Development of a Scalable Process for α-Amino-ω-methoxyl-dodecaethylene Glycol

Abstract

We developed a process for the efficient and scalable preparation of heterofunctionalized dodecaethylene glycol from the readily available tetraethylene glycol and its macrocyclic sulfate. By employing the benzyl group as both a protective group and a separative tag, multiple chromatographic separations were avoided. With this method, α-amino-ω-methyl-dodecaethylene glycol was prepared on a 53-g scale with high purity, 61% overall yield in eight steps and one chromatography separation.

Stepwise PEG synthesis featuring deprotection and coupling in one pot

“…sis [14][15][16][17][18][19][20][21][22][23][24][25][26]. Perhaps, the most widely used methods in academia and in industry involve the use of monomers such as compound 1, which contain the acid-labile DMTr protecting group.…”

Application of Monodisperse PEGs in Pharmaceutics: Monodisperse Polidocanols

“…(2) The polydispersity of PEGs is always supposed to play a minor role in the efficacy and safety of drugs. To address the first issue, many novel synthetic strategies have recently been developed for synthesizing monodisperse PEGs with high efficacy and low cost. − However, as far as we know, there is no research on whether the polydispersity of regular PEGs can compromise the efficacy and safety of PEGylated drugs or not.…”

Direct Measurement of Rupture Force of Single Triazole Molecule by Atomic Force Microscope and Solid Phase Synthesis of Monodisperse Polyethylene Glycols

“…The size distribution (molecular weight) can be characterized statistically by its weight average molecular weight and its number average molecular weight, so they have varying length and molecular weight. 35 If this admixture of PEG is used for PEGylation to prepare drugs then it is difficult to achieve consistent composition. In addition, it can cause difficulty with characterization, loss of biological activities and formation of different size molecules which results in different physical properties.…”

“…12,13,29,[30][31] As a result, significant efforts have been made to synthesize monodisperse PEGs via stepwise organic synthesis. [11][12][13][27][28][29][30][31][32][33][34][35][36][37][38][39][40] Currently, the longest PEGs that can be synthesized using stepwise organic synthesis are those with about 45 ethylene glycol units, which corresponds to molecular weights of about 2K Da. 12,28,29 Challenges for the synthesis of longer PEGs include low efficiency of Williamson ether formation reaction when applied to long PEG substrates, depolymerization of PEG during the ether formation process, 27,40 and the lack of technology to separate PEGs of different lengths.…”

“…The resin was washed extensively (THF/H2O, v/v, 1:1, 0.5 ml × 3; THF, 0.5 ml × 5; DCM, 0.5 ml × 5), and 3.13b was cleaved from the resin using a similar procedure described for 3.13a. Product 3.13b55,35 appeared as a light yellow oil: 26 mg, 0.056 mmol, 82% yield based on 0.9 mmol/g loading of resin 3.2; 1 H and NMR images are inFigures A.6-A.7. ESI-MS (Figure A.14) m/z: [M+NH4] + calcd for C13H40O9Na, 483.3; found 483.4.…”