4-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]benzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chloride 603 (26 g, 0.14 mol, 1.3 equiv) and p-hydroxybenzaldehyde (13 g, 0.11 mol, 1 equiv) were dissolved in dry THF (40 mL). K2CO3 (15 g, 0.11 mol, 1 equiv) was added followed by 18-crown-6 (3.0 g, 11 mmol, 0.11 equiv) and KI (0.20 g, 1.2 mmol, 0.01 equiv). The reaction mixture was stirred at reflux for 48 h. The resulting mixture was cooled to room temperature, and water (200 mL) was added. The product was extracted with 3×350 mL portions of ethyl acetate and the combined organic layers were dried and concentrated. The oil was loaded onto a silica gel column and eluted with a 1:9 mixture of ethyl acetate/hexane, followed by a ratio of 1:4, 3:7, 4:1 of ethyl acetate/hexane and finally washed with ethyl acetate to afford 21 g (70%) of 604 as a clear oil. IR(cm−1): 1697 (s), 1165 (s). 1H NMR (400, CDCl3): δ 3.36 (s, 3), 3.54 (t, 2, J=4.6), 3.63-3.68 (m, 4), 3.72-3.75 (m, 2), 3.88 (t, 2, J=4.8), 4.20 (t, 2, J=4.8), 7.01 (d, 2, J=8.8), 7.82 (d, 2, J=8.8), 9.87 (s, 1). 13C NMR (CDCl3): δ 58.86, 67.59, 69.29, 70.40, 70.47, 70.71, 71.73, 114.71, 129.84, 131.76, 163.69, 190.63. Calcd: [M+H]+ (C14H21O5) m/z=269.13889. Found FAB-HRMS: [M+H]+ m/z=269.134487. Anal. Calcd. for C14H20O5: C, 62.67; H, 7.51. Found: C, 62.47; H, 7.74. at reflux for 48 h The product was extracted with 3×350 mL portions of ethyl acetate the combined organic layers were dried concentrated eluted with a 1:9 mixture of ethyl acetate/hexane finally washed with ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The bisacrylamide triethylene glycol acetal crosslinker (606) or triglyme crosslinker as shown in FIG. 6 was synthesized in four steps on a multigram scale. The first step involved the preparation of 1-chloro-3,6,9-trioxadecane (603) using the procedure of Loth, H. & Ulrich, F. (1998) J. Control Release. 54, 273. Compound 603 was then used to alkylate hydroxy benzaldehyde (605) and produce p-(1,4,7,10-Tetraoxaundecyl)benzaldehyde (604). Compound 603 was chosen as the alkylating agent since it can be easily synthesized on a large scale (100 grams) enabling the preparation of 4 on a 20 gram scale (70% yield), using potassium carbonate as the base and 18-crown-6 as the phase transfer catalyst. Hydroxy-benzaldehyde could also be alkylated using 1-tosyl-3,6,9-trioxadecane and 1-bromo-3,6,9-trioxadecane but these approaches were discontinued because significantly lower yields of the desired product were obtained. was synthesized in four steps on a multigram scale

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The bisacrylamide triethylene glycol acetal crosslinker (606) or triglyme crosslinker as shown in FIG. 6 was synthesized in four steps on a multigram scale. The first step involved the preparation of 1-chloro-3,6,9-trioxadecane (603) using the procedure of Loth, H. & Ulrich, F. (1998) J. Control Release. 54, 273. Compound 603 was then used to alkylate hydroxy benzaldehyde (605) and produce p-(1,4,7,10-Tetraoxaundecyl)benzaldehyde (604). Compound 603 was chosen as the alkylating agent since it can be easily synthesized on a large scale (100 grams) enabling the preparation of 4 on a 20 gram scale (70% yield), using potassium carbonate as the base and 18-crown-6 as the phase transfer catalyst. Hydroxy-benzaldehyde could also be alkylated using 1-tosyl-3,6,9-trioxadecane and 1-bromo-3,6,9-trioxadecane but these approaches were discontinued because significantly lower yields of the desired product were obtained. was synthesized in four steps on a multigram scale

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The bisacrylamide triethylene glycol acetal crosslinker (606) or triglyme crosslinker as shown in FIG. 6 was synthesized in four steps on a multigram scale. The first step involved the preparation of 1-chloro-3,6,9-trioxadecane (603) using the procedure of Loth, H. & Ulrich, F. (1998) J. Control Release. 54, 273. Compound 603 was then used to alkylate hydroxy benzaldehyde (605) and produce p-(1,4,7,10-Tetraoxaundecyl)benzaldehyde (604). Compound 603 was chosen as the alkylating agent since it can be easily synthesized on a large scale (100 grams) enabling the preparation of 4 on a 20 gram scale (70% yield), using potassium carbonate as the base and 18-crown-6 as the phase transfer catalyst. Hydroxy-benzaldehyde could also be alkylated using 1-tosyl-3,6,9-trioxadecane and 1-bromo-3,6,9-trioxadecane but these approaches were discontinued because significantly lower yields of the desired product were obtained. was synthesized in four steps on a multigram scale

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chloride 603 (26 g, 0.14 mol, 1.3 equiv) and p-hydroxybenzaldehyde (13 g, 0.11 mol, 1 equiv) were dissolved in dry THF (40 mL). K2CO3 (15 g, 0.11 mol, 1 equiv) was added followed by 18-crown-6 (3.0 g, 11 mmol, 0.11 equiv) and KI (0.20 g, 1.2 mmol, 0.01 equiv). The reaction mixture was stirred at reflux for 48 h. The resulting mixture was cooled to room temperature, and water (200 mL) was added. The product was extracted with 3×350 mL portions of ethyl acetate and the combined organic layers were dried and concentrated. The oil was loaded onto a silica gel column and eluted with a 1:9 mixture of ethyl acetate/hexane, followed by a ratio of 1:4, 3:7, 4:1 of ethyl acetate/hexane and finally washed with ethyl acetate to afford 21 g (70%) of 604 as a clear oil. IR (cm−1): 1697 (s), 1165 (s). 1H NMR (400, CDCl3): δ 3.36 (s, 3), 3.54 (t, 2, J=4.6), 3.63–3.68 (m, 4), 3.72–3.75 (m, 2), 3.88 (t, 2, J=4.8), 4.20 (t, 2, J=4.8), 7.01 (d, 2, J=8.8), 9.87 (s, 1). 13C NMR (CDCl3): δ 58.86, 67.59, 69.29, 70.40, 70.47, 70.71, 71.73, 114.71, 129.84, 13.1.76, 163.69, 190.63. Calcd: [M+H]+ (C14H21O5) m/z=269.13889. Found FAB-HRMS: [M+H]+ m/z=269.134487. Anal. Calcd. for C14H20O5: C, 62.67; H, 7.51. Found: C, 62.47; H, 7.74. at reflux for 48 h The product was extracted with 3×350 mL portions of ethyl acetate the combined organic layers were dried concentrated eluted with a 1:9 mixture of ethyl acetate/hexane finally washed with ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The bisacrylamide triethylene glycol acetal crosslinker (606) or triglyme crosslinker as shown in FIG. 6 was synthesized in four steps on a multigram scale. The first step involved the preparation of 1-chloro-3,6,9-trioxadecane (603) using the procedure of Loth, H. & Ulrich, F. (1998) J. Control Release. 54, 273. Compound 603 was then used to alkylate hydroxy benzaldehyde (605) and produce p-(1,4,7,10-Tetraoxaundecyl)benzaldehyde (604). Compound 603 was chosen as the alkylating agent since it can be easily synthesized on a large scale (100 grams) enabling the preparation of 4 on a 20 gram scale (70% yield), using potassium carbonate as the base and 18-crown-6 as the phase transfer catalyst. Hydroxy-benzaldehyde could also be alkylated using 1-tosyl-3,6,9-trioxadecane and 1-bromo-3,6,9-trioxadecane but these approaches were discontinued because significantly lower yields of the desired product were obtained. was synthesized in four steps on a multigram scale