2-(4-Chloro-phenoxy)-2-methyl-N-thiazol-2-yl-propionamide

Example Al : 2-(4-Chloro-phenoxy)-2-methyl-N-thiazol-2-yl-propionamide:

To a solution of 2-(4-Chloro-phenoxy)-2-methyl-propionic acid (0.3g, 1.4 mmol) in DCM (10 ml) was added triethylamine (0.23 ml, 1.68 mmol) and HOBt (0.23 g, 1.68 mmol) at 0 ⁰C. After stirring at this temperature for 5 min. added 2-aminothiazole (0.168 g, 1.68 mmol) and followed by EDCI (0.332 g, 1.68 mmol). The resulting solution was stirred for 12 h. then quenched with saturated aqueous NH₄Cl solution (15 mL). The aqueous phase was extracted with CH₂Cl₂ (3 x 50 mL). The organic phase was successively washed with 2% HCl (50 mL), brine (50 mL) and dried over Na₂SO₄. After evaporation, the residue was purified by flash chromatography (1 :10 ethyl acetate: hexanes) to give 2-(4-Chloro-phenoxy)-2-methyl- N-thiazol-2-yl-propionamide (0.325 g, 78 %). ¹H NMR (400 MHz, CDCl₃): δ 1.58 (s, 6H), 6.76 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 3.6 Hz, IH), 7.18 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 3.6 Hz, IH), MS (EI) m/z 296.9 (M+l).





Preparation of 2-(4-Chloro-phenoxy)-2-methyl-propionic acid used in Typical Example Al is described below:

2-(4-Chloro-phenoxy)-2-methyl-propionic acid ethyl ester (Al-I):

To a solution of 4-cholo-phenol (4 g, 31.11 mmol) in DMF (10 ml) anhydrous potassium carbonate (10.73 g, 77.77 mmol) and ethyl-2-bromo-isobutyrate (12.13 g, 62.22 mmol) were added. The resulting mixture was heated at 70 ° C for 12 hours. Upon completion (-25 h), the solution was diluted with EtOAc (100 ml) and washed with brine (2X20 ml). The aqueous layer was then extracted for two additional times with EtOAc (20 ml) and the combined organic fractions were washed with brine (20 ml). The solution was then dried over
Na₂SO₄ and concentrated to give brown oil. Purification on silica gel (hexanes/acetone) yielded 6.O g (79%) of ester as pale yellow oil which was used as such for the next step without further purification.





2-(4-Chloro-phenoxy)-2-methyl-propionic acid (Al-II):

To a solution of 2-(4-Chloro-phenoxy)-2-methyl-propionic acid ethyl ester ( 6 g, 24.79 mmol) in THF (20 ml) was added a solution of LiOH ( 3 g, 74.38 mmol) in H₂O ( 4 mil). The resulting solution was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was diluted with ethyl acetate (100 ml); cool to OoC, acidified with IN HCl (PH- 3-4). The organic phase were washed with, brine (20 ml) and dried over Na₂SO₄. After evaporation, the residue was purified by flash chromatography (1:1 hexanes/ EtOAc) to give 2-(4-Chloro-phenoxy)-2-methyl-propionic acid (1.1 g, 20 %). ¹H NMR (400 MHz, CDCl₃): δ 1.60 (s, 6H), 6.85 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.7 Hz, 2H). MS (EI) mlz: 215.5 (M + 1).

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WO2008104994

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N-cycIopropyl-2-(4-fluorophenyl)-3-(4-((E)-3-(hydroxyamino)-3-oxoprop- l-en-l-yl)phenyl)acrylamide

N-cycIopropyl-2-(4-fluorophenyl)-3-(4-((E)-3-(hydroxyamino)-3-oxoprop- l-en-l-yl)phenyl)acrylamide



Example 1:
Synthesis of N-cycIopropyl-2-(4-fluorophenyl)-3-(4-((E)-3-(hydroxyamino)-3-oxoprop- l-en-l-yl)phenyl)acrylamide.

Step-I
Preparation of methyl (E)-3-(4-formylphenyl)acrylate

A suspension of (E)-3-(4-formylphenyl)acrylic acid (2 g, 10.5 mmol) in methanol (30 mL) was cooled to 5 ºC and then concentrated H₂SO₄ (3 niL) was added under stirring and heated at 60 ºC for 2 hours. The solvent was removed by evaporation and the obtained compound was stirred with water (100 mL) for 15 minutes. The precipitated white solid was filtered, washed with water (300 mL) and dried to get the pure product (1.9 g. 86% yield). Step-II Preparation of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-l-en-l-yl) phenyl)acrylic acid

A mixture of 4-fluorophenylacetic acid (2.5 g, 13.2 mmol) and methyl (E)-3-(4- formylphenyl) acrylate (2.03 g, 13.2 mmol) were dissolved under stirring with acetic anhydride (8 mL). To this mixture, diisopropylethylamine (DIPEA) (3.4 mL, 19.7 mmol) was added and stirred at 30 ºC for 2 hours. Upon completion (as monitored by TLC using 100% ethyl acetate as eluent), the reaction mixture was poured into water and the pH adjusted to 1 using dilute HCl (1 : 1). The aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined ethyl acetate layer was washed with water till the washings were neutral and dried over anhydrous Na₂SC>₄. The ethyl acetate layer was evaporated to dryness to obtain a sticky compound and further triturated with cold dichloromethane
(DCM) to furnish a white solid. The solid obtained was filtered and dried under vacuum to afford the title compound (2 g, 47% yield).
Step-III
Preparation of methyl 3-(E) (4-(3-(cyclopropyIamino)-2-(4-fluorophenyl)-3-oxoprop-l- en-l-yl)phenyl)acrylate

A mixture of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop- l -en-l -yl) phenyl)acrylic acid (0.23 g, 0.71 mmol) and cyclopropylamine (0.03 g, 0.60 mmol), EDCl (0.27 g, 1.4 mmol), HOBt (0.10 g, 0.71 mmol) was dissolved in N,N-dimethyiformamide (DMF) (6 mL) under stirring. Triethylamine (TEA) (0.75 mL, 36 mmol) was added dropwise with constant stirring to the above reaction mixture and it was stirred at 30 ºC for 2 hours. Subsequently the reaction mixture was diluted with ethyl acetate and washed successively with water (3 x 50 mL) and brine (3 x 50 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated to afford the pure compound (0.25 g. 96% yield). Step-IV
Preparation of yV-cyclopropyl-2- (4-fluorophenyl)-3-(4-((E)-3-(hydroxyamino)-3- oxoprop-1-en-l-yl) phenyl) acrylamide.

Hydroxylamine hydrochloride (0.86 g, 12.3 mmol) in methanol (3 mL) was mixed with KOH (0.69 g, 12.3 mmol) in methanol (3 mL) at 0 ºC, and sonicated for 2 minutes, the white precipitate formed was filtered. The filtrate was added to methyl 3-(E)(4-(3- (cyclopropylaιnino)-2-(4-fluorophenyl)-3-oxoprop-l -en-l -yl)phenyl)acrylate (0.25 g, 0.68 mmol) in DCM (1.5 mL) and the mixture was stirred at room temperature, for 30 minutes. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 150 mL). The ethyl acetate layer was dried over anhydrous Na₂SO₄ and concentrated to obtain a sticky compound, which was triturated with DCM (15 mL). The pale brown solid obtained was filtered and washed with DCM (3 x 5 mL) to afford the title compound (0.07g, 28% yield). ¹H NMR (DMSOd₆) δ (ppm): 0.49-0.53 (2H, dd, -CH₂), 0.61 -0.66 (2H, m, - CH₂), 2.72-2.77 (IH, m, -CH), 6.38-6.42 (I H, d, =CH), 7.00-7.02 (2H, d, Ar-H), 7.16-7.27 (5H, m, Ar-H and =CH), 7.33-7.43 (3H, m, Ar-H and =CH), 7.81 -7.82 (I H, d, -NH). 9.04 (I H, s, -OH), 10.73 (IH, s, -NH). MS m/z: 367.1 (M⁺+l).









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