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 H
2SO
4 (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 Na
2SC>
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 Na
2SO
4 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 Na
2SO
4
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 (DMSOd
6) δ (ppm): 0.49-0.53 (2H, dd, -CH
2), 0.61 -0.66 (2H, m, - CH
2),
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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WO2009053808A2
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