ChemicalBook CAS DataBase List METHYL 4-HYDROXY-3-IODOBENZOATE

METHYL 4-HYDROXY-3-IODOBENZOATE synthesis

9synthesis methods

Product Name:METHYL 4-HYDROXY-3-IODOBENZOATE
CAS Number:15126-06-4
Molecular formula:C8H7IO3
Molecular Weight:278.04

99-76-3

15126-06-4

GENERAL STEPS: Methyl 4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of acetic acid, stirred and heated to 65°C. A solution of ICI (37.8 g, 0.233 mol) dissolved in 50 mL of acetic acid was added slowly and dropwise over 40 minutes. The reaction mixture was stirred at 65°C for 5 hours, followed by 16 hours at room temperature. The precipitated product was collected by filtration, washed with water and dried under vacuum to give 27.5 g of the target product (99% purity by LCMS and HNMR). The mother liquor was concentrated and the residue was washed with water and dried under vacuum to give an additional 31 g of the target product (95% purity analyzed by LCMS and HNMR).The total yield of methyl 4-hydroxy-3-iodobenzoate was 58.5 g in 90.3% yield.LCMS m/z 278. Synthesis of methyl 3-cyano-4-hydroxybenzoate 3: Methyl 4-hydroxy-3-iodobenzoate 2 (28 g, 0.1 mol) was dissolved in 100 mL of DMF and CuCN (9.92 g, 0.11 mol) and NaCN (0.49 g, 0.11 mol) were added. After the system was displaced with nitrogen, it was heated to 105 °C and stirred for 18 hours. It was cooled to room temperature, filtered to remove the precipitate and the filter cake was washed with EtOAc. The combined organic phases were diluted with 200 mL of water and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated to dryness. Vacuum drying gave 18 g (100% yield) of product 3, which was characterized by LCMS and HNMR. Synthesis of methyl 3-cyano-4-isopropoxybenzoate 4: Methyl 3-cyano-4-hydroxybenzoate 3 (18 g, 0.11 mol) was dissolved in 100 mL of DMF and 2-bromopropane (14.2 mL, 0.15 mol) and anhydrous potassium carbonate (41.9 g, 0.3 mol) were added. After the system was displaced with nitrogen, it was heated to 90 °C and stirred overnight. Cooled to room temperature, the reaction mixture was diluted with 200 mL of water and extracted with CH2Cl2 (2 x 200 mL). The organic layers were combined, dried with sodium sulfate, filtered and concentrated to dryness to give 20.5 g (99% yield) of the oily product 4, which was characterized by LCMS and HNMR. Synthesis of perfluorophenyl 3-cyano-4-isopropoxybenzoate 6: Methyl 3-cyano-4-isopropoxybenzoate 4 (20.5 g, 0.093 mol) was dissolved in 200 mL of a mixed methanol-water solvent of 6:4, NaOH (5.61 g, 0.14 mol) was added, and stirred for 2 h at room temperature. The solution was filtered through a silica gel plug and the solvent was removed under vacuum. The solid was redissolved in 200 mL of CH2Cl2 and perfluorophenyl 2,α,2-trifluoroacetate 5 (19.3 mL, 0.11 mol) and triethylamine (19.5 mL, 0.14 mol) were added. After standing overnight, the solution was filtered and the solid was washed with CH2Cl2. The combined organic phases were purified on a short silica gel column and concentrated to dryness to give 29 g (83.5% yield) of product 6, which was characterized by LCMS and HNMR.

99-76-3 Synthesis

99-76-3
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15126-06-4
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Yield: 90.3%

Reaction Conditions:

with Iodine monochloride in acetic acid at 20 - 65; for 21.6667 h;

Steps:

68
Methyl 4-hydroxybenzoate (35.5g, 0.233 mol) was dissolved in 200 mL of acetic acid, and the stirred mixture was warmed to 65°C. A solution of ICI (37.8 g, 0.233 mol) in 50 mL of AcOH was added dropwise over 40 min. The mixture was stirred at 65°C for 5 h and then stirred an additional 16 h at room temperature. The precipitated product was isolated via filtration, washed with water and dried under vacuum to give 27.5 g (99% pure by LCMS and HNMR) ) of desired product. The mother liquors were evaporated and resulting residue was washed with water and dried under vacuum to give another 31 g (95% pure by LCMS and NMR) of desired product. The combined yield of methyl 4-hydroxy-3-iodobenzoate was 58.5 g (90.3% yield). LCMS m/z [00438] Methyl 3-cyano-4-hydroxybenzoate 3: 28 g (0.1 mol) of methyl 4-hydroxy-3- iodobenzoate 2 dissolved in 100 mL of DMF was treated with 9.92 g (0.11 mol) of CuCN and 0.49 g (0.11 mol) of NaCN. The system was flushed with nitrogen after which the mixture warmed to 105°C and stirred to 18 h. The mixture was allowed to cool to room temperature, and any precipitates were removed via filtration and washed with EtOAc. The combined organics were diluted with 200 mL of water and then extracted with EtOAc (2x200 mL). The combined layers were dried over sodium sulfate, filtered and evaporated to dryness. After drying under vacuum, the resulting 18 g (100% yield) of 3 was characterized by LCMS and HNMR. [00439] Methyl 3-cyano-4-isopropoxybenzoate 4: Methyl 3-cyano-4-hydroxybenzoate 3 (18 g, 0.1 I mol) was dissolved in 100 mL of DMF and treated with 14.2 mL (0.15 mol) of 2- bromopropane and 41,9 g (0.3 mol) of anhydrous potassium carbonate. The system was flushed with nitrogen, and the mixture was heated to 90°C and stirred ovemight. After cooling to room temperature, the mixture was diluted with 200 mL of water and extracted with CH2CI2 (2x200 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness to give 20.5 g (99% yield) of 4 as an oil that was characterized by LCMS and HNMR. [00440] Perfluorophenyl 3-cyano-4-isopropoxybenzoate 6: 20.5 g (0.093 mol) of methyl 3-cyano-4-isopropoxybenzoate 4 was dissolved in 200 mL of a 6: 4 mixture of methanol and water. To this was added 5.61 g (0.14 mol) of NaOH, and the mixture was stirred for 2 hours at room temperature. The solution was then filtered through a silica gel plug and the solvents removed under vacuum. The resulting solid was re-dissolved in 200 mL of CH2Cl2 and treated with 19.3 mL (0.11 mol) of perfluorophenyl 2,?,2-trifluoroacetate 5 and 19.5 mL (0.14 mol) of triethylamine. After stining overnight, the solution was filtered and any solids rinsed with CH2Cl2. The combined organic mixtures were run through a short silica gel column and then evaporated to dryness to give 29 g (83.5% yield) of 6 which was characterized by LCMS and HNMR

References:

CYTOKINETICS, INC.;SMITHKLINE BEECHAM CORPORATION WO2005/107762, 2005, A2 Location in patent:Page/Page column 253-254

67-56-1 Synthesis