2-(3-Acetylamino-phenoxy)-2-methyl-propionic acid

2-(3-Acetylamino-phenoxy)-2-methyl-propionic acid



Preparation of 2-(3-Acetylaminophenoxy)-2-methylpropionic acid used in Example Il is described below.

(M - I I l) (M - IV )





2-(3-tert-Butoxycarbonylamino-phenoxy)-2-methyl-propionic acid ethyl ester (Il -I)

To a solution of (3-Hydroxy-phenyl)-carbamic acid tert-butyl ester (2.4 g, 11.4 mmol) in 5 ml of dry DMF, anhydrous potassium carbonate (7.9 g, 57.416 mmol) was added. The mixture stirred for 5-10 minutes, added ethyl-2-bromo-isobutyrate (4.5 g, 22.9 mmol). The resulting mixture was heated at 70 ° C for 12 hours. Upon completion (-25 h), the solution was diluted with EtOAc (25 ml) and washed with saturated NH₄Cl (5 ml). The aqueous layer was then extracted for two additional times with EtOAc (10ml) and the combined organic fractions were washed with brine (2X5ml). The solution was then dried over Na₂SO₄ and concentrated to give brown oil. Purification on silica gel (hexanes/acetone) yielded 1.8 g (49 %).1 H-NMR (400 MHz, CDCl₃): δ ¹H NMR (400 MHz, CDCl₃): 1.26 (t, J= 7.2 Hz, 3H), 1.50 (s, 9H), 1.59 (s, 6H), 6.43 (s, IH), 6.47-6.50 (m, IH), 6.96 (t, J=8.4 Hz, 2 H), 7.11 (t, J=8.0, IH).



2-(3-Amino-phenoxy)-2-methyl-propionic acid ethyl ester (Il-II)

To a solution of 2-(3-tert-Butoxycarbonylamino-phenoxy)-2-methyl-propionic acid ethyl ester (0.8 g, 2.4 mmol) in DCM (10 ml) at O⁰C was added TFA (10ml) and stirred at O⁰C for 100 min. The solvent was removed under reduced pressure; residue was dissolved in DCM and treated with 2.5M solution of NaOH. The organic layer was separated and dried over Na₂SO₄, concentrated to yield 2-(3-amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.5 g, mmol, 98 %).1H NMR (400 MHz, CDCl₃): 1.25 (t, J= 7.2 Hz, 3H), 1.56 (s, 6H), 3.62 (brs, 2H), 4.23 (q, J=7.2 Hz, 2H), 6.21-6.22 (m, 2H), 6.32 (d, J=7.2 Hz, IH), 6.99 (t, J=8.4 Hz, IH).



2-(3-Acetylamino-phenoxy)-2-methyl-propionic acid ethyl ester (Il-III):

To a solution of 2-(3-Amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.54 g, 2.42 mmol) in DCM (5ml) at O⁰C was added pyridine (0.23ml, 2.9 mmol). The reaction mixture was cooled to O⁰C and a solution of acetyl chloride (0.21 ml, 2.9 mmol) in DCM (4 ml) was added drop wise over 5 min. The reaction mixture was stirred at r.t. for 18 hrs, quenched with water (10ml) and extracted in DCM (2X20 ml).The organic layer was dried over Na₂SO₄ and concentrated to afford the crude oil (0.64 g) which was used for the next step without purification.


 2-(3-Acetylamino-phenoxy)-2-methyl-propionic acid (Il-IV):

2-(3-Acetylamino-phenoxy)-2-methyl-propionic acid ethyl ester (0.6 g, 2.2 mmol) was dissolved in THF (20 ml) and a solution of lithium hydroxide ( 0.33 g, 7.9 mmol) in water (5.8 ml) was added. The reaction mixture was allowed to stir at RT for 24 h. The solvent was removed under reduced pressure and the aqueous layer was extracted with EtOAc (10 ml). Aqueous layer was basified (pH~ 5) with 1 N HCl at O⁰C, extracted in EtOAc (2X 50 ml) dried over Na₂SO₄ and concentrated under reduced pressure to afford the acid (0.45 g, 85 %). ¹H NMR (400 MHz, CDCl₃): 1.61 (s, 6H), 2.11 (d, J=6.4 Hz, 3H), 4.65 (brs, 3H), 6.68 (d, J=8.0 Hz, IH), 7.07 (d, J=8.0 Hz, IH), 7.17 (t, J=8.0Hz, IH), 7.29 (s, IH), 7.60(s, IH).; MS (EI) mlz: 238.1 (M + 1).




https://www.google.co.in/patents/WO2008104994A2?cl=en



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