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CAS No. :37470-46-5 MDL No. :MFCD00234263
Formula : C7H5IO3 Boiling Point : -
Linear Structure Formula :- InChI Key :BJZXBZGGLXHODK-UHFFFAOYSA-N
M.W : 264.02 Pubchem ID :449473
Synonyms :

Safety of [ 37470-46-5 ]

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

Application In Synthesis of [ 37470-46-5 ]

* 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 [ 37470-46-5 ]
  • Downstream synthetic route of [ 37470-46-5 ]

[ 37470-46-5 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 37470-46-5 ]
  • [ 1311175-63-9 ]
  • [ 25804-49-3 ]
Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 13, p. 5198 - 5206
  • 2
  • [ 67-56-1 ]
  • [ 37470-46-5 ]
  • [ 15126-06-4 ]
YieldReaction ConditionsOperation in experiment
59% at 20 - 55℃; for 20 h; Example 1: Preparation of 3-benzyl-3-methyl-2,3-dihvdrobenzofuran-6-carboxylic acid- piperidine amide (MDA7) [0076] A) 4-Hydroxy-3-iodo-benzoic acid: 4-Hydroxybenzoic acid (0.037 mol, 5.1 g) was dissolved in 100 mL of methanol. One equivalent each of sodium iodide (0.037 mol, 5.54 g) and sodium hydroxide (0.037 mol, 1.48 g) was added, and the solution was cooled to 0° C. Aqueous sodium hypochlorite (64 ml, 4.0percent NaOCl) was added dropwise over 75 min at 0-3° C. As each drop hit the solution, a red color appeared and faded almost instantly. The resulting colorless slurry was stirred for 1 h at 0-2° C. and then was treated with 40 mL of 10percent aqueous sodium thiosulfate. The mixture was acidified by 4M aqueous HC1. A product crystallized and was filtered off to afford 1.1 g. Ethyl acetate (250 mL) was added, and the layers were separated. The organic layer was washed with brine (240 mL), water and then dried over MgS04. After evaporation of the solvent, 4.3 g of a white powder was obtained. The aqueous phase was acidified to pH 1. Ethyl acetate (250 mL) was added, and the layers were separated. The organic layer was washed with brine (240 mL), water and then dried over MgS04. After evaporation of the solvent, 8.22 g of a white powder was obtained. [0077] B) Methyl 4-hydroxy-3-iodobenzoate: A solution of 3-iodo-4-Hydroxybenzoic acid (7.25 g, 27.4 mmol) and sulfuric acid (1.9 ml, 36 mmol) in methanol is stirred at 55° C. for 6 hours. TLC (dichloromethane): 30percent of starting material. The solution is stirred 12 h at room temperature. TLC (dichloromethane): 10percent of starting material and stirred at 55° C. for 2 h. After cooling, ethyl acetate (200 mL) was added and the mixture was adjusted to pH 3 using sodium bicarbonate. The organic layer was washed two times with water and then dried over MgS04. Filtration and rotary evaporation at 40° C. afforded a white solid. The solid was triturated with hexane, filtered off and dried under reduced pressure. M=4.47 g. Yield: 59percent. [0078] C) 4-Iodo-3-(2-methyl-allyloxy)-benzoic acid methyl ester: To a solution of methyl 3- hydroxy-4-iodobenzoate (1.5 g, 5.4 mmol) in anhydrous methyl ethyl ketone (60 mL) was added finely powdered Potassium carbonate (1.49 g, 10.78 mmol) followed by 3-bromo-2- methyl-propene (0.81 mL, 1.1 g, 8.15 mmol). The reaction mixture was heated at 70° C. for 4 h. The mixture was diluted filtrated, washed with water and dried over MgS04. Evaporation of the solvent and of the remaining bromopropene in vacuo afforded the requisite alkylated ester as a yellow oil. M: 1.4 g, Yield: 78percent. [0079] NMR (CDC13, 1H): 1.90 (3H, d, J=1.2 Hz), 194 (3H, s), 4.56 (2H, s), 5.06 (IH, d, J=1.2 Hz), 5.25 (IH, d, J=1.2 Hz), 7.38 (IH, dd, J=8.1 Hz, J=1.8 Hz), 7.44 (IH, d, J=1.8 Hz), 7.88 (IH, d, J=1.8 Hz) [0080] D) 3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester: To a solution of 4-Iodo-3-(2-methyl-allyloxy)-benzoic acid methyl ester (455 mg, 1.37 mmol) in DMF (15 mL) were added Potassium carbonate (379 mg, 2.74 mmol), Tetrabutylammonium chloride (380 mg, 1.37 mmol), Palladium acetate (25.6 mg, 0.136 mmol) in DMF (5 mL) and Phenylboronic acid (200 mg, 1.64 mmol). The resulting mixture was stirred for 3 h at 115° C, cooled to room temperature, filtered over silica, washed with water, dried over MgS04 and concentrated. Column chromatography (silica gel, heptane/CH2Cl2: 4/6) afforded 368 mg (95percent) of the title compound as a slightly brown oil which crystallize. Mp: 52° C. [0081] NMR (CDCI3, 1H): 1.38 (3H, s), 2.86 (IH, d, J=14 Hz), 2.93 (IH, d, J=14 Hz), 3.89 (3H, s), 4.12 (IH, d, J=8.7 Hz), 4.55 (IH, d, J=8.7 Hz), 6.93-6.98 (3H, m), 7.22-7.24 (3H, m), 7.38 (IH, d, J=1.2 Hz), 7.59 (IH, dd, Jl=7.5 Hz, J2=1.2 Hz). [0082] E) 3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid: A mixture of 3- Benzyl-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (300 mg, 1.06 mmol), sodium hydroxide (260 mg, 6.5 mmol), ethanol (10 ml) and water (1 ml) in tetrahydrofuran (10 ml), is stirred for 12 h at room temperature. The reaction medium is acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried (Na2S04), and concentrated in a rotary evaporator. The product is obtained as a white solid (300 mg, 100percent). Mp: 165° C. [0083] NMR (CDCI3, 1H): 1.39 (3H, s), 2.87 (IH, d, J=14 Hz), 2.93 (IH, d, J=14 Hz), 4.14 (IH, d, J=8.7 Hz), 4.57 (IH, d, J=8.7 Hz), 6.96-7.00 (3H, m), 7.22-7.25 (3H, m), 7.45 (IH, d, J=1.2 Hz), 7.65 (IH, dd, Jl=7.8 Hz, J2=1.2 Hz). [0084] F) 3-benzyl-3-methyl-2,3-dihydrobenzofuran-6-carboxylic acid-piperidine amide: To a stirred suspension of the 3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (80 mg, 0.3 mmol) and piperidine (28 mg, 33 μ, 0.33 mmol) in dichloromethane (3 mL) and DMF (2 mL) were added 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafhiorophosphate (HATU) (125 mg, 0.33 mmol) and then a solution of N,N- diisopropylethylamine (58 mg, 78 μ, 0.45 mmol, mL) in DMF (1 mL). The reaction mixture was stirred at ambient temperature for 18 h. The reaction medium is acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried (MgS04), and concentrated to give the amide which is purified by flash chromatography (AcOEt/heptane: 4/6) to afford 50 mg of a white solid (yield: 50percent). [0085] NMR (CDC13, 1H): 1.36 (3H, s), 1.54-1.67 (6H, m), 2.85 (1H, d, J=13.2 Hz), 2.90 (1H, d, J=13.2 Hz), 3.35 (2H, m), 3.68 (2H, m), 4.09 (1H, d, J=8.7 Hz), 4.53 (1H, d, J=8.7 Hz), 6.75 (1H, m), 6.88 (1H, dd, 31=7.5 Hz, J2=1.2 Hz), 6.94 (1H, d, J=7.5 Hz), 7.00 (2H, m), 7.21-7.24 (3H, m).
59% at 20 - 33℃; for 20 h; B) Methyl 4-hydroxy-3-iodobenzoate (0242) A solution of 3-iodo-4-Hydroxybenzoic acid (7.25 g, 27.4 mmol) and sulfuric acid (1.9 ml, 36 mmol) in methanol is stirred at 55° C. for 6 hours. TLC (dichloromethane): 30percent of starting material. The solution is stirred 12 h at room temperature. TLC (dichloromethane): 10percent of starting material and stirred at 55° C. for 2 h. After cooling, ethyl acetate (200 mL) was added and the mixture was adjusted to pH 3 using sodium bicarbonate. The organic layer was washed two times with water and then dried over MgSO4. Filtration and rotary evaporation at 40° C. afforded a white solid. The solid was triturated with hexane, filtered off and dried under reduced pressure. M=4.47 g. Yield: 59percent.
36% With hydrogenchloride In water at 65℃; for 24 h; 4-Hydroxy-3-iodobenzoic acid (59.6 g, 226 mmol) is combined with 3N HCl/MeOH (276 mL, 678 mmol) and heated to 65° C. for 24 h, then concentrated to dryness. The residue is diluted with water, neutralized to pH 7 with 3N NaOH and the resulting solid collected via filtration. The crude material is adsorbed onto silica gel and chromatographed over 1 kg of silica gel with 50percent EtOAc/hexane. Fractions containing product are combined and concentrated to a solid (47.2 g). The material is recrystallized from EtOAc to afford 22.8 g (36percent) of methyl 4-hydroxy-3-iodobenzoate as a white solid. HRMS (FAB) calcd for C8H7IO3+H: 278.9520, found 278.9534 (M+H)+.
36%
Stage #1: at 65℃; for 24 h;
4-Hydroxy-3-iodobenzoic acid (59.6 g, 226 mmol) is combined with 3 N methanolic HC1 (276 ML, 678 mmol) and heated to 65C for 24 h, then concentrated to dryness. The residue is diluted with water, neutralized to pH 7 with 3 N NAOH and the resulting solid collected via filtration. The crude material is adsorbed onto silica gel (230-400 mesh) and chromatographed over 1 kg of silica gel eluting with EtOAc/hexane mixtures. All fractions containing product are combined and concentrated to a solid (47.2 g). The material is recrystallized with EtOAc to afford cleaner material (16.6 g). A second recrystallization of the filtrate in EtOAc resulted in a second solid of comparable purity (6.2 g). The remaining solid (24.5 g) is carried on without further purification. Recrystallized total: 22.8 g (36percent) as a white solid. HRMS (FAB) calcd for CGHPIOS +H: 278.9520, found 278.9534 (M+H) +.

Reference: [1] Patent: WO2014/11949, 2014, A2, . Location in patent: Page/Page column 0077
[2] Patent: US9339486, 2016, B2, . Location in patent: Page/Page column 33; 35
[3] Patent: US2003/232853, 2003, A1, . Location in patent: Page 39
[4] Patent: WO2004/39815, 2004, A2, . Location in patent: Page 54 - 55
[5] Chemische Berichte, 1897, vol. 30, p. 1477
[6] Farmaco, Edizione Scientifica, 1958, vol. 13, p. 121,123
[7] Patent: US2006/167049, 2006, A1, . Location in patent: Page/Page column 4-5
[8] Patent: CN107383024, 2017, A, . Location in patent: Paragraph 0115
  • 3
  • [ 37470-46-5 ]
  • [ 74-88-4 ]
  • [ 15126-06-4 ]
YieldReaction ConditionsOperation in experiment
7.5 g
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1 h;
A stirred solution of 4-hydroxybenzoic acid (5.0 g, 36 mmol) inammonia (200 mL) was treated with iodine (9.2 g, 36 mmol) andKI (29.4 g, 180 mmol) in water (100 mL) dropwise at r.t. After theaddition, the mixture was stirred overnight at the same temperature.Then, hydrochloric acid (2.0 mol L−1) was added to adjust the pH ofthe mixture to pH 2.0 and a white solid precipitated. After filtration,the filter cake was washed with water. The white solid was dried andthen dissolved in DMF (100 mL). Next, K2CO3 (5.0 g, 18 mmol) wasadded to the mixture, and it was stirred for 1 h at r.t. Then MeI (2.5 mL,36 mmol) was added and the mixture was stirred overnight. The mixture was diluted with water and extracted with ethyl acetate (2 ×120 mL). The organic layer was washed with water and then dried withanhydrous sodium sulfate. After concentration under reduced pressure,the crude product was purified by column chromatography to givecompound 2b as: White solid17; yield 7.5 g (75percent); 1H NMR (400 MHz,DMSO-d6): δ 11.30 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.5,2.1 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz,DMSO-d6): δ 164.8, 161.1, 140.2, 131.1, 122.2, 114.6, 84.4, 51.9.
Reference: [1] Journal of Chemical Research, 2017, vol. 41, # 7, p. 394 - 397
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  • [ 37470-46-5 ]
  • [ 18107-18-1 ]
  • [ 15126-06-4 ]
Reference: [1] Tetrahedron Letters, 1998, vol. 39, # 16, p. 2281 - 2284
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  • [ 67-56-1 ]
  • [ 75-45-6 ]
  • [ 37470-46-5 ]
  • [ 1131614-23-7 ]
Reference: [1] Synthesis (Germany), 2012, vol. 44, # 23, p. 3598 - 3602
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