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1st October 2015 @ 10:02

Reaction Scheme

This is a repeat synthesis of TY 3-1 (http://malaria.ourexperiment.org/triazolopyrazine_se/9244/Synthesis_of_5chloro3naphthalen2yl124triazolo43apyrazine_TY31.html) using up all the free TY 2-1 product.

Procedure

TY 2-1 (3.7 g, 13 mmol, 1 equiv) was added with PIDA (5.22 g, 33 mmol, 2.5 equiv) and 131 ml of DCM. Reaction was stirred at room temperature before being left in the fridge for 5 days.

After being left in the fridge the reaction was nearly complete, see below TLC, produced in 7:3 EtoAc: petroleum. 

12084095_841883142594556_655449152_n.jpg

As the next step is a recrystallisation the reaction should be taken to completion. Therefore PIDA (1.32g, 8.3 mmol) was added and the reaction stirred for a further 30 minutes.

After 30 minutes another TLC was run in 7:3 EtoAc: Petroleum, it showed still a faint trace o starting material so the reaction was left stiring over lunch.

12067857_841893095926894_1523263048_n.jpg

After lunch there was little change.

12076901_841958782586992_799249152_n.jpg

So the product was worked up. 100 ml of NaHCO3 (aq) was added to the solution. Unfortunately during the separation an accident with the NaHCO3 and the product resulted in a loss of the product.

Next week the loss will be assessed and plans for using what is left and what needs to be made again will examined.

The remaining product was worked up and dried under a rotary evaporator producing a crystaline solid (1.00g, 27% yield, 3.6mmol).

Due to the accident in the work up the sample was analysed via NMR to determine purity.

TY 3-2 Crude PDF.pdf

A rough melting point was measured, the observed range was around 196-97OC. This range will be refined after further measurements.

Strings

InChI=1S/C15H11ClN4/c16-14-9-17-10-15(19-14)20-18-8-11-5-6-12-3-1-2-4-13(12)7-11/h1-10H,(H,19,20)/b18-8+

TO

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


SMILES

ClC1=CN=CC(N/N=C/C2=CC=C(C=CC=C3)C3=C2)=N1

TO

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

Attached Files
1st October 2015 @ 08:26

Reaction Scheme

This reaction was similiar to TY4-1 ( http://malaria.ourexperiment.org/triazolopyrazine_se/8425/Synthesis_of_3naphthalen2yl5phenethoxy124triazolo43apyrazine_TY41.html) however a different nucleophile was added to produce a different molecule.

Procedure

TY 3-1 (1 mmol, 0.28 g, 1 equiv), was added to toluene (9 mL) and Pyridin-2-ylmethanol (109 mg, 1 mmol, 1 equiv), 18-crown-6 ( 102 µmol, 27 mg, 0.1 equiv) and KOH (3.50 mmol, 197 mg, 3.5 equiv).

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

12087578_840065919442945_1328220150_n.jpg
- TLC before lunch

12064326_840065929442944_636689672_n.jpg
- TLC after lunch

The product was then washed with EtoAc 15 mL and then separated into aqueous and organic layers (with the organic layer sitting on the top). This was done three times. The organic layer was then washed with 15 mL of Brine.

The organic layer was then collected. MgSO4 was then added such that the crystals stopped sticking together in clumps.

The liquid was then extracted and placed in a rotary evaporator at low pressure sufficient to remove EtoAC.

The dried product was then examined via TLC to determine the most efficeint solvent system for column chromatography. Below are two candiate TLC systems, on the left in 100% EtoAc and on the right is 5% methanol, 0.25% Ammonia and ≈95% DCM.

12077131_841883229261214_905373516_n.jpg
12071719_841883162594554_1510046555_n.jpg

12086820_841883145927889_554389202_n.jpg

100% EtoAc was used as it had a satisfactory Rf value (0.11) and avoided the use of the more toxic DCM.

Column chromatography and TLC analysis split the final product into four different samples. See TLC (100% EtoAC) below.

 

12167036_845626062220264_1042376397_n.jpg

 All the spots on the TLC seem to have an Rf value too high for the expected product. However to be sure four fractions were made. Fractions 4-12 were joined, 13-21, 22- 25, 26- 32. Each was evaporated under a rotary evaporator. Each sample was then examined via NMR using CDCl3. All raw NMR data is under attached files.

Fractions 4-12

TY 5-1 4-12 PDF.pdf

The NMR showed this did not contain the product and the sample looked to be unreacted pyridin-2-ylmethanol.

Fractions 13- 21

TY 5-1 13-21 PDF.pdf

The NMR showed this to also not contain the expected product. This also appears to be unreacted pyridin-2-ylmethanol. It is however missing a peak between 7 and 8 ppm but most likely this peak merged with the peak around 7.2 ppm and hence the integration value close to 2 (1.8).

Fractions 22 - 25

TY 5-1 22-25 PDF.pdf

Similiarly this sample did not contain the expected product but rather more pyridin-2-ylmethanol.

Fractions 26 - 32

TY 5-1 26-32 PDF.pdf

This sample did not contain the expected product and the peaks appeared to come from various solvents and perhaps fragments of reactants.

Given that none of the fractions appeared to resemble to expected product according to nmr the column was washed with DCM and methanol on a gradient of increasing methanol from 0-10%.

TLC analysis was promising showing a product with an Rf close to the expected on EtoAc. With the spots from 13-16 showing very dark spots. One TLC was in 100% EtoAc and the other 10% Methanol and 90% DCM.

12165671_848090981973772_1985499316_n.jpg
12165658_848090971973773_1259721274_n.jpg
12170673_848090985307105_1400650952_n.jpg

 The sample was analysed via NMR whilst not completely dried.

TY 5-1 Column Wash.pdf
TZ 5-1 column flush.zip

The nmr showed the peaks of the solvents, DCM, methanol, EtoAc as well as the residual chlorofom from the CDCl3. The nmr was promising for the expected product however two aliphatic protons which were expected were not seen. Although it is quite possible these were hidden under the DCM spike at around 5.3 ppm. This peak was also wider than expected and perhaps this was to do with the alipahtic protons being hidden under the peak.

Therefore the product needs to be dried and analysed via nmr again.

Product was dried under high vac over night (0.0968g, 29% yield, 0.29 mmol).

A rough melting point was measured, the observed range was around 170-173OC. This range will be refined after further measurements.

Strings

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

AND

InChI=1S/C6H7NO/c8-5-6-3-1-2-4-7-6/h1-4,8H,5H2

TO

InChI=1S/C21H15N5O/c1-2-6-16-11-17(9-8-15(16)5-1)21-25-24-19-12-22-13-20(26(19)21)27-14-18-7-3-4-10-23-18/h1-13H,14H2

SMILES

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

AND

OCC1=CC=CC=N1

TO

C12=NN=C(C3=CC(C=CC=C4)=C4C=C3)N1C(OCC5=CC=CC=N5)=CN=C2

Attached Files
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
10th August 2015 @ 13:50

 

Introduction

(E)-2-chloro-6-(2-(naphthalen-2-ylmethylene)hydrazinyl)pyrazine is being oxidatively cyclised to form 5-chloro-3-(naphthalen-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine. This is the next step in the synthesis of a novel antimalarial.

 

Method

3.58g of (E)-2-chloro-6-(2-(naphthalen-2-ylmethylene)hydrazinyl)pyrazine was placed in a flask with 5.33g of PIDA and 250ml of DCM. The flask was stirred at room temperature in a fume hood due to the unknwon toxicity of the chemicals being produced and used. TLC analysis showed whilst a new product had been produced, the reaction was not yet complete.

 

Reaction was left in the fridge for 1 week

Solution after 1 week -

11868895_815245725258298_438148642_n.jpg

Reaction was assumed to have run to completion so the mixture was placed in a separating funnel with ~100mL NaHCO3. The mixture then split into a bottom organic layer and a top aqueous layer. Layers were washed with ~ 100mL dichloromethane before being separated. Both layers were kept.

The second separation invovled the addition of Ethyl Acetate and Brine ~50mL of each. Again the bottom organic layer was collected. Na2SO4 was then added and the solution was evaporated, leaving behind a orange sludge.

Ethyl Acetate (~70mL) was added and the solution was treated with sonication and heat, until the solid had dissolved. It was then cooled down at room temperature before being filtered. The solid was dried under a high vacuum (2.69g, 9.57mmol, 75.6% Yield)

Data

Reaction before PIDA.JPG

Midway through reaction.JPG

Reaction before refrigerator.JPG

1st TLC UV.JPG
1st TLC.JPG

 

Strings

InChI=1S/C15H11ClN4/c16-14-9-17-10-15(19-14)20-18-8-11-5-6-12-3-1-2-4-13(12)7-11/h1-10H,(H,19,20)/b18-8+

TO

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


SMILES

ClC1=CN=CC(N/N=C/C2=CC=C(C=CC=C3)C3=C2)=N1

TO

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

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

Attached Files
4th August 2015 @ 11:01

Summary



A synthesis was performed to create a novel antimalarial which can test the properties of Naphthalene functional group. The molecule will be cyclised to form a triazolopyrazine core.

 

Reagents

Method

2-chloro-6-hydrazinylpyrazine (4.00 g, 27.67 mol, 1 equiv) was added to a 250 mL round bottomed flask with a magnetic stirrer. 160 ml of Ethanol was added as a solvent, NOTE: this was not a sufficient amount for the 4.00 g of 2-chloro-6-hydrazinylpyrazine. However due to the small flask size no more could be added. 

2-napthaldehyde (4.32 g, 27.67 mol, 1 equiv) was then added, colour change indicated reaction completion so sample was analysed via TLC analysis using 1:1 petroleum to ethyl acetate. UV light revealed the sample.

The completed reaction mixture was dried in a rotary evaporator at low pressure before being placed in vials for further synthesis and analysis.

Data

TLC

 

TLC TY2-1.png

TLC of 2-chloro-6-hydrazinylpyrazine, product and 2-chloro-6-hydrazinylpyrazine and just the product

TLC 2 TY2-1.jpg

 Same TLC plate as above

Dried Product ( 7.28 g, 25.75 mmol, 93% yield).

 

InChI Strings

InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)

AND

InChI=1S/C11H8O/c12-8-9-5-6-10-3-1-2-4-11(10)7-9/h1-8H

TO

InChI=1S/C15H11ClN4/c16-14-9-17-10-15(19-14)20-18-8-11-5-6-12-3-1-2-4-13(12)7-11/h1-10H,(H,19,20)/b18-8+

SMILES

ClC1=CN=CC(NN)=N1

AND

O=C([H])C1=CC=C(C=CC=C2)C2=C1

TO

ClC1=CN=CC(N/N=C/C2=CC=C(C=CC=C3)C3=C2)=N1

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

 

Attached Files