vol. 178, p. 1286
[5] Chemische Berichte, 1887, vol. 20, p. 408
37
[ 7732-18-5 ]
[ 7697-37-2 ]
[ 99-06-9 ]
[ 610-37-7 ]
[ 619-14-7 ]
[ 602-00-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1921, vol. 40, p. 624
[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1924, vol. 178, p. 1286
[3] Chemische Berichte, 1887, vol. 20, p. 408
38
[ 7697-37-2 ]
[ 99-06-9 ]
[ 610-37-7 ]
[ 619-14-7 ]
[ 602-00-6 ]
[ 116779-73-8 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1425
[2] Recueil des Travaux Chimiques des Pays-Bas, 1921, vol. 40, p. 623
39
[ 99-06-9 ]
[ 24589-98-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1969, vol. 12, # 3, p. 420 - 424
Reference：
[1] Chemical Communications, 2014, vol. 50, # 14, p. 1694 - 1697
42
[ 74-87-3 ]
[ 99-06-9 ]
[ 85740-98-3 ]
Yield
Reaction Conditions
Operation in experiment
91.3%
Stage #1: at 60℃; for 3 h; Autoclave; Molecular sieve Stage #2: at 20℃; for 4 h; Autoclave; Molecular sieve
1mol 3-hydroxybenzoic acid was dissolved in 2.4 L of CS2, added to the autoclave, and 5 ml of molecular sieve particles loaded with 2.5 mol of hypochlorous acid and 0.07 g of gold nanoparticles were charged to the reaction vessel at a temperature of 60 ° C,After stirring at 95 revolutions per minute for 3 h, the pH was adjusted to 10 with NaOH, 1.3 mol-methyl chloride was added, and the mixture was stirred at room temperature for 4 h. In addition to precipitation of crystals, filtered and dried, that is, 3-methoxy-4-chlorobenzoic acid crude, after recrystallization from ethanol to produce 3-methoxy-4-chlorobenzoic acid. The purity of the product was 84.6percent and the yield was 91.3percent.
Reference：
[1] Patent: CN105732366, 2016, A, . Location in patent: Paragraph 0024; 0025
43
[ 99-06-9 ]
[ 10541-78-3 ]
Reference：
[1] Journal of the Chemical Society, 1912, vol. 101, p. 548
44
[ 99-06-9 ]
[ 394-31-0 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1431
[2] Journal of the Chemical Society, 1921, vol. 119, p. 1431
Reference：
[1] Journal of the American Chemical Society, 1917, vol. 39, p. 452
[2] Tetrahedron, 2012, vol. 68, # 39, p. 8358 - 8366
47
[ 7664-41-7 ]
[ 7553-56-2 ]
[ 99-06-9 ]
[ 57772-57-3 ]
Reference：
[1] Journal of the American Chemical Society, 1917, vol. 39, p. 452
48
[ 100-97-0 ]
[ 99-06-9 ]
[ 619-12-5 ]
Yield
Reaction Conditions
Operation in experiment
36%
Stage #1: With copper(I) oxide In trifluoroacetic acid for 5 h; Reflux Stage #2: With hydrogenchloride In water at 20℃; for 1 h;
General procedure: To a solution of substrates (1a–1q, 0.15 mmol) in trifluoroacetic acid (5 ml), hexamethylenetetramine (0.3 mmol) and cuprous oxide (0.15 mmol) were added. The reaction mixture was refluxed for about 5 h, cooled to room temperature, followed by addition of hydrochloric acid (3 N, 5 ml). After stirring for another 1 h, the solution was concentrated under reduced pressure. The products were purified by silica gel column chromatography (200–300 mesh).
Reference：
[1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8147 - 8158
49
[ 67-66-3 ]
[ 99-06-9 ]
[ 619-12-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1969, vol. 12, # 3, p. 420 - 424
50
[ 328-84-7 ]
[ 99-06-9 ]
[ 63734-62-3 ]
Reference：
[1] Patent: US4330324, 1982, A,
[2] Patent: US4419123, 1983, A,
[3] Patent: US4419124, 1983, A,
[4] Patent: US4358308, 1982, A,
[5] Patent: US4419122, 1983, A,
[6] Patent: US31455, 1983, E1,
[7] Patent: US4063929, 1977, A,
[8] Patent: US4093446, 1978, A,
[9] Patent: US4429146, 1984, A,
51
[ 76-09-5 ]
[ 328-84-7 ]
[ 99-06-9 ]
[ 63734-62-3 ]
Reference：
[1] Patent: US4031131, 1977, A,
52
[ 99-06-9 ]
[ 63734-62-3 ]
Reference：
[1] Patent: CN107032979, 2017, A,
53
[ 70249-37-5 ]
[ 100-06-1 ]
[ 6298-96-0 ]
[ 99-06-9 ]
Reference：
[1] Chemical Communications, 2013, vol. 49, # 2, p. 161 - 163
54
[ 99-06-9 ]
[ 606488-94-2 ]
Yield
Reaction Conditions
Operation in experiment
11 g
With hydrogen; sodium hydroxide In water at 150℃;
A I L pressure tank reactor (60 atm) containing a solution of 3-hydroxybenzoic acid (30 g, 217.20 mmol, 1.00 equiv), Raney Ni (5 g) and sodium hydroxide (6.4 g, 160.00 mmol, 0.74 equiv) in water (500 mL) was introduced H2 (gas, 60 atm) and the resulting solution was stirred overnight at 150°C. After completion of the reaction, the reaction temperature was cooled down to room temperature and the solids were filtered out by filtration. The resulting solution was neutralized with 12 M HCl, extracted with 6 x 100 mL of tetrahydrofuran. The combined organic layers were dried over sodium sulfate and concentrated under vacuum to provide 3- hydroxycyclohexane-l-carboxylic acid (11 g, crude) as a white solid.
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 12, p. 2218 - 2227
[2] Canadian Journal of Chemistry, 1993, vol. 71, # 4, p. 578 - 610
[3] Patent: WO2011/146371, 2011, A1, . Location in patent: Page/Page column 23
[4] Patent: WO2014/11902, 2014, A1, . Location in patent: Paragraph 00280-00281
[5] Patent: WO2014/194242, 2014, A2, . Location in patent: Paragraph 00353-00354
55
[ 99-06-9 ]
[ 34113-69-4 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 3, p. 847
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 3, p. 847
56
[ 99-06-9 ]
[ 51786-10-8 ]
[ 34113-69-4 ]
[ 56961-30-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, # 6, p. 985 - 988
[2] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2001, vol. 40, # 11, p. 1196 - 1202
[3] Journal of the Indian Chemical Society, 2002, vol. 79, # 5, p. 420 - 425
57
[ 99-06-9 ]
[ 56256-14-5 ]
Reference：
[1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273
[2] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273
58
[ 99-06-9 ]
[ 51786-10-8 ]
[ 56961-30-9 ]
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[3] Roczniki Chemii, 1930, vol. 10, p. 761,765,771[4] Chem. Zentralbl., 1931, vol. 102, # I, p. 1427
[5] Recueil des Travaux Chimiques des Pays-Bas, 1921, vol. 40, p. 625
59
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[2] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2001, vol. 40, # 11, p. 1196 - 1202
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[2] Chemical Communications, 2017, vol. 53, # 53, p. 7222 - 7225
A mixture of 3-hydroxybenzoic acid (1.0 g, 138.12 mmol)and acetic anhydride (5 mL) in pyridine (10 mL) wasstirred at 125 C for 2 h, equipped with a refluxing condenserunder argon. After cooling at room temperature, the mixture was quenched with saturated aqueous NaHCO3,acidified with 12 N HCl to pH 2. The resulting solid wasfiltered, washed with H2O (50 mL), and dried under highvacuum to afford compound 2b in 94% yield. 1H NMR(500 MHz, CDCl3) delta 7.99 (d, J = 8.0 Hz, 1H), 7.83 (s,1H), 7.50 (t, J = 8.0 Hz, 1H), 7.37-7.34 (m, 1H), 2.34 (s,3H). 13C NMR (125 MHz, CDCl3) delta 171.1, 169.3, 150.7,130.8, 129.7, 127.7, 127.3, 123.5, 21.1. ESI MS (m/e) = 179.03 [M-1]-.
94%
With pyridine; at 125℃; for 2h;Inert atmosphere;
3-hydroxybenzoic acid (1.0 g, 138.12 mmol)Acetic anhydride (5 mL)Pyridine (10 mL)The mixture was stirred at 125 C. for 2 hours using a reflux condenser under argon.After cooling to room temperature, the mixture was quenched with saturated aqueous NaHCO 3, acidified to pH 2 by addition of 12N HCl, filtered and washed with H 2 O (50 mL) and dried under high vacuum to give 94% of Compound 2b.Obtained in yield.
89.8%
for 5h;Heating / reflux;
Intermediate 9; N-(4-Chloro-3-trifluoromethyl-phenyl)-3-hydroxy-benzamide; A suspension of 3-hydroxybenzoic acid (16.2 g, 117.3 mmol) (Aldrich) in acetic anhydride (20 mL) (Aldrich) was heated at reflux for 5 hours. On heating a clear solution was formed. After cooling to room temperature, mixture was poured into ice-water (400 mL) and stirred. A white crystalline material was formed. This was collected by filtration, washed with water and dried in vacuum oven to give 3-acetoxybenzoic acid as white crystals in two crops. (Yield 18.97 g, 89.8%).
88%
With pyridine; at 20℃;
Acetic anhydride (10 ml, 105.79 mmcl) was added dropwise to a cooled solution of 3-hydroxybenzoic acid (2 g, 14.48 mmcl) in pyridine (20 ml), and the mixture was stirred at RT overnight. The mixture was cooled, poured onto ice and extracted with diethyl ether (50 ml). The product was obtained asa colourless solid (2.29 g, 88%). ?H NMR (400 MHz, DMSO-d6) 6 8.58 (s, J =4.1 Hz, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.66 (s, J = 2.0 Hz, 2H), 7.55 (t, J = 7.9Hz, 2H), 7.39 (d, J = 6.7 Hz, 3H), 2.29 (s, J = 1.9 Hz, 6H) ;13c NMR (100 MHz,DMSO-d6)6 169.7, 167.0, 151.0,132.7,130.3, 127.1, 126.9, 123.1,21.34. The1H NMR and 130 NMR spectra were in accordance with literature: Kesenheimer,C., A. Kalogerakis, A. Meissner and U. Groth. Chemistry, 2010, 16(29): 8805-8821.
77%
In pyridine; at 20℃; for 4h;
Step 1Acetic anhydride (10ml) was added dropwise to a cooled solution of [109] (2 g , 1 eq ) in pyridine (20 ml), and stirred at RT for 4 h. The reaction mixture was cooled and poured over crushed ice. The white precipitate formed was collected by filtration, washed with diethyl ether (50 ml) and dried to afford [110] as a white solid (2.0 g, 77%).ESIMS: 181 (M+ + 1)
74%
With pyridine; at 0 - 20℃; for 6h;
Ac2O (562 mL, 1.5 eq) was added drop wise to a solution of compound 7-1(150 g, 1.08 mol) in Pyridine (700 mL) at 0oC, stirred at r.t. for 6 hrs. Evaporated, poured into ice water, filtered, the filter cake was dried to give compound 7-2 as a white solid (150 g, 74% yield).[0071]1H NMR (400 MHz, CDCl3): delta ppm 8.00~7.98 (d, J = 7.6 Hz, 1H), 8.03(s, 1H), 7.83(s, 1H), 7.51~7.47 (t, J = 8.0 Hz, 1H), 7.36~7.34 (dd, J = 8.0 Hz 1.2 Hz, 1H), 2.34 (s, 3H).
With pyridine; at 20℃; for 1h;
To a solution of 5-hydroxybenzoic acid (5) (17.4mmol) in pyridine (10mL), acetic anhydride was added dropwise (6.6mL, 70.0mmol). The reaction mixture was stirred at room temperature for 1h and was subsequently poured into water (50mL). The water phase was acidified to pH 2 and extracted with EtOAc (3×40mL). The combined organic phases were washed with 0.1M HCl (1×100mL), brine (1×100mL), and dried with Na2SO4. The solvent was evaporated under reduced pressure and the crude product was used without further purification.
With sulfuric acid; at 100℃; for 0.5h;
To a reaction vessel was added 67g 50g 3- hydroxybenzoic acid and 0.35g of acetic anhydride and concentrated sulfuric acid, heated under stirring to 100 deg.] C and reacted for 30 minutes, after the completion of the reaction,The solvent was removed by means of distillation under reduced pressure to give 64.5g of 3-acetoxy benzoic acid as a white solid (crude).
With sodium acetate; In water; at 80℃; for 2h;
A method of preparing hydroxyacetophenone,Including the following steps: Will hydroxybenzoic acid dissolved in water,Acetic anhydride and sodium acetate were added,Warmed to 80 C,Insulation 2h,Cooling precipitated solid,filter,Drying to obtain m-acetoxybenzoic acid,among them,M-hydroxybenzoic acid and acetic anhydride molar ratio of 1: 1,The molar ratio of sodium acetate to m-hydroxybenzoic acid is 0.5: 100,The weight ratio of water to m-hydroxybenzoic acid is 10: 1;
With sodium hydroxide; In water; at 20℃;
The reaction of 12 3-hydroxybenzoic acid with acetic anhydride in aqueous NaOH at room temperature easily gave the white solids of 3-acetoxybenzoic acid. Then 3-acetoxybenzoic acid (1.80g, 10mmol) reacted with SOCl2 (1.1mL, 15.1mmol) at reflux for 5h. After that, the excess SOCl2 was removed under reduced pressure to afford 3-acetoxybenzoyl chloride which was used in the next step without further purification. Next, 3-acetoxybenzoyl chloride was dissolved in CH2Cl2 (25mL) and added dropwise to a stirred solution of N1-butylbenzene-1,2-diamine (1.64g, 10mmol) and Et3N (1.5mL) in dry CH2Cl2 (20mL) at 0C. After stirring at room temperature for 16-24h, the reaction mixture was filtered and evaporated. The residue was purified by column chromatography on silica gel with EtOAc/petroleum ether (1:6, v/v) as eluent to afford the compound 1. White solid (1.32g, 40%).
With sodium hydroxide; sodium hypochlorite; sodium iodide; In methanol; water; at 0 - 20℃;
21.0 g (0.52 mol, 1.05 eq.) of sodium hydroxide and then 78.7 g (0.52 mol, 1.05 eq.) of sodium iodide are added to a solution of 69.1 g (0.5 mol, 1 eq.) of 3-hydroxybenzoic acid in 700 ml of methanol. The reaction mixture is cooled to 0C and then aqueous sodium hypochlorite solution (0.52 mol, 1.05 eq.) is added dropwise. The reaction medium is stirred at 0-5C for 2 hours and then at ambient temperature overnight. The methanol is evaporated and then the reaction medium is acidified with a concentrated hydrochloric acid solution. The precipitated product is filtered off, washed with water and dried. 121 g of 3-hydroxy-4-iodobenzoic acid are obtained in the form of an off-white solid. Yield = 92%
92%
21.0 g (0.52 mol, 1.05 eq) of sodium hydroxide and then 78.7 g (0.52 mol, 1.05 eq) of sodium iodide are added to a solution of 69.1 g (0.5 mol, 1 eq) of 3-hydroxybenzoic acid in 700 ml of methanol. The reaction mixture is cooled to 0C and potassium hypochlorite solution (0.52 mol, 1.05 eq) is then added dropwise. The reaction medium is stirred at 0-5C for 2 hours and then at room temperature overnight. The methanol is evaporated off and the reaction medium is then acidified with concentrated hydrochloric acid solution. The precipitated product is filtered off, washed with water and dried. 121 g of 3-hydroxy-4-iodobenzoic acid are obtained in the form of an off-white solid. Yield = 92%
56%
21 g (520 mmol) of sodium hydroxide and then 79 g (520 mmol) of sodium iodide are added to a solution of 69 g (500 mmol) of 3-hydroxybenzoic acid in 700 ml of methanol. The reaction mixture is cooled to 0 C. and then Javel water (520 mmol) is added dropwise. The reaction mixture is stirred at 0-5 C. for 2 hours and then at room temperature for 15 h. After evaporating the methanol, the reaction mixture is acidified with a concentrated solution of hydrochloric acid. The precipitate is filtered, washed with water and dried. 41.9 g of 3-hydroxy-4-iodobenzoic acid is obtained in the form of a white solid with melting point of 218 C. The aqueous phase is extracted with ethyl acetate, the organic phase obtained is dried over magnesium sulfate, filtered, and evaporated. The residue obtained is taken up in heptane and the precipitate obtained is filtered.Analysis showed that 61.3 g (56%) of 3-hydroxy-4-iodobenzoic acid is obtained.
54%
3-Hydroxybenzoic acid (13.8 g, 100 mmol) is dissolved in concentrated NH4OH (200 mL) using an overhead stirrer and is treated slowly drop-wise with a solution of iodine (23.4 g, 92 mmol) and KI (18.26 g, 110 mmol) in water (100 mL). The solution is stirred for 1 h at RT and then treated rapidly drop-wise with concentrated HCl (180 mL). The solid is collected via filtration, rinsed with water and dried overnight by pulling air through the solid to afford 13.1 g (54%) of 3-hydroxy-4-iodobenzoic acid as a tan solid. 1H NMR (400 MHz, DMSO-d6): delta7.13, 7.43, 7.80, 10.71, 12.98 ppm.
51%
With Iodine monochloride; acetic acid; at 45℃; for 70h;Large scale;
To a solution of 3-hydroxybenzoic acid (18; 1.90 kg, 13.8 mol) in acetic acid (9.0 L) was added iodine monochloride (3.32 kg, 20.6 mol). The resultant dark mixture was stirred and heated at 45 C for 70 h. The mixture was then concentrated under vacuum to a thick slurry, and aqueous Na2S2O3 (1.5%, 10 L). The mixture was stirred for 1 h, filtered, and rinsed with water (3 × 2.5 L). The resultant solid was treated with Na2S2O3 twice more, filtered, and rinsed. The solid was dried to give 1.85 kg (51%) of product as a tan solid: HPLC analysis showed a purity of 95% with a retention time of 3.7 min.
13.05 g (54%)
With hydrogenchloride; Ki; iodine; In ammonium hydroxide; water;
EXAMPLE 13 N-[(1S,2R,4R)-7-Azabicyclo[2.2.1]hept-2-yl]-1-benzofuran-6-carboxamide hydrochloride 3-Hydroxybenzoic acid (13.8 g, 100 mmol) is dissolved in concentrated NH4OH (200 mL) using an overhead stirrer and is treated slowly dropwise with a solution of iodine (23.4 g, 92 mmol) and KI (18.26 g, 110 mmol) in water (100 mL). The solution is stirred for 1 h at RT and then treated rapidly dropwise with concentrated HCl (180 mL). The white solid is collected via filtration, rinsed with water and dried overnight by pulling air through the solid to afford 13.05 g (54%) of 3-hydroxy-4-iodobenzoic acid as a tan solid.
With iodine; sodium carbonate; In water;
3-Hydroxy-4-iodo-benzoic acid To a solution of 26 g 3-Hydroxybenzoic acid and 43 g Na2CO3 in 45 mg H2O at 100 C. was added dropwise a solution of 48 g Kl and 48 g iodine in 135 ml H2O. After heating for additional 3 h the mixture was cooled to RT and acidified with concentrated HCl. The title compound precipitated as a white solid and was collected by filtration. Yield 20 g
-Methyl 3-hydroxy-4-iodobenzoate21 g (520 mmol) of sodium hydroxide and then 78.7 g (520 mmol) of sodium iodide are added to a solution of 69 g (500 mmol) of 3-hydroxybenzoic acid in 700 mL of methanol. The reaction mixture is cooled to 0 C. and aqueous sodium hypochlorite solution is then added (520 mmol). The reaction medium is stirred at 0-5 C. for 2 hours and then at room temperature overnight. The methanol is evaporated off and the reaction medium is then acidified with concentrated hydrochloric acid solution. The precipitated product is filtered off, washed with water and dried. 41.92 g of 3-hydroxy-4-iodobenzoic acid are obtained in the form of an off-white solid. The aqueous phase is extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated and the residue obtained is taken up in heptane and then filtered.
With sodium hypochlorite; sodium iodide; sodium hydroxide; In water; at 25℃; for 2h;Inert atmosphere;
To a stirred solution of 3-hydroxybenzoic acid (25 g, 181 mmol) in water (180 mL) were added 1 M aqueous NaOH (188 mL) and sodium iodide (28.1 g, 188 mmol), followed by slow addition aqueous sodium hypochlorite solution (0.9 M, 209 mL). The mixture was stirred at about 25 C. for about 2 h, then cooled in ice and acidified with concentrated HCl to pH=3. A sufficient quantity of 10% ascorbic acid solution was added to afford a colorless mixture. The remaining precipitate was filtered, washed with water, and dissolved in EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, filtered and concentrated to provide the title compound C12. Yield: 34 g (71%) 1H NMR (400 MHz, dmso-d6) delta 12.98 (br s, 1H), 10.65 (s, 1H), 7.78 (dd, 1H), 7.32 (d, 1H), 7.11 (dd, 1H).
With sodium hypochlorite; sodium iodide; sodium hydroxide; In methanol; at 0 - 20℃;
To a solution of 3-hydroxybenzoic acid (6.91 g, 0.05 mol) in 70 mL of methanol were added sodium hydroxide (2.1 g, 0.052 mol) and sodium iodide ( 7.87 g, 0.052 mol). The reaction mixture was cooled to 0C, followed by dropwise addition of aqueous sodium hypochlorite solution (52 mmol, 0.1 eq). The reaction mixture was stirred at 0-5 C for 2 hr then at r.t. overnight. The resulting mixture was concentrated under reduced pressure. The residue was acidified and filtered. The solid was collected, washed with water and dried under high vacuum to afford the desired product (12.1 g, 92% yield) which was directly used in the next step without any further purification.
280 g
With sodium hypochlorite; sodium iodide; sodium hydroxide; In methanol; water; at -10 - -5℃; for 2h;
(a) Add 2L of methanol, 200g of m-hydroxybenzoic acid, 61g of NaOH and 226g of NaI to a 5L three-necked bottle.1.43L NaClO aqueous solution (mass content 9%, drop rate 2L / h) and control temperature is -10 C ~ -5 C, reaction 2h; concentrated at 50 C under reduced pressure to remove methanol, followed by 1N (ie equivalent concentration) Hydrochloric acid adjusts the pH to about 1, at which time a large amount of white solid precipitates, is filtered, and dried to obtain 280 g of compound II; the nuclear magnetic spectrum of compound II is resolved as:
With ammonium hydroxide; iodine; potassium iodide; In water; at 20℃; for 1.5h;
To a solution of compound 1(200 g) in NH3.H20 (2.9 L) was added 12(338 g) in portions and KI (264 g) in H20 (1.5 L) by funnel. The mixture was stirred at rt for 1.5 h. To the mixture was added con. HCI slowly at 20-35 C and the mixture was stirred for 10 mm (pH<2). The precipitate was collected and recrystallized with ethanol/H20 to give crude compound 2 (141 g, yield 37%) as a slightly yellow solid.
With copper(II) nitrate trihydrate; In tetrahydrofuran; for 3.0h;Reflux;
General procedure: A suspension of 2-methylphenol(18.5 mmol, 1.0 eq) and Cu(NO3)2.3H2O (27.7 mmol, 1.5 eq) in THF was stirred magnetically at 60C or reflux for several hours. Then after the solvent was removed under vacuum, the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (5mL), dried over anhydrous MgSO4 and concentrated under vacuum. The crude residue was purified by column chromatography to afford the product (67-90%).
With bromine; acetic acid; In ethanol; at 20℃; for 0.5h;
To a solution of 3-hydroxybenzoic acid (10, 15.0 g, 109 mmol) in a mixture of ethanol (60 mL) and acetic acid (30 mL), bromine (11.2 mL,218 mmol) was added slowly and dropwise. After stirring for 30 min atroom temp., aq. sodium thiosulfate solution (90 mL) was added andethanol was removed in vacuo. The remaining aq. layer was extracted with ethylacetate (5 x 200 mL) and the combined organic layer was dried with magnesiumsulfate. After removal of the solvent, the crude product was recrystallized from boilingwater and a colourless solid was obtained. Yield: 12.19 g (56.2 mmol, 52%) (ref.[3]: 40%). M. p.: 225 - 227 C.1H NMR (500 MHz, DMSO-d6): delta = 13.04 (br. s, 1H,CO2H), 10.62 (s, 1H, OH), 7.59 (d, 1H,3J = 8.3 Hz, Ar-H-5), 7.51 (d, 1H,4J = 2.0 Hz,Ar-H-2), 7.28 (dd, 1H,3J = 8.3 Hz,4J = 2.0 Hz, Ar-H-6) ppm.13C NMR (125 MHz,DMSO-d6): delta = 167.2 (s, CO2H), 154.6 (s, Ar-C-3), 133.5 (d, Ar-C-5), 131.8 (s, Ar-C-1), 121.6 (d, Ar-C-6), 117.1 (d, Ar-C-2), 115.0 (s, Ar-C-4) ppm. MS (EI, 70 eV): m/z =216/218 (100/97) [M]+·, 199, 201 (73, 70) [M - OH]+.
40%
With bromine; acetic acid; In ethanol; at 20℃; for 0.5h;
Example 56 (2S)-1-{(5R)-5-((5-carboxy-2-bromophenoxy)-methyl)-L-prolyl}-pyrrolidine-2- carbonitrile Example 56A 4-Bromo-3-hydroxy-benzoic acid Bromine (0.37 mL, 7.2 mmol) was added to 3-hydroxy-benzoic acid (500 mg, 3.6 mmol) in ethanol (2 ML) and acetic acid (1 mL). The mixture was stirred at room temperature for 30 min and then concentrated and purified by column chromatography to give the product (314 mg, 40 %). MS (DCI) m/z 234 (M+NH4) +.
40%
With bromine; In ethanol; acetic acid; at 20℃; for 0.5h;
EXAMPLE 56A 4-Bromo-3-hydroxy-benzoic acid Bromine (0.37 mL, 7.2 mmol) was added to 3-hydroxybenzoic acid (500 mg, 3.6 mmol) in ethanol (2 mL) and acetic acid (1 mL). The mixture was stirred at room temperature for 30 min and then concentrated and purified by column chromatography to give the product (314 mg, 40%). MS (DCI) m/z 234 (M+NH4)+.
28%
With bromine; acetic acid;
Reference Example 43 An acetic acid solution (20 mL) of bromine (20 mL, 0.38 mol) was added dropwise to an acetic acid solution (500 mL) containing 3-hydroxybenzoic acid (53 g, 0.384 mol) at room temperature, and the mixture was stirred for 5 days. The reaction mixture was concentrated under reduced pressure, and the residue obtained was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was recrystallized from water, to obtain 4-bromo-3-hydroxybenzoic acid (23.33 g, 28%) as colorless granular crystals. 1H-NMR(DMSO-d6) delta:7.27(1H,dd,J=7.8,2.0Hz)7.52 (1H,d,J=2.0Hz),7.61(1H,d,J=7.8Hz),10.65(1H,brs),13.04 (1H,brs)ppm
21%
With bromine; In acetic acid;
Referential Example 39 4-Bromo-3-hydroxybenzoic acid In acetic acid (24.5 ml), 3-hydroxybenzoic acid (5.00 g) was suspended. To the resulting suspension, a solution of bromine (1.9 ml) in acetic acid (acetic acid: 5 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 33 hours. The reaction mixture was ice cooled. The crystals so precipitated were collected by filtration and then washed with acetic acid, whereby the title compound (1.68 g, 21%) was obtained. 1H-NMR (DMSO-d6) delta: 7.28(1H,dd,J=7.8,2.0 Hz), 7.51(1H,d,J=2.0 Hz), 7.59(1H,d,J=8.3 Hz), 10.54(1H,br s), 12.84.(1H,br).
21%
With bromine; In acetic acid;
[Referential Example 39] 4-Bromo-3-hydroxybenzoic acid In acetic acid (24.5 ml), 3-hydroxybenzoic acid (5.00 g) was suspended. To the resulting suspension, a solution of bromine (1.9 ml) in acetic acid (acetic acid: 5 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 33 hours. The reaction mixture was ice cooled. The crystals so precipitated were collected by filtration and then washed with acetic acid, whereby the title compound (1.68 g, 21%) was obtained. 1H-NMR (DMSO-d6) delta: 7.28(1H,dd,J=7.8,2.0Hz), 7.51(1H,d,J=2.0Hz), 7.59(1H,d,J=8.3Hz), 10.54(1H,br s),12.84(1H,br).
21%
With bromine; In acetic acid; at 20℃; for 33h;
3-Hydroxybenzoic acid (5.00 g) was suspended in acetic acid (24.5 ml). Under ice cooling, an acetic acid solution (acetic acid: 5 ml) of bromine (1.9 ml) was added dropwise to the resulting suspension, followed by stirring at room temperature for 33 hours. The reaction mixture was ice cooled. The crystals thus precipitated were collected by filtration and washed with acetic acid, whereby the title compound (1.68 g, 21%) was obtained.1H-NMR (DMSO-d6) delta 7.28 (1H, dd, J=7.8, 2.0Hz), 7.51(1H, d, J=2.0Hz), 7.59(1H, d, J=8.3Hz), 10.54 (1H, br s), 12.84 (1H, br).
19%
With bromine; In water; acetic acid;
Step 1 Synthesis of ethyl 4-bromo-3-hydroxybenzoate (6). To a solution of 3-hydroxybenzoic acid 5 (18.2 g, 0.132 mol) in 180 ml of glacial acetic acid cooled in a water bath was slowly added over a period of 2 h bromine (21.1 g, 0.132 mmol) in 70 ml of acetic acid. The solution was stirred overnight. After removing bromine and 160 ml of acetic acid under reduced pressure, the mixture was cooled to 0 C., filtered, washed (50 ml of cold water), and dried under vacuum to give a white solid. Crystallization (H2O) gave 4-bromo-3-hydroxybenzoic acid as white crystals (5.5 g, 19%).
15.9%
With bromine; acetic acid; at 18 - 22℃; for 23h;
[00246] This acid was prepared in similar way to that described by Buehler et al (Buehler, C. A., Harris, J. O., Shacklett, C and Block, B. P.; J. Am. Chem. Soc., 68, 574-577 (1946)). To a stirred suspension of 3-hydroxybenzoic acid (50.0 g, 0.362 mol) in acetic acid (495 ml), at RT under argon, was added a solution of bromine (57.97 g, 0.3627 mol) in acetic acid (192 ml) over 2 h. During the addition the internal temperature rose from 18.0 to 22.0 C. The mixture was stirred for 21 h and then concentrated under vacuum, where approximately (500 ml) of distillate was collected. The resulting concentrated solution was stored at 4 C. for 2 h. The resulting white solid was filtered off and washed with cold water (100 ml). This solid was dissolved in a minimum volume of boiling water (220 ml), filtered and allowed to cool to room temperature. The resulting solid was removed by filtration, washed with cold water and dried in a vacuum oven at 58 C. to give the title compound (12.50 g, yield 15.9%), mp=231-232 C., (lit mp 225-226 C.)1. [00247] 1H NMR (400.13 MHz, DMSO-d6): 13.00 (1H, bs, CO2H), 10.64 (1H, bs, OH), 7.60 (1H, d, H-5, J5-6 8.0 Hz), 7.52 (1H, d, H-21 J2-6 2.0 Hz), 7.29 (1H, dd, H-6, J2-6 2.0 Hz, J5-6 8.0 Hz)
12%
With bromine; acetic acid;
4-Bromo-3-hydroxybenzoic acid; The title compound was prepared according to the method reported by Buehler et al. [Buehler, 1946] using 3-hydroxybenzoic acid (18.2 g, 132.0 mmol) and Br2 (6.76 mL, 132.0 mmol) in glacial AcOH (250 mL) to give 4-bromo-3-hydroxybenzoic acid as a colourless crystalline solid (3.43 g, 12%) after recrystallisation from Et20/n-hexane; mp. 225 - 226 C (lit .[Beyer, 1921] 227 - 228 C) ; No.H (270 MHz, DMSO-d6) 7.28 (dd, J = 8.2,2.0, 1H), 7.51 (d, J= 1.7, 1H), 7.60 (d, J= 8.3,1H), 10.66 (bs, 1H, - exchanges with D20, ArOH) and 13.04 (bs, 1H - exchanges with D20, ArCOOH) ; LRMS (FAB+) m/z (rel. intensity) 218 (94, [C7H581BrO3+H] ), 216 (100, [C7H579BrO3+H] ); LC-MS (APCI-): tR = 1.38 min, m/z 216.78 (M-H) ; HPLC: tR = 1.35 min (100%) ; HRMS Found 218.94656; C7H681BrO3 requires 218.94798. Buehler et al. , J. Am. Chem. Soc. 1946, 68, 574 - 577.
With bromine; In acetic acid;
A. 4-Bromo-3-hydroxybenzoic acid Bromine (58 g, 19 mL, 0.36 mol) in acetic acid (50 mL) was slowly added over 2 hours to a solution of 3-hydroxybenzoic acid (50 g, 0.36 mol) in acetic acid (145 mL) with stirring at 15 C. After stirring at 15 C. for an additional hour and then at ambient temperature for 17 hours, the solid formed was filtered and rinsed with acetic acid (20 mL). Drying by pulling air through the filter pack for 4 hours afforded 23.5 g (30%) of compound A.
With bromine; In acetic acid;
A. 4-Bromo-3-hydroxybenzoic acid Bromine (58 g, 19 mL, 0.36 mol) in acetic acid (50 mL) was slowly added over 2 hours to a solution of 3-hydroxybenzoic acid (50 g, 0.36 mol) in acetic acid (145 mL) with stirring at 15 C. After stirring at 15 C. for an additional hour and then at ambient temperature for 17 hours, the solid formed was filtered and rinsed with acetic acid (20 mL). Drying by pulling air through the filter pack for 4 hours afforded 23.5 g (30%) of compound A.
With bromine; In acetic acid; at 0℃; for 0.5h;
Exam ple 16A: Com pound 3001Step 1 Rifliin?. L W Lawrence Woo et al , J M&d Chem 2007, SO, 3540-3560Disscte 3' hydroxy benzoic acri 1USDa1 (18.20 gr 130,4 mmol) in acettc acid (180 ml) and cool to O10C Add bromt?e (2134g, 1332 mmol) as a solution in acetic acid dropwise over about 30 mm Evaporate the solvent under reduced pressure to give a we. sold mass Add water {200 mL) and stir initially at RT( then warm slowiy to SCfC, stirring constantly Coo. stowLambday the now homogeneous mature to CfC, whereupon a solid forms Add a further portion of water (200 mL) and stir the suspension at RT overnight. Filter and dry the solids to provide 16a2,
With thionyl chloride; ammonia; In tetrahydrofuran; benzene;
EXAMPLE 1 Preparation of 3-Hydroxybenzamide Ten g (72.4 mmol) of 3-hydroxybenzoic acid and 10 ml SOCl2 were mixed and allowed to stand for 1 hr, heated on a steam bath for 2 hr, and then cooled and diluted with 25 ml of benzene. The benzene was then evaporated in vacuo to dryness and the residue extracted with 2*50 ml benzene. The extracted residue was dissolved in 25 ml tetrahydrofuran (THF) and this solution added dropwise over a period of 15 min to a stirred, cold (-10 C.) 50 ml solution of concentrated ammonia. The mixture was stirred with cooling for an hour and then at room temperature overnight. The mixture was poured into an open dish and allowed to evaporate to a solid mass. The solid was triturated with 50 ml ice water, collected, and air dried to yield 6.4 g (64%) of the desired product 3-hydroxybenzamide, mp 160-162 C. The identity of the product with the desired 3-hydroxybenzamide was further confirmed using thin layer chromatography (TLC).
With hydrogen; acetic acid;rhodium; In ethyl acetate; at 80℃; under 5171.62 Torr; for 18h;
(lRS SR)-3-(^ (lZ)~2-tert-bntv 2~met YA-oxidoA 5'diazmA-- ylidene]amino}oxy)cyclohexanecarboxylic acidStep A: 3-hydroxycyclohexanecarboxylic acid; A solution of 3-hydroxybeitzoic acid (20.0 g, 145 rrrmol) in 600 mL EtOAc containing acetic acid (10.49 g, 175 mmol) and rhodium (3.0 g, 1.46 mmol) was put on hydrogenation apparatus at 100 psi and 80 C for 18 hours. After the catalyst was removed by filtration, the filtrate was concentrated down to afford the title compound.
11 g
With hydrogen; sodium hydroxide; In water; at 150℃; under 45603.1 Torr;
A I L pressure tank reactor (60 atm) containing a solution of 3-hydroxybenzoic acid (30 g, 217.20 mmol, 1.00 equiv), Raney Ni (5 g) and sodium hydroxide (6.4 g, 160.00 mmol, 0.74 equiv) in water (500 mL) was introduced H2 (gas, 60 atm) and the resulting solution was stirred overnight at 150C. After completion of the reaction, the reaction temperature was cooled down to room temperature and the solids were filtered out by filtration. The resulting solution was neutralized with 12 M HCl, extracted with 6 x 100 mL of tetrahydrofuran. The combined organic layers were dried over sodium sulfate and concentrated under vacuum to provide 3- hydroxycyclohexane-l-carboxylic acid (11 g, crude) as a white solid.
With hydrogen; sodium hydroxide; In water; at 150℃;
[00354] Synthesis of compound 30.2. Into a 1 L pressure tank reactor (60 atm) containing a solution of 3-hydroxybenzoic acid (30 g, 217.20 mmol, 1.00 equiv), Raney Ni (5 g) and sodium hydroxide (6.4 g, 160.00 mmol, 0.74 equiv) in water (500 mL) was introduced H2 (gas, 60 atm) and the resulting solution was stirred overnight at 150C. After completion of the reaction, the reaction temperature was cooled down to room temperature and the solids were filtered out by filtration. The resulting solution was neutralized with 12 M HC1, extracted with 6 x 100 mL of tetrahydrofuran. The combined organic layers were dried over sodium sulfate and concentrated under vacuum to provide 30.2 (11 g, crude) as a white solid.
With potassium hydrogencarbonate; In N,N-dimethyl-formamide;
A) Preparation of benzyl 3-hydroxybenzoate. To a solution of 3-hydroxybenzoic acid (27.6 g, 200 mmol) in DMF (500 mL) was added KHCO3 (20 g, 200 mmol). An addition funnel was charged with benzyl bromide (21.7 mL, 200 mmol). This was added dropwise over a period of 10 minutes and the mixture was allowed to stir 16 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between EtOAc (750 mL) and water (500 mL) and the layers separated. The organic phase was washed once with 1N citric acid (500 mL), twice with saturated aqueous NaHCO3 (500 mL), and twice with brine (500 mL). The organic solution was dried (MgSO4), filtered and concentrated in vacuo to give 42 g (93%) of a straw colored syrup which crystallized upon standing. 1 H NMR FD-MS m/e 228 (M+)
With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 19h;
Benzyl bromide (4.3 mL, 36.2 mmol) was added to amixture of 3-hydroxybenzoic acid (5.00 g, 36.2 mmol) and sodium carbonate (3.84g, 36.2 mmol) in anhydrous N,N-dimethylformamide (50 mL). After stirringfor 19 h at room temperature, the reaction mixture was poured into water (400mL) and extracted with ether (3 100 mL). The combined organic layer was washed with water (3 100 mL) and brine (100 mL), and dried over anhydrous sodium sulfate.The solvent was evaporated to afford the title compound (7.50 g, 91%) as a colorlesssolid. 1H NMR (300 MHz, CDCl3) deltaH 5.35 (2H, s),5.82 (1H, br s), 7.06 (1H, ddd, J =7.9, 2.6, and 1.0 Hz), 7.30 (1H, dd, J= 7.9 and 7.9 Hz), 7.32-7.45 (5H, m), 7.61 (1H, dd, J = 2.6 and 1.5 Hz), 7.64 (1H, ddd, J = 7.9, 1.5, and 1.0 Hz). Anal. Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C,73.63; H, 5.35. HRMS-EI (m/z): [M]+ calcd for C14H12O3,228.0786; found 228.0789.
69%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.25h;
Intermediate 21: Benzyl 3-hydroxy benzoate 3 -Hydroxy benzoic acid (2.40 g, 17.4 mmol) was dissolved in DMF (17 mL). Potassium carbonate was added (2.89 g, 20.9 mmol) followed by benzyl bromide (2.1 mL, 17.4 mmol) and the reaction stirred at room temperature for 15 min after which time TLC analysis (10% ethyl acetate in -hexane) revealed the complete consumption of starting material (R/0.00), a single major product (R/0.18) and excess benzyl bromide (R/0.80). The reaction mixture was diluted with ethyl acetate (100 mL) and the organic phase washed with 100 mL citric acid solution (1 M), then with NaHC03 (sat. aq), 2 x 100 mL and finally with brine (2 chi 100 mL). The organic phase was dried (Na2S04) and the solvents removed under reduced pressure to afford a runny pale yellow oil. The crude was re- dissolved in DCM, preadsorbed on silica and purified using a 50G SNAP column to afford benzyl 3- hydroxy benzoate as a white solid (2.73 g, yield: 69%). Vppm (400 MHz, CDC13): 7.67-7.65 (1H), 7.56 (1H), 7.46-7.30 (6H), 7.06 (1H), 5.36 (2H), 5.21 (1H).
(3S)-3-([{(9H-fluoren-9-yl)methoxy}carbonyl]amino)-2-hydroxy-4-phenylbutanoic acid[ No CAS ]
Fmoc-Leu-OHFmoc-Val-OH[ No CAS ]
3-[(2R,3S)-3-((S)-2-{(S)-2-[(S)-2-Amino-3-(3-hydroxy-benzoylamino)-propionylamino]-3-methyl-butyrylamino}-4-methyl-pentanoylamino)-2-hydroxy-4-phenyl-butyrylamino]-benzoic acid[ No CAS ]
With copper(I) oxide; 1D-1-O-Methyl-muco-inostol; sodium hydroxide; In water; at 100℃; for 6h;
In the l00mL hydrothermal synthesis reactor,Add sodium hydroxide (3 mmol), water (5 mL), stir and dissolve,Add m-iodobenzoic acid (0.5 mmol), cuprous oxide (0.05 mmol),White lignan (0.05 mmol), the reaction was stirred at 100 C for 6 hours.After cooling, adjust the pH to 2 with dilute hydrochloric acid, and extract with ethyl acetate.The liquid was concentrated and subjected to column chromatography to obtain m-hydroxybenzoic acid, 60.7 mg.The yield was 88%.
86%
General procedure: A typical method for preparation of phenols: A Schlenk test tube with a magnetic stirring bar was charged with CuSO4·5H2O (13 mg, 5 mol %), NaAsc (20 mg, 10 mol %), benzene halide (1.0 mmol), KOH (168-336 mg, 3.0-6.0 equiv) in DMSO/H2O (v/v=1:1, 3.0 mL) at 120 C for 24h. After cooling to room temperature, carefully acidified with dilute aqueous HCl to pH=2-3 and the mixture were stirred for half hour. Then the resultant mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. Purification via silica gel column chromatography with a mixture of ethyl acetate/petroleum ether. Details as follows:
77%
With copper(I) oxide; 2-(N,N-dimethylamino)athanol; water; potassium hydroxide; In dimethyl sulfoxide; at 110℃; for 24h;Inert atmosphere;
General procedure: To a test tube containing a magnetic bar was added aryl halide (1.0 mmol), Cu2O (14.3 mg, 0.1 mmol), KOH (169 mg, 3.0 mmol), 2-dimethylaminoethanol (0.3 mL, 3.0 mmol), and DMSO/H2O (1.5 mL/0.5 mL). After flushing with argon, the mixture was stirred in a preheated oil bath at 100 C for 24 h. After cooled to ambient temperature, the reaction mixture was distributed in aqueous HCl (5 %) and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated under vacuum. The crude product was further purified by column chromatography (EtOAc/n-Hexane) to provide the phenols.
With potassium carbonate; In N,N-dimethyl-formamide;
A. 3-(2-quinolinylmethyloxy)benzoic acid. A mixture of 28.16 g (0.132 mol) of 2-quinolinylmethyl chloride HCl, 18 g (0.132 mol) of 3-hydroxybenzoic acid and 39.6 g of potassium carbonate in 110 ml of DMF is heated at 70 C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 3-(2quinolinylmethyloxy)benzoic acid.
With potassium carbonate; In N,N-dimethyl-formamide;
A. 3-(2-quinolinylmethyloxy)benzoic acid A mixture of 28.16 g (0.132 mol) of 2-quinolinylmethyl chloride HCl, 18 g (0.132 mol) of 3-hydroxybenzoic acid and 39.6 g of potassium carbonate in 110 ml of DMF is heated at 70 C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 3-(2quinolinylmethyloxy)benzoic acid.
With potassium carbonate; In N,N-dimethyl-formamide;
A. 3-(2-quinolinylmethyloxy)benzoic acid. A mixture of 28.16 g (0.132 mol) of 2-quinolinylmethyl chloride HCl, 18 g (0.132 mol) of 3-hydroxybenzoic acid and 39.6 g of potassium carbonate in 110 ml of DMF is heated at 70 C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 3-(2-quinolinylmethyloxy)benzoic acid.
Step 3 Synthesis of 3-hydroxy-4-iodobenzoic acid 30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the obtained solution at room temperature. After stirring at 45 C. for 15 hours, the solvent was evaporated under reduced pressure. The residue was washed with 500 ml of 1% aqueous sodium thiosulfate solution twice and with 500 ml of water twice and then dried to solid at 80 C. under reduced pressure to obtain the title compound. Yield: 17.2 g (65.2 mmol) (yield: 30%) MS (FAB, m/z) 265 (MH+) H-NMR (DMSO-d6) delta7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)
With Iodine monochloride; In water; acetic acid;
Step 1 3-Hydroxy-4-Iodobenzoic acid: 30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the obtained solution at room temperature. They were stirred at 45 C. for 15 hours and then the solvent was evaporated under reduced pressure. The residue was washed with 500 ml of 1% aqueous sodium thiosulfate solution twice and with 500 ml of water twice and then dried to solid at 80 C. under reduced pressure to obtain the title compound. Yield: 17.2 g (65.2 mmol) (30%) MS (FAB, m/z) 265 (MH+) H-NMR (DMSO-d6) delta 7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)
With Iodine monochloride; In water; acetic acid;
Step 3 Synthesis of 3-hydroxy-4-iodobenzoic acid: 30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the obtained solution at room temperature. After stirring at 45 C. for 15 hours, the solvent was evaporated under reduced pressure. The residue thus obtained was washed with 500 ml of 1% aqueous sodium thiosulfate solution twice and with 500 ml of water twice and then dried to solid at 80 C. under reduced pressure to obtain the title compound. Yield: 17.2 g (65.2 mmol) (30%) MS (FAB, m/z) 265 (MH+) H-NMR (DMSO-d6) delta 7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)
With Iodine monochloride; In water; acetic acid;
Step 2 Synthesis of 3-hydroxy-4-iodobenzoic acid: 30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the obtained solution at room temperature. After stirring at 45 C. for 15 hours, the solvent was evaporated under reduced pressure, and the obtained residue was washed with 500 ml of 1% aqueous sodium thiosulfate solution twice and then with 500 ml of water twice, and dried to solid at 80 C. under reduced pressure to obtain the title compound. Yield: 17.2 g (65.2 mmol) (30%) MS (FAB, m/z) 265 (MH+) H-NMR (DMSO-d6) delta: 7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)
With Iodine monochloride; In water; acetic acid;
Step 1 Synthesis of 3-hydroxy-4-iodobenzoic acid: 30.0 g (217 mmol)) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the solution at room temperature. After stirring at 45C for 15 hours, the solvent was evaporated under reduced pressure. The residue was washed with 500 ml of 1 % aqueous sodium thiosulfate solution twice and 500 ml of water twice, and then dried at 80C under reduced pressure to obtain the title compound. Yield; 17.2 g (65.2 mmol) (30 %) MS (FAB, m/z) 265 (MH+) H-NMR (DMSO-d6) delta 7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d).
With Iodine monochloride; In water; acetic acid;
Step 1 Synthesis of 3-hydroxy-4-iodobenzoic acid: 30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the solution at room temperature. After stirring at 45C for 15 hours, the solvent was evaporated under reduced pressure. The residue was washed with 500 ml of 1 % aqueous sodium thiosulfate solution twice and then with 500 ml of water twice, and dried to solid at 80C under reduced pressure to obtain the title compound. Yield: 17.2 g (65.2 mmol) (30 %) MS (FAB, m/z) 265 (MH+) H-NMR (DMSO-d6) delta 7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)
With Iodine monochloride; In water; acetic acid;
Step 1: Synthesis of 3-hydroxy-4-iodobenzoic acid: 30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the obtained solution at room temperature. They were stirred at 45C for 15 hours. The solvent was evaporated under reduced pressure, and the obtained residue was washed with 500 ml of 1 % aqueous sodium thiosulfate solution twice and then with 500ml of water twice, and dried to solid at 80C under reduced pressure to obtain the title compound. Yield: 17.2 g (65.2 mmol) (30 %) MS (FAB, m/z) 265 (MH+) H-NMR (DMSO-d6) delta 7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)
With sodium hydroxide; sodium iodide; In methanol;
(a) 3-Hydroxy-4-iodobenzoic Acid. 25.00 g (180.0 mmol) of 3-hydroxybenzoic acid, 7.20 g (180.0 mmol) of sodium hydroxide pellets, 27.13 g (180.0 mmol) of sodium iodide and 500 ml of methanol are introduced into a one-litre three-necked flask under a stream of nitrogen. The mixture is cooled to 0 C. and 374.30 g (180.0 mmol) of an aqueous sodium hypochlorite solution are added dropwise over one hour and fifty minutes. The reaction medium is stirred for two hours at 0 C., a sodium thiosulphate solution is then added, the mixture is acidified at pH 5, extracted with ethyl ether, the organic phase is washed with water to neutral pH, dried over magnesium sulphate and filtered and the solvents are evaporated off. 43.80 g (92%) of the expected compound are collected in the form of a beige-coloured powder with a melting point of 198 C. 1H NMR (CDCl3) delta 7.13 (dd, 1H, J=8.1/1.9 Hz), 7.43 (d, 1H, J=1.8 Hz), 7.80 (d, 1H, J=8.1 Hz), 10.69 (br s, 1H), 12.98 (br s, 1H).
With sodium hydroxide; sodium iodide; In methanol;
(a) 3-Hydroxy-4-iodobenzoic acid: 25.00 g (180.0 mmol) of 3-hydroxybenzoic acid, 7.20 g (180.0 mmol) of sodium hydroxide pellets, 27.13 g (180.0 mmol) of sodium iodide and 500 ml of methanol are introduced into a one-liter three-necked flask under a stream of nitrogen. The mixture is cooled to 0 C. and 374.30 g (180.0 mmol) of aqueous sodium hypochlorite solution are added dropwise over one hour fifty minutes. The reaction medium is stirred for two hours at 0 C., then sodium thiosulphate solution is added, the mixture is acidified to pH 5 and extracted with ethyl ether, the organic phase is washed with water to neutral pH, dried over magnesium sulphate and filtered and the solvents are evaporated off. 43.80 g (92%) of the expected compound are collected in the form of a beige-coloured powder with a melting point of 198 C. 1 H NMR (DMSO D6) delta 7.13 (dd, 1H, J=8.1/1.9 Hz), 7.43 (d, 1H, J=1.8 Hz), 7.80 (d, 1H, J=8.1 Hz), 10.69 (br s, 1H), 12.98 (br s, 1H).
Synthesis Example 26 Synthesis of 4-acetyl-3-hydroxybenzoic Acid Concentrated sulfuric acid (0.2 ml) was added to a solution of 10.07 g (72.9 mol) of 3-hydroxybenzoic acid in 10 ml of acetic anhydride. The resulting mixture was stirred at 60 C. for 1 hour and was then allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with benzene, and then dried in air. The precipitate was recrystallized from acetone-hexane, whereby 8.92 g of 3-acetoxybenzoic acid were obtained as colorless prisms (yield: 67.9%, melting point: 149-151 C.).
With sodium hydroxide; acetic anhydride; In water;
(a) 1st Stage--Preparation of 3-Acetoxybenzoic Acid 3-Hydroxybenzoic acid (1 g; 7.29 mM) was added to a cooled solution of sodium hydroxide (0.61 g; 15.2 mM dissolved in 2 ml of water). Cooled acetic anhydride (0.81 g; 7.9 mM) was added with crushed ice (2 g). The mixture was stirred for 1 hour, and acidified with 6M hydrochloric acid (3 ml) to yield a white precipitate. The organics were extracted into dichloromethane (3*30 ml), and dried over magnesium sulphate. The solvent was filtered and then removed under vacuum to yield a white solid which was recrystallized from boiling water. Solvent for Thin-layer chromatography (T.L.C.): 10% methanol/90% dichloromethane NMR: 200 MHz: d6 DMSO: delta=2.4 (s;3H;CH3); 7.45(m;1H;Hdelta) 7.6(t;1H;Hbeta); 7.78(m;1H;H); 7.9(t;1H;Halpha); 13.1(s;1H;OH)
With pyridine; formic acid; acetic anhydride; In ethyl acetate;
Example 6 3-Acetoxybenzoic acid (6). A suspension of 3-hydroxybenzoic acid in ethyl acetate was cooled in an ice-bath. Acetic anhydride and pyridine were added and the reaction allowed proceeding for 60 minutes. The resultant homogenous solution was then stirred at room temperature overnight. Formic acid and further ethyl acetate were then added and the reaction poured onto ice-water. The organic phase was separated and washed six times with water, then dried, filtered and rotary evaporated to give a white solid. This solid was recrystallized from EtOAc/hexane (1:1) to produce 3-acetoxybenzoic acid as a white powder. Rf 0.46 (2:1 EtOAc/hexane); mp 133.0-133.5 C.; 1H NMR (CDCl3): delta 2.33 (s, 3H, OAc), 7.34-7.38 (m, 1H, H-4), 7.49 (t, 1H, Jortho=7.8 Hz, H-4), 7.84 (t, 1H, Jmeta=2.0 Hz, H-2), 8.00 (dt, 1H, H-6); 13C JMOD NMR (CDCl3): delta 20.00 (OC(O)CH3), 122.42 (2), 126.21 (4), 126.60 (6), 128.56 (5), 129.84 (1), 149.70 (3), 168.19 (COCH3), 170.27 (COOH); LRESI positive ion mass spectrum; m/z 203 (MNa+, 100%), 204 (11%).
3-[2-chloro-5-(trifluoromethyl)phenoxy] benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; potassium carbonate; In methanol;
(b) Preparation of 3(2-chloro-5-trifluoromethylphenoxy)benzoic acid. 3-Hydroxybenzoic acid (3.45 g) was added to a solution of potassium hydroxide (2.8 g) in methanol. The solution was evaporated under reduced pressure to give a white solid. This was taken up in dry dimethylsulphoxide (25 ml). The resulting solution was stirred and heated at 170 with anhydrous potassium carbonate (1.25 g) and <strong>[32137-20-5]4-chloro-3-fluorobenzotrifluoride</strong> (5 g) for 12 hours. The mixture was then cooled and poured into water, (500 ml). The mixture was extracted with ether and then acidified (HCl). The precipitate which formed was recrystallized from petroleum (b.p. 60-80) to give the required acid (4.5 g) with a melting point of 142-143.
2-nitro-5(2,6-difluoro-4-trifluoromethyl)benzoic acid[ No CAS ]
[ 80172-07-2 ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N-methyl-acetamide;
EXAMPLE 6 This Example illustrates the preparation of 3-(2,6-difluoro-4-trifluoromethylphenoxy)benzoic acid by the process of claim 1. A solution of 3-hydroxybenzoic acid (5.5 g) and <strong>[80172-04-9]3,4,5-trifluorobenzotrifluoride</strong> (8.3 g) in dimethylformamide (50 ml) was stirred with anhydrous potassium carbonate (14 g) for 4 hours at 100. The mixture was then diluted with water (200 ml) and acidified. The mixture was extracted with ether and the ether extract dried and evaporated to give the required compound (7.2 g) with a melting point of 140-146. Nitration of this product gave 2-nitro-5(2,6-difluoro-4-trifluoromethyl)benzoic acid.
5-(2-cyano-4-trifluoromethylphenoxy)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N-methyl-acetamide; water;
(a) Preparation of 3-(2-cyano-4-trifluoromethylphenoxy)benzoic acid 3-Hydroxybenzoic acid (27.6 g), 4-chloro-3-cyano-benzotrifluoride (41.1 g) and anhydrous potassium carbonate (55.2 g) were stirred together for 71/2 hours at 100 C. in dry dimethylformamide (500 ml) and then left at room temperature for 65 hours. The solvent was then removed under reduced pressure and the residue taken up in water and acidified with dilute hydrochloric acid. The solid which separated was washed with water, dissolved in ether and the solution dried and concentrated. The colourless solid which separated was recrystallized to give the benzoic acid derivative (24.0 g) with a melting point of 224-226 C.
With potassium carbonate; In N-methyl-acetamide; water;
(a) Preparation of 3-(2-cyano-4-trifluoromethylphenoxy)-benzoic acid 3-Hydroxybenzoic acid (27.6 g), <strong>[328-87-0]4-chloro-3-cyanobenzotrifluoride</strong> (41.1 g) and anhydrous potassium carbonate (55.2 g) were stirred together for 71/2 hours at 100 C. in dry dimethylformamide (500 ml) and then left at room temperature for 65 hours. The solvent was then removed under reduced pressure and the residue taken up in water and acidified with dilute hydrochloric acid. The solid which separated was washed with water, dissolved in ether and the solution dried and concentrated. The colourless solid which separated was recrystallized to give the benzoic acid derivative (24.0 g) with a melting point of 224-226 C.
5-(2,4-bis-trifluoromethylphenoxy)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen fluoride; potassium carbonate; In water; dimethyl sulfoxide;
(a) Preparation of 5-(2,4-bis-trifluoromethylphenoxy)benzoic acid 2,4-Bis-trifluoromethylbromobenzene (5.86 g prepared by treatment of 2,4-di-carboxybromobenzene with hydrogen fluoride and sulphur tetrafluoride), 3-hydroxybenzoic acid (2.76 g) and anhydrous potassium carbonate (5.52 g) were heated in dimethylsulphoxide (5 ml) to 125-130 for 14 hours. The mixture was cooled and poured into ice and water (500 ml). The mixture was acidified (HCl) and extracted with ether (300 ml). The extract was washed with water (2*300 ml), dried (MgSO4), and evaporated to give a solid. Further solid was obtained by re-extraction of the aqueous fractions with ether (250 ml). The solids were combined, taken up in hot toluene (60 ml) and diluted with petroleum (b.p. 60-80) to precipitate 3-hydroxybenzoic acid. The mixture was filtered and the filtrate evaporated to give a solid. This was washed with petroleum (b.p. 30-40). The washings were evaporated to give more solid. The solids were combined and re-crystallized from petroleum (b.p. 80-100) to give the required carboxylic acid (0.5 g) having a melting point of 133-134.
With potassium carbonate; In methanol; nitrogen; dimethyl sulfoxide;
(a) 3-(2-Chloro-4-trifluoromethylphenoxy) benzoic acid To a loosely stoppered 500 ml single-necked flask is charged methanol (250 ml) and potassium hydroxide pellets (85percent, 13.2 g 0.20 mole). When the exotherm has subsided and all the potassium hydroxide is in solution, 3-hydroxybenzoic acid (13.8 g. 0.10 mole) is charged rapidly. After stirring for 10 minutes, the methanol is removed in vacuo and the white glossy solid (21.4 g.) is scraped from the flask (in a glove bag through which nitrogen is flowing) and used directly. To a 300 ml. 3-necked flask fitted with a magnetic stirring bar, condenser, drying tube and thermometer is charged the solid from above dimethylsulfoxide (100 ml), 3,4-dichlorobenzotrifluoride (21.5 g. 0.10 mole) and anhydrous potassium carbonate (5.0 g) to assure an alkaline pH. The reaction temperature is taken rapidly to 138°-144° C. while vigorous stirring is maintained. After 4 hours a significiant conversion is realized and heating is continued overnight (total 22 hrs.) The reaction mixture is then cooled to room temperature and poured into water (1000 ml) and the aqueous reaction mixture extracted with CCl4 (200 ml). The aqueous layer is then decanted and acidified to pH 1 with concentrated hydrochloric acid. The white solid that precipitated is collected by filtration and vacuum dried at 60° C. overnight to give 27 g of an off-white solid 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (85percent yield), mp 124°-5° C.
With potassium carbonate; In methanol; nitrogen; dimethyl sulfoxide;
(a) 3-(2-Chloro-4-trifluoromethylphenoxy) benzoic acid To a loosely stoppered 500 ml single-necked flask is charged methanol (250 ml) and potassium hydroxide pellets (85percent, 13.2 g. 0.20 mole). When the exotherm has subsided and all the potassium hydroxide is in solution, 3-hydroxybenzoic acid (13.8 g. 0.10 mole) is charged rapidly. After stirring for 10 minutes, the methanol is removed in vacuo and the white glossy solid (21.4 g.) is scraped from the flask (in a glove bag through which nitrogen is flowing) and used directly. To a 300 ml. 3-necked flask fitted with a magnetic stirring bar, condenser, drying tube and thermometer is charged the solid from above, dimethylsulfoxide (100 ml), 3,4-dichlorobenzotrifluoride (21.5 g. 0.10 mole) and anhydrous potassium carbonate (5.0 g) to assure an alkaline pH. The reaction temperature is taken rapidly to 138°-44° C. while vigorous stirring is maintained. After 4 hours a significant conversion is realized and heating is continued overnight (total 22 hrs.). The reaction mixture is then cooled to room temperature and poured into water (1000 ml) and the aqueous reaction mixture extracted with CCl4 (200 ml). The aqueous layer is then decanted and acidified to pHl with concentrated hydrochloric acid. The white solid that precipitated is collected by filtration and vacuum dried at 60° C. overnight to give 27 g of an off-white solid 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (85percent yield), mp 124°-5° C.
With potassium carbonate; In methanol; nitrogen; dimethyl sulfoxide;
(a) 3-(2-Chloro-4-trifluoromethylphenoxy) benzoic acid To a loosely stoppered 500 ml single-necked flask is charged methanol (250 ml) and potassium hydroxide pellets (85percent, 13.2 g. 0.20 mole). When the exotherm has subsided and all the potassium hydroxide is in solution, 3-hydroxybenzoic acid (13.8 g. 0.10 mole) is charged rapidly. After stirring for 10 minutes, the methanol is removed in vacuo and the white glossy solid (21.4 g.) is scraped from the flask (in a glove bag through which nitrogen is flowing) and used directly. To a 300 ml. 3-necked flask fitted with a magnetic stirring bar, condenser, drying tube and thermometer is charged the solid from above, dimethylsulfoxide (100 ml), 3,4-dichlorobenzotrifluoride (21.5 g. 0.10 mole) and anhydrous potassium carbonate (5.0 g) to asure an alkaline pH. The reaction temperature is taken rapidly to 138°-44° C. while vigorous stirring is maintained. After 4 hours a significant conversion is realized and heating is continued overnight (total 22 hrs.). The reaction mixture is then cooled to room temperature and poured into water (1000 ml) and the aqueous reaction mixture extracted with CCl4 (200 ml). The aqueous layer is then decanted and acidified to pH 1 with concentrated hydrochloric acid. The white solid that precipitated is collected by filtration and vacuum dried at 60° C. overnight to give 27 g of an off-white solid 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (85percent yield), mp 124°-5° C.
With potassium carbonate; In methanol; nitrogen; dimethyl sulfoxide;
(a) 3-(2-Chloro-4-trifluoromethylphenoxy) benzoic acid To a loosely stoppered 500 ml single-necked flask is charged methanol (250 ml) and potassium hydroxide pellets (85percent, 13.2 g. 0.20 mole). When the exotherm has subsided and all the potassium hydroxide is in solution, 3-hydroxybenzoic acid (13.8 g. 0.10 mole) is charged rapidly. After stirring for 10 minutes, the methanol is removed in vacuo and the white glossy solid (21.4 g.) is scraped from the flask (in a glove bag through which nitrogen is flowing) and used directly. To a 300 ml. 3-necked flask fitted with a magnetic stirring bar, condenser, drying tube and thermometer is charged the solid from above, dimethylsulfoxide (100 ml), 3,4-dichlorobenzotrifluoride (21.5 g. 0.10 mole) and anhydrous potassium carbonate (5.0 g) to asure an alkaline pH. The reaction temperature is taken rapidly to 138°-44° C. while vigorous stirring is maintained. After 4 hours a significant conversion is realized and heating is continued overnight (total 22 hrs.). The reaction mixture is then cooled to room temperature and poured into water (1000 ml) and the aqueous reaction mixture extracted with CCl4 (200 ml). The aqueous layer is then decanted and acidified to pHl with concentrated hydrochloric acid. The white solid that precipitated is collected by filtration and vacuum dried at 60° C. overnight to give 27 g of an off-white solid 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (85percent yield), mp 124°-5° C.
With potassium carbonate; In methanol; nitrogen; dimethyl sulfoxide;
a. 3-(2-Chloro-4-trifluoromethylphenoxy)benzoic acid To a loosely stoppered 500 ml single-necked flask is charged methanol (250 ml) and potassium hydroxide pellets (85percent, 13.2 g. 0.20 mole). When the exotherm has subsided and all the potassium hydroxide is in solution, 3-hydroxybenzoic acid (13.8 g. 0.10 mole) is charged rapidly. After stirring for 10 minutes, the methanol is removed in vacuo and the white glossy solid (21.4 g.) is scraped from the flask (in a glove bag through which nitrogen is flowing) and used directly. To a 300 ml. 3-necked flask fitted with a magnetic stirring bar, condenser, drying tube and thermometer is charged the solid from above dimethylsulfoxide (100 ml), 3,4-dichlorobenzotrifluoride (21.5 g. 0.10 mole) and anhydrous potassium carbonate (5.0 g) to assure an alkaline pH. The reaction temperature is taken rapidly to 138°-44° C. while vigorous stirring is maintained. After 4 hours a significant conversion is realized and heating is continued overnight (total 22 hrs.). The reaction mixture is then cooled to room temperature and poured into water (1000 ml) and the aqueous reaction mixture extracted with CCl4 (200 ml). The aqueous layer is then decanted and acidified to pHl with concentrated hydrochloric acid. The white solid that precipitated is collected by filtration and vacuum dried at 60° C. overnight to give 27 g of an off-white solid 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (85percent yield), mp 124°-5° C.
With potassium carbonate; In methanol; nitrogen; dimethyl sulfoxide;
a. 3-(2-Chloro-4-trifluoromethylphenoxy)benzoic acid To a loosely stoppered 500 ml single-necked flask is charged methanol (250 ml) and potassium hydroxide pellets (85percent, 13.2 g. 0.20 mole). When the exotherm has subsided and all the potassium hydroxide is in solution, 3-hydroxybenzoic acid (13.8 g. 0.10 mole) is charged rapidly. After stirring for 10 minutes, the methanol is removed in vacuo and the white glossy solid (21.4 g.) is scraped from the flask (in a glove bag through which nitrogen is flowing) and used directly. To a 300 ml. 3-necked flask fitted with a magnetic stirring bar, condenser, drying tube and thermometer is charged the solid from above dimethylsulfoxide (100 ml), 3,4-dichlorobenzotrifluoride (21.5 g. 0.10 mole) and anhydrous potassium carbonate (5.0 g) to assure an alkaline pH. The reaction temperature is taken rapidly to 138°-44° C while vigorous stirring is maintained. After 4 hours a significant conversion is realized and heating is continued overnight (total 22 hrs.). The reaction mixture is then cooled to room temperature and poured into water (1000 ml) and the aqueous reaction mixture extracted with CCl4 (200 ml). The aqueous layer is then decanted and acidified to pH1 with concentrated hydrochloric acid. The white solid that precipitated is collected by filtration and vacuum dried at 60° C. overnight to give 27 g of an off-white solid 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (85percent yield), mp 124°-5° C.
With potassium carbonate; In methanol; nitrogen; dimethyl sulfoxide;
a. 3-(2-Chloro-4-trifluoromethylphenoxy) benzoic acid To a loosely stoppered 500 ml single-necked flask is charged methanol (250 ml) and potassium hydroxide pellets (85percent, 13.2 g. 0.20 mole). When the exotherm has subsided and all the potassium hydroxide is in solution, 3-hydroxybenzoic acid (13.8 g. 0.10 mole) is charged rapidly. After stirring for 10 minutes, the methanol is removed in vacuo and the white glossy solid (21.4 g.) is scraped from the flask (in a glove bag through which nitrogen is flowing) and used directly. To a 300 ml. 3-necked flask fitted with a magnetic stirring bar, condenser, drying tube and thermometer is charged the solid from above dimethylsulfoxide (100 ml), 3,4-dichlorobenzotrifluoride (21.5 g. 0.10 mole) and anhydrous potassium carbonate (5.0 g) to assure an alkaline pH. The reaction temperature is taken rapidly to 138°-44° C while vigorous stirring is maintained. After 4 hours a significant conversion is realized and heating is continued overnight (total 22 hrs.). The reaction mixture is then cooled to room temperature and poured into water (1000 ml) and the aqueous reaction mixture extracted with CCl4 (200 ml). The aqueous layer is then decanted and acidified to pH1 with concentrated hydrochloric acid. The white solid that precipitated is collected by filtration and vacuum dried at 60° C. overnight to give 27 g of an off-white solid 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (85percent yield), mp 124°-5° C.
With hydrogenchloride; potassium hydroxide; In dimethyl sulfoxide;
(A) 5-(2-Chloro-4-trifluoromethylphenoxy)benzoic acid. m-Hydroxybenzoic acid (828.4 g, 6.0 mole) was added to a solution of potassium hydroxide (840 g, 12.7 mole) and DMSO (2500 g). 3,4-Dichlorobenzotrifluoride (1000 ml) was added after distilling off 200 ml of DMSO and water. The resultant mixture was heated at 140°-150° C. for 54 hrs. The solvent was then removed under reduced pressure and the remaining brownish slurry was poured into an ice water mixture (8 liters). The aqueous solution was extracted with methylene chloride and the yellowish product was precipitated out at pH 2 with conc. HCl (400 ml) filtration, washing with water and recrystallization from toluene (3000 ml) and MeOH (400 ml) afforded 1148.7 g of the desired product; m.p. 111°-118° C.
With potassium carbonate; In tetrachloromethane; hexane; water; dimethyl sulfoxide;
Method 2 To a 300 ml, 3-necked flask equipped with a condenser, stirrer, drying tube and thermometer is charged dimethylsulfoxide (100 ml), anhydrous potassium carbonate (30 g. >0.20 mole), 3,4-dichlorobenzotrifluoride (21.5 g., 0.10 mole), pinacol (10 g.) and 3-hydroxybenzoic acid (13.8 g., 0.10 mole). The reaction temperature is then taken slowly to 140°-5° C. while stirring vigorously and maintained as such for 4 days. The reaction mixture is then cooled to room temperature and the inorganic solids removed by filtration prior to pouring the filtrate into water (1200 ml). The aqueous solution is then triturated with CCl4 (2 * 200 ml), decanted and then acidified to pH1 (conc. HCl) to give a tan colored solid, 25,6 g., mp 114°-17° C. This solid is further purified by dissolving in CCl4 (500 ml) and drying with anhydrous MgSO4. The CCl4 solution is reduced in vacuo to give 19.6 g. (62percent) of a yellow solid, mp 116°-19° C. Recrystallization of the yellow solid from hexane gives a tan colored solid, 3-(2-chloro-4-trifluoromethylphenoxy)-benzoic acid, mp 122°-3° C.
Reference Example 23 Methyl (E)-2-(3,4-dimethoxycinnamoylamino)-5-hydroxybenzoate (E)-3,4-Dimethoxycinnamoyl chloride (147 mg) and methyl 5-hydroxyanthranilate (100 mg) were added to pyridine (2 ml), and the mixture was stirred at 80 C for 5 hours. The reaction mixture was poured into water, and the mixture was stirred. The resulting precipitates were collected by filtration and washed with 1 N hydrochloric acid and water to give methyl (E)-2-(3,4-dimethoxycinnamoylamino)-5-hydroxybenzoate (100 mg). 1H-NMR (DMSO-d6, 400MHz) delta ppm: 3.80 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 6.78 (d J=15.5Hz, 1H), 6.95-7.4 (m, 5H), 7.51 (d, J=15.5Hz, 1H), 8.16 (d, J=9.0Hz, 1H), 9.68 (brs, 1H), 10.42 (s, 1H)
With sodium hypochlorite; sodium iodide; In methanol;
a-3-hydroxy-4-iodobenzoic acid 1319 g (1.52 mol) of commercial 9.6% sodium hypochlorite solution are added dropwise to a solution of 200 g (1.45 mol) of 3-hydroxybenzoic acid, 61 g (1.52 mol) of sodium hydroxide powder and 228 g (1.52 mol) of sodium iodide in 2 l of methanol cooled beforehand to 0 C. The reaction medium is stirred at room temperature for 72 hours. After evaporating off the methanol, the solution is cooled to 10 C. and acidified with aqueous hydrochloric acid solution to pH 2. The mixture is stirred for 2 hours and the product precipitates. The product is filtered off, washed thoroughly with water and dried under vacuum at 50 C. 150 g (39%) of 3-hydroxy-4-iodobenzoic acid are obtained in the form of a white solid.
Stage 1: 3-Hydroxybenzoic acid (V) is iodinated in the presence of sodium iodide and of sodium hypochlorite in order to give <strong>[58123-77-6]4-iodo-3-hydroxybenzoic acid</strong> (VI).
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 24h;Inert atmosphere;
A mixture of <strong>[51762-67-5]3-nitrophthalonitrile</strong> (0.87g, 5mmol), 3-hydroxybenzoic acid (0.69g, 5mmol), and anhydrous K2CO3 (2.07g, 15mmol) in dry DMSO (20mL) was stirred at room temperature for 24h under nitrogen atmosphere. The reaction mixture was filtered by sand core funnel and the filtrate was poured into ice water (200mL). Subsequently, HCl aqueous solution (2M) was added to the filtrate until pH=1-3 to give white precipitate, which was collected by filtration, washed with water until pH=7 and dried in vacuum. The crude product was purified by recrystallization with DMF/water to afford white solid (1.11g, 84%). Rf=0.53 (EtOH). IR (KBr, cm-1): 3078.4 (Ar-H); 1585.6, 1466.7, 1450.9 (C=C, Ar); 1303.7, 1278.7, 1208.9 (Ar-O-Ar); 2232.9 (C?N); 1688.8 (C=O). MS (ESI): m/z 263.1 [M-H]-. 1H NMR (DMSO-d6, ppm): delta 13.16 (br., 1H), 7.81-7.88 (m, 3H), 7.62-7.67 (m, 2H), 7.52 (t, J=0.6Hz, 1H), 7.32 (d, J=4.2Hz, 1H). Anal. Calcd for C15H8N2O3: C, 68.18; H, 3.05; N, 10.60. Found: C, 67.99; H, 3.27; N, 10.86.
78%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 30h;Inert atmosphere;
With 3-hydroxybenzoic acid (15mmol) and 3-nitro-phthalonitrile (15mmol) as reactants, the solvent is anhydrous DMSO (30ml), potassium carbonate (45mmol) under nitrogen and the presence, stirred at room temperature The reaction 30 hours, by thin layer chromatography to monitor the end of reaction.The reaction mixture was diluted with sand core funnel filtration, the filtrate was collected, and the filtrate was added to 500ml of ice water mixture, adjusted with 1M hydrochloric acid solution until the solution was acidic precipitation heavy precipitate, was allowed to stand, an organic microporous membrane, repeated washing more times until the solution was neutral, the solid was collected and lyophilized to give a white solid, further use DMF- water purified by recrystallization to give a white desired product, a yield of about 78%.
The synthesis of the co-crystals was carried out in solution crystallization experiments. Co-crystal 1 was obtained by the following procedure: stoichiometric amounts of PZA (0.5 mmol, 61.5 mg) and MHBA (0.5 mmol, 69.1 mg) were dissolved separately in a beaker with 10 ml of methanol solution, then combined and slowly evaporated at room temperature. A week later, we got club-shaped colorless crystals (yield 91 % based on MHBA).
3-(3-chloro-4-nitro-phenoxy)-benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 1.5h;
A mixture of <strong>[2106-50-5]2-chloro-4-fluoro-1-nitro-benzene</strong> (1 g, 5.7 mmol), 3-hydroxybenzoic acid (0.79 g, 5.7 mmol) and Cs2CO3 (3.7 g, 11.4 mmol) in DMF (7 mL) was heated at 120 C for 1.5 h. Waterand EtOAc were added, and the mixture was made acidic to pH 2 by adding aqueous 1 M HC1. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered, and evaporated. The residue was purified by chromatography (silica gel, 0-7% MeOH/CH2C12) to give 3-(3-chloro-4-nitro- phenoxy)-benzoic acid (1 g, 60%) as a yellow solid. ?H NMR (400 MHz, CDC13) oe ppm 8.03 (m,J=8.5, 0.9 Hz, 1 H), 8.00 (d, J=9.1 Hz, 1 H), 7.79 - 7.83 (m, 1 H), 7.55 - 7.60 (m, 1 H), 7.35 (ddd, J=8.1, 2.5, 1.0 Hz, 1 H), 7.09 (d, J=2.5 Hz, 1 H), 6.96 (dd, J=9.0, 2.7 Hz, 1 H). MS calcd. for C,3H7C1N05 [(M-H)i 292, obsd. 292.
General procedure: To a solution of substrates (1a-1q, 0.15 mmol) in trifluoroacetic acid (5 ml), hexamethylenetetramine (0.3 mmol) and cuprous oxide (0.15 mmol) were added. The reaction mixture was refluxed for about 5 h, cooled to room temperature, followed by addition of hydrochloric acid (3 N, 5 ml). After stirring for another 1 h, the solution was concentrated under reduced pressure. The products were purified by silica gel column chromatography (200-300 mesh).
3-hydroxy-N-[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
1: 1 THF / DCM (20ml) of 3-hydroxy benzoic acid (0.69g, 5.0mmol) to a stirred solution of thionyl chloride (0.65g, 5.5mmol) and a drop of DMF was added . The reaction mixture was heated under reflux for 2.5 hours. The reaction mixture was cooled to room temperature, the mixture to a stirred solution of dehydrothiotoluidine in 0C in THF (20ml) (1.20g, 5.0mmol), was transferred via cannula. The mixture was stirred for 2 hours at 0C , then was raised to left to room temperature overnight. The yellow precipitate is collected by filtration under vacuum, washed with THF and water (600ml). Oven for 5 hours the solid at 80 C. and dried to give the title compound (0.59g, 33%) as a pale yellow solid.
1mol 3-hydroxybenzoic acid was dissolved in 2.4 L of CS2, added to the autoclave, and 5 ml of molecular sieve particles loaded with 2.5 mol of hypochlorous acid and 0.07 g of gold nanoparticles were charged to the reaction vessel at a temperature of 60 C,After stirring at 95 revolutions per minute for 3 h, the pH was adjusted to 10 with NaOH, 1.3 mol-methyl chloride was added, and the mixture was stirred at room temperature for 4 h. In addition to precipitation of crystals, filtered and dried, that is, 3-methoxy-4-chlorobenzoic acid crude, after recrystallization from ethanol to produce 3-methoxy-4-chlorobenzoic acid. The purity of the product was 84.6% and the yield was 91.3%.
3-((4-cyano-6-(trifluoromethyl)pyridin-2-yl)oxy)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Ca. 100%
With caesium carbonate; In N,N-dimethyl-formamide; at 25 - 35℃; for 69h;
20g of <strong>[1196155-38-0]2-chloro-6-(trifluoromethyl)isonicotinonitrile</strong> (Compound A-1) and CS2CO3 (78 g, 0.242 mol, 2.5 eq) were suspended in 80mL DMF in the reactor. A solution of 3- hydroxybenzoic acid (13.4 g, 0.096 mol, 1.0 eq) in 40mL DMF, was slowly added to the reactor maintaining the temperature below 30°C. The reactor's contents were heated to 30±5°C and aged until reaction completion (69 hours). The reaction was deemed completed with Compound A-1 = 1percent. The reaction mixture was diluted with 1L purified process H20 and washed with 2 x 200mL EtOAc. The pH of the aqueous solution was ~9 and was adjusted to pH -3-4 via the addition of 97 mL of 3M HCl(aq) while maintaining a temperature of 20±5°C. The aqueous layer was extracted 2 x 300mL with EtOAc and the organic layers were washed with 150mL brine, dried (Na2S04) and concentrated to dryness for afford compound A-6. Appearance: tan solid. (0609) Mass=29.98g
3-(3-(methylsulfonyl)propoxy)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium phosphate; In N,N-dimethyl-formamide; at 20℃;
m-hydroxybenzoic acid (138 mg, 1 mmol),3-(Methanesulfonyl)propyl-4-methylbenzenesulfonyl ester (229 mg, 1 mmol) and anhydrous potassium carbonate (276 mg, 2 mmol) were added to 10 mL of DMF solution and stirred at room temperature overnight.Then, the reaction liquid was poured into 50 mL of water, and the pH was adjusted to 3-4 with dilute hydrochloric acid (1.0 M), and solid was precipitated, filtered, washed with water and dried to give a solid (210 mg), yield 81%.
Finasteride (2.3 g; 6.2 mmol) and 3-hydroxybenzoic acid (0.86 g;6.2 mmol) were dissolved in methanol (2 ml) under stirring at 50C resulting in a clear solution. Under stirring, isopropyl acetate (2m1) was added and the almost clear solution was left at ambient temperature overnight, resulting in a thick whiteprecipitate. The sample was left for maturation (eight hours heat/cool cycle between 23C/50C) for 48 hours. To the samples seeds of the corresponding cocrystal were added and the mixture was left at room temperature under stirring. The mixture was filtered under suction, washed with cold isopropyl acetate (3 ml) and dried at 40C in vacuum oven (20 mbar) to yield 1.88 g (59.5%) of <strong>[98319-26-7]finasteride</strong>10 3-hydroxybenzoic acid cocrystal.
59.5%
In methanol; at 50℃;
Finasteride (2.3 g; 6.2 mmol) and 3-hydroxybenzoic acid (0.86 g; 6.2 mmol) were dissolved in methanol (2 ml) under stirring at 50C resulting in a clear solution.Under stirring, isopropyl acetate (2 ml) was added and the almost clear solution was left at ambient temperature overnight, resulting in a thick white precipitate. The sample was left for maturation (eight hours heat/cool cycle between 23C/50C) for 48 hours. To the sample seeds of the corresponding cocrystal were added and the mixture was left at room temperature under stirring. The mixturewas filtered under suction, washed with cold isopropyl acetate (3 ml) and dried at40C in vacuum oven (20 mbar) to yield 1.88 g (59.5%) of <strong>[98319-26-7]finasteride</strong>-3- hydroxybenzoic acid cocrystal.
45.0 mg of <strong>[184475-35-2]gefitinib</strong> and 11.6 mg of 3-hydroxybenzoic acid were added to the mortar, 0.5 mL of methanol was added dropwise thereto, and the mixture was thoroughly ground for 35 minutes, and then further stirred for 15 minutes by adding 1 mL of methanol to obtain a transparent solution. The crystal was allowed to stand at 5 to 10 C for 48 hours, filtered, and dried under vacuum at 55 C for 8 hours to obtain <strong>[184475-35-2]gefitinib</strong>-3-hydroxybenzoic acid co-crystal, yield 91.12%, HPLC: 99.94%.
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