Honors Cup Synthetic Proposal

Honors Cup Synthetic Proposal

Section: 291

Group Members: Paul Baciu, Andrew Kim, Hien Lam

Title: Formation of Acetaminophen

Introduction:

Acetaminophen belongs to two classes of drugs called analgesics (pain relievers)and antipyretics (fever reducers). It is a major ingredient in numerous cold andflu medications and many prescription pain relievers, such as Tylenol, and isused for the relief of fever, headaches, and other minor aches and pains. Acetaminophen has the benefit of being completely free of problems withaddiction, dependence, tolerance and withdrawal.

Overall syntheticreaction scheme:

1)MeOH, NH4OAc, EtOAc

2)Bis(cyclopentadienyl)titanium(IV) dichloride, indium powder, THF, ether

3)HCl, anhydride, NaHCO3, H2O, EtOAc, Na2SO4

Step 1

Synthetic transformation 1:

Experimental 1:

To a solution of 4-Nitrophenylacetate (1.450g,8.0 mmol) in aqueous MeOH (1:4, 80.0 mL) NH4OAc(4.94 g, 64.0 mmol) was added. The resulting mixture wasstirred at room temperature and the progress of the reactionwas monitored by TLC. After 2.5 h the mixture was concentratedand the residue was extracted with EtOAc (3x80.0 mL). Evaporation of the solvent afforded the deprotectedproduct, 4-nitrophenol (1.102 g 7.92 mmol, 99%).

All solid and solvent amounts were multiplied by a factor of 8 in order to start with 1 g 4-nitrophenylacetate in order to end with ~0.5g Acetaminophen with 20% lower expected yield.

Expected yield: 79% 879.4 mg (99% in literature)

Safety, disposal and green issues 1:

Methanol- handle with gloves in hood

Ethyl Acetate- keep away from fire, work in hood with gloves. Keep away from static discharge. Wear goggles. In case of contact with eyes rinse immediately and seek medical advice.

Step 2

Synthetic transformation 2:

Experimental 2:

Bis(cyclopentadienyl)titanium(IV) dichloride (11.07 g, 44.24 mmol,Aldrich, 97%), indium powder (100 mesh, 2.17 g, 18.96 mmol, Aldrich,99.99%) and THF(126.4 mL) were mixed under nitrogen atmosphere and theresulting mixture was stirred at reflux for 30 min. A dark-red solution of thelow-valent titanium–indium complex was obtained and cooled to room temperature.To this solution, 4-nitrophenol (879.4.0 mg, 6.32 mmol) was added. Thereaction mixture was stirred for 10 min at room temperature under nitrogen.The solvent was evaporated under reduced pressure and the residue wasdiluted with ether and filtered. The crude product was purified by silica gelcolumn chromatography (hexane : ethyl acetate¼6 : 1) to afford 4-aminophenol(489.7 mg, 91%).

A factor of 25.28 was used in this experiment.

Expected yield: 71% 0.490g (91% in literature)

Safety, disposal and green issues 2:

THF – Keep away from fire, do not empty into drains, keep away from static discharge, Keep in Hood

bis(cyclopentadienyl) titanium (IV) dichloride – keep in hood

indium – keep in hood and away from fire

diethyl Ether – extremely flammable – do not pour down drain – work in hood.

Step 3

Synthetic transformation 3:

Experimental 3:

To a stirred heterogeneous suspension of amine (0.490 g 4.49 mmol) inwater (22.5 mL) was added 6N HCl (in the volume range of 1.077-1.796mL) until the solution becamehomogeneous (pH ca.1.5). The resulting homogenous solution was cooled in an ice bath. To thiswas then added anhydride (4.49-6.74 mmol) followed by solid sodium bicarbonate (0.83-1.35 g)until there was no further effervescence or pH of the mixture becomes ca 5.5. The precipitateproduct was filtered, washed with water (2 × 4.49 mL), dried by pressing between folds of filterpaper and finally dried in a vacuum desiccator. In cases, where product did not precipitate outthe reaction mixture was extracted with ethyl acetate (2 × 44.9 mL). The organic extract was driedover anhydrous Na2SO4 and the solvent was evaporated in a rotary evaporator under reducedpressure to yield the pure product.

Solvents and reagents were scaled by a factor of 4.49

Expected yield: 75 % 0.509g (95% in literature)

Safety, disposal and green issues 3:

HCL – wear gloves, keep in hood, do not empty into drains

Overall budget:

Chemical / Supplier / Cost / Amt. Needed / Total
4-Nitrophenyl Acetate / Aldrich / $98.30 per 100g / 1.45g per synthesis / $1.42535 per synthesis
Methanol / Aldrich / $48.00 per 4L / 64 mL per synthesis / $0.768 per synthesis
Ammonium Acetate / Aldrich / $39.80 per 500g / 3.411g per synthesis / $0.271516 per synthesis
Ethyl Acetate / Aldrich / $1750 per 200L / 240 mL per synthesis / $2.10 per synthesis
bis(cyclopentadienyl) titanium (IV) dichloride / Aldrich / $90 per 50g / 11.07g / $19.926
indium powder (100 mesh) / Aldrich / $147/25g / 2.17g / $12.7596
Ethyl Ether / Aldrich / $37.10/1L / ~10mL / $0.371
Tetrahydrofuran (THF) / Aldrich / $96.00 per 4L / 26.786mL per synthesis / $0.642864 per synthesis
Sodium Bicarbonate (NaHCO3) / Aldrich / $38.10 per 1kg / ~1g per synthesis / $0.0381 per synthesis
Anhydrous Na2SO4 / Aldrich / $30.60/50g / ~3g per synth. / $1.836
Hydrochloric Acid 6M / Pelletlab / $12.50/1000ml / ~1mL / $.0125 per synthesis

Total costs per synthesis: $40.12

References:

Ogbru, Omudhome. Acetaminophen. 19 June, 2002. MedicineNet.com. February 05,

2005 {

Ramesh, C.; Mahender, N.; Ravindranath, N.; Das, B. Tetrahedron2003, 59, 1049-1054.

Yoo, B.W.; Lee, S. J.; Yoo, B. S.; Choi, I. C.; Kim, J. H. Synthetic Communications 2002, 32, 2489.

Naik, S.; Bhattacharjya, G.; Kavala V.; Patel, B. ARKIVOC2004, 1, 55-63.

Sigma-Aldrich. February 05, 2005. {