New and Simple Synthetic Method for Carboxylic Acid Functionalized Poly(ethylene glycol)

Abstract

Alkylation of methyl 4-hydroxybenzoate with α-methoxy-ω-methanesulfonylpoly(ethylene glycol) (M = 5 000) and α,ω-bismethanesulfonylpoly(ethylene glycol) (M = 10 000) has been used to prepare 4-poly(ethylene glycol)oxybenzoic acids. Reactions of chlorides of these acids with 2-amino-2-methylpropanenitrile or 2-amino-2,3-dimethylbutanenitrile were used to prepare the corresponding acylaminonitriles, which were subsequently cyclized and hydrolyzed to give the following acylamino acids: 2-{4-[α-methoxy­poly(ethylene glycol)]oxybenzoylamino}-2,3-dimethyl­butyric acid and 2-(4-{α-[4-(1-carbonyl-1-methylethylcarb­amoyl)phenoxy]poly(ethylene glycol)-ω-yloxy}benzoylamino)-2-methylpropionic acid.

Key words

functionalized poly(ethylene glycol) - liquid-phase reaction - multistep reaction - ring closure - ring opening

References and Notes

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• 4b

  Synthesis of α-Methoxy-ω-methane-sulfonylpoly(ethylene glycol) (M = 5 000) and α,ω-Bismethanesufonylpoly(ethylene glycol) (M = 10 000) α-Methoxypoly(ethylene glycol) (M = 5 000, 25 g, 5 mmol) or poly(ethylene glycol) (M = 10 000, 25 g, 2.5 mmol) was dissolved in toluene (150 mL), which was then distilled off. The evaporation residue was treated with MsCl (50 g, 435 mmol), and the mixture was heated under argon at the temperature of 70 °C. After 72 h, the excess MsCl was distilled off at reduced pressure, and the residue was dissolved in CH₂Cl₂ (50 mL). The solution formed was poured onto Et₂O (1 L), and the precipitated solid was collected by filtration, washed with Et₂O, and recrystallized from propan-2-ol (20-23 g).

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5

General Method for the Synthesis of 1a,b
A melt of α-methoxy-ω-methanesulfonylpoly(ethylene glycol) (M = 5 000, 5 g, 1 mmol) or α,ω-bismethane-
sulfonylpoly(ethylene glycol) (M = 10 000, 10 g, 1 mmol), methyl 4-hydroxybenzoate (2.7 g, 15 mmol), and K₂CO₃ (2.3 g, 15 mmol) was stirred and heated under argon at a temperature of 65 °C for a period of 72 h. After cooling, the reaction mixture was dissolved in NaOH (5 M, 50 mL) and stirred at r.t. for a period of 8 h, whereupon it was acidified with aq HCl to pH 1-2. The obtained solution was saturated with NaCl and extracted with CH₂Cl₂ (8 × 50 mL). The combined extracts were dried and concentrated to a volume of ca 15 mL, and the resulting solution was treated with Et₂O (350 mL). The precipitated solid was collected, washed with Et₂O, and twice recrystallized from propan-2-ol.

6

Compound 1a: yield 4.6 g, 92%. ¹H NMR (500 MHz, CDCl₃): δ = 3.36 (s, 3 H, CH₃O), 3.52-4.27 [m, 460 H, (CH₂CH₂O)₁₁₅], 3.82 (t, J = 4.5 Hz, 2 H, CH₂-β), 4.51 (t, J = 4.5 Hz, 2 H, CH₂-α), 6.90 (d, J = 8.7 Hz, 2 H-arom), 7.62 (d, J = 8.7 Hz, 2 H-arom) ppm.

7

Compound 1b: yield 8.7 g, 87%. ¹H NMR (500 MHz, CDCl₃): δ = 3.52-4.27 [m, 476 H, (CH₂CH₂O)₁₁₉], 3.83 (t, J = 4.5 Hz, 2 H, CH₂-β), 4.52 (t, J = 4.5 Hz, 2 H, CH₂-α), 6.89 (d, J = 8.8 Hz, 2 H-arom), 7.64 (d, J = 8.8 Hz, 2 H-arom) ppm.

9

General Method for the Synthesis of 2a,b
A mixture of α-(4-carboxyphenyloxy)-ω-methoxy-
poly(ethylene glycol) (1a, 2 g, 0.4 mmol) or α,ω-bis(4-carboxyphenyloxy)poly(ethylene glycol) (1b, 2 g, 0.4 mmol) and triphosgene (1 g, 3.37 mmol) was treated with dry CH₂Cl₂ (20 mL) with a drop of DMF, and the mixture was stirred under argon atmosphere at r.t. for a period of 2 h. Then it was refluxed for a period of 5 h, whereupon the solvent was distilled off under reduced pressure. Another portion of anhyd CH₂Cl₂ (20 mL) was added and after several minutes of stirring again removed under reduced pressure. This operation was repeated twice, whereupon the residue was treated with freshly distilled 2-amino-2-methylpropanenitrile or 2-amino-2,3-dimethylbutanenitrile (50 mmol). The obtained homogeneous solution was kept under argon at a temperature of 80 °C for a period of 24 h, whereupon the excess nitrile was distilled off under reduced pressure. The residue was mixed with Et₂O (250 mL), and the separated crude product was recrystallized from propan-2-ol.

11

Compound 2a: yield 1.74 g, 87%. ¹H NMR (500 MHz, CDCl₃): δ = 1.04 (d, J = 6.8 Hz, 3 H, i-PrCH₃), 1.44 (d, J = 6.8 Hz, 3 H, i-PrCH₃), 1.67 (s, 3 H, CH₃), 2.50 (m, 1 H, CH), 3.35 (s, 3 H, CH₃O), 3.52-4.27 [m, 460 H, (CH₂CH₂O)₁₁₅], 3.74 (m, 2 H, CH₂-β), 4.12 (m, 2 H, CH₂-α), 6.19 (s, 1 H, NH), 6.89 (d, J = 8.6 Hz, 2 H-arom), 7.69 (d, J = 8.6 Hz, 2 H-arom) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.9, 16.6, 19.3, 32.3, 52.7, 57.6, 62.7, 68.2-71.7, 112.8, 124.8, 128.5, 160.4, 165.1 ppm.

12

Compound 2b: yield 1.84 g, 92%. ¹H NMR (500 MHz, CDCl₃): δ = 1.77 (s, 6 H, CH₃), 3.52-4.27 [m, 476 H, (CH₂CH₂O)₁₁₉], 3.76 (m, 2 H, CH₂-β), 4.14 (m, 2 H, CH₂-α), 6.59 (s, 1 H, NH), 6.90 (d, J = 8.9 Hz, 2 H-arom), 7.77 (d,
J = 8.9 Hz, 2 H-arom) ppm. ¹³C NMR (125 MHz, CDCl₃):
δ = 15.8, 52.7, 57.6, 62.7, 68.2-71.9, 113.8, 124.8, 128.5, 160.4, 165.2 ppm.

14

General Method for the Synthesis of 3a,b
Nitrile 2a (1 g) or nitrile 2b (1 g) was dissolved in polyphosphoric acid (20 g; 14.3 g 85% H₃PO₄ plus 5.7 g P₂O₅). After 50 h at the temperature of 25 °C, the mixture was treated with ice (100 g). After another 1 h, the mixture was treated with NaCl and extracted with CH₂Cl₂ (8 × 50 mL). The combined extracts were dried, concentrated, and treated with Et₂O (150 mL). The precipitated solid was collected, washed with Et₂O, and recrystallized from propan-2-ol.

15

Compound 3a: yield 0.82 g, 82%. ¹H NMR, (500 MHz, CDCl₃): δ = 0.95 (d, J = 6.8 Hz, 3 H, i-PrCH₃), 1.01 (d, J = 6.8 Hz, 3 H, i-PrCH₃), 1.58 (s, 3 H, CH₃), 2.62 (m, 1 H, CH), 3.35 (s, 3 H, CH₃O), 3.52-4.27 [m, 460 H, (CH₂CH₂O)₁₁₅], 3.74 (m, 2 H, CH₂-β), 4.12 (m, 2 H, CH₂-α), 6.67 (s, 1 H, NH), 6.92 (d, J = 8.8 Hz, 2 H-arom), 7.71 (d, J = 8.8 Hz, 2 H-arom), 15.90 (s, 1 H, CO₂H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 16.7, 17.6, 18.6, 32.7, 42.3, 58.6, 62.9, 69.2, 70.1-71.5, 113.8, 126.6, 128.4, 161.2, 166.4, 174.7 ppm.

16

Compound 3b: yield 0.86 g, 93%. ¹H NMR (500 MHz, CDCl₃): δ = 1.67 (s, 6 H, CH₃), 3.52-4.27 [m, 476 H, (CH₂CH₂O)₁₁₉], 3.77 (m, 2 H, CH₂-β), 4.15 (m, 2 H, CH₂-α), 6.59 (s, 1 H, NH), 6.90 (d, J = 8.9 Hz, 2 H-arom), 7.77 (d,
J = 8.9 Hz, 2 H-arom) ppm. ¹³C NMR (125 MHz, CDCl₃):
δ = 18.7, 18.6, 32.7, 62.9, 69.2, 70.1-71.6, 113.8, 126.6, 128.4, 161.2, 166.4, 174.7 ppm.

17

The ¹H NMR and ¹³C NMR spectra were measured on a Bruker Avance 500 apparatus equipped with a 5 mm broadband probe with Z-gradients and with triple resonance probe with Z-gradients (for ¹H: 500.13 MHz, for ¹³C: 125.77 MHz, respectively).

18

The gel permeation chromatography measurements of the prepared acids 3a,b were performed with HEMA-BIO columns (hydrophilic modified HEMA-Gel, particle size 10 µm porosity 40/100/300/1000) at r.t. using an RI detector and a UV/Vis detector. Redistilled H₂O (pH 7.1) was used as the eluent. The columns were calibrated with a series of standard PEG with varying molecular weights (PSS, Polymer Standard Service GmbH, Mainz, Germany).