Org Prep Daily

March 10, 2007

4-(2′,4′-difluorophenylamino)-piperidine dihydrochloride

Filed under: procedures — milkshake @ 2:56 am

dif.gif

1-Cbz-4-piperidone 4.012g (17.2 mmol) with 4A powdered activated molecular sieves 9.1g and 2,4-difluoroaniline 2.582g (20 mmol) was suspended in anhydrous 1,2-dichloroethane (150mL) and acetic acid 6mL was added. The mixture was stirred under Ar overnight (11h30 min). Solid sodium triacetoxyborohydride 12.72g (60mmol) was added and the reaction was continued at RT over an extended weekend (3 days). The reaction mixture was then filtered, the solids were washed with ethyl acetate 350mL. The combined filtrates were washed with saturated NaHCO3 250mL and then with half-saturated NaHCO3 (250mL), the aqueous phases were re-extracted with ethyl acetate (250mL). The combined organic extracts were dried (MgSO4) and evaporated. The residue was dried on highvac to remove some of the difluoroaniline,  then purified on a column of silica (190g) in a 3:1 mixture hexane-EtOAc.

The obtained Cbz-protected piperidine (pink syrup, 3.8g, 64%Y) was hydrogenated under baloon of H2 in ethanol 200mL in presence of Pd-C(10%),  2.5g and 4M HCl in dioxane 5mL for 19 hours (overnight). The catalyst was removed by filtration through a pad of Celite, the filtrated were evaporated and the residue dried on highvac. Y=3.075g (62.5% overall) of a white hygroscopic solid.  LC/MS(+ESI): 213 (M+1)

1H(d6-DMSO, 400MHz): 9.5-7.5(very br s, 2H), 9.272(br m, 1H), 8.975(br m, 1H), 7.158(m, 1H), 6.940(m, 2H), 3.547(m, 1H), 3.268(br d, 13.0Hz, 2H), 2.930(br q, 10.4Hz, 2H), 2.008(br d, 11.5Hz, 2H), 1.703(m, 2H) 

2 Comments »

  1. Why not a higher yield? any idea what the by-prods are?

    Comment by Organic Chemistry — March 15, 2007 @ 10:21 pm

  2. The difficulty is that 2,4-difluoroaniline is a pretty unreactive amine. You can try to push the imine formation under Dien-Stark conditions but you risk getting some brown oligomeric stuff that may be painful to purify away. So I added sieves and let it stir for few days and did other thing meanwhile, and pumped away the excess of aniline in the end. I think I saw some of the corresponding piperidinol and also the starting piperidone on TLC but they separated nicely on silica.
    I agree that this is not an optimized procedure; when you are making a building block that you need to try in your project (but you are unsure how useful is it going to be in the end) and if the starting material is cheap, you can sacrifice on yield for sake of simplicity. I think 64% is a bit average and certainly would have to be optimized, for a process scale-up.

    Comment by milkshake — March 16, 2007 @ 1:28 pm


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