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31st August 2015 @ 02:25

This experiment involved a nucleophilic aromatic substitution of last weeks product TY3-1, replacing a chlorine atom with a phenethyl group.

http://malaria.ourexperiment.org/triazolopyrazine_se/9244/Synthesis_of_5chloro3naphthalen2yl124triazolo43apyrazine_TY31.html

 

Procedure

TY 3-1 (200mmol, 0.56g, 1 equiv) was added to toluene (10mL) and 2-phenylethanol (2.00mmol, 244.33mg, 1 equiv), 18-crown-6 ( 400µmol, 106mg, 0.2 equiv) and KOH (7.00mmol, 393 mg, 3.5 equiv).

The reaction was stirred at room temperature for 10 minutes before being heated to 40OC until TLC showed reaction completion.

The product was then allowed to cool down to room temperature before being diluted with 4mL of water. The product was then washed with EtOAc (3x 10 mL) and separated into aqueous and organic layers. The Organic layer was washed with water (4mL) and brine (3mL) before being dried with Na2SO4. The solution was then evaporated under a rotary evaporator at low pressure.

TLC

IMG_2388.JPG

The spots on the TLC from left to right correspond to TY3-1, final product, 2-phenylethanol and a mixture of all three. TLC solvent was 7:3 EtoAC: Petroleum.

Column Purification

To determine the solvent to be used for column purification a range of solvents had to be test on TLC.

IMG_2690.JPG

The following TLC solvents were tested, 1:1 EtoAC: Petroleum, 9:2 EtoAC: Petroleum, 9:1 DCM: EtoAC and 7:3 EtoAC:DCM.

9:2 EtoAC: Petroleum was used for the column on the account of 7:3 EtoAC:DCM being an unfavourable mixture despite its desirable Rf value.

IMG_2698.JPG

The above picture comes from the column machine which performed a UV scan as it ran the solvent through the column. One of these peaks was originally thought to contain the product but after TLC analysis (shown below) it was realised to not contain the product.

IMG_2699.JPG

After not finding the product in the TLC the mixtures were remixed and put under a rotary evaporator. The column was checked for any remaining material and a very sharp UV spike was noticed. This was then extracted and analysed by TLC. It was shown to contain the product.

IMG_2703.JPG

Tubes 18-26 were mixed and placed in the fridge for later evaporation and analysis.

________________________________________________________________________________

TY4-1.cdxml
HIRAC TY4-1.doc

Sample was dried under a rotary evaporated under low pressure. This was followed by further evaporation under low presure with liquid nitrogen being used as a coolant.

Sample was weighed (0.36g, 0.98 mmol, 50% yield).

12080796_838793306236873_217857228_n.jpg

A rough melting point was measured, the observed range was around 182-83OC. This range will be refined after further measurements.

Strings

SMILES

ClC1=CN=CC2=NN=C(C3=CC(C=CC=C4)=C4C=C3)N21

TO

C12=NN=C(C3=CC(C=CC=C4)=C4C=C3)N1C(OCCC5=CC=CC=C5)=CN=C2

InChI

InChI=1S/C15H9ClN4/c16-13-8-17-9-14-18-19-15(20(13)14)12-6-5-10-3-1-2-4-11(10)7-12/h1-9H

TO

InChI=1S/C23H18N4O/c1-2-6-17(7-3-1)12-13-28-22-16-24-15-21-25-26-23(27(21)22)20-11-10-18-8-4-5-9-19(18)14-20/h1-11,14-16H,12-13H2

This reaction is the third in the process towards a final potential antimalarial - https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/338

Attached Files
26th August 2015 @ 05:19

Yield is terrible. Needs optimization.

Reaction started at 17:00.

Reaction Scheme.

 

Procedure

To a solution of 3-bromo-5-chloro-[1,2,4]trizolo[4,3- a]pyrazine (80 mg, 0.34mmol, 1 equiv.) in a co-solvent of toluene(1.2ml), ethanol(0.26ml), and water(1.2ml) was added sodium carbonate (267 mg) followed by Tetrakis(triphenylphosphine)palladium(0) (12 mg) and phenylboronic acid (53 mg) under argon in a flask. The reaction mixture was heated at 80 Celsius degree for 17 hours. TLC showed that reaction was completed.

Saturated ammoniun chloride solution (~20ml) was added to the mixture and extracted with ethyl acetate (70ml*3). The organics were collected in the flask, dried over sodium sulfate and evapotated under reduced pressure to give a yellow solid which was then dired on vacuum. Crude NMR showed purification is needed.

The reaction mixture was dissolved in toluene (~2ml) and purified by conlum machine using PE/EA (50:50) as eluent to give a yellow solid (less 10 mg) which was then dried on vacuum. NMR confirmed that they are the desired products.

 

Data

NMR(crude)

TZ 9-1 crude.pdf

NMR(column fractions. NOTE: both pure and less pure are the desried products)

TZ 9-1 less pure column spot.pdf
TZ 9-1 most pure column spot.pdf

HIRAC

HIRAC TZ9-1.pdf

Strings

InChI=1S/C5H2BrClN4/c6-5-10-9-4-2-8-1-3(7)11(4)5/h1-2H

and
InChI=1S/C6H7BO2/c8-7(9)6-4-2-1-3-5-6/h1-5,8-9H
to
InChI=1S/C11H7ClN4/c12-9-6-13-7-10-14-15-11(16(9)10)8-4-2-1-3-5-8/h1-7H
 
 
 
ClC1=CN=CC2=NN=C(Br)N21
and
OB(C1=CC=CC=C1)O
to
ClC1=CN=CC2=NN=C(C3=CC=CC=C3)N21


Attached Files
26th August 2015 @ 04:59

Reaction started at 17:00.

Reaction scheme

Procedure

A mixture of 3-bromo-5-chloro-[1,2,4]trizolo[4,3- a]pyrazine (80 mg, 0.34 mmol, 1 euqiv.), phenylboronic acids (62 mg, 0.68mmol, 1.5 equiv.), Pd(OAc)2 (0.26 mol %), K3PO4(144 mg, 0.68mmol 2 equiv.) in mixture of isopropanol (1.7 mL) and water (1.7 mL) was stirred at 80°C for overnight. 

The mixture was added to brine and extracted 4 times with ethyl acetate (60ml*4). The solvent was removed under reduced pressure.

 

Data

Crude NMR

TZ 8-1 crude.pdf

HIRAC

HIRAC 8-1.pdf

 

Strings

InChI=1S/C5H2BrClN4/c6-5-10-9-4-2-8-1-3(7)11(4)5/h1-2H

and
InChI=1S/C6H7BO2/c8-7(9)6-4-2-1-3-5-6/h1-5,8-9H
to
InChI=1S/C11H7ClN4/c12-9-6-13-7-10-14-15-11(16(9)10)8-4-2-1-3-5-8/h1-7H
 
 
 
ClC1=CN=CC2=NN=C(Br)N21
and
OB(C1=CC=CC=C1)O
to
ClC1=CN=CC2=NN=C(C3=CC=CC=C3)N21


 

Attached Files
25th August 2015 @ 02:10

Reaction started at 12:50 .

Reaction Scheme:

Procedure:

3-bromo-5-chloro-[1,2,4]trizolo[4,3-a]pyrazine (100mg, 0.428mmol, 1 equiv.) and phenyl boronic acid (78.34mg, 0.643mmol, 1.5 equiv.) were combined in a flask. Catalyst Pd(PPh3) (5mol%, 21.42mmol, 24.75 mg) and K2CO(1.29mmol, 177.6mg, 3 equiv.) were added to the flask. THF (6.06ml) and H2O (0.18ml) were added to the flask. The reaction mixture was then heated at 80 celsius degree for 10 hours under argon atmosphere.

Reaction was monitored by TLC. 

Water (~15ml) was added to the reaciton mixture and the mixture was extracted with ethyl acetate (80ml*3). The combined organics were washed with brine (~10ml), dried over sodium sulfate and evaporated under reduced pressure to give yellow oil. The yellow oil was then dried on vacuum.

NMR of the crude showed that purification is needed. The yellow oil was dissolved in toluene(~2ml) and purified by automatic column machine (50% ethly acetate in hexane) to give a yellow solid(43mg, yield 44%).

Data

NMR(crude)

TZ 7-2 crude.pdf

NMR(columned)

TZ 7-2 columned.pdf

HIRAC

see TZ 7-1

Strings

InChI=1S/C5H2BrClN4/c6-5-10-9-4-2-8-1-3(7)11(4)5/h1-2H

and
InChI=1S/C6H7BO2/c8-7(9)6-4-2-1-3-5-6/h1-5,8-9H
to
InChI=1S/C11H7ClN4/c12-9-6-13-7-10-14-15-11(16(9)10)8-4-2-1-3-5-8/h1-7H
 
 
 
ClC1=CN=CC2=NN=C(Br)N21
and
OB(C1=CC=CC=C1)O
to
ClC1=CN=CC2=NN=C(C3=CC=CC=C3)N21


Attached Files
25th August 2015 @ 01:46

Aim of this experiment is to perform nucleophilic aromatic substitution on the upper left hand corner of the triazolopyrazine core produced in BSX 2-1. The Cl atom was substituted by a phenylethyl group.

 

Procedure

The triazolopyrazine core (533 mg, 2.00 mmol), phenylethanol (244 mg, 1 equivalent), KOH (393 mg, 7.00 mmol, 3.5 equiv.) and 18-crown-6 (37 mg, 140.00 micromol, 0.07 equiv.) were stirred with 10 ml toluene at 40C in a small vial. TLC analysis was taken at 30mins showing no presence of starting reagents in the final reaction mixture, suggesting the reaction had completed. Reaction product was quite viscous and dark orange in colour.

The mixture was left to cool to room temperature before 5 ml of water was introduced to dilute the product to transfer into the separating funnel where it was washed three times with 10 ml EtOAc each time. The organic layer was run off and washed with 4 ml water and 3 ml brine. Sufficient Na2SO4 was added to dehydrate the mixture and eventually removed via filtration. The remaining solution was evaporated using a rotary evaporator at low pressure.

The final product was collected and analysed with TLC. This analysis proved difficult as a solvent mixture with appropriate polarity was required. Experimenting with different ratios of dichloromethane, EtOAc and methanol were generally not polar enough to lift the product from the TLC baseline. These plates were recorded in the image TLC1. In the end, 100% EtOAc was used as the solvent and the resulting plate is shown in TLC2 with Rf value approximately 0.45.

An automatic column was then used to purify the product mixture, observing the peak absorbances at individual wavelengths and collecting the filtrate in a rack of test tubes. Initially, the first peak absorbance was collected and analysed using TLC, yielding poor and inconsistent results where some dots failed to rise and others did by different distances. After continuing the column, another absorbance peak was observed and the filtrate was collected into 14 test tubes. TLC analysis results are shown in image CTTLC. The produced plate reflects presence of the desired compound as all dots rose from the baseline to an approximately equal height. Although, the solvent mixture was different to the initial crude product TLC as 1:1 ETOAc and petroleum ether was used. The solutions in the 14 test tubes were then combined and placed into a 500 mL round bottom flask for further rotary evaporation.

Yield for this experiment was 59.9%.


Hazard and Risk Assessment

Attached below.

 

Strings

SMILES

ClC1=CN=CC2=NN=C(C3=CC(F)=CC(F)=C3)N21

and

OCCC1=CC=CC=C1

to

FC1=CC(F)=CC(C2=NN=C3N2C(OCCC4=CC=CC=C4)=CN=C3)=C1

 

InChi

InChI=1S/C11H5ClF2N4/c12-9-4-15-5-10-16-17-11(18(9)10)6-1-7(13)3-8(14)2-6/h1-5H

and

InChI=1S/C8H10O/c9-7-6-8-4-2-1-3-5-8/h1-5,9H,6-7H2

to

InChI=1S/C19H14F2N4O/c20-15-8-14(9-16(21)10-15)19-24-23-17-11-22-12-18(25(17)19)26-7-6-13-4-2-1-3-5-13/h1-5,8-12H,6-7H2

 

 

The aim of this experiment series is to synthesise a new series 4 analog based on the triazolopyrazine core. More specifically, the attachment of the 3-5-difluorophenyl group on the north-east portion of the molecule. For more information: https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/338

Attached Files