Org Prep Daily

November 6, 2014

Pleasures of Process Development

Filed under: industry life — milkshake @ 8:32 pm

BreakingBad

A reflux in 12 molar HCl
Carefully watched for a frothing
Painstakingly drained from the reactor
To strip down and scrub off that gross thing

My bosses, I tried please believe me
I’m doing my best as you insist
I’m ashamed of the material I burned through
I’m ashamed of the deadlines I missed

But if you could just see the beauty
These things I could never describe
These pleasures a wayward distraction
This is my one lucky prize

refrain: Product isolation…

My apologies to Joy Division

July 4, 2014

Happy 4th of July!

Filed under: Uncategorized — milkshake @ 9:50 pm

In Dependency Day
Credit: Jiri Sliva

May 22, 2014

A kilo-scale hydrogenation reactor?

Filed under: procedures — milkshake @ 8:22 pm

I have been running some hydrogenations of our polymers on kilo scale, at atmospheric pressure under balloons, and it is a bit of a chore. It would be nice to have something akin to a beer keg-sized Parr shaker and run the hydrogenation under few bars of H2, to reduce the catalyst loading and shorten the reaction time.

I wanted to ask the readers from process groups if they worked with a low-pressure batch stirred hydrogenation reactor that they liked and could recommend – for us to buy. Specifically,  we would need a hydrogenator that can accommodate 8-10 liters of a reaction mixture that has tendency to initially foam under reduced pressure (this means that the total available volume should be about 15-20 liters). Maximum operating pressure 3 bar would be enough, no heating or cooling is required and the typical solvent is water. I am not really interested in flow hydrogenation systems because they would be unsuitable to our particular case. A glass vessel or at least a glass window on the top would be nice to have, because of the foaming problem during evacuation.  Thank you for your suggestions!

Image

September 24, 2013

O-selective acetylation of tyrosine

Filed under: procedures — milkshake @ 7:30 pm

1. HTyr(Ac)OH.MsOH:

Methanesulfonic acid 80mL (1.2 mol) solution in acetic acid 0.5L was added to L-tyrosine 181.2g (1.0 mol, Aldrich 97%+) in a 5L 29/42 joint flask and the mixture was stirred vigorously without cooling until complete tyrosine dissolution (about 2 hours). The flask was placed in +10C water bath and the mixture was stirred till the internal temperature was about 15C. Neat acetanhydride 105mL (1.1 mol) was added dropwise over a 30 min period with a vigorous stirring and cooling on cold water bath, then continued at 15-20C for additional 90 min, at which time a voluminous precipitate solidified the reaction mixture. Peroxide-free THF 1L was added to the crystalline mass, the mixture was mashed up with a large spatula to break the lumps and then stirred vigorously for 20 min. The precipitate was collected by filtration, washed thoroughly with THF, the product was dried by suction under N2 blanket and then in vacuo until only a faint smell of AcOH remained with the product (10 Torr, 1 day). Y=259.8g of white solid (84% th)
1H(d6-DMSO, 400MHz): 8.28(br s, 3H), 7.29(app d, 8.6Hz, 2H), 7.10(app d, 8.6Hz, 2H), 4.20(br t, 6.4Hz, 1H), 3.10(br d, 6.4Hz, 2H), 2.33(s, 3H), 2.26(s, 3H)

2. HTyr(Ac)OH:

The O-acetyl tyrosine mesylate salt from the first step was dissolved in D.I. water 0.5L in a 4L large beaker, a solution of triethylamine 118mL (0.84 mol; 1 eq.) in ethanol 0.5L was added rapidly with stirring, the crystallized mixture was combined with additional ethanol 1L and agitated with a large spatula, then stirred for 30 min and finally placed into a refrigerator (+ 4C) overnight. The precipitated product was collected by filtration, rinsed thoroughly with chilled 200-proof ethanol (0.5L, +4C) and then with few small portions of ambient ethanol (4x20mL), dried by suction under N2 blanket and then thoroughly dried in vacuo. Y=168.4g (79.5% overall) of a white fluffy solid.
1H(D2O 0.7mL/10mg, 400MHz): 7.36(app d, 8.4Hz, 2H), 7.14(app d, 8.4Hz, 2H), 4.79(s, 3H; HOD), 3.98(dd, 8.0Hz, 5.5Hz, 1H), 3.29(dd-ABX, 14.7Hz, 5.3Hz, 1H), 3.14(dd-ABX, 14.7Hz, 7.8Hz, 1H), 2.34(s, 3H)

Note:  Effective stirring and cooling during the Ac2O addition is important for achieving good results. Using a cheap grade of tyrosine (a yellowish muddy powder, with some impurities detectable on NMR in aromatic region) is tolerable – and MsOH from an old bottle that was already a bit dark worked fine in this procedure – but the used THF should be aldehyde+peroxide free.

September 4, 2013

nitrilotriacetic acid anhydride

Filed under: procedures — milkshake @ 1:48 pm

NTA

 

30 mL of acetanhydride (317 mmol) was added to a slurry of nitrilotriacetic acid N(CH2CO2H)3 50.0g (261.5 mmol) in DMF 100mL. N-methylimidazole 0.21mL (1 mol%) was added and the mixture was stirred and heated on a 60 C oil bath for 6 hours under Ar – the mixture gradually became homogenous. Neat allyl bromide 0.5mL (2.2 mol%) was then added and the heating was continued for additional 30 min, to inactivate the catalyst. The flask was finally equipped with a shortpath distillation adapter and the mixture was concentrated by vacuum distillation from a 60 C oil bath (1 to 0.1 Torr; the receiving flask was chilled with liquid nitrogen). With most volatiles removed and the distillation residue solidifying, the distillation was terminated and the distillation flask was cooled to ambient temperature under Ar. The residue was dissolved in acetone 300mL (15 min stirring at ambient temperature. Fisher histology grade acetone was used straight from the can). The obtained cloudy solution was diluted with 1,2-dichloroethane 200mL and filtered through a fine-porosity Buchner funnel. The filtrates were slowly concentrated on rotovap from an ambient water bath down to about 150mL total volume. The precipitated crude product (35g) was collected by filtration, washed with dichloroethane and dried in vacuo. The crude product was dissolved in acetone 250mL, the solution was diluted with dichloroethane 250mL and then slowly concentrated on rotovap from ambient water bath, down to about 200mL total volume. The precipitated purified product was collected by filtration, rinsed with dichloroethane and dried in vacuo. Y=31.81g (70% theory) of a light-pink colored crystalline solid that gradually turns white upon storage.

1H(d6-acetone, 400 MHz): 3.920(s, 4H), 3.620(s, 2H); 13C(d6-acetone, 100 MHz): 171.18, 165.51(2C), 54.79, 52.54(2C)

Note: The crude product from reaction mixture evaporation residue contains another anhydride species, up to 15% by NMR (similar spectra but shifted downfield), which “disappears” during the workup. It is probably a dimeric bis-anhydride because it gets hydrolyzed by traces of moisture during the workup whereas the desired product is reasonably stable in non-dried acetone (in the absence of N-methylimidazole). The starting material N(CH2CO2H)3 is insoluble in acetone, so it is removed by filtration

July 4, 2013

Happy 4th

Filed under: Uncategorized — milkshake @ 3:22 am
“The difference between theory and practice is much bigger in practice than in theory”

The difference between theory and practice is far greater in practice than in theory

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Credit: Jiri Sliva

 

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