A New Route to Prepare Pomalidomide

A NEW ROUTE TO PREPARE POMALIDOMIDE

Daowei Huang,1,2,aChengwu Shen,3,bWenya 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:

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 RapidoBoetius apparatus and are uncorrected. 1H NMR and 13C NMR spectra were recorded on a Bruker 400NMR 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. Intermediate11(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 cyclizationdirectlywithout 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 cyclizationdirectly 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 collectedto 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]

Figure S1: HRMS spectra of 11

Figure S2: 1H NMR spectra of compound 11

Figure S3: 13C NMR spectra of compound 11

Figure S4: ESI-MS of 12

Figure S5: HRMS spectra of 1

Figure S6: 1H NMR spectra of compound 1

Figure S7: 13C NMR spectra of compound 1

Figure S8: HPLC purity of9

Figure S9: HPLC purity of11

Figure S10: HPLC purity of1

Figure S11: The content of palladium in product 1 (route 2)

Figure S12: The content of palladium in product 1 (new route)