1-Hydroxybenzotriazole → Artelinate

4-Arm PEG (MW 20 Kda, 20 g, ˜1 mmol) (Shearwater Corporation) was azeotropically dried in vacuo with CHCl3 (3×200 ml) and was redissolved in CH2Cl2 (250 ml). To this clear solution was added artelinic acid (3.30 g, 7.88 mmol), N,N-dimethylaminopyridine (DMAP) (catalytic amount), and 1-hydroxybenzotriazole (HOBT) (0.680 g, 5.03 mmol). N,N-dicyclohexylcarbodiimide (DCC) (1.74 g, 8.43 mmol in about 10 ml of CH2Cl2) was then added and the mixture was allowed to reflux under of argon for 17 hours. The mixture was then concentrated in vacuo and the residual syrup was dissolved in toluene (˜200 ml) and filtered. The toluene was removed in vacuo at about 45° C. and the residue was treated with 5 ml of CH2Cl2 and triturated with 2-propanol (300 ml). The resulting precipitate was collected by vacuum filtration and dried in vacuo to obtain a pure water-soluble product (18.5 g, 92% yield) with >95% substitution as indicated by 1H NMR. Partial 1H NMR data (CDCl3, 300 MHz): δ 0.94 (s, 12H, C9—CH3), 0.95 (s, 12H, C6—CH3), 1.44 (s, 12H, C3—CH3), 2.68 (m, 4H, H-9), 3.63 (bs, 1818H, PEG backbone), 4.45 (t, 8H, J 4.4 Hz, PEG—OCH2CH2O—COAr), 4.56 (d, 4H, J 13.1 Hz, OCHAHB—Ar), 4.91-4.96 (m, 8H, H-10 overlapped with OCHAHB—Ar), 5.44 (s, 4H, H-12), 7.37 (d, 4H, J 7.8 Hz, Ar), 8.01 (d, 4H, Ar).

1. dry with material4-Arm PEG (MW 20 Kda, 20 g, ˜1 mmol) (Shearwater Corporation) was azeotropically dried in vacuo with CHCl3 (3×200 ml)
2. dissolutionwas redissolved in CH2Cl2 (250 ml)
3. temperatureto reflux under of argon for 17 hours
4. concentrationThe mixture was then concentrated in vacuo
5. dissolutionthe residual syrup was dissolved in toluene (˜200 ml)
6. filtrationfiltered
7. customThe toluene was removed in vacuo at about 45° C.
8. additionthe residue was treated with 5 ml of CH2Cl2
9. customtriturated with 2-propanol (300 ml)
10. filtrationThe resulting precipitate was collected by vacuum filtration
11. customdried in vacuo

ORD-Eintrag

ord-e8350c947ae442baae5232ca0b586247

Quelldatensatz

uspto-grants-2002_10

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06461603B2