1H, J = 7.8 Hz, 3.0 Hz, 8.7 Hz), 3.62 (q, 1H, J = 3.3 Hz, 7.5 Hz,
3.9 Hz), 3.42 (s, 3H), 3.01 (s, 3H).
(S)-2-Chloro-N-(2-hydroxy-1-phenylethyl)acetamide (17d)
A vigorously-stirred solution of 16d (4.0 g, 29.2 mmol) in 20 mL
of water at 0 ◦C was treated successively and slowly with a solution
of chloroacetyl chloride (2.78 mL, 35 mmol) in 20 mL of CH2Cl2,
then was added 4.5 mL of 1 N NaOH solution. When the addition
was complete, it was stirred at r.t. for 1 h. After the solvent was
removed in vacuo, the residue was diluted with EtOAc, washed with
brine and dried over anhydrous Na2SO4. Concentration in vacuo
left a yellow solid, which was subjected to the recrystallization
The mixture of the mesylate (1062 mg, 3.56 mmol), alanine
methyl ester (741 mg, 7.12 mmol) and dry K2CO3 (738 mg,
5.34 mmol) in 20 mL of CH3CN was refluxed for 4 days.
The reaction was monitored by TLC until all the mesylate was
consumed. After the solvent was removed in vacuo, the residue was
diluted with EtOAc, washed with brine and dried over anhydrous
Na2SO4. Concentration in vacuo left a yellowish oil, which was
chromatographed (PE–EtOAc = 6 : 1) to give the desired (R,S)
diastereomer 12 (654 mg, 60% yield). 1H NMR (CDCl3, 300 MHz)
d 7.58 (d, 2H, J = 8.7 Hz), 7.48 (d, 2H, J = 8.1 Hz), 3.96 (t, 1H,
J = 6.6 Hz), 3.71 (s, 3H), 3.39 (s, 3H), 3.36 (q, 1H, J = 3.6 Hz),
1
(PE–EtOAc) to give 17d as white solid (4.0 g, 64.3% yield). H
NMR (CDCl3, 400 MHz): d 7.36–7.27 (m, 6H), 5.06–5.04 (m,
1H), 4.05 (dd, 2H, J = 15.2, 8.8 Hz), 3.90–3.82 (m, 2H), 2.74 (br-s,
1H). [a]2D0 = +31.8 (c 0.9, CHCl3).
3.10 (q, 1H, J = 7.5 Hz, 6.9 Hz, 6.9 Hz), 2.59 (br-s, 1H). [a]D24
−111.3 (c = 3.8, CHCl3).
=
(S)-2-Chloro-N-(2-chloro-1-phenylethyl)acetamide (18d)
The procedure is similar to the preparation for 18a to give 18d
(450 mg, 31% yield). 1H NMR (CDCl3, 400 MHz) d 7.40–7.29 (m,
5H), 4.25 (dd, 1H, J = 4.0 Hz, 9.2 Hz), 3.72 (dd, 1H, J = 4.0 Hz,
10.8 Hz), 3.68–3.56 (m, 3H), 2.96 (br-s, 2H). EIMS: 217 (M+).
(4,6-Dimethylpyrimidin-5-yl)(4-((S)-4-((R)-2-methoxy-1-
(4-(trifluoromethyl)phenyl)ethyl)-3-methylpiperazin-1-yl)-4-
methylpiperidin-1-yl)methanone (Sch-D)
To the solution of compound 14 (136 mg, 0.25 mmol) in methylene
chloride (5 mL) was added trifluoroacetic acid (0.4 mL). The
mixture was stirred at room temperature for 1.0 h, and was
evaporated under reduced pressure. The resulting residue was
dissolved in 5 mL of THF, then borane–dimethylsulfide complex
(1.25 mL, 2 M in Et2O) was added dropwise. The mixture was
stirred at reflux under nitrogen overnight, then it was quenched
with 2 mL of methanol in an ice bath. The solvent was evaporated
in vacuo. The residue was used for the next reaction without
further purification. The crude piperazine was dissolved in DCM
(3 mL) and treated with 4,6-dimethylpyrimidine-5-carboxylic acid
(43 mg, 0.28 mmol), EDCI (76 mg, 0.38 mmol), HOBt (53 mg,
0.38 mmol) and DIPEA (0.1 mL). The mixture was stirred at
room temperature for 24 h. Then the mixture was diluted with
EtOAc, usual work-up was applied. The residue was purified
by chromatography (10–50% EtOAc-CH2Cl2, then 5% CH3OH–
CH2Cl2) to give the title compound as white foam (31 mg, 30%
tert-Butyl 4-methyl-4-((S)-3-phenyl-4-((S)-1-(4-(trifluoromethyl)-
phenyl)ethyl)piperazin-1-yl)piperidine-1-carboxylate (20d)
The procedure is similar to the preparation for 20a to give 20d
as white foam (42.5% yield), and the other isomer (14.1% yield).
1H NMR (CDCl3, 400 MHz) d 7.68–7.20(m, 9H ), 4.78 (brs, 1H),
3.95–3.48 (m, 2H), 3.45–3.40 (m, 2H), 3.04–2.8 (m,2H), 2.50–2.32
(m, 5H), 1.92–1.84 (m, 2H), 1.46 (s, 9H), 1.50–1.32 (m, 2H), 1.15
(d, 3H, J = 6.4 Hz), 0.9 (s, 3H).
Acknowledgements
National Natural Science Foundation of China (No. 30672528)
and Chinese Academy of Sciences (No. KSCX2-YW-R-20) are
greatly appreciated for financial support. The authors thank Prof.
Gang Pei at Shanghai Institute of Biochemistry and Cell Biology
for his helpful advice on the biological assay.
1
yield for 3 steps). H NMR (CDCl3, 300 MHz): d 8.94 (s, 1H),
7.58–7.51 (dd, 4H, J = 9.0 Hz, 2.1 Hz), 4.24–4.20 (br-d, 1H, J =
13.2 Hz), 4.03 (br-s, 1H), 3.80–3.69 (m, 2H), 3.49–3.39 (m, 2H),
3.34 (s, 3H), 3.10 (br-s, 1H), 3.00–2.95 (m, 1H), 2.69–2.62 (m, 1H),
2.48 (s, 3H), 2.45 (s, 3H), 2.44 (br-s, 1H), 2.37–2.23 (m, 3H), 2.00–
1.80 (m, 2H), 1.46–1.36 (m, 1H), 1.30–1.23 (m, 2H), 1.19–1.17 (d,
3H, J = 6.3 Hz), 0.93 (s, 3H). ESI-MS (m/z): 534.2 [M+H]+, 535.3
References
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(S)-2-Amino-2-phenylethanol (16d)
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1
(4.4 g, 97% yield). H NMR (CDCl3, 400 MHz) d 7.39–7.23 (m,
5H), 4.04 (dd, 1H, J = 4.4 Hz, 8.0 Hz), 3.70 (dd, 1H, J = 4.4 Hz,
10.8 Hz), 3.54 (dd, 1H, J = 8.0 Hz, 10.8 Hz), 2.60 (br-s, 3H).
2696 | Org. Biomol. Chem., 2007, 5, 2690–2697
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