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[ CAS No. 133232-56-1 ]

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Product Details of [ 133232-56-1 ]

CAS No. :133232-56-1 MDL No. :MFCD00270112
Formula : C8H7IO2 Boiling Point : -
Linear Structure Formula :- InChI Key :XGNKIHYPOWUMKL-UHFFFAOYSA-N
M.W :262.04 g/mol Pubchem ID :2734888
Synonyms :

Calculated chemistry of [ 133232-56-1 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 51.08
TPSA : 37.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.15 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.6
Log Po/w (XLOGP3) : 2.46
Log Po/w (WLOGP) : 2.3
Log Po/w (MLOGP) : 2.82
Log Po/w (SILICOS-IT) : 2.63
Consensus Log Po/w : 2.36

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -3.35
Solubility : 0.116 mg/ml ; 0.000445 mol/l
Class : Soluble
Log S (Ali) : -2.89
Solubility : 0.34 mg/ml ; 0.0013 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.11
Solubility : 0.203 mg/ml ; 0.000774 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 1.57

Safety of [ 133232-56-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 133232-56-1 ]

* 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.

  • Upstream synthesis route of [ 133232-56-1 ]
  • Downstream synthetic route of [ 133232-56-1 ]

[ 133232-56-1 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 118-90-1 ]
  • [ 7499-08-3 ]
  • [ 7499-06-1 ]
  • [ 133232-56-1 ]
  • [ 54811-38-0 ]
YieldReaction ConditionsOperation 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] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 11-12
  • 2
  • [ 118-90-1 ]
  • [ 7499-08-3 ]
  • [ 7499-06-1 ]
  • [ 133232-56-1 ]
  • [ 54811-38-0 ]
YieldReaction ConditionsOperation 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] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 11-12
  • 3
  • [ 133232-56-1 ]
  • [ 52570-33-9 ]
YieldReaction ConditionsOperation in experiment
92% at 0℃; for 3 h; Heating / reflux To a solution of compound 2 (63.0 g, 0.24 mol) in MeOH (300 mL) was added dropwise a freshly prepared solution of SOCI2 (52 mL, 0.72 mol) in MeOH (100 mL) at 0 0C. The mixture was heated to reflux for 3 hours. TLC (petroleum ether: ethyl acetate = 10:1) showed the reaction was complete, then the mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether) to afford compound 3 (60 g, 92percent) as brown oil. 1H NMR (400 MHz, CDCI3): δ 7.94-7.96 (d, J = 8.0 Hz, 1 H), 7.71-7.73 (d, J = 8.0 HzJ H), 6.87- 6.91 (t, J = 8.0 Hz, 1 H), 3.88 (s, 3H), 2.65 (s, 3H).
87.5% for 5 h; Heating / reflux 3-Iodo-2-methylbenzoic acid (10.00 g, 38.16 mmol), methanol (50 ml) and concentrated sulfuric acid (0.6 ml, 11.45 mmol) were mixed, and the mixture was stirred for 5 hours while heating to reflux. The reaction solution was concentrated, ethyl acetate (80 ml) and water (30 ml) were added to the residue. The organic layer was separated and washed three times with a saturated aqueous sodium bicarbonate solution (30 ml) and once with 10percent brine (30 ml) . The organic layer was concentrated, to yield the title compound (9.22 g) (yield 87.5percent) .1H-NMR (CDCl3, TMS, 300 MHz) δ (ppm) : 2.67 (3H, s) , 3.90 (3H, s), 6.92 (IH, t, J = 7.8 Hz), 7.74 (IH, dd, J = 1.2 Hz, 7.8 Hz) , 7.98 (IH, dd, J = 1.2 Hz, 7.9 Hz) .
80.4% at 0 - 80℃; for 16 h; [0469] To a solution of 3-iodo-2-methylbenzoic acid (2.0 g, 3.82 mmol) in dry MeOH (10 mL) at 0 °C was added thionyl chloride (681mg, 5.72 mmol). Then the reaction was heated to 80 °C for 16 hrs. TLC showed the starting material was consumed and one main spot was present. The reaction was cooled to rt and the solvent was removed. The residue was diluted with water (20 mL) and extracted with EA (40 mL) twice. The combined organic layers were washed with saturated sodium bicarbonate aqueous (30 mL), brine, dried over sodium sulfate, filtered and concentrated providing crude product, which was purified by column chromatography on silica-gel elution with petroleum ether:EA (from 0percent to 8percent) providing methyl 3-iodo-2-methylbenzoate (1.7 g, 80.4percent yield) as a colorless oil. MS (ESI) m/z 277.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 1.2, 8.0 Hz, 1 H), 7.73 (dd, J = 0.8, 8.0 Hz, 1 H), 6.92 (t, J = 8.0 Hz, 1 H), 3.89 (s, 3 H), 2.66 (s, 3 H).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 23, p. 6273 - 6278
[2] Patent: WO2006/117669, 2006, A1, . Location in patent: Page/Page column 41; 108
[3] Patent: WO2008/16184, 2008, A1, . Location in patent: Page/Page column 119-120
[4] Patent: WO2017/201069, 2017, A1, . Location in patent: Paragraph 0469
[5] Patent: WO2007/90068, 2007, A2, . Location in patent: Page/Page column 62
  • 4
  • [ 118-90-1 ]
  • [ 133232-56-1 ]
  • [ 54811-38-0 ]
YieldReaction ConditionsOperation 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

Reference: [1] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 6
[2] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 6-7; 11; 13
[3] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 8
[4] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 11
[5] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 11
[6] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 8
[7] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 12
[8] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 8
[9] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 10-11
[10] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 10
[11] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 12
[12] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 8-9
[13] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 12
[14] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 9-11
[15] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 7-8
[16] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 12
[17] Patent: EP1642881, 2006, A1, . Location in patent: Page/Page column 8
[18] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 12
[19] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 10
[20] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 10
[21] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 10
[22] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 10
[23] Patent: JP2018/76289, 2018, A, . Location in patent: Paragraph 0075; 0076; 0077; 0078; 0079; 0080; 0081-0088
[24] Patent: JP2018/70601, 2018, A, . Location in patent: Paragraph 0084; 0085; 0088; 0089; 0090; 0091; 0092; 0094
  • 5
  • [ 118-90-1 ]
  • [ 7499-08-3 ]
  • [ 7499-06-1 ]
  • [ 133232-56-1 ]
  • [ 54811-38-0 ]
YieldReaction ConditionsOperation 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] Patent: EP1595862, 2005, A1, . Location in patent: Page/Page column 11-12
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