JOURNAL OF CHEMICAL RESEARCH 2018 283
chloride was added to quench the reaction. The product was extracted
with ethyl acetate (50 mL), washed with brine and dried over anhydrous
Na2SO4. After evaporation of the solvent, the crude residue was purified
by silica gel column chromatography with petroleum ether/ethyl acetate
(v/v, 70/1) to give 6 (2.8 g, 81% yield over two steps) as a light yellow oil;
1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.23 (t, J = 7.8 Hz, 1H),7.04 (d,
J = 7.6 Hz, 1H), 6.95 (t, J = 2.1 Hz, 1H), 6.76 (dd, J = 8.0, 1.9 Hz, 1H), 6.02
(d, J = 6.1 Hz, 1H), 5.30 (dd, J = 6.2, 2.4 Hz, 1H), 3.48 (d, J = 2.3 Hz, 1H),
0.95 (s, 9H), 0.19 (s,6H); 13C NMR (101 MHz, DMSO-d6): δ (ppm) 155.4,
144.1, 129.8, 119.9, 119.3, 118.2, 85.9, 76.2, 62.5, 26.0, 18.4, −4.1; HRMS
(ESI): m/z 285.1280 [M+Na]+; Calcd for C15H22O2NaSi: 285.0378.
for 24 h at r.t., the mixture was diluted with ethyl acetate (50 mL) and
washed with brine. The organic layer was dried over anhydrous sodium
sulfate and concentrated in vacuo. The residue was purified by silica
gel column chromatography with dichloromethane/methanol (v/v,
50/1) as eluent to give 10 (605 mg, 62% yield) as a white solid; m.p.
68–70°C (recrystallised from ethyl acetate); [α]2ꢁꢀ = −20.0 (c 1,
1
CH3OH); H NMR (400 MHz, DMSO-d6): δ (ppm) 9.29 (s, 1H), 9.12
(d, J = 7.7 Hz,1H), 8.53 (t, J = 5.8 Hz, 1H), 7.77 (dd, J = 5.0, 1.1 Hz, 1H),
7.69 (dd, J = 3.7, 1.2 Hz, 1H), 7.34 (s, 2H), 7.16 (dd, J = 5.0, 3.8 Hz, 1H),
7.10 (t, J = 7.8 Hz, 1H), 6.76 (t, J = 2.1 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H),
δ 6.61 (dd, J = 8.0, 1.7 Hz, 1H), 5.25 (d, J = 4.4 Hz, 1H), 4.74 (m, 1H),
4.41 (m, 1H), 3.65 (s, 3H), 3.60 (dd, J =13.3, 6.8 Hz, 2H), 2.74–2.56 (m,
2H), 1.84 (m, 2H); 13C NMR (101 MHz, DMSO-d6): δ (ppm) 170.7,
164.2, 161.9, 157.7, 147.9, 146.7, 139.9, 133.7, 131.44, 131.41, 129.4,
128.8, 128.4, 128.3, 116.9, 114.1, 113.1, 71.7, 52.5, 52.1, 40.8, 39.4, 31.3.
Methyl-4-(3-(3-((t-butyldimethylsilyl)oxy)phenyl)-3-hydroxyprop-1-yn-
1-yl)-2,6-dichlorobenzoate (7)
Under a nitrogen atmosphere, Pd(PPh3)2Cl2 (393 mg, 0.56 mmol), cuprous
iodide (212 mg, 1.13 mmol) and trimethylamine (7.9 ml, 56.7 mmol) were
added to a solution of 2 (3.75g, 11.3 mmol) and 6 (3.0 g, 11.4 mmol) in
ethyl acetate (50 mL). The mixture was stirred for 10 h at r.t. and then an
aqueous solution of NaHCO3 was added. The product was extracted with
ethyl acetate (50 mL), and the organic layer was washed with brine, dried
over anhydrous sodium sulfate and concentrated in vacuo. The crude
product was purified by silica gel column chromatography with petroleum
ether/ethyl acetate (v/v, 50/1) as eluent to give 7 (4.8 g, 91%) as a light
(2S)-2-(2,6-Dichloro-4-(3-hydroxy-3-(3-hydroxyphenyl)propyl)
benzamido)-3-(thiophene-2-carboxamido)
propanoic
acid
‘Compound 4’ (1)
A solution of 10 (605 mg, 1.1 mmol) in THF/water (15 mL/5 mL) was
treated with lithium hydroxide (78 mg, 3.39 mmol). After the mixture
was stirred for 10 h at r.t., 1 N hydrochloric acid was added to adjust the
pH to 3, and then the product was extracted with ethyl acetate
(3 × 30 mL), dried over anhydrous sodium sulfate and concentrated in
vacuo. The residue was purified by silica gel column chromatography
with ethyl acetate/methanol (v/v, 30/1) as eluent to give 1 (510 mg,
85%) as a white solid; m.p. 109–111 °C (recrystallised from methyl
t-butyl ether); [α]2ꢁꢀ = −17.3 (c 1, CH3OH); 1H NMR (400 MHz,
DMSO-d6): δ (ppm) 12.84 (s, 1H), 9.29 (s, 1H), 8.97 (d, J = 8.1 Hz,
1H), 8.47 (t, J = 5.7 Hz, 1H), 7.76 (dd, J = 5.0, 0.9 Hz, 1H), 7.70 (dd,
J = 3.7, 1.3 Hz, 1H), 7.33 (s, 2H), 7.16 (dd, J = 5.0, 3.7 Hz, 1H), 7.11 (t,
J = 7.8 Hz, 1H), 6.77 (t, J = 2.1 Hz, 1H), 6.74 (d, J = 7.3 Hz, 1H), 6.62
(dd, J = 8.0, 1.8 Hz, 1H), 5.25 (d, J = 4.5 Hz, 1H), 4.73 (m, 1H), 4.41 (m,
1H), 3.72–3.55 (m, 2H), 2.75–2.56 (m, 2H), 1.85 (m, 2H); 13C NMR
(101 MHz, CD3OD): δ (ppm) 171.1, 166.1, 163.4, 157.2, 146.4, 146.2,
138.5, 133.0, 131.7, 130.5, 129.0, 128.6, 127.8, 127.4, 116.8, 113.9, 112.4,
72.4, 52.2, 40.7, 39.8, 31.0; HRMS (ESI): m/z 537.0651 [M+H]+; Calcd
for C24H23N2O6SCl2: 537.0654.
1
brown oil; H NMR (400 MHz, DMSO-d6): δ (ppm) 7.68 (s, 2H), 7.27
(t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 2.2 Hz, 1H), 6.80
(dd, J = 8.0, 1.9 Hz, 1H), 6.30 (d, J = 6.1 Hz, 1H), 5.60 (d, J = 6.1 Hz, 1H),
3.92 (s, 3H), 0.95 (s, 9H), 0.19 (s, 6H); 13C NMR (101 MHz, DMSO-d6):
δ (ppm) 164.6, 155.6, 143.5, 133.2,131.3, 131.1, 130.0, 126.6, 120.1, 119.7,
118.4, 95.9, 81.5, 63.0, 53.9, 26.0, 18.4, −4.1; HRMS (ESI): m/z 487.0869
[M+Na]+; Calcd for C23H26Cl2O4NaSi: 486.0875.
Methyl-4-(3-(3-((t-butyldimethylsilyl)oxy)phenyl)-3-hydroxy-propyl)-
2,6-dichloro-benzoate (8)
To a solution of 7 (3.5 g, 7.5 mmol) in degassed methanol (100 mL) was
added wet Raney nickel (440 mg, 7.5 mmol), and then one balloonful of
hydrogen was passed through the solution. The mixture was stirred for 7 h
under a hydrogen atmosphere at r.t. to complete hydrogenation, and then
the mixture was filtered through diatomite and concentrated in vacuo.
The crude residue was purified by silica gel column chromatography
with petroleum ether/ethyl acetate (v/v, 50/1) as eluent to give 8 (3.2 g,
91% yield) as a light brown oil; 1H NMR (400 MHz, DMSO-d6): δ (ppm)
7.40 (s, 2H), 7.18 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.82 (t,
J = 2.1 Hz, 1H), 6.69 (dd, J = 8.0, 1.7 Hz, 1H), 5.32 (d, J = 4.6 Hz, 1H),
4.53–4.41 (m, 1H), 3.89 (s, 3H), 2.80–2.54 (m, 2H), 1.86 (m, 2H), 0.94 (s,
9H), 0.17 (s, 6H); 13C NMR (101 MHz, DMSO-d6): δ (ppm) 165.2, 155.4,
148.2, 147.9, 130.7, 130.67, 129.5, 128.6, 119.4, 118.5, 117.7, 71.6, 53.6, 40.5,
31.4, 26.0, 18.4, −4.0; HRMS (ESI): m/z 491.1183 [M+Na]+; Calcd for
C23H30Cl2O4NaSi: 491.1188.
Acknowledgements
This work was supported in part by the National Natural
Science Foundation of China (30973621) and Six Major Talents
of Jiangsu Province of China (2014).
Electronic supplementary information
The supplementary data associated with this paper can be
found at:
2,6-Dichloro-4-(3-hydroxy-3-(3-hydroxyphenyl)propyl)benzoic acid (9)
Compound 8 (1.0 g, 2.1 mmol) was dissolved in methanol (10 mL) and
water (10 mL), and potassium hydroxide (358 mg, 6.4 mmol) was added
and the reaction mixture was stirred at r.t. for 20 h. After completion of
the reaction, 1 N hydrochloric acid was added to adjust the pH to 3–4. The
mixture was extracted with ethyl acetate (3 × 20 mL), and the combined
organic layer was dried over anhydrous sodium sulfate, concentrated in
vacuo to give 9 (650 mg, 89%) as a light brown oil, which was used for the
Received 2 April 2018; accepted 9 May 2018
Paper 1805354
Published online: 30 May 2018
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Methyl-(2S)-2-(2,6-dichloro-4-(3-hydroxy-3-(3-hydroxyphenyl)
propyl)benzamido)-3- (thiophene-2-carboxamido)propanoate (10)
To a solution of 9 (600 mg, 1.76 mmol) in DMF (20 mL) at r.t., EDC
(674 mg, 3.52 mmol), HOBt (356 mg, 2.64 mmol),
5 (465 mg,
8
1.76 mmol) and DIPEA (1.56 ml, 8.79 mmol) were added. After stirring