H-[(N-Ropinirole)10(EOZ)190]-COOH 20K

Example 9 Preparation of H-[(N-Ropinirole)₁₀(EOZ)₁₉₀]-COOH 20K by attachment of Ropinirole 3-azidocarbamate to Polyoxazoline 10 pendent acid 20K

Ropinirole-N-bromoethylcarboxylate To a solution of ropinerole ropinirole hydrochloride (0.558 g, 1.88 mmol) in dioxane (38 ml) was added triethylamine (2.10 ml, 15.1 mmol). After stirring for 5 minutes, 2-bromoethyl chloroformate (1.61 ml, 15.1 mmol) was added slowly and the mixture was allowed to stir overnight at room temperature. Water (40 mL) was added to give a mixture with pH of 9.5. After stirring overnight, the mixture was stirred with dichloromethane (40 mL) and brine solution (10 mL) for 10 minutes. The two layers were separated and the top layer was extracted with dichloromethane (40 mL). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated to give dark red thick oil. Further purification was performed by silica gel column chromatography, eluting with dichloromethane/EtOAc (starting from 9:1, 4:1, and then 100% EtOAc) to give the desired N-acylated product as a dark red oil (0.170 g, 22.01% yield).). ¹H NMR (Varian, 500 MHz, 10 mg/mL DMSO-d₆, δ): 0.83 (t, J=7.5 Hz, 6H, —CH₂CH₂CH₃), 1.39 (m, 4H, —CH₂CH₂CH₃), 2.39 (t, J=7.5 Hz, 4H, —CH₂CH₂CH₃), 2.62 (m, 4H, Pr₂NCH₂CH₂—Ar), 3.80 (s, 2H, —CH₂C(═O)—), 3.80 (t, J=5.5 Hz, 2H, —OCH₂CH₂Br), 4.65 (t, 2H, —OCH₂CH₂Br), 7.04 (d, J=8.0 Hz, 1H, Ar H), 7.25 (t, J=8.0 Hz, 1H, Ar H), 7.63 (d, J=8.0 Hz, 1H, Ar H).
Ropinirole-N-azidoethylcarboxylate To a solution of Ropinirole-N-bromoethylcarboxylate (0.170 g, 0.414 mmol) in DMF (2 ml) was added sodium azide (0.027 g, 0.414 mmol) to give a clear yellow solution. After stirring overnight at room temperature, the mixture was quenched with 1 mL of 0.1 N HCl and then diluted with 2 mL of water. All the volatiles were removed using a rotary evaporator and the aqueous solution was extracted twice with dichloromethane (3 mL each). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated to give Ropinirole-N-azidoethylcarboxylate (0.12 g, 78% yield) as thick yellow oil. ¹H NMR (Varian, 500 MHz, 10 mg/mL DMSO-d₆, δ): 0.93 (t, J=Hz, 6H, —CH₂CH₂CH₃), 1.70 (m, 4H, —CH₂CH₂CH₃), 2.99 (m, J=Hz, 4H, Pr₂NCH₂CH₂—Ar), 3.07 (m, 4H, —CH₂CH₂CH₃), 3.22 (m, 4H, Pr₂NCH₂CH₂—Ar), 3.92 (s, 2H, —CH₂C(═O)—), 3.98 (t, 2H, —OCH₂CH₂N₃), 4.48 (t, 2H, —OCH₂CH₂Br), 7.14 (d, J=7.5 Hz, 1H, Ar H), 7.33 (t, J=8.0 Hz, 1H, Ar H), 7.69 (d, J=8.0 Hz, 1H, Ar H).
H-[(N-Ropinirole)₁₀(EOZ)₁₉₀]-COOH 20K Ropinirole-N-azidoethylcarboxylate hydrochloride (0.12 g, 0.293 mmol) was dissolved in THF (15 ml). H-[(Ptyn)₁₀(Ethyl)₂₀₀]-T-PA (0.488 g, 0.024 mmol) was added and the mixture was stirred to form a solution. Cul (0.019 g, 0.098 mmol) and triethylamine (0.014 ml, 0.098 mmol) were added to give a clear red solution. After stirring for 16 hours at 45° C., the mixture was quenched with 2 mL of 0.1N HCl to give a solution with pH of 3. All the volatiles were removed and the residue was dissolved in methanol. The resulting mixture was passed through a Dowex and Amberlite IR-120 column using methanol as an eluent. After removing methanol, the resulting aqueous solution was extracted twice with dichloromethane (5 mL each). The organic solution was dried over Na₂SO₄, filtered, concentrated to 10 mL, and precipitated by adding into 70 mL of diethyl ether. The precipitate was filtered and dried in vacuo to give H-[(N-Ropinirole)₁₀(Ethyl)₂₀₀]-T-PA (0.50 g, 86% yield) as a pale yellow powder. In addition to the usual polymer backbone peaks, ¹H NMR (Varian, 500 MHz, 10 mg/mL DMSO-d₆, δ) shows the polymer chain contained an average of 6.4 units of rotigotine with major Ropinirole peaks at 0.97 (m, 6H, —CH₂CH₂CH₃), 4.62 (m, 2H, —OCH₂CH₂Br and m, 2H, —OCH₂CH₂-triazole ring), 7.19-7.39 (br m, 3H, Ar H), and 7.91 (m, 1H, triazole H).

 https://www.google.com/patents/US8383093