mattodd
commented
3 years ago Hi @kym834 - I see you have the procedures here, great. I'm mentioning this chemistry to @AndyBishopSevenoaks to see if he's interested. I missed the second half of the meeting today, but do we have some potency in this series? I'm not sure where I ought to be looking for the SAR - @wwjvdsande I think you said you'd uploaded it, but does the Series 2 data need to be split off and put in this repository? Once we have it here we can plan what might be usefully made?
wwjvdsande
AndyBishopSevenoaks
kym834
This year we engaged the special studies students at The University of Sydney in the Open Source Mycetoma project. The students (and demonstrators) looked at the synthesis of a number of compounds based off the MMV006357 hit found through the screening of the Statis Box. They all explored changes to the substituents on the aromatic ring at the 4 position (this ring is green in the structures shown below).
The synthesis we followed was the same used for the resynthesis of MMV006357 (#4) replacing the α-bromoketone to yield the desired products in the final step of the synthesis (see step 3). This was completed over 3 steps and they are detailed in this post with scheme, experimental and notes.
The students and demonstrators made the all of the following compounds and completed characterisation of them in the final week of labs. These compounds have been assigned MYOS numbers, added to the master list and are being prepared to ship to ErasmusMC this week.
Step 1:
Reaction Scheme
Experimental Procedure In a round bottom flask fitted with a reflux condenser benzoyl chloride (2 mL, 17.2 mmol) was added to a suspension of potassium thiocyanate (1.83 g, 18.8 mmol) in acetone (30 mL). The reaction was heated to reflux (60 °C) and stirred for 20 min. The reaction was then cooled slightly and 2-amino-4-methylpyridine (1.69 g, 15.7 mmol) was added. The reaction was returned to reflux and stirred for a further 30 min. After cooling the reaction mixture was poured over ice water (100 mL) and stirred for 10 mins. The precipitate was collected via vacuum filtration and washed with cold water (10 mL) followed by cold isopropanol (2 × 10 ml).
Notes As the benzoyl isothiocyanate is a category 1 for eye damage/irritation and skin sensitisation we had the students make it in situ so as to avoid handling of this compound.
Step 2:
Reaction Scheme
Experimental Procedure In a round bottom flask fitted with a reflux condenser N-((4-methylpyridin-2-yl)carbamothioyl)benzamide (2.00 g, 7.37 mmol) was added to a 2.5M aq. NaOH solution (7.5 mL, 73.7 mmol) and the reaction heated to 80 °C. After 15 min at 80 °C the reaction was cooled. The pH was adjusted to 4-5 using 1M HCl to quench the remaining NaOH followed by adjusted to pH 8 using a sat. aq. Na2CO3 solution to precipitate the product. The precipitate was collected via vacuum filtration and washed with cold water (2 × 25 ml) before being dried in a desiccator overnight.
Notes These thioureas were quite smelly and it was best to keep them in the fumehood.
Step 3:
Reaction Scheme
Experimental Procedure 1-(4-methylpyridin-2-yl)thiourea (1 eq.) was added to the desired α-bromoketone (1.00 g, 1 eq.) in ethanol (20 mL). The reaction was heated to reflux (80 °C) and stirred until completion as determined via TLC (20% EtOAc/hexane). After cooling the reaction mixture was poured over ice water (25 mL). The pH was adjusted to pH 8 using a sat. aq. Na2CO3 solution to precipitate the product. The precipitate was collected via vacuum filtration and washed with cold water (2 × 10 mL) and cold hexane (2 × 10 mL).
Notes Many of the final compounds had great purity though a couple required further purification. We found purification via column chromatography to be difficult due to a very limited solubility of the final compounds. Some were only soluble in DMSO out of all the solvents we tried. These issues were with the methoxy analogues.
α-Bromoketones (7a-k)
Experimental Procedure α-Bromoketone general procedure: To a solution of the desired acetophenone (1 eq.) and p-toluenesulfonic acid monohydrate (1.5 eq) in acetonitrile (200 mL/gram acetophenone) was slowly added n-bromosuccinimide (1.1 eq.) allowing each portion to dissolve fully before the next addition. The solution was then heated to reflux and stirred until completion as monitored via TLC (20% EtOAC/hexane, vanillin dip - starting material and product have same Rf the vanillin dip stains them different colours). The solution was concentrated under reduced pressure, dissolved in dichloromethane (50mL) and washed with water (2 x 50 mL). The organic extract was dried over magnesium sulfate and concentrated under reduced pressure to give the products that often readily crystallised in excellent yields.