2-(4-Chlorophenoxy)phenylacetic acid

Example 9. Preparation of asenapine via the lactam trans-5-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-1 H-dibenz [2, 3:6, 7] oxepino [4, 5-c] pyrrol-1-one (VII). A: [2-(4-Chloro-phenoxy)-phenyl-acetic acid (IX) Methyl 2-bromophenylacetate (47.0 grams 216.3 mmol) and 4-chlorophenol (27.8 grams, 215.8 mmol) were dissolved in dioxane (790 ml) while warming to 50 °C. To the resulting solution were added, under stirring in an inert nitrogen atmosphere, cesium carbonate (141 grams, 432.2 mmol) and copper(I) chloride (18.56 g, 86.2 mmol). Finally, N, N-dimethylglycine (4.46 grams, 43.2 mmol) was added to the green suspension. The reaction mixture was heated at 110 °C (reflux temperature) for 4 days while stirring. The reaction mixture was filtered over dicalite, which was washed with dioxane (40 ml). The dioxane was removed in vacuo to leave a brownish oil. Ethyl acetate (100 ml) was added to the oil and the pH of the resulting mixture was adjusted to 1 by addition of 1 M HCl (300 ml). The organic phase was washed with saturated brine (300 ml), dried on magnesium sulphate and then concentrated under vacuum to yield 57.2 grams (206 mmol; 95 percent) of 2-(4-chloro-phenoxy)-phenyl]-acetic acid methyl ester as a brown oil. The oil was dissolved in methanol (250 ml), whereupon KOH (16.2 grams; 1.4 eq) was added. The resulting solution was heated for 3 h at 60 °C. The reaction mixture was cooled and the methanol (200 ml) was removed under vacuum. To the residue water (100 ml) was added and the pH was adjusted to 1 by addition of 1 M HCl (25 ml). The resulting crystals were filtered off and dried in vacuum at 40 °C to yield 47.3 grams (180 mmol; 87 percent) of [2-(4-chloro-phenoxy)-phenyl]-acetic acid (IX). Preparation of Asenapine Via the Lactam trans-5-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-1H-dibenz [2, 3:6, 7]oxepino[4, 5-c]pyrrol-1-one (VII); A: [2-(4-Chloro-phenoxy)-phenyl]-acetic acid (IX) Methyl 2-bromophenylacetate; (47.0 grams 216.3 mmol) and 4-chloro-phenol (27.8 grams, 215.8 mmol) were dissolved in dioxane (790 ml) while warming to 50° C. To the resulting solution were added, under stirring in an inert nitrogen atmosphere, cesium carbonate (141 grams, 432.2 mmol) and copper(l) chloride (18.56 g, 86.2 mmol). Finally, N, N-dimethylglycine (4.46 grams, 43.2 mmol) was added to the green suspension. The reaction mixture was heated at 110° C. (reflux temperature) for 4 days while stirring. The reaction mixture was filtered over dicalite, which was washed with dioxane (40 ml). The dioxane was removed in vacuo to leave a brownish oil. Ethyl acetate (100 ml) was added to the oil and the pH of the resulting mixture was adjusted to 1 by addition of 1 M HCl (300 ml). The organic phase was washed with saturated brine (300 ml), dried on magnesium sulphate and then concentrated under vacuum to yield 57.2 grams (206 mmol; 95 percent) of 2-(4-chloro-phenoxy)-phenyl]-acetic acid methyl ester as a brown oil. The oil was dissolved in methanol (250 ml), whereupon KOH (16.2 grams; 1.4 eq) was added. The resulting solution was heated for 3 h at 60 ° C. The reaction mixture was cooled and the methanol (200 ml) was removed under vacuum. To the residue water (100 ml) was added and the pH was adjusted to 1 by addition of 1 M HCl (25 ml). The resulting crystals were filtered off and dried in vacuum at 40° C. to yield 47.3 grams (180 mmol; 87 percent) of [2-(4-chloro-phenoxy)-phenyl]-acetic acid (IX).Example 1. Synthesis of 2-(4-chlorophenoxy)phenylacetic acid (compound XIVb) [Show Image] 27.8 g (216 mmol) of 4-chlorophenol and 47 g (205 mmol) of methyl 2-bromophenylacetate were suspended in 790 mL of dioxane. The mixture was heated to 48 C and 141 g of cesium carbonate, 4.5 g of glycine and 8.6 g of cuprous chloride were added. The resulting suspension was heated to reflux and stirred at this temperature for 5 days. After cooling down to room temperature, the solid was removed by filtration, washed with 100 mL of dioxane, and discarded. The mother liquors were combined and concentrated under vacuum. 100 mL of ethyl acetate were added to the residue, and the pH was adjusted to 1 with HCl 2 M. The organic phase was extracted, washed with brine and dried. The solvent was removed under vacuum. 100 mL of water were added to the residue, and the pH was adjusted to 1 with HCl 2 M. The resulting suspension was stirred and filtered, to obtain 41 g of 2-(4-chlorophenoxy)phenylacetic acid (compound XIVb) as a brown solid. Yield: 76.1 percent.Potassium carbonate (109 gm) was charged into a clean and dry RBF at below 20°C under N[Reference Synthesis of 2-(2-(4-chlorophenoxy)phenyl)acetic acid] A mixture of 552.0 g (4.0 mol) of potassium carbonate and 1500 mL of diglyme was kept at 0-20°C while adding 283.1 g (2.2 mol) of 4-chlorophenol thereto and mixing, and then 5.74 g (0.04 mol) of copper(I) bromide was added. The obtained mixture was heated to 100°C, and 90.3 g (0.53 mol) of 2-chlorophenylacetic acid was added. This mixture was stirred at the same temperature for 1 hour, and then 159.4 g (0.93 mol) of 2-chlorophenylacetic acid was further added. After stirring the obtained mixture at 120-130°C for approximately 8 hours, completion of the reaction was confirmed by high-performance liquid chromatography. The reacted mixture was cooled to near room temperature, and then approximately 700 mL of water and approximately 650 mL of 35 wtpercent hydrochloric acid water were added in that order. The pH of the aqueous layer was below 1. After further adding about 500 mL of water to the obtained mixture, it was extracted once with 400 mL and once with 200 mL of toluene, in that order. The obtained organic layers were combined and washed 3 times with 500 mL of water and once with 500 mL of brine, in that order. The obtained organic layer was subjected to dehydration treatment with anhydrous magnesium sulfate, and 100 mL of heptane was added dropwise to approximately 400 g of the residue obtained by partially concentrating the treated organic layer. The internal temperature of the mixture after the dropwise addition was about 70°C, and crystals precipitated in the mixture. Upon completion of the dropwise addition, the mixture was cooled to 20-25°C and the crystals were separated off by filtration. The obtained crystals were washed with 100 mL of a heptane/toluene = 1/1 mixed solvent and dried under reduced pressure to obtain 245.6 g of 2-(2-(4-chlorophenoxy)phenyl)acetic acid as a white solid. The yield was 68.8percent.

Molecular Weight:262.69
XLogP3:4.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:262.0396719
Monoisotopic Mass:262.0396719
Topological Polar Surface Area:46.5
Heavy Atom Count:18
Complexity:274
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes