Honors Cup Synthetic Proposal

Transcription

1 onors Cup Synthetic Proposal Section: 230-IV Group Members: Alex yla, Lauren eath, Sahar Rahmani Title: Synthesis of Melatonin from 3-(3-phthalimidopropyl) ethyl acetacetate using Green Chemistry Introduction: Melatonin (5-methoxy--acetyltryptamine) is a neurohormone naturally synthesized in the brain by the pineal gland. It is a hormone found in all living creatures and thus proved to have a profound impact on life in various ways. The primary role it serves is the regulation of the body s circadian rhythm. Much research has gone into developing drugs containing melatonin that can be used to treat various sleep disorders. Interestingly, research suggests that Melatonin also has strong antioxidant properties and can be used as a part of the treatment of a multitude of serious disorders: cancer, immune disorders, cardiovascular diseases, depression and sexual dysfunction. Melatonin can be formed synthetically from 3-(3-phthalimidopropyl) ethyl acetacetate, as shown in the following set of reactions. verall synthetic reaction scheme: 1) 2 3-(3-phthalimidopropyl) ethyl acetacetate 4-methoxyphenyl hydrazine R: Cl, S: Bu, S: 2, 15 min, reflux; overnight

2 2) 1.1 R:a, S: 2, 5 min., reflux. 1.2 R: 2 S 4, S: 2, 10 min: 10 min., reflux 2 3) Ac 2 R:C 5 5, S:C 5 5, 2 min. 2 Step 1 Synthetic transformation 1: 2 3-(3-phthalimidopropyl) ethyl acetacetate 4-methoxyphenyl hydrazine R: Cl, S: Bu, S: 2, 15 min, reflux; overnight

3 Citations: e, W.; Li, X.; Zhang, B.; Li, Z. Disi Junyi Daxue Xuebao. 2000, 21, e, L.; Li, J.L.; Zhang, J.J.; Su, P.; Zheng, S.L.; Synth. Commun. 2003, 5, Experimental 1: This step in the literature calls for a large amount of starting material to be used. ur synthesis will not need to create as much as the synthesis in the article created, so we are only using 1.58g of the starting material instead of the recommended 9.5g. We also scaled down the amount of reagents based on the scale needed to create the desired amount of product. Add 1.7 ml of n-butanol dropwise with a solution of hydrochloride acid to a solution of 4-methoxyphenyl hydrazine (0.664g) and 3-(3-phthalimidopropyl) ethyl acetacetate (1.577g) in 11.6 ml of n-butanol (0.2 mol acetochloride + n-butanol). Reflux the mixture under microwave irradiation for 15 min, then let cool and put in refrigerator overnight. Collect the resulting yellow solid by filtration and recystallize the solid from ethanol. Expected yield: 80 % 1.26g Safety, disposal and green issues 1: n-butanol can cause minor irritation if it comes in contact with your skin. Wash the area thoroughly with water. It can be disposed of in the non halogenated waste container. Acetochloride and n-butanol should be disposed of in the halogenated organics container. 4-methoxyphenyl hydrazine should be disposed in the non-halogenated waste container. The use of microwaves is a green issue because it cuts down on time needed for reactions and requires less energy to complete. Step 2 Synthetic transformation 2: 1.1 R:a, S: 2, 5 min., reflux. 1.2 R: 2 S 4, S: 2, 10 min: 10 min., reflux 2

4 Citations: e, W.; Li, X.; Zhang, B.; Li, Z. Disi Junyi Daxue Xuebao. 2000, 21, e, L.; Li, J.L.; Zhang, J.J.; Su, P.; Zheng, S.L.; Synth. Commun. 2003, 5, Experimental 2: This step will be on a smaller scale than the literature s synthesis since the first step was reduced in scale. Reflux a mixture of 2-ethoxycarbonyl-3-phthalimido-ethyl-5-methoxylindole (1.826 g) and sodium hydroxide (10%, 5mL) under microwave irradiation for 5 min, and then add sulfuric acid (20%, 21.6 ml) dropwise, slowly over 10 min. ext, reflux the mixture in a microwave oven for 10 min and extract using ethyl acetate (3 x 8.3 ml). Adjust the p of the aqueous layer to 8 9 with 40% sodium hydroxide and extracted with ethyl acetate. Wash the combined extract with saturated brine and dry using sodium sulfate anhydrous. Use a vacuum to remove the solvent and recystallize the residue from benzene. The final product should appear as a light yellow crystals substance. This should be characterized using MR to confirm the synthesis of 5-methoxytryptamine. Expected yield: 70 % 0.882g Safety, disposal and green issues : 5-methoxytryptamine is harmful if swallowed, and is an irritant to the skin and eyes. If it gets in contact with your skin, wash with water for about 15 minutes. Spills can be cleaned up by throwing the extra in the solid waste bucket. Try to reduce the creation of dust, because breathing becomes more heavily when inhaled. Sodium ydroxide and Sulfuric Acid should be treated with care. Wash areas thoroughly if they come in contact with these chemicals. Step 3 Synthetic transformation 3: Ac 2 R:C 5 5, S:C 5 5, 2 min. 2

5 Citations: Revial, G.; Jabin, I.; Lim, S.; Pfau, M. J. rg. Chem. 2002, 67, e, L.; Li, J.L.; Zhang, J.J.; Su, P.; Zheng, S.L.; Synth. Commun. 2003, 5, Experimental 3: This step, similar to the previous ones, will be on a smaller scale than the one proposed in the literature. Mix 5-methoxytryptamine ( g), pyridine ( g), and acetic anhydride (3.32 ml). Warm the mixture under microwave irradiation and the prescence of 2 for 2 minutes. Pour the mixture into ice-water (50 ml) to solidify it. Collect the solid, melatonin, and characterize it using MR. Expected yield: 85% 0.75g Safety, disposal and green issues: Acetic Anhydride is a corrosive liquid, so be careful when handling. If ingested, digestive and respiratory damage is probable. It also causes skin burns. Melatonin is an irritant if it gets in touch with skin and is hazardous if ingested. Work with it under a hood and make sure to have gloves, goggles, and aprons on at all times. If it comes in contact with your skin, wash the area immediately with plenty of water. Melatonin is a solid and can be disposed of in the solid waste bucket. verall budget: Chemical Supplier Cost Amt. Total eeded 3-(3-phthalimidopropyl) 3B $4.30/g g $7.81 ethyl acetacetate Corporation 4-methoxyphenyl AK $5.60/g g $3.72 hydrazine Inc. n-butanol Thermo Fisher $62.70/1L 13.3 ml $0.834 Pyridine Waterstone $0.18/g 0.03 g $5.40 Technology Ethyl Acetate Thermo Fisher $26.2/L 17.1 ml $0.45 Acetic Anhydride Acros $128.11/1L 3.32 ml $0.425 rganics Acetochloride Pfaltz & Bauer Inc. $0.853/g 6.05 g $5.16

6 Sodium ydroxide Sulfuric Acid Thermo Fisher Thermo Fisher $28.88/L 5 ml $0.14 $30.40/L 21.6 ml $0.657 Total costs per synthesis: $ References: e, W.; Li, X.; Zhang, B.; Li, Z. Disi Junyi Daxue Xuebao. 2000, 21, e, L.; Li, J.L.; Zhang, J.J.; Su, P.; Zheng, S.L.; Synth. Commun. 2003, 5, Revial, G.; Jabin, I.; Lim, S.; Pfau, M. J. rg. Chem. 2002, 67,