octanedioyl dichloride

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

Procedure: To a stirred solution of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (6.8 g) in 1M potassium carbonate (45 ml), octanedioyl dichloride (3.2 g) was added dropwise under ice-cooling. After the addition, the reaction mixture was stirred for 1 hour at the same temperature and for additional 1 hour at room temperature. The solution was acidified with dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residual oil was purified by silica gel column chromatography to give 7.6 g (86%) of the titled compound: mp 93°-97° C. (dec.); [α]D27 +123.6° (c=0.5, methanol). IR (nujol, cm-1): 1720 (COOH), 1620 (CON), 1600 (aromatic), 1230, 1090, 855, 765. NMR (CD3OD) δ: 0.7-1.7 (8H, m, --CH2 --CH2)4CH2 --), 1.8-2.4 (4H, m, --CH2 --CH2)4CH2), 3.25 (4H, d, J=7.5 Hz, C5 --H), 4.81 (2H, t, J=7.5 Hz, C4 --H), 6.35 (2H, s, C2 --H), 6.7-8.0 (8H, m, arom. H). TLC: Rf value* 0.34. cooling After the addition extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried over anhydrous magnesium sulfate evaporated in vacuo The residual oil was purified by silica gel column chromatography

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

Procedure: (4R)-2-(2-Hydroxyphenyl)-4-thiazolidinecarboxylic acid (6.8 g), in N sodium hydroxide (30 ml) and octanedioyl dichloride (6.3 g), were added dropwise to 1M potassium carbonate (60 ml) with stirring under ice-cooling. After the addition, the reaction mixture was stirred for 1 hour at the same temperature and for additional 1 hour at room temperature. The solution was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residual oil*2 was purified by silica gel column chromatography to give 7.0 g (61%) of the titled compound: mp 155°-157° C. (dec.) (ethyl acetate); [α]D27 +134.1° (c=0.5, methanol). IR (nujol, cm-1): 3220 (OH), 1710 (COOH), 1620 (CON), 1600 (aromatic), 1415, 1235, 1172, 950, 760. NMR (DMSO-d6,δ): 0.53-1.73 (8H, m, -- CH2 --CH2)4CH2 --), 1.77-2.57 (4H, m, --CH2 --CH2)4CH2 --), 3.03 (1H, ABq (A part), d, J=11.5, 8.5 Hz, C5*1 --HA), 3.37 (1H, ABq (B part), d, J=11.5, 6.5 Hz, C5 --HB), 4.60 (1H, dd, J=8.5, 6.5 Hz, C4 --H), 6.28 (1H, s, C2 --H), 6.45-8.07 (4H, m, arom. H), 9.77 (1H, s, C2 --H), 6.45-8.07 (4H, m, arom. H), 9.77 (1H, s, --COOH). TLC: Rf value*3 0.52. pyrrolidine ring. The same shall be applied hereinafter. cooling After the addition the reaction mixture was stirred for 1 hour at the same temperature and for additional 1 hour at room temperature extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried over anhydrous magnesium sulfate evaporated in vacuo The residual oil*2 was purified by silica gel column chromatography

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

Procedure: (4R)-2-(2-Hydroxyphenyl)-4-thiazolidinecarboxylic acid (6.8 g), in N sodium hydroxide (30 ml) and octanedioyl dichloride (6.3 g), were added dropwise to 1M potassium carbonate (60 ml) with stirring under ice-cooling. After the addition, the reaction mixture was stirred for 1 hour at the same temperature and for additional 1 hour at room temperature. The solution was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residual oil*2 was purified by silica gel column chromatography to give 7.0 g (61%) of the titled compound: mp 155°-157° C. (dec.) (ethyl acetate); [α]D27 +134.1° (c=0.5, methanol). IR (nujol, cm-1): 3220 (OH), 1710 (COOH), 1620 (CON), 1600 (aromatic), 1415, 1235, 1172, 950, 760. NMR (DMSO-d6,δ): 0.53-1.73 (8H, m, -- CH2 --CH2)4CH2 --), 1.77-2.57 (4H, m, --CH2 --CH2)4CH2 --), 3.03 (1H, ABq (A part), d, J=11.5, 8.5 Hz, C5*1 --HA), 3.37 (1H, ABq (B part), d, J=11.5, 6.5 Hz, C5 --HB), 4.60 (1H, dd, J=8.5, 6.5 Hz, C4 --H), 6.28 (1H, s, C2 --H), 6.45-8.07 (4H, m, arom. H), 9.77 (1H, s, C2 --H), 6.45-8.07 (4H, m, arom. H), 9.77 (1H, s, --COOH). TLC: Rf value*3 0.52. pyrrolidine ring. The same shall be applied hereinafter. cooling After the addition the reaction mixture was stirred for 1 hour at the same temperature and for additional 1 hour at room temperature extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried over anhydrous magnesium sulfate evaporated in vacuo The residual oil*2 was purified by silica gel column chromatography

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

Procedure: To a stirred solution of 25 g of 4-aminophenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 250 ml of a dry mixture of pyridine-acetonitrile (1:1) was added a solution of 3.55 g of suberoyl chloride in 10 ml of acetonitrile. This mixture was allowed to stand, under argon, for 18 hours. An additional 0.2 ml of suberoyl chloride was added, the solution was allowed to stand for an additional 18 hours and was then poured into 2 liters of water. After stirring for 15 minutes, the oil was separated and extracted into 500 ml of dichloromethane. The extract was washed twice with 500 ml portions of 0.5 N hydrochloric acid, then with saturated aqueous sodium chloride solution, dried and taken to dryness, giving 28 g of the desired product as a white foam. to stand for an additional 18 hours the oil was separated extracted into 500 ml of dichloromethane The extract was washed twice with 500 ml portions of 0.5 N hydrochloric acid with saturated aqueous sodium chloride solution, dried

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

Procedure: To a stirred solution of 25 g of 4-aminophenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 250 ml of a dry mixture of pyridine-acetonitrile (1:1) was added a solution of 3.55 g of suberoyl chloride in 10 ml of acetonitrile. This mixture was allowed to stand, under argon, for 18 hours. An additional 0.2 ml of suberoyl chloride was added, the solution was allowed to stand for an additional 18 hours and was then poured into 2 liters of water. After stirring for 15 minutes, the oil was separated and extracted into 500 ml of dichloromethane. The extract was washed twice with 500 ml portions of 0.5 N hydrochloric acid, then with saturated aqueous sodium chloride solution, dried and taken to dryness, giving 28 g of the desired product as a white foam. to stand for an additional 18 hours the oil was separated extracted into 500 ml of dichloromethane The extract was washed twice with 500 ml portions of 0.5 N hydrochloric acid with saturated aqueous sodium chloride solution, dried

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

Procedure: Suberoyl chloride (40.8 g, 0.1933 mol) was added over a 30-45 minute period to a mechanically stirred suspension of aluminum chloride (64.4 g, 0.483 mol) in fluorobenzene (181 ml, 1.93 mol) maintained at 5°-10° C. The yellow slurry was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured onto approximately 1000 g of ice containing 75 ml of concentrated hydrochloric acid. The resulting suspension was separated by decantation and washed several times with water. The organic layer was distilled to remove excess fluorobenzene and the solid residue collected by filtration, washed with water, and dried at 100° C. The crude solid was recrystallized from approximately 500 ml of toluene to afford 43.0 g (67% yield) of 1,6-bis(4-fluorobenzoyl)hexane; mp 123°-124° C.; 'H NMR (CDCl3) δ1.0-2.1 (m, 8H, CH2), 2.97 (t, 4H, O=CCH2, J=7.0 Hz), 6.9-8.3 (m, 8H, aromatic). Anal. Calcd. for C20H20F2O2 : C, 72.71%; H, 6.10%; F, 11.50%. Found: C, 72.50%; H, 5.86%; F, 11.19%. maintained at 5°-10° C The resulting suspension was separated by decantation washed several times with water The organic layer was distilled to remove excess fluorobenzene the solid residue collected by filtration washed with water dried at 100° C The crude solid was recrystallized from approximately 500 ml of toluene

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

Procedure: To a stirred solution of suberoyl chloride (1.00 mL, 5.55 mmol) in THF (40 mL) at 0° C. was added a solution of benzylamine (0.61 mL, 5.55 mmol) and DIEA (1.45 mL, 8.33 mmol) in THF (10 mL) dropwise. The mixture was allowed to warm to ambient temperature and stirred for 1 h. Then, HCl (10 mL, 1 N) was added and the mixture stirred for 0.5 h. The contents were diluted with EtOAc (30 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×10 mL), the organics combined, washed with brine (5 mL), and dried over MgSO4. Filtration and concentration under reduced pressure left 49 as an off-white solid. 1H-NMR (300 MHz, DMSO-d6) δ 11.98 (br s, 1H), 9.80 (t, 1H), 7.32 (m, 2H), 7.23 (m, 3H), 4.25 (d, 2H), 2.19 (t, 2H), 2.12 (t, 2H), 1.50 (m, 4H), 1.25 (m, 4H). the mixture stirred for 0.5 h the layers separated The aqueous portion was extracted with EtOAc (3×10 mL) washed with brine (5 mL) dried over MgSO4 Filtration and concentration under reduced pressure left 49 as an off-white solid

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

Procedure: To a stirred solution of suberoyl chloride (1.00 mL, 5.55 mmol) in THF (40 mL) at 0° C. was added a solution of benzylamine (0.61 mL, 5.55 mmol) and DIEA (1.45 mL, 8.33 mmol) in THF (10 mL) dropwise. The mixture was allowed to warm to ambient temperature and stirred for 1 h. Then, HCl (10 mL, 1 N) was added and the mixture stirred for 0.5 h. The contents were diluted with EtOAc (30 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×10 mL), the organics combined, washed with brine (5 mL), and dried over MgSO4. Filtration and concentration under reduced pressure left 49 as an off-white solid. 1H-NMR (300 MHz, DMSO-d6) δ 11.98 (br s, 1H), 9.80 (t, 1H), 7.32 (m, 2H), 7.23 (m, 3H), 4.25 (d, 2H), 2.19 (t, 2H), 2.12 (t, 2H), 1.50 (m, 4H), 1.25 (m, 4H). the mixture stirred for 0.5 h the layers separated The aqueous portion was extracted with EtOAc (3×10 mL) washed with brine (5 mL) dried over MgSO4 Filtration and concentration under reduced pressure left 49 as an off-white solid

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

Procedure: To a stirred solution of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (6.8 g) in 1M potassium carbonate (45 ml), octanedioyl dichloride (3.2 g) was added dropwise under ice-cooling. After the addition, the reaction mixture was stirred for 1 hour at the same temperature and for additional 1 hour at room temperature. The solution was acidified with dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residual oil was purified by silica gel column chromatography to give 7.6 g (86%) of the titled compound: mp 93°-97° C. (dec.); [α]D27 +123.6° (c=0.5, methanol). IR (nujol, cm-1): 1720 (COOH), 1620 (CON), 1600 (aromatic), 1230, 1090, 855, 765. NMR (CD3OD) δ: 0.7-1.7 (8H, m, --CH2 --CH2)4CH2 --), 1.8-2.4 (4H, m, --CH2 --CH2)4CH2), 3.25 (4H, d, J=7.5 Hz, C5 --H), 4.81 (2H, t, J=7.5 Hz, C4 --H), 6.35 (2H, s, C2 --H), 6.7-8.0 (8H, m, arom. H). TLC: Rf value* 0.34. cooling After the addition extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried over anhydrous magnesium sulfate evaporated in vacuo The residual oil was purified by silica gel column chromatography

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

Procedure: (4R)-2-(2-Hydroxyphenyl)-4-thiazolidinecarboxylic acid (6.8 g), in N sodium hydroxide (30 ml) and octanedioyl dichloride (6.3 g), were added dropwise to 1M potassium carbonate (60 ml) with stirring under ice-cooling. After the addition, the reaction mixture was stirred for 1 hour at the same temperature and for additional 1 hour at room temperature. The solution was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residual oil*2 was purified by silica gel column chromatography to give 7.0 g (61%) of the titled compound: mp 155°-157° C. (dec.) (ethyl acetate); [α]D27 +134.1° (c=0.5, methanol). IR (nujol, cm-1): 3220 (OH), 1710 (COOH), 1620 (CON), 1600 (aromatic), 1415, 1235, 1172, 950, 760. NMR (DMSO-d6,δ): 0.53-1.73 (8H, m, -- CH2 --CH2)4CH2 --), 1.77-2.57 (4H, m, --CH2 --CH2)4CH2 --), 3.03 (1H, ABq (A part), d, J=11.5, 8.5 Hz, C5*1 --HA), 3.37 (1H, ABq (B part), d, J=11.5, 6.5 Hz, C5 --HB), 4.60 (1H, dd, J=8.5, 6.5 Hz, C4 --H), 6.28 (1H, s, C2 --H), 6.45-8.07 (4H, m, arom. H), 9.77 (1H, s, C2 --H), 6.45-8.07 (4H, m, arom. H), 9.77 (1H, s, --COOH). TLC: Rf value*3 0.52. pyrrolidine ring. The same shall be applied hereinafter. cooling After the addition the reaction mixture was stirred for 1 hour at the same temperature and for additional 1 hour at room temperature extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried over anhydrous magnesium sulfate evaporated in vacuo The residual oil*2 was purified by silica gel column chromatography

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

Procedure: To a stirred solution of suberoyl chloride (1.00 mL, 5.55 mmol) in THF (40 mL) at 0° C. was added a solution of benzylamine (0.61 mL, 5.55 mmol) and DIEA (1.45 mL, 8.33 mmol) in THF (10 mL) dropwise. The mixture was allowed to warm to ambient temperature and stirred for 1 h. Then, HCl (10 mL, 1 N) was added and the mixture stirred for 0.5 h. The contents were diluted with EtOAc (30 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×10 mL), the organics combined, washed with brine (5 mL), and dried over MgSO4. Filtration and concentration under reduced pressure left 49 as an off-white solid. 1H-NMR (300 MHz, DMSO-d6) δ 11.98 (br s, 1H), 9.80 (t, 1H), 7.32 (m, 2H), 7.23 (m, 3H), 4.25 (d, 2H), 2.19 (t, 2H) 2.12 (t, 2H), 1.50 (m, 4H), 1.25 (m, 4H). the mixture stirred for 0.5 h the layers separated The aqueous portion was extracted with EtOAc (3×10 mL) washed with brine (5 mL) dried over MgSO4 Filtration and concentration under reduced pressure left 49 as an off-white solid

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

Procedure: To a stirred solution of 25 g of 4-aminophenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 250 ml of a dry mixture of pyridine-acetonitrile (1:1) was added a solution of 3.55 g of suberoyl chloride in 10 ml of acetonitrile. This mixture was allowed to stand, under argon, for 18 hours. An additional 0.2 ml of suberoyl chloride was added, the solution was allowed to stand for an additional 18 hours and was then poured into 2 liters of water. After stirring for 15 minutes, the oil was separated and extracted into 500 ml of dichloromethane. The extract was washed twice with 500 ml portions of 0.5 N hydrochloric acid, then with saturated aqueous sodium chloride solution, dried and taken to dryness, giving 28 g of the desired product as a white foam. to stand for an additional 18 hours the oil was separated extracted into 500 ml of dichloromethane The extract was washed twice with 500 ml portions of 0.5 N hydrochloric acid with saturated aqueous sodium chloride solution, dried