* 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, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1995, # 10, p. 1857 - 1862
8
[ 79985-01-6 ]
[ 118-90-1 ]
[ 86128-85-0 ]
[ 529-20-4 ]
[ 89-92-9 ]
[ 91-13-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1995, # 10, p. 1857 - 1862
9
[ 118-90-1 ]
[ 612-13-5 ]
Reference：
[1] Russian Journal of Organic Chemistry, 1996, vol. 32, # 10, p. 1447 - 1470
10
[ 118-90-1 ]
[ 79-19-6 ]
[ 59565-54-7 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 8, p. 2345 - 2350
[2] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 3, p. 1011 - 1016
[3] Journal of Medicinal Chemistry, 1988, vol. 31, # 5, p. 902 - 906
[4] Heterocyclic Communications, 2007, vol. 13, # 6, p. 387 - 392
[5] European Journal of Medicinal Chemistry, 2009, vol. 44, # 7, p. 2782 - 2786
[6] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4292 - 4295
[7] Asian Journal of Chemistry, 2012, vol. 24, # 6, p. 2739 - 2743
[8] Journal of the Chemical Society of Pakistan, 2013, vol. 35, # 5, p. 1349 - 1353
[9] RSC Advances, 2014, vol. 4, # 99, p. 55827 - 55831
[10] Oriental Journal of Chemistry, 2015, vol. 31, # 4, p. 1873 - 1885
11
[ 118-90-1 ]
[ 7499-08-3 ]
[ 7499-06-1 ]
[ 133232-56-1 ]
[ 54811-38-0 ]
Yield
Reaction Conditions
Operation in experiment
38%
With sulfuric acid; Iodine monochloride; periodic acid In water; acetic acid at 90℃; for 5.66667 h;
Suspended in a 100 mL three-necked flask equipped with a reflux condenser were 25 mL of 30 weight percent sulfuric acid and 1.36 g (10 mmol) of 2-methylbenzoic acid, and 2.4 g (15 mmol) of iodine monochloride dissolved in 5 g of acetic acid was dropwise added thereto in 40 minutes. Reaction was carried out at 90°C for 5 hours, and the reaction mixture was poured into 90 mL of water. The precipitate was filtered and washed with a sodium sulfite aqueous solution to obtain a crystalline solid (yield: 1.6 g) as the product. This solid was analyzed to find that the product showed the following distribution: [] 2-methylbenzoic acid33 percent5-chloro-2-methylbenzoic acid13 percent3- chloro -2-methylbenzoic acid9 percent5-iodo-2-methylbenzoic acid38 percent3-iodo-2-methylbenzoic acid5 percentothers2 percent The above mixture was purified by recrystallization using acetic acid or isopropyl alcohol to try to isolate 5-iodo-2-methylbenzoic acid. However, a purity of the mixture was scarcely improved, and it was difficult to obtain 5-iodo-2-methylbenzoic acid.
Reference：
[1] Journal of the Society of Chemical Industry, London, 1940, vol. 59, p. 92,94
[2] Journal of the Society of Chemical Industry, London, 1940, vol. 59, p. 92,94
[3] Patent: CN105906523, 2016, A,
18
[ 118-90-1 ]
[ 2386-64-3 ]
[ 2040-14-4 ]
Reference：
[1] Journal of the American Chemical Society, 2005, vol. 127, # 28, p. 10028 - 10038
19
[ 118-90-1 ]
[ 2040-14-4 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11313 - 11316
20
[ 118-90-1 ]
[ 802294-64-0 ]
[ 2040-14-4 ]
Reference：
[1] Annales de Chimie (Cachan, France), 1913, vol. <8> 28, p. 313
[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1911, vol. 152, p. 91[3] Bulletin de la Societe Chimique de France, 1911, vol. <4> 9, p. 949
21
[ 118-90-1 ]
[ 7719-09-7 ]
[ 75-09-2 ]
[ 103-49-1 ]
[ 134-62-3 ]
Reference：
[1] Chemical Physics Letters, 2017, vol. 689, p. 148 - 151
22
[ 118-90-1 ]
[ 1975-50-4 ]
[ 1975-52-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 169
[2] Chemische Berichte, 1883, vol. 16, p. 1959[3] Chemische Berichte, 1884, vol. 17, p. 164
[4] Chemische Berichte, 1884, vol. 17, p. 161
[5] Justus Liebigs Annalen der Chemie, 1870, vol. 156, p. 235
[6] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 246
[7] Chemische Berichte, 1883, vol. 16, p. 1959[8] Chemische Berichte, 1884, vol. 17, p. 164
[9] Gazzetta Chimica Italiana, 1935, vol. 65, p. 840,842
[10] Chemische Berichte, 1883, vol. 16, p. 1959[11] Chemische Berichte, 1884, vol. 17, p. 164
[12] Tetrahedron Letters, 2002, vol. 43, # 27, p. 4789 - 4791
[13] Tetrahedron Letters, 2008, vol. 49, # 28, p. 4449 - 4451
[14] Tetrahedron Letters, 2011, vol. 52, # 13, p. 1452 - 1455
23
[ 118-90-1 ]
[ 7499-08-3 ]
[ 7499-06-1 ]
[ 133232-56-1 ]
[ 54811-38-0 ]
Yield
Reaction Conditions
Operation in experiment
38%
With sulfuric acid; Iodine monochloride; periodic acid In water; acetic acid at 90℃; for 5.66667 h;
Suspended in a 100 mL three-necked flask equipped with a reflux condenser were 25 mL of 30 weight percent sulfuric acid and 1.36 g (10 mmol) of 2-methylbenzoic acid, and 2.4 g (15 mmol) of iodine monochloride dissolved in 5 g of acetic acid was dropwise added thereto in 40 minutes. Reaction was carried out at 90°C for 5 hours, and the reaction mixture was poured into 90 mL of water. The precipitate was filtered and washed with a sodium sulfite aqueous solution to obtain a crystalline solid (yield: 1.6 g) as the product. This solid was analyzed to find that the product showed the following distribution: [] 2-methylbenzoic acid33 percent5-chloro-2-methylbenzoic acid13 percent3- chloro -2-methylbenzoic acid9 percent5-iodo-2-methylbenzoic acid38 percent3-iodo-2-methylbenzoic acid5 percentothers2 percent The above mixture was purified by recrystallization using acetic acid or isopropyl alcohol to try to isolate 5-iodo-2-methylbenzoic acid. However, a purity of the mixture was scarcely improved, and it was difficult to obtain 5-iodo-2-methylbenzoic acid.
Reference：
[1] Justus Liebigs Annalen der Chemie, 1893, vol. 274, p. 311
[2] Justus Liebigs Annalen der Chemie, 1893, vol. 274, p. 308
[3] Justus Liebigs Annalen der Chemie, 1893, vol. 274, p. 311
[4] Justus Liebigs Annalen der Chemie, 1893, vol. 274, p. 311
27
[ 118-90-1 ]
[ 7499-06-1 ]
Reference：
[1] Israel Journal of Chemistry, 1971, vol. 9, p. 111 - 118
28
[ 118-90-1 ]
[ 7782-50-5 ]
[ 64-19-7 ]
[ 7499-08-3 ]
[ 7499-06-1 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1893, vol. 274, p. 308
29
[ 118-90-1 ]
[ 35572-78-2 ]
Reference：
[1] Journal of the Society of Chemical Industry, London, 1940, vol. 59, p. 92,94
[2] Journal of the Society of Chemical Industry, London, 1940, vol. 59, p. 92,94
30
[ 118-90-1 ]
[ 1975-50-4 ]
[ 1975-52-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 169
[2] Chemische Berichte, 1883, vol. 16, p. 1959[3] Chemische Berichte, 1884, vol. 17, p. 164
[4] Chemische Berichte, 1884, vol. 17, p. 161
[5] Justus Liebigs Annalen der Chemie, 1870, vol. 156, p. 235
[6] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 246
[7] Chemische Berichte, 1883, vol. 16, p. 1959[8] Chemische Berichte, 1884, vol. 17, p. 164
[9] Gazzetta Chimica Italiana, 1935, vol. 65, p. 840,842
[10] Chemische Berichte, 1883, vol. 16, p. 1959[11] Chemische Berichte, 1884, vol. 17, p. 164
[12] Tetrahedron Letters, 2002, vol. 43, # 27, p. 4789 - 4791
[13] Tetrahedron Letters, 2008, vol. 49, # 28, p. 4449 - 4451
[14] Tetrahedron Letters, 2011, vol. 52, # 13, p. 1452 - 1455
31
[ 118-90-1 ]
[ 1975-52-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3420 - 3422
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 5004 - 5008
32
[ 118-90-1 ]
[ 74-88-4 ]
[ 99548-54-6 ]
[ 79669-50-4 ]
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1732 - 1744
Reference：
[1] Patent: WO2005/100351, 2005, A1, . Location in patent: Page/Page column 13; 17
[2] Patent: US2007/203116, 2007, A1, . Location in patent: Page/Page column 8; 10
[3] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1732 - 1744
[4] Arkivoc, 2011, vol. 2011, # 6, p. 29 - 44
[5] Patent: WO2011/80718, 2011, A1, . Location in patent: Example 1
[6] Organic and Biomolecular Chemistry, 2017, vol. 15, # 48, p. 10172 - 10183
42
[ 118-90-1 ]
[ 79669-49-1 ]
Yield
Reaction Conditions
Operation in experiment
19%
Stage #1: at 20℃; for 2 h; Stage #2: With hydrogenchloride In methanol; water at 20℃;
2-Methylbenzoic acid (40.0 g, 290 mmol) was added to a suspension of Br2 (160 mL) and iron powder (3.20 g, 57.0 mol) under N2 atmosphere in an ice bath. The mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was poured into water and the reddish solid was collected by filtration. The solid was dried under vacuum at 50° C. The solid was dissolved in 400 mL of methanol before 640 mL of 0.1N aqueous HCl was added at room temperature. The mixture was stirred and a white solid was produced. This solid was recrystallized from ethanol to afford 5-bromo-2-methyl-benzoic acid (12.0 g, 19percent). 1H NMR (300M Hz, CDCl3) δ 8.17 (d, J=2.1, 1H), 7.56 (dd, J=8.1, 2.1, 1H), 7.15 (d, J=8.1, 1H), 2.59 (s, 3H).
Reference：
[1] Patent: US2009/143381, 2009, A1, . Location in patent: Page/Page column 55
[2] Chemische Berichte, 1883, vol. 16, p. 1959[3] Chemische Berichte, 1884, vol. 17, p. 164
[4] Justus Liebigs Annalen der Chemie, 1887, vol. 239, p. 84[5] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1888, vol. 106, p. 949
[6] Journal of the Indian Chemical Society, 1930, vol. 7, p. 503
[7] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
[8] Inorganic Chemistry, 2014, vol. 53, # 6, p. 2932 - 2942
[9] Patent: CN103980263, 2016, B,
43
[ 118-90-1 ]
[ 76006-33-2 ]
[ 79669-49-1 ]
Reference：
[1] Patent: WO2005/100351, 2005, A1, . Location in patent: Page/Page column 13; 17
[2] Patent: US2007/203116, 2007, A1, . Location in patent: Page/Page column 8; 10
[3] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1732 - 1744
[4] Arkivoc, 2011, vol. 2011, # 6, p. 29 - 44
[5] Patent: WO2011/80718, 2011, A1, . Location in patent: Example 1
[6] Organic and Biomolecular Chemistry, 2017, vol. 15, # 48, p. 10172 - 10183
Reference：
[1] Chemische Berichte, 1895, vol. 28, p. 183
[2] Chemische Berichte, 1883, vol. 16, p. 1959[3] Chemische Berichte, 1884, vol. 17, p. 164
46
[ 118-90-1 ]
[ 54811-38-0 ]
Yield
Reaction Conditions
Operation in experiment
94.5%
at 40℃;
500ml reaction flask, add solvent acetic acid (54.4g), concentrated sulfuric acid (16.3g), stir and mix well, Next add o-toluic acid (13.6 g, 0.1 mol), iodine (25.3 g, 0.06 mol) in succession.Niobium nitrite (28 g, 0.0001 mol) was directly passed through concentrated sulfuric acid-dried air. The reaction was maintained at a temperature of 40°C and TLC monitored the disappearance of the starting material. After the reaction is complete, 200 ml of water is added to the system. A large amount of solids precipitated out, which was filtered, washed with water and dried to obtain a solid. The reaction yield was 94.5percent, and the HPLC purity was 99.3percent. The NMR spectrum of 2-methyl-5-iodobenzoic acid is shown in Figure 1.
93.8%
With hydrogen iodide; iodine; acetic anhydride; acetic acid In water at 122℃; for 4 h;
[Example 9]; The reaction was repeatedly performed six times in a manner similar to that of Example 6 including washing zeolite with acetic acid. After completion of reactions, H-β-form zeolite (238 g) was recovered. The thus-recovered H-β-form zeolite was placed in a muffle furnace, where zeolite was dried at 150°C for two hours in air and then calcined at 550°C for three hours. The calcined H-β-form zeolite had a weight of 150 g. In a manner similar to that of Example 5 or 6, reaction operations were repeated utilizing the obtained H-β-form zeolite. As is clear from Table 3 below, excellent reaction results were obtained again after the seventh reaction. Table 3 Reaction 7th 8th 9th 10thConversion1) 97.0 97.5 97.2 96.7Yield2) 94.3 94.7 94.4 93.8Selectivity3) 97.2 97.1 97.1 97.0Crystal purity4) 99.7 99.7 99.7 99.7
88%
at 20℃; Molecular sieve
A, 2-methyl benzoic acid as the starting material,The supported molecular sieves are loaded with iron oxide,With iodic acid and molar multiple of 0.5 iodine reaction intermediates a 5-iodo-2-methyl benzoic acid,After the treatment process using cooling after cooling filter,Mother liquid to use the method,As follows: the reaction temperature dropped to 20 degrees Celsius, a large number of solid precipitation, at this temperature will be mixed with catalyticCan be applied 5 times, the filtrate after dissolution, the crude with 2.5 times, the product can be used for 5 times, the filtrate after the dissolution of the solution, By weight of ethyl acrylate to obtain a white product in a yield of 88percent or more;
69%
With sulfuric acid; iodine; iodic acid In water; acetic acid at 20 - 118℃; for 6 h; Heating / reflux
The same procedure as in Example 1 was carried out, except that iodic acid (5.3 g, 0.03 mol) was substituted for periodic acid as the oxidizing agent in Example 1. A conversion of 2-methylbenzoic acid was 78 percent; the yields were 1) 69 percent for 5-iodo-2-methylbenzoic acid and 2) 3 percent for the regioisomers of other iodides; and a ratio of 1)/2) was 23.
66.2%
With hydrogen iodide; iodine; acetic anhydride; acetic acid In water at 122℃; for 4 h;
[Example 11]; The procedure of Example 9 was repeated, except that the calcining temperature was adjusted to 380°C. As is clear from Table 5 below, catalytic activity was revived to a certain extent. However, as is clear from the Table 5, the activity was lowered as the reaction repeated. Table 5 Reaction 7th 8th 9th 10thConversion1) 95.2 90.2 82.5 70.2Yield2) 90.4 87.0 78.2 66.2Selectivity3) 95.0 96.5 94.8 94.3Crystal purity4) 99.7 99.6 99.5 99.5
63%
at 25 - 30℃; for 2.75 h;
5-Iodo-2-methylbenzoic Acid (31). NaIO4 (295 mg, 1.38 mmol) and KI (685 mg, 4.13 mmol) were added over 45 min slowly portionwise to stirred 95percent H2SO4 (15 mL). Stirring was continued for 1 h at 25-30° C. to give a dark-brown iodinating solution at 25-30° C. To a stirred solution of 2-toluic acid 30 (680 mg, 5 mmol) in 95percent H2SO4 (5 mL), the iodinating solution was added dropwise over 45 min while maintaining the temperature at 25-30° C. Stirring was continued for 2 h, and the iodination reaction was quenched by slowly pouring the final reaction mixture into stirred ice water. The mixture was extracted with AcOEt and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and purification by silica gel flash column chromatography to afford compound 31 in 63percent yield. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=1.8 Hz), 7.75 (dd, 1H, J=8.1, 1.8 Hz), 7.02 (d, 1H, J=8.1 Hz), 2.59 (s, 3H).
53%
With sulfuric acid; iodine; iodic acid In water; acetic acid at 20 - 118℃; for 6 h; Heating / reflux
The same procedure as in Example 9 was carried out, except that H- β zeolite was not used in Example 9. A conversion of 2-methylbenzoic acid was 79 percent; the yields were 1) 53 percent for 5-iodo-2-methylbenzoic acid and 2) 23 percent for the regioisomers of other iodides; and a ratio of 1)/2) was 2.3.
Reference：
[1] Patent: CN107652175, 2018, A, . Location in patent: Paragraph 0054-0098
[2] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 10
[3] European Journal of Organic Chemistry, 2017, vol. 2017, # 22, p. 3234 - 3239
[4] Patent: CN103980263, 2016, B, . Location in patent: Paragraph 0032; 0033
[5] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 10
[6] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 11
[7] Journal of Medicinal Chemistry, 2009, vol. 52, # 16, p. 5228 - 5240
[8] Patent: US2011/269834, 2011, A1, . Location in patent: Page/Page column 28
[9] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 10
[10] Journal of the Indian Chemical Society, 1930, vol. 7, p. 503
[11] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1974, p. 2405 - 2409
47
[ 118-90-1 ]
[ 133232-56-1 ]
[ 54811-38-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 122℃; for 4 h;
5-iodo-2-methylbenzoic acid: 99.7percent (purity in crystals) The thus-obtained crystals (1 g) were dissolved in methanol (25 mL), and a 4percent aqueous KI solution (25 mL) and 17percent sulfuric acid (5 mL) were added to the solution. The resultant solution was titrated with a 0.02M aqueous sodium thiosulfate solution. The free iodine content was found to be 5 ppm. Through ICP-basis total element analysis, Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected, and the Group 1 element content and the Group 2 element content were both 1 ppm or less. [Example 15]; In a 10-L reactor equipped with a reflux condenser, acetic acid (2,678 g), acetic anhydride (823 g), 2-methylbenzoic acid (700 g), iodine (502 g), a 70percent aqueous iodic acid solution (299 g), and H-β-form zeolite (161 g) were placed. The mixture was allowed to react at a reflux temperature of 122°C for four hours. After completion of reaction, H-β-form zeolite was removed from the reaction mixture through filtration. A 10percent aqueous sodium thiosulfate solution (200 g) and water (2,500 g) were added to the filtrate, and the mixture was cooled to 30°C. The precipitated crystals were collected through filtration, to thereby yield 1,204 g (after drying) of a product. Through HPLC (high-performance liquid chromatography) analysis of the collected crystals and the mother liquor, the following reaction results were obtained. 2-methylbenzoic acid: 97.0percent (conversion) 5-iodo-2-methylbenzoic acid: 94.3percent (yield) 97.2percent (selectivity) 3-iodo-2-methylbenzoic acid: 0.7percent (yield) 0.7percent (selectivity) 5-iodo-2-methylbenzoic acid crystals: 89.6percent (yield) 5-iodo-2-methylbenzoic acid: 99.7percent (purity in crystals) The thus-obtained crystals (1 g) were dissolved in methanol (25 mL), and a 4percent aqueous KI solution (25 mL) and 17percent sulfuric acid (5 mL) were added to the solution. The resultant solution was titrated with a 0.02M aqueous sodium thiosulfate solution. The iodine content was found to be 5 ppm. Through ICP-basis total element analysis, Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected, and the Group 1 element content and the Group 2 element content were both 1 ppm or less.
89.3%
at 122℃; for 4 h;
[Example 2] The procedure of Example 1 was repeated, except that acetic acid (96.0 g), acetic anhydride (9.2 g), iodine (15.6 g), and periodic acid (5.5 g) instead of iodic acid were employed, to thereby yield 28.5 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 93.0percent (conversion) 5-iodo-2-methylbenzoic acid crystals: 73.7percent (yield) 5-iodo-2-methylbenzoic acid: 99.5percent (purity in crystals) Through analysis of the thus-obtained crystals, the free iodine content was found to be 5 ppm, and Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected. The Group 1 element content and the Group 2 element content were both 1 ppm or less. [Example 13]; The procedure of Example 12 was repeated, except that acetic acid (3,360 g), acetic anhydride (322 g), iodine (544 g), and periodic acid (191 g) instead of iodic acid were employed, to thereby yield 994 g of a product as white crystals. The following reaction analysis results were obtained. 2-methylbenzoic acid: 93.0percent (conversion) 5-iodo-2-methylbenzoic acid: 90.0percent (yield) 96.8percent (selectivity) 3-iodo-2-methylbenzoic acid: 0.2percent (yield) 0.2percent (selectivity) 5-iodo-2-methylbenzoic acid crystals: 73.7percent (yield) 5-iodo-2-methylbenzoic acid: 99.5percent (purity in crystals) Through analysis of the thus-obtained crystals, the iodine content was found to be 5 ppm, and Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected. The Group 1 element content and the Group 2 element content were both 1 ppm or less.; [Example 16]; The procedure of Example 15 was repeated, except that acetic acid (3,360 g), acetic anhydride (322 g), iodine (544 g), and periodic acid (191 g) instead of iodic acid were employed, to thereby yield 1.149 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 93.0percent (conversion) 5-iodo-2-methylbenzoic acid: 90.0percent (yield) 96.8percent (selectivity) 3-iodo-2-methylbenzoic acid: 0.2percent (yield) 0.2percent (selectivity) 5-iodo-2-methylbenzoic acid crystals: 85.2percent (yield) 5-iodo-2-methylbenzoic acid: 99.5percent (purity in crystals) Through analysis of the thus-obtained crystals, the iodine content was found to be 5 ppm, and Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected. The Group 1 element content and the Group 2 element content were both 1 ppm or less.
72%
With sulfuric acid; iodine; periodic acid In water; acetic acid at 20 - 118℃; for 6 h; Heating / reflux
A three-necked flask of 200 mL equipped with a reflux condenser and a stirrer was charged with acetic acid (100 g), H- β zeolite (4.6 g), iodine (20.2 g, 0.16 mol), 2-methylbenzoic acid (20 g, 0.15 mol), periodic acid dihydrate (7.3 g, 0.03 mol) and sulfuric acid (0.24 g), and they were sufficiently mixed and stirred at a room temperature. The mixture temperature was raised up to 110°C on a mantle heater, and then the reaction was carried out for one hour. Further, the reaction was carried out at refluxing temperature (about 118°C) of acetic acid for 5 hours. After finishing the reaction, the reaction mixture was filtered to recover H-β zeolite, and a 10 weight percent sodium sulfite aqueous solution (100 mL) was added to the filtrate to treat remaining iodine. Next, water (800 g) was added thereto to precipitate crystal, and then it was filtered and recovered. The crystal thus obtained and the filtrate were analyzed by means of HPLC (high performance liquid chromatography) to investigate the performance enhancement, and it resulted in finding that a conversion of 2-methylbenzoic acid was 88 percent and the yields of the products were 72 percent for 5-iodo-2-methylbenzoic acid and 6 percent for 3-iodo-2-methylbenzoic acid. The ratio of (5-iodo/3-iodo) regioisomer was 12.
72%
With sulfuric acid; iodine; iodic acid In water; acetic acid at 115℃; for 6 h; Heating / reflux
A recovered product 13 g was obtained by the same method as in Example 16, except that 4.3 g of iodic acid was substituted for periodic acid. As a result of analysis, the following data were obtained: [] conversion of 2-methylbenzoic acid80 percentyield of 5-iodo-2-methylbenzoic acid72 percentyield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 243 percentpurity of 5-iodo-2-methylbenzoic acid in crystal95 percent
70%
With sulfuric acid; iodine; periodic acid In water; acetic acid at 115℃; for 6 h; Heating / reflux
A 100 mL three-necked flask equipped with a reflux condenser was charged with acetic acid 50 g, 2-methylbenzoic acid 10 g, iodine 10.4 g, periodic acid 3.7 g, H-β zeolite 2.2 g and sulfuric acid 0.12 g, and they were reacted at a refluxing temperature (115°C) of acetic acid for 6 hours. After finishing the reaction, H-β zeolite was separated by filtration, and 20 g of a 10 weight percent sodium sulfite aqueous solution and 250 mL of water were added to the filtrate and cooled down to a room temperature. Crystal precipitated was recovered by filtration to obtain 15 g (weight after drying) of a product. The crystal recovered and the mother liquor was analyzed by means of HPLC (high pressure liquid chromatography) to evaluate in obtaining the following results: [] conversion of 2-methylbenzoic acid85 percentyield of 5-iodo-2-methylbenzoic acid70 percentyield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 107 percentpurity of 5-iodo-2-methylbenzoic acid in crystal95 percent; Reaction was carried out on the same conditions as in Example 16, except that an amount of acetic acid was changed to 40 g, and the filtrate was cooled down to a room temperature after H-β zeolite was separated. Crystal precipitated was recovered by filtration to obtain 10 g of a product. As a result of analysis, the following data were obtained: [] conversion of 2-methylbenzoic acid88 percentyield of 5-iodo-2-methylbenzoic acid72 percentyield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 98 percentpurity of 5-iodo-2-methylbenzoic acid in crystal95 percent
69%
With sulfuric acid; iodine; acetic acid; periodic acid In n-heptane at 120℃; for 7 h;
[Comparative Example 2]; In the same apparatus as employed in Example 1, acetic acid (92 mL), 2-methylbenzoic acid (15.0 g), iodine (12.0 g), a 50percent aqueous periodic acid solution (7.2 g), and concentrated sulfuric acid (4.7 g) were placed. The mixture was allowed to react at a reflux temperature of 120°C for seven hours. After completion of reaction, the reaction mixture was cooled to room temperature. The precipitated crystals were collected through filtration, to thereby yield 16.4 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 94.0percent (conversion) 5-iodo-2-methylbenzoic acid: 69.0percent (yield) 73.4percent (selectivity) 3-iodo-2-methylbenzoic acid: 20.0percent (yield) 21.3percent (selectivity) 5-iodo-2-methylbenzoic acid crystals: 54.0percent (yield) 5-iodo-2-methylbenzoic acid: 95.0percent (purity in crystals) Thus, when concentrated sulfuric acid was employed as an acid catalyst, purity and yield of 5-iodo-2-methylbenzoic acid were unsatisfactory.
69%
With sulfuric acid; iodine; acetic acid; periodic acid In water at 120℃; for 7 h;
[Comparative Example 5] In the same apparatus as employed in Example 12, acetic acid (3,680 mL), 2-methylbenzoic acid (600 g), iodine (480 g), a 50percent aqueous periodic acid solution (288 g), and concentrated sulfuric acid (188 g) were placed. The mixture was allowed to react at a reflux temperature of 120°C for seven hours. After completion of reaction, the reaction mixture was cooled to 30°C. The precipitated pale gray crystals were collected through filtration, to thereby yield 624 g of a product. The following reaction analysis results were obtained. Through analysis of the thus-obtained crystals, the iodine content was found to be 620 ppm. Through ICP-basis total element analysis, Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected. The Group 1 element content and the Group 2 element content were both 1 ppm or less. Thus, when concentrated sulfuric acid was employed as an acid catalyst, purity and yield of 5-iodo-2-methylbenzoic acid were unsatisfactory.
66%
With sulfuric acid; iodine; periodic acid In water; acetic acid at 20 - 118℃; for 6 h; Heating / reflux
The same procedure as in Example 1 was carried out, except that H-β zeolite was not used in Example 1. A conversion of 2-methylbenzoic acid was 98 percent; the yields were 66 percent for 5-iodo-2-methylbenzoic acid and 25 percent for 3-iodo-2-methylbenzoic acid. The ratio of (5-iodo/3-iodo) regioisomer was 2.6.
65%
With iodine; iodic acid In water; acetic acid at 115℃; for 3 h; Heating / reflux
The same procedure as in Example 1 was carried out, except that in Example 1, sulfuric acid was not used; 8.8 g of iodic acid was substituted for periodic acid; and the reaction was carried out at a refluxing temperature (115°C) of acetic acid for 3 hours. The results are shown below: [] conversion of 2-methylbenzoic acid70 percentyield of 5-iodo-2-methylbenzoic acid65 percentyield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 332 percentpurity of 5-iodo-2-methylbenzoic acid in crystal97 percent 5-Iodo-2-methylbenzoic acid obtained by recrystallizing the crystal of 5-iodo-2-methylbenzoic acid described above having a purity of 97 percent with a solvent of water : 2-propanol = 1 : 1 (weight ratio) had a purity of 99 percent or more. The recrystallized product of 5-iodo-2-methylbenzoic acid described above contained 4 ppm of free iodine. This crystal was subjected to ICP all element analysis to result in finding that Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb and S were not detected and that all the elements of group 1 and group 2 in the periodic table had a content of 1 ppm or less.
64%
With sodium persulfate; sulfuric acid; iodine In water; acetic acid at 20 - 110℃; for 13 h;
The same apparatus as in Example 1 was used and charged with acetic acid (90 g), water (10 g), H-β zeolite (2.3 g), iodine (10.3 g, 0.08 mol), 2-methylbenzoic acid (10 g, 0.074 mol), sodium persulfate (11.8 g, 0.05 mol) and sulfuric acid (0.12 g). After they were sufficiently mixed and stirred at a room temperature, the mixture temperature was elevated up to 90°C, and then the reaction was carried out for 5 hours. Further, the reaction was carried out at 110°C for 8 hours, and then the reaction was finished. H-β zeolite was separated by filtration, and remaining iodine was treated by a 10 weight percent sodium sulfite aqueous solution. Then, 800 mL of water was added thereto, and crystal precipitated was filtered off. A conversion of 2-methylbenzoic acid was 86 percent; the yields were 1) 64 percent for 5-iodo-2-methylbenzoic acid and 2) 12 percent for 3-iodo-2-methylbenzoic acid; and a ratio of 1)/2) was 5.3.
60.2%
With hydrogen iodide; iodine; acetic acid In water at 122℃; for 4 h;
[Comparative Example 7]; The procedure of Example 12 was repeated, except that acetic anhydride was not employed, to thereby yield 598 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 65.8percent (conversion) 5-iodo-2-methylbenzoic acid: 60.2percent (yield) 91.5percent (selectivity) 3-iodo-2-methylbenzoic acid: 2.2percent (yield) 3.3percent (selectivity) 5-iodo-2-methylbenzoic acid crystals: 45.8percent (yield) 5-iodo-2-methylbenzoic acid: 95.2percent (purity in crystals) Through analysis of the thus-obtained crystals, the iodine content was found to be 480 ppm. Through ICP-basis total element analysis, Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected. The Group 1 element content and the Group 2 element content were both 1 ppm or less. Thus, when acetic anhydride was not employed, purity and yield of 5-iodo-2-methylbenzoic acid were unsatisfactory.
60.2%
at 122℃; for 4 h;
[Comparative Example 4]; The procedure of Example 1 was repeated, except that acetic anhydride was not employed, to thereby yield 18.5 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 65.8percent (conversion) 5-iodo-2-methylbenzoic acid: 60.2percent (yield) 91.5percent (selectivity) 3-iodo-2-methylbenzoic acid: 2.2percent (yield) 3.3percent (selectivity) 5-iodo-2-methylbenzoic acid crystals: 45.8percent (yield) 5-iodo-2-methylbenzoic acid: 95.2percent (purity in crystals) Thus, when acetic anhydride was not employed, purity and yield of 5-iodo-2-methylbenzoic acid were unsatisfactory.
56%
With sulfuric acid; iodine; periodic acid In water; acetic acid at 115℃; for 6 h; Heating / reflux
Reaction was carried out by the same method as in Example 16 to obtain 15 g of a product, except that H-β zeolite was not used. As a result of analysis, the following data were obtained: [] conversion of 2-methylbenzoic acid85 percentyield of 5-iodo-2-methylbenzoic acid56 percentyield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 2.820 percentpurity of 5-iodo-2-methylbenzoic acid in crystal80 percent
46.3%
With hydrogen iodide; iodine; acetic anhydride; acetic acid In water at 122℃; for 4 h;
[Example 5]; In a 10-L reactor equipped with a reflux condenser, acetic acid (2,678 g), acetic anhydride (823 g), 2-methylbenzoic acid (700 g), iodine (502 g), a 70percent aqueous iodic acid solution (299 g), and H-β-form zeolite (161 g) were placed. The mixture was allowed to react at a reflux temperature of 122°C for four hours. After completion of reaction, H-β-form zeolite was removed from the reaction mixture through filtration through suction by use of a membrane filter. The H-β-form zeolite left on the filter was washed with acetic acid (350 g), and the wash liquid and the filtrate were combined, followed by cooling to room temperature. The precipitated crystals were collected through filtration, to thereby yield 970 g (after drying) of a product. Through HPLC (high-performance liquid chromatography) analysis of the collected crystals and the mother liquor, the following reaction results were obtained. 2-methylbenzoic acid: 97.0percent (conversion) 5-iodo-2-methylbenzoic acid: 94.3percent (yield) 97.2percent (selectivity) 3-iodo-2-methylbenzoic acid: 0.7percent (yield) 0.7percent (selectivity) 5-iodo-2-methylbenzoic acid: 99.7percent (purity in crystals); [Example 6]; In Example 6, H-β-form zeolite (245 g) which had been recovered after filtration and washing performed in Example 5 was used. In a manner similar to that of Example 5, reaction, separation/recovery of H-β-form zeolite, and recovery of reaction products from mother liquor were repeatedly carried out. The results are shown in Table 1. As is clear from Table 1, excellent results were obtained in repetition of operations. However, after completion of the sixth reaction, conversion of 2-methylbenzoic acid and yield of 5-iodo-2-methylbenzoic acid were lowered. Table 1 Reaction 1st 2nd 3rd 4th 5th 6thConversion1) 97.0 97.5 97.2 96.7 95.9 93.0Yield2) 94.3 94.5 94.5 93.8 92.9 90.2Selectivity3) 97.2 96.9 97.2 97.0 96.9 97.0Crystal purity4) 99.7 99.7 99.7 99.7 99.6 99.6 1)2-methylbenzoic acid (conversion) (percent) 2)5-iodo-2-methylbenzoic acid (yield) (percent) 3)5-iodo-2-methylbenzoic acid (selectivity) (percent) 4)5-iodo-2-methylbenzoic acid (purity in crystals) (percent)The same definitions are applied to the following Tables.; [Example 7]; The procedure of Example 5 was repeated, except that H-β-form zeolite separated through filtration from the reaction mixture was recovered without washing with acetic acid. The following reaction analysis results were obtained. 2-methylbenzoic acid: 97.0percent (conversion) 5-iodo-2-methylbenzoic acid: 94.1percent (yield) 97.0percent (selectivity) 3-iodo-2-methylbenzoic acid: 0.7percent (yield) 0.7percent (selectivity) 5-iodo-2-methylbenzoic acid: 99.7percent (purity in crystals); [Example 8]; In Example 8, H-β-form zeolite (287 g) which had been separated from the reaction mixture in Example 7 but had not been washed with acetic acid was used. In a manner similar to that of Example 7, reaction, separation/recovery of H-β-form zeolite, and recovery of reaction products from mother liquor were repeatedly carried out. The results are shown in Table 2. As is clear from Table 2, excellent results were obtained in repetition of operations. However, after completion of the sixth reaction, conversion of 2-methylbenzoic acid and yield of 5-iodo-2-methylbenzoic acid were lowered. Table 2 Reaction 1st 2nd 3rd 4th 5th 6thConversion1) 97.0 97.2 97.2 96.8 96.0 94.2Yield2) 94.1 94.6 94.6 93.7 93.2 89.8Selectivity3) 97.0 97.3 97.3 96.8 97.1 95.8Crystal purity4) 99.7 99.7 99.7 99.7 99.6 99.6; [Example 9]; The reaction was repeatedly performed six times in a manner similar to that of Example 6 including washing zeolite with acetic acid. After completion of reactions, H-β-form zeolite (238 g) was recovered. The thus-recovered H-β-form zeolite was placed in a muffle furnace, where zeolite was dried at 150°C for two hours in air and then calcined at 550°C for three hours. The calcined H-β-form zeolite had a weight of 150 g. In a manner similar to that of Example 5 or 6, reaction operations were repeated utilizing the obtained H-β-form zeolite. As is clear from Table 3 below, excellent reaction results were obtained again after the seventh reaction. Table 3 Reaction 7th 8th 9th 10thConversion1) 97.0 97.5 97.2 96.7Yield2) 94.3 94.7 94.4 93.8Selectivity3) 97.2 97.1 97.1 97.0Crystal purity4) 99.7 99.7 99.7 99.7; [Example 10]; The reaction was repeatedly performed six times in a manner similar to that of Example 6. Subsequently, the reaction was further repeated in the same manner. The reaction results are shown in Table 4. Table 4 Reaction 7th 8th 9th 10thConversion1) 88.2 80.2 68.5 50.2Yield2) 84.2 76.8 64.7 46.3Selectivity3) 95.5 95.8 94.5 92.2Crystal purity4) 99.6 99.5 99.5 99.1; [Example 12]; In a 10-L reactor equipped with a reflux condenser, acetic acid (2,678 g), acetic anhydride (823 g), 2-methylbenzoic acid (700 g), iodine (502 g), a 70percent aqueous iodic acid solution (299 g), and H-β-form zeolite (161 g) were placed. The mixture was allowed to react at a reflux temperature of 1.22°C for four hours. After completion of reaction, H-β-form zeolite was removed from the reaction mixture through filtration, and the filtrate was cooled to 30°C. The precipitated white crystals were collected through filtration, to thereby yield 1,042 g (after drying) of a product. Through HPLC (high-performance liquid chromatography) analysis of the collected crystals and the mother liquor, the following reaction results were obtained. 2-methylbenzoic acid: 97.0percent (conversion) 5-iodo-2-methylbenzoic acid: 94.3percent (yield) 97.2percent (selectivity) 3-iodo-2-methylbenzoic acid: 0.7percent (yield) 0.7percent (selectivity) 5-iodo-2-methylbenzoic acid crystals: 77.3percent (yield) 5-iodo-2-methylbenzoic acid: 99.7percent (purity in crystals) The thus-obtained crystals (1 g) were dissolved in methanol (25 mL), and a 4percent aqueous KI solution (25 mL) and 17percent sulfuric acid (5 mL) were added to the solution. The resultant solution was titrated with a 0.02M aqueous sodium thiosulfate solution. The iodine content was found to be 5 ppm. Through ICP-basis total element analysis, Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected, and the Group 1 element content and the Group 2 element content were both 1 ppm or less.
40.6%
With sulfuric acid; Iodine monochloride In n-heptane at 90℃; for 5 h;
[Comparative Example 1] To a 100-mL three-neck flask equipped with a reflux condenser, 30percent sulfuric acid (25 mL) and 2-methylbenzoic acid (1.36 g, 10 mmol) were fed to form a suspension. Iodine monochloride (2.4 g, 15 mmol) was added dropwise to the suspension. The mixture was allowed to react at 90°C for five hours, and the reaction mixture was poured into water (90 mL). The precipitated product was collected through filtration, followed by washing with an aqueous sodium sulfite solution, to thereby yield a crystalline solid as a reaction product (yield: 1.6 g). The following reaction analysis results were obtained. The above mixture was purified through recrystallization from acetic acid, isopropyl alcohol, or a similar solvent, so as to isolate 5-iodo-2-methylbenzoic acid. However, the purity of the mixture was not virtually enhanced, and 5-iodo-2-methylbenzoic acid was difficult to obtain.
37%
With sodium periodate; sulfuric acid; sodium iodide In water; acetic acid at 85℃; for 2.58333 h;
The same apparatus as in Example 16 was used to dissolve 1.36 g of 2-methylbenzoic acid in 9 mL of acetic acid. The temperature of the mixture was maintained at 85°C, and 11 ml of conc. sulfuric acid was dropwise added thereto in 25 minutes. Further, 0.6 g of sodium periodate was added thereto, and then a solution prepared by dissolving 1.1 g of sodium iodide in 5 mL of acetic acid was dropwise added thereto in 10 minutes. Thereafter, the reaction was carried out for 2 hours, and after cooling, the reaction mixture was poured into 90 mL of water and the produced muddy mixture was filtered. Sodium sulfite 1 g was added thereto to remove unreacted iodine. After drying, the product thus obtained was analyzed to result in obtaining the following data: [] 2-methylbenzoic acid35 percent5-iodo-2-methylbenzoic acid37 percent3-iodo-2-methylbenzoic acid18 percentothers5 percent It was tried to obtain 5-iodo-2-methylbenzoic acid from the above mixture as was the case with Comparative Example 11, but the purity was scarcely improved, and it was difficult to obtain 5-iodo-2-methylbenzoic acid.
9.5%
at 122℃; for 4 h;
[Comparative Example 3]; The procedure of Example 1 was repeated, except that iodic acid was not employed, to thereby yield 5 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 15.8percent (conversion) 5-iodo-2-methylbenzoic acid: 9.5percent (yield) 60.1percent (selectivity) 3-iodo-2-methylbenzoic acid: 2.8percent (yield) 18.0percent (selectivity) 5-iodo-2-methylbenzoic acid crystals: 7.4percent (yield) 5-iodo-2-methylbenzoic acid: 57.0percent (purity in crystals) Thus, when iodic acid was not employed, purity and yield of 5-iodo-2-methylbenzoic acid were unsatisfactory.
3%
With sulfuric acid; iodine In water; acetic acid at 115℃; for 6 h; Heating / reflux
Reaction was carried out by the same method as in Example 16 to obtain 0.8 g of a product, except that periodic acid was not used. As a result of analysis, the following data were obtained: [] conversion of 2-methylbenzoic acid5 percentyield of 5-iodo-2-methylbenzoic acid3 percentyield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 3.30.9 percentpurity of 5-iodo-2-methylbenzoic acid in crystal75 percent
With sulfuric acid; Iodine monochloride; periodic acid In water; acetic acid at 90℃; for 5.66667 h;
Suspended in a 100 mL three-necked flask equipped with a reflux condenser were 25 mL of 30 weight percent sulfuric acid and 1.36 g (10 mmol) of 2-methylbenzoic acid, and 2.4 g (15 mmol) of iodine monochloride dissolved in 5 g of acetic acid was dropwise added thereto in 40 minutes. Reaction was carried out at 90°C for 5 hours, and the reaction mixture was poured into 90 mL of water. The precipitate was filtered and washed with a sodium sulfite aqueous solution to obtain a crystalline solid (yield: 1.6 g) as the product. This solid was analyzed to find that the product showed the following distribution: [] 2-methylbenzoic acid33 percent5-chloro-2-methylbenzoic acid13 percent3- chloro -2-methylbenzoic acid9 percent5-iodo-2-methylbenzoic acid38 percent3-iodo-2-methylbenzoic acid5 percentothers2 percent The above mixture was purified by recrystallization using acetic acid or isopropyl alcohol to try to isolate 5-iodo-2-methylbenzoic acid. However, a purity of the mixture was scarcely improved, and it was difficult to obtain 5-iodo-2-methylbenzoic acid.
Reference：
[1] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1938, vol. 7/, p. 216
51
[ 118-90-1 ]
[ 62-53-3 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium hydroxide In dimethyl sulfoxide at 130℃; for 18 h;
The reaction was conducted at 130°C in DMSO (3mL) with substituted amine (3 mmol), substituted benzoic acid (1.3mmol), KOH (7 mmol), and 200 mL of the solution containing CuNP- or NiNP-PNF. The progress of the reaction was monitored by TLC. After reaction completion, the mixture was cooled to room temperature and was extracted with ethyl acetate (220mL). The organic extract was washed twice with water and dried with anhydrous Na2SO4, and then filtered and the solvent was evaporated to give the corresponding aryl amine. The crude product was purified by preparative TLC.
Reference：
[1] Australian Journal of Chemistry, 2017, vol. 70, # 10, p. 1127 - 1137
Reference：
[1] Chemische Berichte, 1883, vol. 16, p. 1959[2] Chemische Berichte, 1884, vol. 17, p. 164
54
[ 118-90-1 ]
[ 89001-57-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 0 - 145℃;
[CHLOROSULFONIC] acid (50 [ML,] 752 mmol) was added to a 250-mL round-bottom flask and [COOLED TO 0 °C IN THE] presence of nitrogen. o-Toluic acid (7,10. 0 g, 73.4 mmol) was added in small portions over 2 min to give a brownish solution. The solution was warmed to room temperature and heated to [145 °C] overnight. The reaction mixture was then cooled to room temperature and poured over ice (ca 750 [G) L THE] resulting precipitate was filtered, washed with water and dried in a vacuum oven at [80 °C] for 7 h to afford 15.53 g (90percent) of 8 as an off-white solid [: 1H] NMR (DMSO-d6) 8 2.53 (s, 3H), 7.26 (d, J= 7.9 Hz, [1H),] 7.63 (d, J= 7.9 Hz, 1H), 8.07 (s, [1H),] 13.60 (br s, 1H).
78%
at 100℃; for 2.5 h;
EXAMPLE 102: δ-Chlorosulfonyl^-methyl-benzoic acid; A mixture of o-toluic acid (15 g, 0.11 mol) and chlorosulfonic acid (30 ml) was heated at 1000C under nitrogen for 2.5 h. The reaction mixture was then poured onto ice (500 ml) and the resulting precipitate was filtered, yielding the title compound as an off-white solid (20 g, 78percent yield). MP 151-155 0C. MS: 233.4 (M- 1)
Reference：
[1] Tetrahedron, 2013, vol. 69, # 12, p. 2640 - 2646
[2] Patent: WO2004/18414, 2004, A2, . Location in patent: Page 133-134
[3] Patent: WO2007/91140, 2007, A1, . Location in patent: Page/Page column 65
[4] Patent: US2237974, 1939, ,
[5] Journal of the American Chemical Society, 2013, vol. 135, # 15, p. 5656 - 5668
[6] Journal of Chemical Sciences, 2015, vol. 127, # 3, p. 439 - 445
55
[ 118-90-1 ]
[ 7790-94-5 ]
[ 89001-57-0 ]
Yield
Reaction Conditions
Operation in experiment
78%
at 100℃; for 2.5 h;
A mixture of o-toluic acid (15 g, 0.11 mol) and chlorosulfonic acid (30 ml) was heated at 100 °C under nitrogen for 2.5 h. The reaction mixture was then poured onto ice (500 ml) a nd the resulting precipitate was filtered, yielding the title compound as an off-white solid (20 g, 78percent yield). MP 151-155 °C.
With ammonium cerium (IV) nitrate; sulfuric acid; iodine; acetic acid; at 40℃;
500ml reaction flask, add solvent acetic acid (54.4g), concentrated sulfuric acid (16.3g), stir and mix well, Next add o-toluic acid (13.6 g, 0.1 mol), iodine (25.3 g, 0.06 mol) in succession.Niobium nitrite (28 g, 0.0001 mol) was directly passed through concentrated sulfuric acid-dried air. The reaction was maintained at a temperature of 40C and TLC monitored the disappearance of the starting material. After the reaction is complete, 200 ml of water is added to the system. A large amount of solids precipitated out, which was filtered, washed with water and dried to obtain a solid. The reaction yield was 94.5%, and the HPLC purity was 99.3%. The NMR spectrum of 2-methyl-5-iodobenzoic acid is shown in Figure 1.
93.8 - 94.7%
With hydrogen iodide; iodine; acetic anhydride; acetic acid;H-beta-form zeolite calcined at 550 C for 3 h; In water; at 122℃; for 4h;Product distribution / selectivity;
[Example 9]; The reaction was repeatedly performed six times in a manner similar to that of Example 6 including washing zeolite with acetic acid. After completion of reactions, H-beta-form zeolite (238 g) was recovered. The thus-recovered H-beta-form zeolite was placed in a muffle furnace, where zeolite was dried at 150C for two hours in air and then calcined at 550C for three hours. The calcined H-beta-form zeolite had a weight of 150 g. In a manner similar to that of Example 5 or 6, reaction operations were repeated utilizing the obtained H-beta-form zeolite. As is clear from Table 3 below, excellent reaction results were obtained again after the seventh reaction. Table 3 Reaction 7th 8th 9th 10thConversion1) 97.0 97.5 97.2 96.7Yield2) 94.3 94.7 94.4 93.8Selectivity3) 97.2 97.1 97.1 97.0Crystal purity4) 99.7 99.7 99.7 99.7
>= 88%
With iodic acid; at 20℃;Molecular sieve;
A, 2-methyl benzoic acid as the starting material,The supported molecular sieves are loaded with iron oxide,With iodic acid and molar multiple of 0.5 iodine reaction intermediates a 5-iodo-2-methyl benzoic acid,After the treatment process using cooling after cooling filter,Mother liquid to use the method,As follows: the reaction temperature dropped to 20 degrees Celsius, a large number of solid precipitation, at this temperature will be mixed with catalyticCan be applied 5 times, the filtrate after dissolution, the crude with 2.5 times, the product can be used for 5 times, the filtrate after the dissolution of the solution, By weight of ethyl acrylate to obtain a white product in a yield of 88% or more;
74%
With N-iodo-succinimide; sulfuric acid; In water; at 0℃; for 5h;
To the stirred solution of 2-methyl benzoic acid (50.0 g, 367.6 mmol) inconc.H2S04 (500 mL) was added N-iodosuccinimide (78.6 g, 349.2 mmol) slowlyat 0C. The reaction was stirred at 0C for 5 hours. After completion of the reaction it was quenched with ice. The solid precipitated was filtered, washed with water and dried under vacuum to yield 5-iodo-2-methylbenzoic acid (70.0 g, 74%) as pale brown solid.
69%
With sulfuric acid; iodine; iodic acid;H-beta zeolite; In water; acetic acid; at 20 - 118℃; for 6h;Heating / reflux;Product distribution / selectivity;
The same procedure as in Example 1 was carried out, except that iodic acid (5.3 g, 0.03 mol) was substituted for periodic acid as the oxidizing agent in Example 1. A conversion of 2-methylbenzoic acid was 78 %; the yields were 1) 69 % for 5-iodo-2-methylbenzoic acid and 2) 3 % for the regioisomers of other iodides; and a ratio of 1)/2) was 23.
66.2 - 90.4%
With hydrogen iodide; iodine; acetic anhydride; acetic acid;H-beta-form zeolite calcined at 380 C for 3 h; In water; at 122℃; for 4h;Product distribution / selectivity;
[Example 11]; The procedure of Example 9 was repeated, except that the calcining temperature was adjusted to 380C. As is clear from Table 5 below, catalytic activity was revived to a certain extent. However, as is clear from the Table 5, the activity was lowered as the reaction repeated. Table 5 Reaction 7th 8th 9th 10thConversion1) 95.2 90.2 82.5 70.2Yield2) 90.4 87.0 78.2 66.2Selectivity3) 95.0 96.5 94.8 94.3Crystal purity4) 99.7 99.6 99.5 99.5
63%
With sodium periodate; sulfuric acid; potassium iodide; at 25 - 30℃; for 2.75h;
5-Iodo-2-methylbenzoic Acid (31). NaIO4 (295 mg, 1.38 mmol) and KI (685 mg, 4.13 mmol) were added over 45 min slowly portionwise to stirred 95% H2SO4 (15 mL). Stirring was continued for 1 h at 25-30 C. to give a dark-brown iodinating solution at 25-30 C. To a stirred solution of 2-toluic acid 30 (680 mg, 5 mmol) in 95% H2SO4 (5 mL), the iodinating solution was added dropwise over 45 min while maintaining the temperature at 25-30 C. Stirring was continued for 2 h, and the iodination reaction was quenched by slowly pouring the final reaction mixture into stirred ice water. The mixture was extracted with AcOEt and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and purification by silica gel flash column chromatography to afford compound 31 in 63% yield. 1H NMR (400 MHz, CDCl3): delta 8.38 (d, 1H, J=1.8 Hz), 7.75 (dd, 1H, J=8.1, 1.8 Hz), 7.02 (d, 1H, J=8.1 Hz), 2.59 (s, 3H).
53%
With sulfuric acid; iodine; iodic acid; In water; acetic acid; at 20 - 118℃; for 6h;Heating / reflux;Product distribution / selectivity;
The same procedure as in Example 9 was carried out, except that H- beta zeolite was not used in Example 9. A conversion of 2-methylbenzoic acid was 79 %; the yields were 1) 53 % for 5-iodo-2-methylbenzoic acid and 2) 23 % for the regioisomers of other iodides; and a ratio of 1)/2) was 2.3.
With n-butyllithium; diethylamine; In tetrahydrofuran; hexane; at -78 - 0℃; for 25h;
Diethylamine (1.4 ml) was dissolved in tetrahydrofuran (26 ml), and a solution (1.59 M, 42 ml) of n-butyllithium in hexane was added dropwise at -78C. The mixture was stirred at 0C for 30 min and cooled to -78C. A solution (26 ml) of 2-methylbenzoic acid (4.1 g) in tetrahydrofuran was added dropwise to the reaction solution. The mixture was stirred at 0C for 30 min and cooled to -78C. A solution (26 ml) of <strong>[161609-84-3]1-benzyloxycarbonyl-4-cyanopiperidine</strong> (7.2 g) in tetrahydrofuran was added dropwise to the reaction solution, and the mixture was stirred at -78C for one day. After the completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was concentrated. The obtained residue was subjected to silica gel column chromatography. A chloroform:methanol=30:1 effluent fraction was concentrated, and diisopropyl ether was added to the precipitated crystals. The crystals were collected by filtration. Recrystallization from isopropanol gave 3-(1-benzyloxycarbonylpiperidin-4-yl)-2H-isoquinolin-1-one (1.2 g) as white crystals. melting point: 179-181C. 3-(1-Benzyloxycarbonylpiperidin-4-yl)-2H-isoquinolin-1-one (1.2 g) was suspended in chloroform (10 ml), and a solution (5 ml) of hydrobromic acid in acetic acid was added dropwise. After the completion of the reaction, the solvent was concentrated, and acetone was added to the obtained residue. The precipitated crystals were collected by filtration to give 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrobromide (1.1 g). melting point: >270C.
With sulfuric acid; Iodine monochloride; periodic acid;H-beta zeolite; In water; acetic acid; at 90℃; for 5.66667h;Product distribution / selectivity;
Suspended in a 100 mL three-necked flask equipped with a reflux condenser were 25 mL of 30 weight % sulfuric acid and 1.36 g (10 mmol) of 2-methylbenzoic acid, and 2.4 g (15 mmol) of iodine monochloride dissolved in 5 g of acetic acid was dropwise added thereto in 40 minutes. Reaction was carried out at 90C for 5 hours, and the reaction mixture was poured into 90 mL of water. The precipitate was filtered and washed with a sodium sulfite aqueous solution to obtain a crystalline solid (yield: 1.6 g) as the product. This solid was analyzed to find that the product showed the following distribution: [] 2-methylbenzoic acid33 %5-chloro-2-methylbenzoic acid13 %3- chloro -2-methylbenzoic acid9 %5-iodo-2-methylbenzoic acid38 %3-iodo-2-methylbenzoic acid5 %others2 % The above mixture was purified by recrystallization using acetic acid or isopropyl alcohol to try to isolate 5-iodo-2-methylbenzoic acid. However, a purity of the mixture was scarcely improved, and it was difficult to obtain 5-iodo-2-methylbenzoic acid.
With hydrogen iodide; iodine; acetic anhydride; acetic acid;H-beta-form zeolite; at 122℃; for 4h;Product distribution / selectivity;
5-iodo-2-methylbenzoic acid: 99.7% (purity in crystals) The thus-obtained crystals (1 g) were dissolved in methanol (25 mL), and a 4% aqueous KI solution (25 mL) and 17% sulfuric acid (5 mL) were added to the solution. The resultant solution was titrated with a 0.02M aqueous sodium thiosulfate solution. The free iodine content was found to be 5 ppm. Through ICP-basis total element analysis, Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected, and the Group 1 element content and the Group 2 element content were both 1 ppm or less. [Example 15]; In a 10-L reactor equipped with a reflux condenser, acetic acid (2,678 g), acetic anhydride (823 g), 2-methylbenzoic acid (700 g), iodine (502 g), a 70% aqueous iodic acid solution (299 g), and H-beta-form zeolite (161 g) were placed. The mixture was allowed to react at a reflux temperature of 122C for four hours. After completion of reaction, H-beta-form zeolite was removed from the reaction mixture through filtration. A 10% aqueous sodium thiosulfate solution (200 g) and water (2,500 g) were added to the filtrate, and the mixture was cooled to 30C. The precipitated crystals were collected through filtration, to thereby yield 1,204 g (after drying) of a product. Through HPLC (high-performance liquid chromatography) analysis of the collected crystals and the mother liquor, the following reaction results were obtained. 2-methylbenzoic acid: 97.0% (conversion) 5-iodo-2-methylbenzoic acid: 94.3% (yield) 97.2% (selectivity) 3-iodo-2-methylbenzoic acid: 0.7% (yield) 0.7% (selectivity) 5-iodo-2-methylbenzoic acid crystals: 89.6% (yield) 5-iodo-2-methylbenzoic acid: 99.7% (purity in crystals) The thus-obtained crystals (1 g) were dissolved in methanol (25 mL), and a 4% aqueous KI solution (25 mL) and 17% sulfuric acid (5 mL) were added to the solution. The resultant solution was titrated with a 0.02M aqueous sodium thiosulfate solution. The iodine content was found to be 5 ppm. Through ICP-basis total element analysis, Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected, and the Group 1 element content and the Group 2 element content were both 1 ppm or less.
0.2%; 89.3 - 90.0%
With iodine; acetic anhydride; acetic acid; periodic acid;H-beta-form zeolite; at 122℃; for 4h;Product distribution / selectivity;
[Example 2] The procedure of Example 1 was repeated, except that acetic acid (96.0 g), acetic anhydride (9.2 g), iodine (15.6 g), and periodic acid (5.5 g) instead of iodic acid were employed, to thereby yield 28.5 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 93.0% (conversion) 5-iodo-2-methylbenzoic acid crystals: 73.7% (yield) 5-iodo-2-methylbenzoic acid: 99.5% (purity in crystals) Through analysis of the thus-obtained crystals, the free iodine content was found to be 5 ppm, and Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected. The Group 1 element content and the Group 2 element content were both 1 ppm or less. [Example 13]; The procedure of Example 12 was repeated, except that acetic acid (3,360 g), acetic anhydride (322 g), iodine (544 g), and periodic acid (191 g) instead of iodic acid were employed, to thereby yield 994 g of a product as white crystals. The following reaction analysis results were obtained. 2-methylbenzoic acid: 93.0% (conversion) 5-iodo-2-methylbenzoic acid: 90.0% (yield) 96.8% (selectivity) 3-iodo-2-methylbenzoic acid: 0.2% (yield) 0.2% (selectivity) 5-iodo-2-methylbenzoic acid crystals: 73.7% (yield) 5-iodo-2-methylbenzoic acid: 99.5% (purity in crystals) Through analysis of the thus-obtained crystals, the iodine content was found to be 5 ppm, and Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected. The Group 1 element content and the Group 2 element content were both 1 ppm or less.; [Example 16]; The procedure of Example 15 was repeated, except that acetic acid (3,360 g), acetic anhydride (322 g), iodine (544 g), and periodic acid (191 g) instead of iodic acid were employed, to thereby yield 1.149 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 93.0% (conversion) 5-iodo-2-methylbenzoic acid: 90.0% (yield) 96.8% (selectivity) 3-iodo-2-methylbenzoic acid: 0.2% (yield) 0.2% (selectivity) 5-iodo-2-methylbenzoic acid crystals: 85.2% (yield) 5-iodo-2-methylbenzoic acid: 99.5% (purity in crystals) Through analysis of the thus-obtained crystals, the iodine content was found to be 5 ppm, and Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected. The Group 1 element content and the Group 2 element content were both 1 ppm or less.
6%; 72%
With sulfuric acid; iodine; periodic acid;H-beta zeolite; In water; acetic acid; at 20 - 118℃; for 6h;Heating / reflux;Product distribution / selectivity;
A three-necked flask of 200 mL equipped with a reflux condenser and a stirrer was charged with acetic acid (100 g), H- beta zeolite (4.6 g), iodine (20.2 g, 0.16 mol), 2-methylbenzoic acid (20 g, 0.15 mol), periodic acid dihydrate (7.3 g, 0.03 mol) and sulfuric acid (0.24 g), and they were sufficiently mixed and stirred at a room temperature. The mixture temperature was raised up to 110C on a mantle heater, and then the reaction was carried out for one hour. Further, the reaction was carried out at refluxing temperature (about 118C) of acetic acid for 5 hours. After finishing the reaction, the reaction mixture was filtered to recover H-beta zeolite, and a 10 weight % sodium sulfite aqueous solution (100 mL) was added to the filtrate to treat remaining iodine. Next, water (800 g) was added thereto to precipitate crystal, and then it was filtered and recovered. The crystal thus obtained and the filtrate were analyzed by means of HPLC (high performance liquid chromatography) to investigate the performance enhancement, and it resulted in finding that a conversion of 2-methylbenzoic acid was 88 % and the yields of the products were 72 % for 5-iodo-2-methylbenzoic acid and 6 % for 3-iodo-2-methylbenzoic acid. The ratio of (5-iodo/3-iodo) regioisomer was 12.
3%; 72%
With sulfuric acid; iodine; iodic acid;H-beta zeolite; In water; acetic acid; at 115℃; for 6h;Heating / reflux;Product distribution / selectivity;
A recovered product 13 g was obtained by the same method as in Example 16, except that 4.3 g of iodic acid was substituted for periodic acid. As a result of analysis, the following data were obtained: [] conversion of 2-methylbenzoic acid80 %yield of 5-iodo-2-methylbenzoic acid72 %yield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 243 %purity of 5-iodo-2-methylbenzoic acid in crystal95 %
7 - 8%; 70 - 72%
With sulfuric acid; iodine; periodic acid;H-beta zeolite; In water; acetic acid; at 115℃; for 6h;Heating / reflux;Product distribution / selectivity;
A 100 mL three-necked flask equipped with a reflux condenser was charged with acetic acid 50 g, 2-methylbenzoic acid 10 g, iodine 10.4 g, periodic acid 3.7 g, H-beta zeolite 2.2 g and sulfuric acid 0.12 g, and they were reacted at a refluxing temperature (115C) of acetic acid for 6 hours. After finishing the reaction, H-beta zeolite was separated by filtration, and 20 g of a 10 weight % sodium sulfite aqueous solution and 250 mL of water were added to the filtrate and cooled down to a room temperature. Crystal precipitated was recovered by filtration to obtain 15 g (weight after drying) of a product. The crystal recovered and the mother liquor was analyzed by means of HPLC (high pressure liquid chromatography) to evaluate in obtaining the following results: [] conversion of 2-methylbenzoic acid85 %yield of 5-iodo-2-methylbenzoic acid70 %yield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 107 %purity of 5-iodo-2-methylbenzoic acid in crystal95 %; Reaction was carried out on the same conditions as in Example 16, except that an amount of acetic acid was changed to 40 g, and the filtrate was cooled down to a room temperature after H-beta zeolite was separated. Crystal precipitated was recovered by filtration to obtain 10 g of a product. As a result of analysis, the following data were obtained: [] conversion of 2-methylbenzoic acid88 %yield of 5-iodo-2-methylbenzoic acid72 %yield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 98 %purity of 5-iodo-2-methylbenzoic acid in crystal95 %
20.0%; 69.0%
With sulfuric acid; iodine; acetic acid; periodic acid;H-beta-form zeolite; In n-heptane; at 120℃; for 7h;Product distribution / selectivity;
[Comparative Example 2]; In the same apparatus as employed in Example 1, acetic acid (92 mL), 2-methylbenzoic acid (15.0 g), iodine (12.0 g), a 50% aqueous periodic acid solution (7.2 g), and concentrated sulfuric acid (4.7 g) were placed. The mixture was allowed to react at a reflux temperature of 120C for seven hours. After completion of reaction, the reaction mixture was cooled to room temperature. The precipitated crystals were collected through filtration, to thereby yield 16.4 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 94.0% (conversion) 5-iodo-2-methylbenzoic acid: 69.0% (yield) 73.4% (selectivity) 3-iodo-2-methylbenzoic acid: 20.0% (yield) 21.3% (selectivity) 5-iodo-2-methylbenzoic acid crystals: 54.0% (yield) 5-iodo-2-methylbenzoic acid: 95.0% (purity in crystals) Thus, when concentrated sulfuric acid was employed as an acid catalyst, purity and yield of 5-iodo-2-methylbenzoic acid were unsatisfactory.
20.0%; 69.0%
With sulfuric acid; iodine; acetic acid; periodic acid;H-beta-form zeolite; In water; at 120℃; for 7h;Product distribution / selectivity;
[Comparative Example 5] In the same apparatus as employed in Example 12, acetic acid (3,680 mL), 2-methylbenzoic acid (600 g), iodine (480 g), a 50% aqueous periodic acid solution (288 g), and concentrated sulfuric acid (188 g) were placed. The mixture was allowed to react at a reflux temperature of 120C for seven hours. After completion of reaction, the reaction mixture was cooled to 30C. The precipitated pale gray crystals were collected through filtration, to thereby yield 624 g of a product. The following reaction analysis results were obtained. Through analysis of the thus-obtained crystals, the iodine content was found to be 620 ppm. Through ICP-basis total element analysis, Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected. The Group 1 element content and the Group 2 element content were both 1 ppm or less. Thus, when concentrated sulfuric acid was employed as an acid catalyst, purity and yield of 5-iodo-2-methylbenzoic acid were unsatisfactory.
25%; 66%
With sulfuric acid; iodine; periodic acid; In water; acetic acid; at 20 - 118℃; for 6h;Heating / reflux;Product distribution / selectivity;
The same procedure as in Example 1 was carried out, except that H-beta zeolite was not used in Example 1. A conversion of 2-methylbenzoic acid was 98 %; the yields were 66 % for 5-iodo-2-methylbenzoic acid and 25 % for 3-iodo-2-methylbenzoic acid. The ratio of (5-iodo/3-iodo) regioisomer was 2.6.
2%; 65%
With iodine; iodic acid;H-beta zeolite; In water; acetic acid; at 115℃; for 3h;Heating / reflux;Product distribution / selectivity;
The same procedure as in Example 1 was carried out, except that in Example 1, sulfuric acid was not used; 8.8 g of iodic acid was substituted for periodic acid; and the reaction was carried out at a refluxing temperature (115C) of acetic acid for 3 hours. The results are shown below: [] conversion of 2-methylbenzoic acid70 %yield of 5-iodo-2-methylbenzoic acid65 %yield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 332 %purity of 5-iodo-2-methylbenzoic acid in crystal97 % 5-Iodo-2-methylbenzoic acid obtained by recrystallizing the crystal of 5-iodo-2-methylbenzoic acid described above having a purity of 97 % with a solvent of water : 2-propanol = 1 : 1 (weight ratio) had a purity of 99 % or more. The recrystallized product of 5-iodo-2-methylbenzoic acid described above contained 4 ppm of free iodine. This crystal was subjected to ICP all element analysis to result in finding that Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb and S were not detected and that all the elements of group 1 and group 2 in the periodic table had a content of 1 ppm or less.
12%; 64%
With sodium persulfate; sulfuric acid; iodine;H-beta zeolite; In water; acetic acid; at 20 - 110℃; for 13h;Product distribution / selectivity;
The same apparatus as in Example 1 was used and charged with acetic acid (90 g), water (10 g), H-beta zeolite (2.3 g), iodine (10.3 g, 0.08 mol), 2-methylbenzoic acid (10 g, 0.074 mol), sodium persulfate (11.8 g, 0.05 mol) and sulfuric acid (0.12 g). After they were sufficiently mixed and stirred at a room temperature, the mixture temperature was elevated up to 90C, and then the reaction was carried out for 5 hours. Further, the reaction was carried out at 110C for 8 hours, and then the reaction was finished. H-beta zeolite was separated by filtration, and remaining iodine was treated by a 10 weight % sodium sulfite aqueous solution. Then, 800 mL of water was added thereto, and crystal precipitated was filtered off. A conversion of 2-methylbenzoic acid was 86 %; the yields were 1) 64 % for 5-iodo-2-methylbenzoic acid and 2) 12 % for 3-iodo-2-methylbenzoic acid; and a ratio of 1)/2) was 5.3.
2.2%; 60.2%
With hydrogen iodide; iodine; acetic acid;H-beta-form zeolite; In water; at 122℃; for 4h;Product distribution / selectivity;
[Comparative Example 7]; The procedure of Example 12 was repeated, except that acetic anhydride was not employed, to thereby yield 598 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 65.8% (conversion) 5-iodo-2-methylbenzoic acid: 60.2% (yield) 91.5% (selectivity) 3-iodo-2-methylbenzoic acid: 2.2% (yield) 3.3% (selectivity) 5-iodo-2-methylbenzoic acid crystals: 45.8% (yield) 5-iodo-2-methylbenzoic acid: 95.2% (purity in crystals) Through analysis of the thus-obtained crystals, the iodine content was found to be 480 ppm. Through ICP-basis total element analysis, Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb, or S was not detected. The Group 1 element content and the Group 2 element content were both 1 ppm or less. Thus, when acetic anhydride was not employed, purity and yield of 5-iodo-2-methylbenzoic acid were unsatisfactory.
2.2%; 60.2%
With hydrogen iodide; iodine; acetic acid;H-beta-form zeolite; at 122℃; for 4h;Product distribution / selectivity;
[Comparative Example 4]; The procedure of Example 1 was repeated, except that acetic anhydride was not employed, to thereby yield 18.5 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 65.8% (conversion) 5-iodo-2-methylbenzoic acid: 60.2% (yield) 91.5% (selectivity) 3-iodo-2-methylbenzoic acid: 2.2% (yield) 3.3% (selectivity) 5-iodo-2-methylbenzoic acid crystals: 45.8% (yield) 5-iodo-2-methylbenzoic acid: 95.2% (purity in crystals) Thus, when acetic anhydride was not employed, purity and yield of 5-iodo-2-methylbenzoic acid were unsatisfactory.
20%; 56%
With sulfuric acid; iodine; periodic acid; In water; acetic acid; at 115℃; for 6h;Heating / reflux;Product distribution / selectivity;
Reaction was carried out by the same method as in Example 16 to obtain 15 g of a product, except that H-beta zeolite was not used. As a result of analysis, the following data were obtained: [] conversion of 2-methylbenzoic acid85 %yield of 5-iodo-2-methylbenzoic acid56 %yield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 2.820 %purity of 5-iodo-2-methylbenzoic acid in crystal80 %
0.7%; 46.3 - 94.6%
With hydrogen iodide; iodine; acetic anhydride; acetic acid;H-beta-form zeolite; In water; at 122℃; for 4h;Product distribution / selectivity;
[Example 5]; In a 10-L reactor equipped with a reflux condenser, acetic acid (2,678 g), acetic anhydride (823 g), 2-methylbenzoic acid (700 g), iodine (502 g), a 70% aqueous iodic acid solution (299 g), and H-beta-form zeolite (161 g) were placed. The mixture was allowed to react at a reflux temperature of 122C for four hours. After completion of reaction, H-beta-form zeolite was removed from the reaction mixture through filtration through suction by use of a membrane filter. The H-beta-form zeolite left on the filter was washed with acetic acid (350 g), and the wash liquid and the filtrate were combined, followed by cooling to room temperature. The precipitated crystals were collected through filtration, to thereby yield 970 g (after drying) of a product. Through HPLC (high-performance liquid chromatography) analysis of the collected crystals and the mother liquor, the following reaction results were obtained. 2-methylbenzoic acid: 97.0% (conversion) 5-iodo-2-methylbenzoic acid: 94.3% (yield) 97.2% (selectivity) 3-iodo-2-methylbenzoic acid: 0.7% (yield) 0.7% (selectivity) 5-iodo-2-methylbenzoic acid: 99.7% (purity in crystals); [Example 6]; In Example 6, H-beta-form zeolite (245 g) which had been recovered after filtration and washing performed in Example 5 was used. In a manner similar to that of Example 5, reaction, separation/recovery of H-beta-form zeolite, and recovery of reaction products from mother liquor were repeatedly carried out. The results are shown in Table 1. As is clear from Table 1, excellent results were obtained in repetition of operations. However, after completion of the sixth reaction, conversion of 2-methylbenzoic acid and yield of 5-iodo-2-methylbenzoic acid were lowered. Table 1 Reaction 1st 2nd 3rd 4th 5th 6thConversion1) 97.0 97.5 97.2 96.7 95.9 93.0Yield2) 94.3 94.5 94.5 93.8 92.9 90.2Selectivity3) 97.2 96.9 97.2 97.0 96.9 97.0Crystal purity4) 99.7 99.7 99.7 99.7 99.6 99.6 1)2-methylbenzoic acid (conversion) (%) 2)5-iodo-2-methylbenzoic acid (yield) (%) 3)5-iodo-2-methylbenzoic acid (selectivity) (%) 4)5-iodo-2-methylbenzoic acid (purity in crystals) (%)The same definitions are applied to the following Tables.; [Example 7]; The procedure of Example 5 was repeated, except that H-beta-form zeolite separated through filtration from the reaction mixture was recovered without washing with acetic acid. The following reaction analysis results were obtained. 2-methylbenzoic acid: 97.0% (conversion) 5-iodo-2-methylbenzoic acid: 94.1% (yield) 97.0% (selectivity) 3-iodo-2-methylbenzoic acid: 0.7% (yield) 0.7% (selectivity) 5-iodo-2-methylbenzoic acid: 99.7% (purity in crystals); [Example 8]; In Example 8, H-beta-form zeolite (287 g) which had been separated from the reaction mixture in Example 7 but had not been washed with acetic acid was used. In a manner similar to that of Example 7, reaction, separation/recovery of H-beta-form zeolite, and recovery of reaction products from mother liquor were repeatedly carried out. The results are shown in Table 2. As is clear from Table 2, excellent results were obtained in repetition of operations. However, after completion of the sixth reaction, conversion of 2-methylbenzoic acid and yield of 5-iodo-2-methylbenzoic acid were lowered. Table 2 Reaction 1st 2nd 3rd 4th 5th 6thConversion1) 97.0 97.2 97.2 96.8 96.0 94.2Yield2) 94.1 94.6 94.6 93.7 93.2 89.8Selectivity3) 97.0 97.3 97.3 96.8 97.1 95.8Crystal purity4) 99.7 99.7 99.7 99.7 99.6 99.6; [Example 9]; The reaction was repeatedly performed six times in a manner similar to that of Example 6 including washing zeolite with acetic acid. After completion of reactions, H-beta-form zeolite (238 g) was recovered. The thus-recovered H-beta-form zeolite was placed in a muffle furnace, where zeolite was dried at 150C for two hours in air and then calcined at 550C for three hours. The calcined H-beta-form zeolite had a weight of 150 g. In a manner similar to that of Example 5 or 6, reaction operations were repeated utilizing the obtained H-beta-form zeolite. As is clear from Table 3 below, excellent reaction results were obtained again after the seventh reaction. Table 3 Reaction 7th 8th 9th 10thConversion1) 97.0 97.5 97.2 96.7Yield2) 94.3 94.7 94.4 93.8Selectivity3) 97.2 97.1 97.1 97.0Crystal purity4) 99.7 99.7 99.7 99.7; [Example 10]; The reaction was repeatedly performed six times in a manner similar to that of Example 6. Subsequently, the reaction was further repeated in the same manner. The reaction results are shown in Table 4. Table 4 Reaction 7th 8th 9th 10thConversion1) 88.2 80.2 68.5 50.2Yield2) 84.2 76.8 64.7 46.3Selectivity3) 95.5 95.8 94.5 92.2Crystal purity4) 99.6 99.5 99.5 99.1; [Example 12]; In a 10-L reactor equipped with a reflux condenser, acetic acid (2,678 g), acetic anhydride (823 g), 2-methylbenzoic acid (700 g), iodine (502 g), a 70% aqueous iodic acid solution (299 g), and H-beta-form zeolite (161 g) were placed. The mixture was allowed to react at a reflux temperature of 1.22C for fo...
12.0%; 40.6%
With sulfuric acid; Iodine monochloride; In n-heptane; at 90℃; for 5h;Product distribution / selectivity;
[Comparative Example 1] To a 100-mL three-neck flask equipped with a reflux condenser, 30% sulfuric acid (25 mL) and 2-methylbenzoic acid (1.36 g, 10 mmol) were fed to form a suspension. Iodine monochloride (2.4 g, 15 mmol) was added dropwise to the suspension. The mixture was allowed to react at 90C for five hours, and the reaction mixture was poured into water (90 mL). The precipitated product was collected through filtration, followed by washing with an aqueous sodium sulfite solution, to thereby yield a crystalline solid as a reaction product (yield: 1.6 g). The following reaction analysis results were obtained. The above mixture was purified through recrystallization from acetic acid, isopropyl alcohol, or a similar solvent, so as to isolate 5-iodo-2-methylbenzoic acid. However, the purity of the mixture was not virtually enhanced, and 5-iodo-2-methylbenzoic acid was difficult to obtain.
18%; 37%
With sodium periodate; sulfuric acid; sodium iodide; In water; acetic acid; at 85℃; for 2.58333h;Product distribution / selectivity;
The same apparatus as in Example 16 was used to dissolve 1.36 g of 2-methylbenzoic acid in 9 mL of acetic acid. The temperature of the mixture was maintained at 85C, and 11 ml of conc. sulfuric acid was dropwise added thereto in 25 minutes. Further, 0.6 g of sodium periodate was added thereto, and then a solution prepared by dissolving 1.1 g of sodium iodide in 5 mL of acetic acid was dropwise added thereto in 10 minutes. Thereafter, the reaction was carried out for 2 hours, and after cooling, the reaction mixture was poured into 90 mL of water and the produced muddy mixture was filtered. Sodium sulfite 1 g was added thereto to remove unreacted iodine. After drying, the product thus obtained was analyzed to result in obtaining the following data: [] 2-methylbenzoic acid35 %5-iodo-2-methylbenzoic acid37 %3-iodo-2-methylbenzoic acid18 %others5 % It was tried to obtain 5-iodo-2-methylbenzoic acid from the above mixture as was the case with Comparative Example 11, but the purity was scarcely improved, and it was difficult to obtain 5-iodo-2-methylbenzoic acid.
2.8%; 9.5%
With iodine; acetic anhydride; acetic acid;H-beta-form zeolite; at 122℃; for 4h;Product distribution / selectivity;
[Comparative Example 3]; The procedure of Example 1 was repeated, except that iodic acid was not employed, to thereby yield 5 g of a product. The following reaction analysis results were obtained. 2-methylbenzoic acid: 15.8% (conversion) 5-iodo-2-methylbenzoic acid: 9.5% (yield) 60.1% (selectivity) 3-iodo-2-methylbenzoic acid: 2.8% (yield) 18.0% (selectivity) 5-iodo-2-methylbenzoic acid crystals: 7.4% (yield) 5-iodo-2-methylbenzoic acid: 57.0% (purity in crystals) Thus, when iodic acid was not employed, purity and yield of 5-iodo-2-methylbenzoic acid were unsatisfactory.
0.9%; 3%
With sulfuric acid; iodine;H-beta zeolite; In water; acetic acid; at 115℃; for 6h;Heating / reflux;Product distribution / selectivity;
Reaction was carried out by the same method as in Example 16 to obtain 0.8 g of a product, except that periodic acid was not used. As a result of analysis, the following data were obtained: [] conversion of 2-methylbenzoic acid5 %yield of 5-iodo-2-methylbenzoic acid3 %yield of 3-iodo-2-methylbenzoic acid ratio of (5-iodo/3-iodo) regioisomer = 3.30.9 %purity of 5-iodo-2-methylbenzoic acid in crystal75 %
With sulfuric acid; iodine; periodic acid;ZSM-5; In water; acetic acid; at 20 - 118℃; for 6h;Heating / reflux;Product distribution / selectivity;
The same procedure as in Example 1 was carried out, except that mordenite, Y, L and ZSM-5 which are microporous materials each were substituted for H-beta zeolite in Example 1. When using respective zeolites, The ratio of (5-iodo/3-iodo) regioisomer is shown below. [] mordenite (Example 11)5.0zeolite Y (Example 12)4.8zeolite L (Example 13)5.2ZSM-5 (Example 14)4.0 A ratio of (5-iodo/3-iodo) regioisomer in the case of H-beta zeolite (Example 1) was 12, and that in the case where zeolite was not used (Comparative Example 1) was 2.6. It was found that the selectivity was high as well in the cases where zeolites other than H-beta zeolite were used.
With sulfuric acid; iodine; periodic acid;mordenite; In water; acetic acid; at 20 - 118℃; for 6h;Heating / reflux;Product distribution / selectivity;
The same procedure as in Example 1 was carried out, except that mordenite, Y, L and ZSM-5 which are microporous materials each were substituted for H-beta zeolite in Example 1. When using respective zeolites, The ratio of (5-iodo/3-iodo) regioisomer is shown below. [] mordenite (Example 11)5.0zeolite Y (Example 12)4.8zeolite L (Example 13)5.2ZSM-5 (Example 14)4.0 A ratio of (5-iodo/3-iodo) regioisomer in the case of H-beta zeolite (Example 1) was 12, and that in the case where zeolite was not used (Comparative Example 1) was 2.6. It was found that the selectivity was high as well in the cases where zeolites other than H-beta zeolite were used.
With sulfuric acid; iodine; periodic acid;zeolite L; In water; acetic acid; at 20 - 118℃; for 6h;Heating / reflux;Product distribution / selectivity;
The same procedure as in Example 1 was carried out, except that mordenite, Y, L and ZSM-5 which are microporous materials each were substituted for H-beta zeolite in Example 1. When using respective zeolites, The ratio of (5-iodo/3-iodo) regioisomer is shown below. [] mordenite (Example 11)5.0zeolite Y (Example 12)4.8zeolite L (Example 13)5.2ZSM-5 (Example 14)4.0 A ratio of (5-iodo/3-iodo) regioisomer in the case of H-beta zeolite (Example 1) was 12, and that in the case where zeolite was not used (Comparative Example 1) was 2.6. It was found that the selectivity was high as well in the cases where zeolites other than H-beta zeolite were used.
With sulfuric acid; iodine; periodic acid;Zeolite Y; In water; acetic acid; at 20 - 118℃; for 6h;Heating / reflux;Product distribution / selectivity;
The same procedure as in Example 1 was carried out, except that mordenite, Y, L and ZSM-5 which are microporous materials each were substituted for H-beta zeolite in Example 1. When using respective zeolites, The ratio of (5-iodo/3-iodo) regioisomer is shown below. [] mordenite (Example 11)5.0zeolite Y (Example 12)4.8zeolite L (Example 13)5.2ZSM-5 (Example 14)4.0 A ratio of (5-iodo/3-iodo) regioisomer in the case of H-beta zeolite (Example 1) was 12, and that in the case where zeolite was not used (Comparative Example 1) was 2.6. It was found that the selectivity was high as well in the cases where zeolites other than H-beta zeolite were used.
With N-iodo-succinimide; sulfuric acid; at 5℃; for 2h;
In a reaction vessel equipped with a magnetic stirrer, sulfuric acid(6.0 ml, 11 g) were charged,Saturated sulfuric acid (in the reaction system)Was set to 5 C. ). Then, under stirring,NIS (N-iodosuccinimide;Halogenating agent) (0.23 g, 1.0 mmolActive oxygen content 1.0 mmol) was added to the reaction vessel and stirring was continued for 30 minutes.Thereafter, while maintaining the temperature in the reaction system at 5 C. under stirring, o-toluic acid was added under light shielding;"2-methylbenzoic acid"(0.14 g; 1.0 mmol) was added to the reaction vessel and stirring was continued for 2 hours (reaction was carried out).The reaction product was purified by high performance liquid chromatography(HPLC). As a result, the conversion rate of o-toluic acid iodinated was 99%. Also,The target product ((5-I) in the following formula)And an isomer ((3-I) in the following formula), The target compound: isomer = 3.4: 1Met. The reaction conditions and results are summarized in Table 1.
With Oxone; sulfuric acid; potassium iodide; In acetic acid; at 25℃; for 2h;
Sulfuric acid (3.0 ml, 5.5 g) was charged into a reaction vessel equipped with a magnetic stirrer at 25 C., and acetic acid (3.0 ml, 3.2 g) as a solvent was added. While stirring, potassium iodide (halogen0.17 g; 1.0 mmol) was added to the reaction vessel. While stirring, while maintaining the temperature in the reaction system at 25 C., a double salt of potassium peroxymonosulfate (2 KHSO 5 .KHSO 4K2 SO4); registered trademark "Oxone" (0.34 g; 0.5 mmol, 1.0 mmol in terms of active oxygen) was added to the reaction vessel and stirring was continued for 30 minutes.Thereafter, o-toluic acid, "2-methylbenzoic acid" (0.14 g; 1.0 mmol) was added into the reaction vessel under shielding while maintaining the temperature inside the reaction system at 25 C. under stirring , At the same temperature 2Stirring was continued for a while (the reaction was carried out).When the reaction product was confirmed by high performance liquid chromatography (HPLC), the conversion of o-toluic acid by halogenation (iodination) was 75%. In addition, target substance (in the following formula(5-I)) and the isomer ((3-I) in the following formula) was the target compound: isomer = 3.3: 1. The reaction conditions and results are summarized in Table 1.
(a) 2-Methyl-5-(trifluoromethylcarbonylamino-methyl)benzoic acidN-(Hydroxymethyl)trifluoroacetamide (300 mmol; 42.9 g) was added to a mixture of2-methylbenzoic acid (300 mmol; 40.8 g) and concentrated H2S04 (750 mL). The mixture was stirred at rt overnight and poured into ice water. The precipitate was collected by filtration, dried and recrystallised from toluene/butan-2-one (7:1 ) to give the desired product. Yield: 31 g (40%). MS [M-H]" = 260.
40%
With sulfuric acid; at 20℃;
N-(Hydroxymethyl)trifluoroacetamide (300 mmol; 42.9 g) was added to a mixture of 2-methylbenzoic acid (300 mmol; 40.8 g) and concentrated H2SO4 (750 mL). The mixture was stirred at rt overnight and poured into ice water. The precipitate was collected by filtration, dried and recrystallised from toluene/butan-2-one (7:1) to give the desired product. Yield: 31 g (40%). MS [M-H]-=260.
General procedure: At room temperature, organic carbonyl acid 3 (R-COOH, 0.5 mmol) was added into a reaction tube equipped with a small magnet. Then a solution of tertiary amine 1 (R1CH2-NR2R3, 0.5 mmol ) in DCM (2.5 mL) was added dropwise in 2 min. After the mixture was stirred at room temperature for a few minutes, 1 equivalents of dimethyl acetylenedicarboxylate (DMAD, 2) was added. The reaction was stirred overnight at room temperature, and then monitored by TLC with silica gel coated plates. After being stirred for 14 h, the solvent was removed and the residue was purified by a flash column chromatography with silica gel with ethyl acetate/hexane (1:25-30) as eluent to give the desired products 4, 5, and 7. Most of compounds are known and confirmed by NMR, ESI-MS, IR.
methyl N<SUP>2</SUP>,N<SUP>6</SUP>-bis(2-methylbenzoyl)-L-lysinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 2-Methylbenzoic acid (1.36 g, 10 mmol) in DCM (50 mL), Et3N (1.12 g, 11 mmol) and TBTU (3.60 g,11 mmol) were added in turn. After 20 min, compound b (n =4, 1.17 g, 5 mmol) and Et3N (0.50 g, 5 mmol) were added. The reaction solution was stirred at room temperature for 8 h.Then, the solvent was evaporated with the residue being takenup in EtOAc (50 mL). the EtOAc solution was washed with saturated citric acid (3 × 20 mL), NaHCO3 (3 × 20 mL), and brine (3 × 20 mL), dried over MgSO4, and evaporated under vacuum. The desired compound c (1.50 g, 76 percent yield) was derived by crystallization in EtOAc/petroleum ether (1/4) as white powder. ESI-MS: m/z: 397.8 [M+H]+.
General procedure: To a solution of 3a (1 g) in ethanol was added Pd/C (5%, 0.1 g) and the mixture was stirred for 24 hrs at room temperature in a hydrogen atmosphere under atmospheric pressure. Insoluble matters were removed using Celite, and the filtrate was concentrated in vacuo to give the desired product 4a (0.76 g) as a yellow solid. To a solution of carboxylic acid (1 equiv) in CH2Cl2 (15 mL) at 0 C was added DMAP (1 equiv) and EDCI (1 equiv). The reaction mixture was stirred at 0 C for 45 minutes. At this time 4a (1 equiv) was added and the mixture was warmed to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo, partitioned between 1.0 M HCl (20 ml) and ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2 × 15 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatograph using a mixture of petroleum ether/ethyl acetate (20 : 5, v/v) as eluent to afford the product as a white solid. To a solution of the obtained solid (1 equiv) in 2:3:1 THF/MeOH/H2O (18 ml) was added LiOH·H2O (1.5 equiv). After stirring at room temperature for 4 h, the volatiles were removed under reduced pressure. The residue was acidified with 1N hydrochloric acid solution, and then filtered and the filter cake was washed with 5 mL of water, dried in vacuum to afford a white powder. Recrystallization from 75% EtOH gave the desired compounds 2-17 as white solid.
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