pentanedial

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: Combine phthalimido-(S)-phenyalanine amide (3.0 g, 10 mmol) and a solution of glutaric dialdehyde (2.0 g, 50% by weight in water) in dichloromethane (200 mL). Heat to reflux with azeotropic removal of water from the refluxate. Add p-toluenesulfonic acid (60 mg). Continue heating at reflux. Pass the refluxate through oven dried 4 Å molecular sieves. After 4 days, cool the reaction mixture to ambient temperature. Extract with 5% sodium bicarbonate solution. Extract the 5% sodium bicarbonate solution with dichloromethane. Combine the organic layers and dry over Na2SO4, filter, and evaporate invacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% tetrahydrofuran/dichloromethane to give the title compound. Heat Continue heating at reflux Pass the refluxate through oven dried 4 Å molecular sieves Extract with 5% sodium bicarbonate solution Extract the 5% sodium bicarbonate solution with dichloromethane dry over Na2SO4 filter evaporate invacuo to give a residue

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

Procedure: Eudragit E™ 100 and Eudragit RS™ were purchased from Rohm Pharma (Germany). Ethyl Cellulose was purchased from Hercules (USA). Sodium salicylate powder (BP, USP) was supplied by Merck (Germany). Sodium diclofenac was purchased from Prosintex (UK). Ethyl alcohol was USP grade. Calcium pectinate powder containing 4% and 2% calcium was prepared by the addition of calcium chloride to a suspension of low methoxy pectin (Copenhagen Pectin) in a water/isopropyl alcohol mixture. Pectin/calcium pectinate core tablets which weighed ~300 mg and contained 30 mg sodium salicylate were prepared by standard dry granulation techniques. Microcrystalline cellulose core tablets weighing 250 mg and containing 30 mg sodium salicylate, were prepared by dry granulation techniques. Pectin/calcium pectinate core tablets weighing ~300 mg and containing 100 mg sodium diclofenac were prepared by standard dry granulation techniques. Crospovidone was purchased from GAF (USA). Crosslinked Byco gelatin was prepared by a crosslinking reaction of Byco hydrolyzed gelatin (Croda (UK)) with glutaraldehyde (Merck (Germany)). Microcrystalline cellulose was purchased from FMC (Belgium). The coating calcium pectinate/Eudragit™ suspension was prepared by dissolving Eudragit E™ (10% w/v (22.5 g Eudragit™/200 g solution)) in ethanol and then adding the calcium pectinate powder, to the desired weight ratio of, 70, 50 and 30% (g calcium pectinate/g Eudragit™ plus calcium pectinate), to the Eudragit™ solution. The suspension was then continuously stirred vigorously throughout the coating process to prevent the calcium pectinate deposition. The other polymer--particulate combinations were prepared similarly by first dissolving the polymer (Eudragit RS™ or ethylcellulose) in ethanol and then adding the particulate (calcium pectinate, Crospovidone, microcrystalline cellulose, or crosslinked Byco protein). were prepared by standard dry granulation techniques were prepared by dry granulation techniques containing 100 mg sodium diclofenac were prepared by standard dry granulation techniques The other polymer--particulate combinations were prepared similarly

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

Procedure: Combine phthalimido-(S)-phenyalanine amide (3.0 g, 10 mmol) and a solution of glutaric dialdehyde (2.0 g, 50% by weight in water) in dichloromethane (200 mL). Heat to reflux with azeotropic removal of water from the refluxate. Add p-toluenesulfonic acid (60 mg). Continue heating at reflux. Pass the refluxate through oven dried 4 Å molecular sieves. After 4 days, cool the reaction mixture to ambient temperature. Extract with 5% sodium bicarbonate solution. Extract the 5% sodium bicarbonate solution with dichloromethane. Combine the organic layers and dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% tetrahydrofuran/dichloromethane to give the title compound. Heat Continue heating at reflux Pass the refluxate through oven dried 4 Å molecular sieves Extract with 5% sodium bicarbonate solution Extract the 5% sodium bicarbonate solution with dichloromethane dry over Na2SO4 filter evaporate in vacuo to give a residue

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

Procedure: A 5-liter 3-necked flask was charged with 140 grams of 50% aqueous glutaric dialdehyde (Aldrich, 0.7 moles), 630 ml of water and 70.7 grams of CH3NH2.HCl (1.036 moles) which was first dissolved in 700 ml of water, 116.6 grams of acetonedicarboxylic acid (0.8 moles) which had been dissolved in 1162 ml of water, and a solution of 123.2 sodium phosphate dibasic and 10.22 grams of NaOH dissolved in 280 ml of water. The heterogeneous orange solution was stirred at room temperature for 24 hours during which time the evolution of CO2 (g) was noted.

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

Procedure: BSA(Bovine Serum Albumin fraction V, Armour Pharm.Co.,600 mg) was dissolved in 0.2 M phosphate buffer (pH 7.0,30 ml). To the solution was added an aqueous solution (adjusted to pH 7.0 with NaHCO3, 30 ml) of 7-amino-2-propylheptanoic acid hydrochloride (prepared in Example 1, 180 mg), followed by the dropwise addition of 0.02 M aqueous glutaraldehyde solution (30 ml). The mixture was stirred for 2 hours at ambient temperature. After adding 1 M lysine solution (pH 7.5,3.0 ml), the mixture was further stirred for an hour and dialyzed for 48 hours against 0.15 M sodium chloride solution (2 liters) at 4° C., while the outer solution was renewed four times, then dialyzed against deionized water (2 liters) for 24 hours. The dialyzed solution was lyophilized to give the conjugate (550 mg). the mixture was further stirred for an hour dialyzed for 48 hours against 0.15 M sodium chloride solution (2 liters) at 4° C., while the outer solution dialyzed against deionized water (2 liters) for 24 hours to give the conjugate (550 mg)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Glutaraldehyde (25% solution in water) (910 mL, 2.4 mol) and benzylamine hydrochloride (344.1 g, 2.4 mol) in water (1050 mL) was cooled to 0° C. 3-Oxopentanedioic acid (350.0 g, 2.4 mol) was added followed by addition of sodium acetate (aq.) (79.7 g in 797 mL water) resulting in formation of a thick orange precipitate. The reaction mixture was heated to 50° C. and stirred at this temperature for 4 h. It was then cooled to ambient temperature and allowed to stand for 24 h. The reaction mixture was acidified to pH2 with 5N aqueous hydrochloric acid (˜150 mL) and the resulting aqueous mixture was washed with diethyl ether (2×500 mL). The aqueous extracts were basified to pH12 with 4N aqueous sodium hydroxide (˜650 mL) and extracted with dichloromethane (6×500 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a red oil. Purification by chromatography on silica gel with dichloromethane:methanol (49:1, v/v) as eluent afforded 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (300.0 g, 1.3 mol, 54%) as a pale orange solid. resulting in formation of a thick orange precipitate It was then cooled to ambient temperature to stand for 24 h the resulting aqueous mixture was washed with diethyl ether (2×500 mL) extracted with dichloromethane (6×500 mL) The organic phase was dried (MgSO4) concentrated under reduced pressure to afford the crude product as a red oil Purification by chromatography on silica gel with dichloromethane:methanol (49:1

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Glutaraldehyde (25% solution in water) (910 mL, 2.4 mol) and benzylamine hydrochloride (344.1 g, 2.4 mol) in water (1050 mL) was cooled to 0° C. 3-Oxopentanedioic acid (350.0 g, 2.4 mol) was added followed by addition of sodium acetate (aq.) (79.7 g in 797 mL water) resulting in formation of a thick orange precipitate. The reaction mixture was heated to 50° C. and stirred at this temperature for 4 h. It was then cooled to ambient temperature and allowed to stand for 24 h. The reaction mixture was acidified to pH2 with 5N aqueous hydrochloric acid (˜150 mL) and the resulting aqueous mixture was washed with diethyl ether (2×500 mL). The aqueous extracts were basified to pH12 with 4N aqueous sodium hydroxide (˜650 mL) and extracted with dichloromethane (6×500 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a red oil. Purification by chromatography on silica gel with dichloromethane:methanol (49:1, v/v) as eluent afforded 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (300.0 g, 1.3 mol, 54%) as a pale orange solid. resulting in formation of a thick orange precipitate It was then cooled to ambient temperature to stand for 24 h the resulting aqueous mixture was washed with diethyl ether (2×500 mL) extracted with dichloromethane (6×500 mL) The organic phase was dried (MgSO4) concentrated under reduced pressure to afford the crude product as a red oil Purification by chromatography on silica gel with dichloromethane:methanol (49:1

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

Procedure: Compound 20 (120 mg, 0.47 mmol) and glutaraldehyde (46 mg, 0.23 mmol) was dissolved in 10 mL 1,2-dichloroethane and sodium triacetoxyborohydride (400 mg, 1.89 mmol) was added portionwise over 6 hrs and reaction was stirred overnight. The reaction was quenched with sat. sodium carbonate, extracted with EtOAc (2×25 mL), washed with water and then brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography provide the compound 22 (55 mg, 0.17 mmol, 36% yield). 1H NMR (CDCl3, 400 MHz) δ 7.23-7.28 (m, 2H), 6.68-6.94 (m, 7H), 4.10 (t, J=6.4 Hz, 2H), 3.72 (t, J=6.4 Hz, 2H), 3.50 (q, J=7.2 Hz, 2H), 3.05 (t, J=5.6 Hz, 4H), 1.72-1.78 (m, 4H), 1.54-1.60 (m, 2H), 1.22 (t, J=6.8 Hz, 3H); HRMS (ESI, positive) m/z calcd. for C21H29N2O [M+H]+: 325.2280, found: 325.2227. reaction The reaction was quenched with sat. sodium carbonate extracted with EtOAc (2×25 mL) washed with water brine and dried over Na2SO4 The solvent was evaporated the residue was purified by silica gel column chromatography

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

Procedure: To a 50 ml round bottom flask was added 1.065 g (0.005 mol) 2-(nitromethylene)-1-((tetrahydrofuran-3-yl)methyl)imidazolidine, 30 ml acetonitrile, 3 ml 25% glutaraldehyde aqueous solution and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as yellow powder with 36% yield. After completion, the mixture was evaporated to remove solvent purified by column chromatography

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

Procedure: To a 50 ml round bottom flask was added 1.27 g (0.005 mol) 2-chloro-5-((2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine, 30 ml acetonitrile, 3 ml 25% glutaraldehyde aqueous solution and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 86% yield. After completion, the mixture was evaporated to remove solvent purified by column chromatography