Diphenhydramine

[mxtlrr_chem]

In the book Synthesis Of Essential Drugs, the authors say

Diphenhydramine, N,N-dimethyl-(diphenylmethoxy)ethylamine (16.1.1), is synthesized by a simple reaction of benzhydrylbromide and 2-dimethylaminoethanol[1–3].

Is there any more literature on the synthesis of this drug using these two chemicals?

 

[41Dxflatline]

It's a simple williamson ether reaction where you just reflux them with sodium hydride

 

[41Dxflatline]

Precursor synth:

Step 1 Benzophenone to Diphenylmethanol:

(i) Photochemical reduction
Dissolve benzophenone (4.0 g) in 2-propanol (35 mL) by swirling in a 125 mL Erlenmeyer flask and warming on the steam bath. Add one drop of glacial acetic acid, to neutralise alkaline impurities, and fill a Pyrex test tube with the solution to within 2 cm of the top. Cork the tube loosely, irradiate it using a medium pressure mercury lamp for 3-4 hours.

Once you've recovered your solution, filter the precipitated product from the solution using a Buchner funnel, wash with cold ethanol and air-dry. Recrystallize the product from acetone, and record the yield, melting point and IR spectrum.*

(ii) Sodium borohydride reduction

In a 250 mL round-bottom flask, prepare a solution of benzophenone (1.0 g) in aqueous ethanol (8 mL ethanol + 2 mL water). Add sodium borohydride (0.25 g) and swirl the flask to assist solution. After about 30-40 minutes add ice-water (100 mL) and extract the product into ether (3 X 25 mL). Wash the combined ether extracts with aqueous 2M hydrochloric acid (40 mL) and then with water (40 mL). Dry the solution with anhydrous sodium sulfate, filter, and isolate the crude product using the rotary evaporator or a distillation apparatus. Recrystallize the product from a minimum amount of petroleum ether. Record the yield, melting point, and IR spectrum of the product.

Step 2 Diphenylmethanol to Bromodiphenylmethane

Diphenylmethanol (0.480 g, 2.61 mmol) was dissolved in dichloromethane (5 mL) and
cooled to 0 °C. Phosphorus tribromide (0.370 mL, 3.90 mmol) was added to the solution
dropwise over one minute. The reaction mixture was stirred at room temperature for 16 hours
with a drying tube containing calcium chloride attached. Water (10 mL) was added to quench
the reaction. The aqueous layer was extracted with dichloromethane (3 x 20 mL). The
combined organic extracts were washed with water (3 x 40 mL) and saturated aqueous
sodium bicarbonate (3 x 40 mL) then dried with magnesium sulphate. The solution was
filtered and the solvent removed under reduced pressure to give a colourless oil. This oil was
stored at -20 °C for 1 hour to assist with crystallisation, which afforded a white solid (0.550
g, 2.23 mmol, 86%). m.p. 36-38 °C (lit.1 37-39 °C). 1 H NMR (400 MHz, acetone-d6 ) 6.55(s, 1H, BrCH),

2-(dimethylamino)ethanol should be easily available