Org Prep Daily

September 28, 2006


Filed under: procedures — milkshake @ 2:08 pm


Chloroacetic anhydride is a nasty irritant: use gloves, do not spill, do not inhale vapors. The anhydride should look like a nice white crystalline solid. If soggy or dark, purify it before use by vacuum distillation (on Kugelrohr).

LAH 12.5g was added in 1 gram-sized portions into a vigorously-stirred solution of Cbz-D-Serine(OtBu)-OH 25.05g (84.8mmol) in anh. THF 0.5L in a 2L flask with cooling on ice bath. After complete LAH addition, the mix was refluxed for 6 hours. The reaction mixture was cooled to 0C, quenched very slowly by carefull addition of water 12.5mL (dropwise!), then 15% aq. NaOH (37.5mL) and then additional water (12.5mL). The mixture was stirred for 12 hours (overnight), filtered, the salts were thoroughly washed with THF and discarded. The filtrates were evaporated. The residue was dissolved in dichloromethane 100mL, cooled to 0C and a solution of chloroacetic anhydride 17.10g (100mmol) in dichloromethane (40mL) was added dropwise over 90min with cooling at 0C (addition funnel was used). The mixture was stirred at 0C for additional 30 min, the cooling bath was removed, the acylation was quenched by addition of sat NaHCO3 (300mL), stirred in an open flask at RT for 30 min. The org. phase was separated, washed with sat. NaHCO3 300ML, the aqueous phases were re-extracted with dichloromethane (2x150mL). The combined org. extracts were dried (MgSO4) and evaporated, the residue was dried on highvac. (0.5Torr, 60C, 1h). The residue was dissolved in anhydrous ethanol 150mL (non-denaturated), sodium methoxide 5.40g (100mmol) was added (in 3 portions) with cooling on ambient water bath. The mixture was stirred at RT for 10 min, then at 60C for 30 min. The obtained heterogennos mixture was evaporated, the residue was portioned between sat. ammonium chloride 150mL and chloroform 100mL. The aqueous phase was re-extracted with additional chloroform (3x100mL). The combined extracts were dried (MgSO4) and evaporated, the residue was distilled on Kugelrohr at 0.5 Torr, 90-130C air bath temp.

The obtained crude tBu-protected morpholinone (semi-solid distillate from Kugelrohr) was combined with TFA 100mL. The mixture was stirred for 2 hours, evaporated on highvac and re-evaporated with toluene. The obtained trifluoroacetate ester was dissolved in methanol 60mL, made basic by addition of concentrated aq. NH3 (12mL), stirred for 1 hour then evaporated and dried on highvac. The residue was stirred twice with cyclohexane (2x100mL), the upper phase decanted off, the bottom phase was heated with  toluene 100mL to reflux, cyclohexane 100mL was added, stirred for 1 hour at RT, the upper phase was decanted off. (This washing excersize was done to remove benzyl alcohol that carried over from the LAH reduction). The residue was dissolved in a 10:1 mixture of chloroform-methanol (10:1, 60mL), stirred for 30 min, the precipitated salts were removed by filtration (and washed with the 10:1 mixture), the filtrates were evaporated. The residue was purified on a column of silica (200g) in 10:1 chloroform-methanol mixture. The purified product was dried on highvac. Y=11.61g (94% overall) of a colorless honey.

1H(CDCl3, 400MHz): 4.143(m, 3H), 3.834(m, 3H), 3.294(m, 1H), 3.046(s, 3H), 2.719(br s, 1H); 13C(CDCl3, 100MHz): 167.73, 67.77, 64.73, 60.27, 58.93, 33,36(br s)

Using identical procedure, Cbz-L-Ser(OtBu)OH provided the S-enantiomer in 94%Y overall (11.63g)


  1. Any chance of some indication of enantiomeric purity for these? Or can we assume that there is no erosion over the procedures?



    Comment by SJB — September 28, 2006 @ 2:34 pm

  2. I have not done assay on the optical purity. Aminoalcohols are configurationaly stable and they are routinely prepared from aminoacids by LAH reduction. Since the aminoacid was from chiral pool, I hoped it would be fine. But you are right, if would be worth checking. I could think of chiral derivatisation of the alcohol with both enantiomers of Phe-CH(Me)NCO and check NMR the crude mix. Or Mosher ester. Unfortunatelly, I don’t have the material anymore. (I took it all into the corresponding amine and I don’t know what became of the the amine, the whole project has been dead for some time.)

    Comment by milkshake — September 28, 2006 @ 2:47 pm

  3. No problem, I appreciate these are from projects that are, shall we say, not the cutting edge of what you’re doing today in the lab.

    Invariably I guess if you neded to know, it would probably only be in the last few steps that it would be worth assaying.

    Comment by SJB — October 1, 2006 @ 4:15 pm

  4. It is quite opposite about the cutting edge and my daily routine – 90% of the work in a medchem lab is actualy trying to make some ugly cyclization to go, and nitrating stuff to access anilines – so that one could couple them and make analogs number 57 to 62 of some heterocyclic monster.
    Actually, if you do something with a Pd catalyst and a boronic acid, get a 50% yield and product crystallizes at the end, you call it a good day.
    (If one gets seriously lucky, some of his compounds turn out to be active and stable, and maybe will eventually make it through animal studies all the way to clinical trials). Beauty is not why medicinal chemistry is done – and most of the time the simplier the better.

    Comment by milkshake — October 1, 2006 @ 9:20 pm

  5. Did you miss a methyl in the structure of the starting material?

    Comment by nectar — June 21, 2019 @ 11:06 am

    • no no, the methyl in the product comes from the LAH reduction of Cbz group

      Comment by milkshake — June 21, 2019 @ 3:34 pm

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