Benadryl Synthesis

The main ingredient in Benadryl, the infamous anti-allergy medicine that also conveniently puts you to sleep, is diphenhydramine. From the name, you can infer that it's got not one, but two phenyl groups in the structure. You can also tell that it's a type of amine. As for the "hydra".. I'm not immediately sure what that means.

It's ironic, I'm sneezing as I write this post. Better get to this synthesis quickly..

As you'd expect (or perhaps not), the structure (click here) is fairly simple. We have our two phenyl groups, and the tertiary amine in the top right.

Step 1: I'd first monobrominate a benzene ring using Br2 and FeBr3, a catalyst. Next, I'd throw in some lithium and form an organolithium reagent.

Step 2: I'd react 2 equivalents of the organolithium with methanoic acid. The first organolithium will abstract a proton from the acid, and the second equiv. will attack the carbonyl carbon. The sp3 intermediate will be frozen in time, until we perform the work-up step that will produce an aldehyde.

Step 3: Work-up - H30+/H20

Step 4: At this point, I would throw in another equivalent of our phenyl organolithium. I'm not going to perform a work-up step to produce the tertiary alcohol though, and you'll see why in a second.

Step 5: Next, I'm going to take an amino acid (shown in the synthesis) and hit it with SOCl2 to turn into an acyl chloride.

Step 6: I'm going to mix the acyl chloride with our product from Step 4. The O- (that was coordinating with Li+) will attack the acyl chloride (hard goes w/ hard) and undergo an addition-substitution type reaction.

Step 7: Next, I'll simply remove the C=O group using hydrazine and base.

Ta-da. We have our diphenhydramine a.k.a. Benadryl.

Note: Perhaps instead of preparing an acyl chloride, I could have just used a haloalkane and proceeded with some SN2 type of substitution that would ultimately save us a step as we wouldn't have any C=O group left to remove. However, my only problem with this idea is that O- is quite hard, while R-X is soft... This is why we typically use softer nucleophiles like organocuprates to perform SN2's. Maybe I'm wrong though, who knows.