Synthesis of Sulotroban
Faculty
Mentor: Tim Hoyt
Project TA: Will Pfalzgraff (wpfalzgraff@ups.edu)
Nuhrich, A.; Varache-Lembége, M.; Lacan, F.; Devaux, G. J. Chem. Ed. 1996, 73, 1185-1187.
Sulfonamide containing molecules have played an important role in
the history of medicinal chemistry. For example, some of the first
antibiotics were sulfonamides. Sulotroban is an antithrombotic drug
that also contains a sulfonamide. The synthesis of Sulotroban begins by
forming the sulfonamide by reacting benzenesulfonyl chloride with
4-(methoxyphenyl)ethylamine. The phenolic methyl ether is then cleaved
using the lewis acid BBr3. Coupling of the resulting phenol
with ethyl bromoacetate is then followed by hydrolysis to yield
Sulotroban. To avoid the major difficulty encountered in the past, the
formation of two additional products in the coupling with ethyl
bromoacetate at the amide nitrogen, the nitrogen will be protected with
a benzyl which can be cleaved after the coupling step.
Students Working on This Project
| Lab Day | Name | ||||
|---|---|---|---|---|---|
| Monday | Michelle Hager | mhager@upugetsound.edu | |||
| Monday | Hannah Chase | hchase@pugetsound.edu | |||
| Tuesday | Mandeep Gill | mgill@pugetsound.edu | |||
| Tuesday | Alena Golubkova | agolubkova@pugetsound.edu | Wednesday | Jack Corrigan | jcorrigan@pugetsound.edu |
| Wednesday | Charlie Nguyen | csnguyen@pugetsound.edu | |||
| Thursday Aft. | Miranda Kent | mkent@pugetsound.edu | |||
| Thursday Aft. | Rochel Burke | rburke@pugetsound.edu | Thursday Aft. | Liza Fazzino | lfazzino@pugetsound.edu |
| Thursday Eve. | Mary Krauszer | mkrauszer@pugetsound.edu | Thursday Eve. | Westley Dang | wdang@pugetsound.edu |
Table of Reagents and Amounts Available for this Project
The table below lists the chemicals that we will have available for this project. If you need something that is not on this list, consult with the mentor for your project. Also note the "Amount/group" column. This is the total amount of material available for each group to use on the project.
| Reagent | Source | Amount/group | Location | Comments |
|---|---|---|---|---|
| 4-methoxyphenethylamine | Aldrich Cat. # 18,730-5 |
7 g | TA room | |
| Benzenesulfonyl chloride | Aldrich Cat. # 10,813-8 | 10 g | TA room | |
| Boron tribromide | Aldrich Cat. # 41,950-8 | 10 g | TA room | Caution: Use in the hood! Dispense under Nitrogen. |
| Ethyl bromoacetate | 2 g | TA room | We also have available a large amount of benzyl 2-bromoacetate in the main stockroom. |
General Notes
Step 1 Notes
As it turns out, with so many teams working on this project, we will need a large quantity of the sulfonamide. This means that we will all do the first step of the original procedure (below) at the stated scale. You can use this procedure as it is written, though you still need to get it checked off by a professor.
Macro scale preparation of N-[2-(4-Methoxyphenyl)ethyl]benzenesulfonamide.
A 250 mL round-bottom flask was equipped with a claisen adapter, sep funnel, water condenser, septum, and stir bar. In the flask 10 g (0.25 mols) of sodium hydroxide and 100 mL (6.25 mols) of water were added. Under nitrogen the solution was cooled to 0°C and 6.05 g (0.04 mols) of 2-(4-methoxyphenyl)ethylamine was added. Then, 7.95 g (0.045 mols) of benzenesulfonyl chloride was added drop wise. The solution was stirred for two hours at room temperature, and cooled in an ice bath. About 40 mL of 6 M hydrochloric acid was added. The product was extracted three times with 30 mL (0.91 mols) of ethyl acetate. The organic layer was washed with brine and dried with sodium sulfate. The solvent was removed by rotary evaporation to give an oily yellow residue that solidified upon cooling. The solid was washed twice with 10 mL (0.19 mols) portions of diethyl ether and allowed to dry at room temperature to yield 7.37 g (0.025 mols, 63.3%) of N-[2-(4-Methoxyphenyl)ethyl]benzenesulfonamide(1).
The yields have ranged from 40 - 65 %.
Write up this procedure in your notebook. Be sure to note the sizes of the reaction flasks and include a scketch of the probable setup. Modify the sketch if you need after getting the reaction setup. All procedures must be approved by one of the professors before you begin.
We will perform
all subsequent reactions initially at "small scale" until we have
success with a reasonable yield and can identify the components of the
reaction mixture, especially our desired product.
Be sure you
have the NMRs and IRs of all significant reagents as well as those of
the SOLVENTS you are likely to encounter. Please purify a small sample
of your sulfonamide to use for good mp, IR and NMR.
Step 2 Notes
Prep of N-(benzyl)-[2-(4-Methoxyphenyl)ethyl]benzenesulfonamide
Adding Protecting Group
This is an adapted procedure for the Protection Step.
N-(benzyl)-[2-(4-Methoxyphenyl)ethyl]benzenesulfonamide.
To a solution of NaH (30 mmol, 60% dispersion in mineral oil) in DMF (50 mL) at 0 degrees C under an nitrogen atmosphere was added a solution of sulfonamide (27 mmol) in DMF (20 mL) through a septum, followed by benzyl chloride (30.0 mmol) dropwise. The resulting mixture was warmed to 25 degrees C, and the reaction flask was equipped with a reflux condenser and was heated to reflux (bath temperature 110°C) for 2.5 h. After being cooled to 25°C, the reaction was quenched with water, and the resulting mixture was extracted with ethyl acetate. The extracts were washed with water three times and finally with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give product. Recrystallization of the crude product from CH2Cl2-hexanes afforded product as a colorless crystalline solid.
(1) This is procedure adapted from one that used saccharin. Be sure to check all the amounts using our sulfonamide, NaH and benzyl chloride and scale relative to the mmol ratios. Calculate the # of g of NaH, sulfonamide and mL (use the density) benzyl chloride. The reaction should be run in a small scale (~1.0g of our sulfonamide) first with complete ID of the product via NMR and IR.
(2) Use the claisen adapter the set up of your apparatus. Flame dry. Have the top covered by a septum and the side arm have the nitrogen balloon attached to the top of condenser.
(3) The NaH is in a dispersion with mineral oil. To remove the oil place the NaH in the RB with a stir bar. Recap and flush the air out with the nitrogen bleed. Add about 10 ml hexane and stir briefly. Let the NaH settle and draw off the hexane with the syringe. Repeat 2X. The NaH is now ready (and very reactive - keep dry.)
Step 3 Notes
Here is a procedure for Step 3, Prep of N-(benzyl)-[2-(4-Hydroxyphenyl)ethyl]benzenesulfonamide3.
Boron Tribromide Reaction.
N-(benzyl)-[2-(4-Methoxyphenyl)ethyl]benzenesulfonamide (10 mmol) was added to a 20 mL of anhydrous CH2Cl2 in a 50 mL round-bottom flask and stirred with a magnetic stir bar. Solution was cooled in an ice-bath to 0°C under a nitrogen atmosphere. Boron tribromide (12 mmol, 1.13 mL) was added via syringe dropwise to solution. The flask was removed from the ice-bath and allowed to equilibrate to room temperature, followed by one hour of stirring. The solution was decanted into 50 mL of ice water in a 150 mL beaker. After 30 minutes of hydrolysis with stirring, the organic layer was extracted with 2 x 10 mL of CH2Cl2. The organic layer was washed with 4 x 15 mL of cold water to neutralize any excess BBr3. A litmus test was performed for each was to ensure the organic layer was neutralized. Solution was dried with sodium sulfate and the solvent was evaporated using a rotary evaporator to afford 2.66 g (75%) of a tan colored crystalline solid.
Notes:
(1) Use the claisen adapter the set up of your apparatus. Flame dry. Have the top covered by a septum and the side arm have the nitrogen balloon attached to the top of condenser. Use enough CH2Cl2 to have a decent amount of solution to stir. Our first time through we had too small an amount.
(2) USE ICE WITH WATER IN IT. If your size reaction calls for 50 mL of ice water, fill the beaker with ice first to the 50 mL point. This way you don't have a fire on your hands.
(3) Do the litmus test on your washes of the organic layer. We didn't do this and just washed twice with water, which might have been why our first time through we had an oil product and not a solid like the second time.
(4) Don't bother with the diethyl ether stuff at the end for purification, your product dissolves in diethyl ether, so it doesn't help purify it.
Step 4 Notes
Alkylation of N-(benzyl)-[2-(4-Hydroxyphenyl)ethyl]benzenesulfonamide3.