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A NEW ROUTE TO PREPARE POMALIDOMIDE
Daowei Huang,1,2,a Chengwu Shen,3,b Wenya Wang,1,2 Lei Huang,1,2 Feng Ni,1,2
Jianqi Li1,2,*
1Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of
Pharmaceutical Industry, Shanghai, 201203, China;
2Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai,
201203, China;
3Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021,
China.
*Corresponding author: Tel.: +86-021-20572128. E-mail: lijianqb@126.com
a and b, Authors contributed equally to this article.
SUPPLEMENTARY INFORMATION
All reagents and solvents were commercially available and used without further
purification unless otherwise stated. Melting points were obtained on a Rapido
Boetius apparatus and are uncorrected. 1H NMR and 13C NMR spectra were recorded
on a Bruker 400 NMR spectrometer in DMSO-d6 with tetramethylsilane (TMS) as an
internal standard. Electron impact–mass spectrometry (EI-MS) spectra were obtained
on a FinniganMAT 95 mass spectrometer. All equipment, instruments and other
devices used to measure the physical properties of substances is regularly calibrated,
validated and verified. Intermediate 11 (CAS registry number: 1001852-10-3 ) was
prepared as reported in the literature.[12] Intermediate 12 (CAS registry number:
1001852-15-8) was known and can undergo the next cyclization directly without
separating, but no reported spectroscopic or characterization data.
2-((2, 6-dioxopiperidin-3-yl)carbamoyl)-3-nitrobenzoic acid (11)
Et3N (23.27 g, 0.23 mol) was added dropwise into the solution of 3-nitro-phthalic
anhydride (7, 44.0 g, 0.23 mol) and 3-aminopiperidine-2,6-dione hydrochloride (8,
37.9 g, 0.23 mol) in THF (600 ml). After reacting for 30 min below 20 ℃, the
precipitation was filtered, washed with THF (30 mL×3), and then dried in vacuo to
give intermediate 11 (67.20 g, 91.0%) as a white solid (HPLC, 95.24%). Mp>250 ℃
(literature [12]: 289~291 ℃), 1H NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H,
COOH), 10.85 (s, 1H, -CONHCO-), 8.99 (d, 1H, J = 7.6 Hz, CONH), 8.17~8.26 (m,
2H, Ar-H), 7.76 (t, 1H, J = 8.0 Hz, Ar-H), 4.71~4.77 (m, 1H, NHCHCO), 2.68~2.77
(m, 1H, COCHaCHb), 2.50~2.58 (m, 1H, COCHaCHb), 2.21 (t, 1H, J = 4.0 Hz,
CHCHaCHb), 1.70~1.90 (m, 1H, CHCHaCHb); 13C NMR (DMSO-d6/TMS) δ 173.04,
171.41, 165.91, 164.07, 147.46, 134.70, 132.43, 132.17, 130.19, 127.29, 49.74, 30.29,
23.76; MS (ESI) m/z calcd. for C13H11N3O7: 321.06, found 322.07 (M+H+), 360.02
(M+K+).
3-amino-2-((2,6-dioxopiperidin-3-yl)carbamoyl)benzoic acid (12)
10% Pd/C(1.5 g)was added to the solution of 11(15.0 g,46.72 mmol) in
methanol (750 mL) in Parr hydrogenater. Then, replace the air with nitrogen three
times, and react for 30 min at r.t. in 1.0 MPa. Filter the solution to remove Pd/C
through Celite filter agent to yield a solution of intermediate 12 in methanol, which
can undergo the next cyclization directly without any work-up.
4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1, pomalidomide)
The above solution of intermediate 12 in methanol was heated to reflux for 2
hours. On cooling, the precipitate was collected to deliver desired product (1) as a
yellow solid (9.11 g, 71.43%), 99.56% (HPLC). Mp>250 ℃ (literature:[6]
315.5~317.5 ℃), 1H-NMR (DMSO-d6) δ: 11.08 (s, 1H, -CONHCO-), 7.47 (t, 1H, J =
7.6 Hz, Ar-H), 7.02 (t, 2H, J = 8.4 Hz, Ar-H), 6.51 (s, 2H, NH2), 5.03~5.08 (m, 1H,
NHCHCO), 2.85~2.94 (m, 1H, COCHaCHb), 2.49~2.58 (m, 2H, COCHaCHb and
CHCHaCHb), 2.05~2.09 (m, 1H, CHCHaCHb); 13C NMR (DMSO-d6/TMS) δ 172.91,
170.20, 168.67, 167.46, 146.76, 135.50, 132.04, 121.77, 111.11, 108.66, 48.60, 31.07,
22.24; MS (ESI) m/z calcd. for C13H11N3O4: 273.07, found 274.08 (M+H+),
296.07(M+Na+).
Figures S1~S12 show the 1H NMR, 13C NMR and HRMS spectra of compounds
11 and 1, and HPLC of 9, 11 and 1, the content of palladium in product 1 (route 2 and
new route). The data of 1H-NMR were consistent with that reported in the reference.[6]
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