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1st October 2015 @ 07:57

Reaction Scheme

Summary

Oxidative cyclisation of (E)-N-(2-(benzo[d][1,3]dioxol-5-yl)vinyl)-6-chloropyrazin-2-amine to produce 3-(benzo[d][1,3]dioxol-5-yl)-5-chloro-[1,2,4]triazolo[4,3-a]pyrazine. Creating more CX 3-2 to allow later nucleophillic addition of chloride group in our analog synthesis 


Hazard & Risk Assessment

HIRAC CX 3-2.docx


Procedure

CX 2-1 (3.57g, 13.30 mmol) was added into a flask with  CH2Cl(130mL) at room temperature along with PhI(OAc)(4.16g). Reaction was left to stir overnight then stored in refrigerator for a week.

TLC analysis showed that reaction had reached completion.

12092715_10206148016833257_2013841737_n.jpg

 

Reaction mixture was transferred to a separating funnel and quenched with saturated NaHCO3 (100 mL) , then diluted with DCM (50 mL). Aqueous layer was washed with EtOAc (50 mL). Organic layer was then washed with brine (50 mL) and MgSO4 (6 spatulas), then filtered and solvent was removed in rotary evaporator. Total yield 2.2967 + 0.0707g = 2.3684g

 

1H NMR Crystalisation 1

CX 3-2 cryst 1.pdf
  
CX 3-2 cryst two (1).zip

Data NMR analysis indicates product obtained was pure. The sample indicated presence of water. All hydrogen environments are present, indicated by the correct number of and integrals of all 7 peaks.

1H NMR Crystalisation 2

CX 3-2 cryst 2.pdf
 
CX 3-2 cryst actual 2 (1).zip

Data NMR analysis indicates product obtained was pure. The sample indicated presence of water, along with satellite peaks. All hydrogen environments are present, indicated by the correct number of and integrals of all 7 peaks. 

SMILES

ClC1=CN=CC(N/C=C/C2=CC=C(OCO3)C3=C2)=N1

to

ClC1=CN=CC2=NN=C(C3=CC(OCO4)=C4C=C3)N21


InChi

InChI=1S/C13H10ClN3O2/c14-12-6-15-7-13(17-12)16-4-3-9-1-2-10-11(5-9)19-8-18-10/h1-7H,8H2,(H,16,17)/b4-3+

to

InChI=1S/C12H7ClN4O2/c13-10-4-14-5-11-15-16-12(17(10)11)7-1-2-8-9(3-7)19-6-18-8/h1-5H,6H2

 


This series of molecule synthesised are part of a first year TSP (talented students program) under OSM Series 4 research group, working with a certain triazolopyrazine target. More specifically, synthesising a molecule with  a 1,3 benzodioxole on the north east of the triazolopyrazine core.  Previous posts on this analog may be viewed here.

Other students’ works may be viewed here and here.


Attached Files
1st October 2015 @ 03:07

Reaction Scheme

 

Summary


Nucleophillic substitution of chloride with a pyridin-2-ylmethanol on the north-west of the Triazolopyrazine 4 Series, using previously synthesised CX 3-1. Procedure for this reaction is very similar to CX 4-1


Hazard & Risk Assessment

HIRAC CX 5-1.doc


Procedure


3-(benzo[d][1,3]dioxol-5-yl)-5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (CX 3-1) (273 mg, 1.00 mmol, 1 equiv),  powdered KOH (216 mg, 3.5 equiv),  2-phenylethanol (1 mL, 1.131 g/mL) and 18-crown-6 dissolved (26.2mg, 0.07equiv) was stirred into toulene (8 mL) in a vial. Mixture for a quite insoluble, dark brown sludge.

Reaction was left to stir for 10 mins, without applying any heat and the first TLC analysis using 100% EtOAc, showed reaction had not yet reached completion. After another 10 mins, another TLC analysis was taken and showed reaction was nearly at completion

CX 5-1 tlc #1.jpg
CX 5-1 tlc #2.jpg

However reaction was left to stir, heated at 40 degrees for 1 hour to ensure completion

CX 5-1 tlc #3.jpg


For purification, proproduct was then washed with EtOAc (3x20mL) to seperate aqueous and organic layers. Addition of water and intermittent sonication aided in dissolving the mixture. Organic layer was washed with water (4mL) and brine (3mL), and then dried with MgSO4. Solvent was then removed in a rotary evaporator.

Reaction vessel (96.0056g) was left in a refrigerator for a week. It had formed a highly crystalline yellow solid.

12092577_10206148017073263_490288021_n.jpg

TLC analysis using solvent system of Methanol, Ammonia, DCM (1:0.1:9) obtained an rf value of 0.678. A solvent system involving Methanol & DCM (1:9) is also suitable, however addition of Ammnoia obtained clearer and more distinct lines on TLC plate.

12077154_10206148016873258_279863269_n.jpg

A column purification was then run, and fractions 2-3, 4-5, 6-7 were then collected and solvent was removed using rotary evaporator. However mishandling of rotary evaporator led to water entering flask containing fraction 4-5. A small workup involving ____ was then carried out. 

12071706_10206148016953260_2039728022_n.jpg
12086796_10206148016633252_1764660981_n.jpg

NMR analysis was carried out.

 

 

Total yields 

Tubes 4-5: 0.8026g

 1H NMR Tubes 2-3 

CX 5-1 T2+3 pdf.pdf
CX 5-1 T2+3.zip

Least pure fraction, making it hard to discern peaks in NMR. NMR also suggest there is some contamination downfield at 2.16ppm

1H NMR Tubes 4-5

CX 5-1 T4+5 pdf.pdf
CX 5-1 T4+5.zip

Fraction contains some contaminants downfield, perhaps water at around 1-2ppm. Correct no. of peaks correspond to the number of hydrogen environments.

 1H NMR Tubes 6-7

CX 5-1 T6+7 pdf.pdf
CX 5-1 T6+7.zip

Last fraction appears to be most pure by the clear distinguished 13 peaks corresponding to the correct amount of hydrogen environments. NMR analysis shows that  there is some contamination of water in this sample (@1.635ppm)

SMILES

ClC1=CN=CC2=NN=C(C3=CC=CC=C3)N21    and    OCC1=CC=CC=N1

to 

C12=NN=C(C3=CC(OCO4)=C4C=C3)N1C(OCC5=CC=CC=N5)=CN=C2

 

InChi


InChI=1S/C11H7ClN4/c12-9-6-13-7-10-14-15-11(16(9)10)8-4-2-1-3-5-8/h1-7H

and

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

to

InChI=1S/C18H13N5O3/c1-2-6-20-13(3-1)10-24-17-9-19-8-16-21-22-18(23(16)17)12-4-5-14-15(7-12)26-11-25-14/h1-9H,10-11H2

 

This series of molecule synthesised are part of a first year TSP (talented students program) under OSM Series 4 research group, working with a certain triazolopyrazine target. More specifically, synthesising a molecule with  a 1,3 benzodioxole on the north east of the triazolopyrazine core.  Previous posts on this analog may be viewed here.

Other students’ works may be viewed here and here.

Attached Files
1st September 2015 @ 13:42

Reaction Scheme

 


Summary

Nucleophillic aromatic substitution of CX 3-1, using 2-phenylethanol nucleophillic to substitute alkyl chloride on triazolopyrazine core.

Hazard and Risk Assessment

HIRAC CX 4-1.doc

Procedure

CX 3-1 (549.33 mg, 2.00 mmol, 1 equiv),  powdered KOH (393 mg, 3.5 equiv),  2-phenylethanol (240 mmL) and 18-crown-6 dissolved (50 mg) was stirred into toulene (~10 mL) in a vial. Reaction mixture formed a thick, dark brown sludge.

Reaction was left to stir for 1.5 hours, and a TLC analysis using 1:1 hexane and petroleum ether (16 mL solvent) showed reaction was near completion.

tlc#1 CX 4-1.jpg

Another TLC analysis was performed 1 hr later and showed reaction had reached completion.

tlc#2 CX4-1.jpg

For purification, product was then washed with EtOAc (3x20mL) to seperate aqueous and organic layers. Organic layer was washed with water (4mL) and brine (3mL), and then dried with Na2SO4. solvent was then evaporated off in a rotary evaporator.

Reaction Vessel was left in refrigrator for a week, and when taken out a brown crystalline prodcut had formed 

An appropriate TLC solvent was then determined for product. A 9:2 EtOAc/petrol produced an appropriate Rf value of 0.186 (0.5/2.7) .

12071834_10206123401177881_531883599_n.jpg

Solution was run through column purification. Using TLC analysis it was determined that Tubes 12-35 were to be recollected.

12077419_10206123401137880_505913353_n.jpg
12047645_10206123401257883_617426174_n.jpg

Solvent was removed by rotary evaporator, and then placed under vacuum to dry. Light brown sticky residue was observed. Total yield 0.342g (62%)

Data

1H NMR, crude, DCM, 200MHz

CX 4-1 columned.pdf
 
CX 4-1 columned.zip

Analysis by 1H NMR showed correct product had formed, all expected peaks were present as well as apppearing clear and defined. However an additional peak was present at , contamination due to presence ethyl acetate solvent - the product had not been completely dried. Integrals also matched with correct product.

SMILES

ClC1=CN=CC2=NN=C(C3=CC(OCO4)=C4C=C3)N21

to

OCCC1=CN=CC2=NN=C(C3=CC(OCO4)=C4C=C3)N21

InChi Strings


InChI=1S/C12H7ClN4O2/c13-10-4-14-5-11-15-16-12(17(10)11)7-1-2-8-9(3-7)19-6-18-8/h1-5H,6H2

to

InChI=1S/C14H12N4O3/c19-4-3-10-6-15-7-13-16-17-14(18(10)13)9-1-2-11-12(5-9)21-8-20-11/h1-2,5-7,19H,3-4,8H2


References:

http://malaria.ourexperiment.org/triazolopyrazine_se/9715/Synthesis_of_tertbutyl_352phenyl2tetrahydro2Hpyran2yloxyethoxy124triazolo43apyrazin3ylpiperidine1carboxylate_AEW_2461.html

 

 

This series of molecule synthesised are part of a first year TSP (talented students program) under OSM Series 4 research group, working with a certain triazolopyrazine target. More specifically, synthesising a molecule with  a 1,3 benzodioxole on the north east of the triazolopyrazine core.  Previous posts on this analog may be viewed here.

Other students’ works may be viewed here and here.

Attached Files
11th August 2015 @ 04:39

Reaction Scheme 

 


Summary

Oxidative cyclisation of (E)-N-(2-(benzo[d][1,3]dioxol-5-yl)vinyl)-6-chloropyrazin-2-amine to produce 3-(benzo[d][1,3]dioxol-5-yl)-5-chloro-[1,2,4]triazolo[4,3-a]pyrazine

 

Hazard & Risk Assessment

 

HIRAC CX 3-1.docx

 

Tabulated Chemicals and Quantities

 

Procedure

CX 2-1 (3.67g, 13.30 mmol) was stirred into a flask with  CH2Cl(200mL) at room temperature. PhI(OAc)(5.56g)  was added.  After 2 hours, analysis by TLC using 1:1 hexane and petroleum ether (16 mL solvent) showed reaction reached was almost at completion, and was left to stir overnight.

1st TLC performed.jpg

The initial orange suspension turned to a transparent dark red solution.  Reaction vessel was then placed to chill in a fridge for one week. A later TLC analysis showed reaction had reached completion.

2nd TLC.jpg

Reaction mixture was transferred to a separating funnel and quenched with saturated NaHCO3 (~100 mL) , then diluted with DCM (50 mL). Aqueous layer was preserved. Organic layer was then washed with Ethyl acetate  (50 mL) and brine (~50 mL) and Na2SO4 (6 spatulas), then filtered and evaporated to give a brown sludge.

Ethyl acetate was added to mixture and after heating along with sonication, solid had dissolved. Solution was cooled in ice bath and washed with cold ethyl acetate (~15 mL). After filtration solid was dried at the high vacuum (1.78 g, 48% yield).

Analysis by 1H NMR showed that desired product had formed. All expected peaks were present and correct integrals were displayed

CX 3-1 cryst.pdf

Residue was kept in fridge for a week. Solid was filtered and washed with cold ethyl acetate. TLC analysis showed product was not contaminated and was left aside for possible later use.

 

Conclusion


A pure product was succesfully obtained from this reaction, verified by TLC analysis as well as 1H NMR, with a 48% yield in original product. Residue obtained was also pure, as indicated by TLC analysis.


References

Synthesis of 5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (AEW 205)

 

InChi Strings


InChI=1S/C13H10ClN3O2/c14-12-6-15-7-13(17-12)16-4-3-9-1-2-10-11(5-9)19-8-18-10/h1-7H,8H2,(H,16,17)/b4-3+

to

InChI=1S/C12H7ClN4O2/c13-10-4-14-5-11-15-16-12(17(10)11)7-1-2-8-9(3-7)19-6-18-8/h1-5H,6H2


SMILES

ClC1=CN=CC(N/C=C/C2=CC=C(OCO3)C3=C2)=N1

to

ClC1=CN=CC2=NN=C(C3=CC(OCO4)=C4C=C3)N21

 

 

This series of molecule synthesised are part of a first year TSP (talented students program) under OSM Series 4 research group, working with a certain triazolopyrazine target. More specifically, synthesising a molecule with  a 1,3 benzodioxole on the north east of the triazolopyrazine core.  Previous posts on this analog may be viewed here.

Other students’ works may be viewed here and here.



Attached Files
10th August 2015 @ 01:41

Reaction Scheme

Summary


Condensation reaction involving benzo[d][1,3]dioxole-5-carbaldehyde and 2-chloro-6-hydrazinylpyrazine to produce (E)-N-(2-(benzo[d][1,3]dioxol-5-yl)vinyl)-6-chloropyrazin-2-amine. This is the first step in a series 4 synthesis. 


Hazard & Risk Assessment

HIRAC CX 2-1.doc

 

 Procedure

 2-chloro-6-hydrazinylpyrazine (4.00 g) was stirred into ethanol (200 mL) in a flask. Benzo[d][1,3]dioxole-5-carbaldehyde (4.15 g) was then added to intitate the condensation reaction. After 1.5 hrs a TLC analysis using 1:1 hexane and petroleum ether (16 mL solvent) showed reaction had almost reached.

1st TLC analysis.jpg

Reaction vessel was left to stir overnight. TLC analysis was carried out to show that the reaction had gone to completion, solvent was evaporated. Formed a yellow powder, which was then transferred to vials, for later reactions.

 

2nd TLC analysis.jpg

 

Conclusion


This reaction was successfully completed, formation of product was indicated by TLC analysis. A yield of 3.67 g was obtained from an expected 7.63 g (48.1% 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/C8H6O3/c9-4-6-1-2-7-8(3-6)11-5-10-7/h1-4H,5H2

to

InChI=1S/C12H9ClN4O2/c13-11-5-14-6-12(16-11)17-15-4-8-1-2-9-10(3-8)19-7-18-9/h1-6H,7H2,(H,16,17)/b15-4+

 

SMILES

ClC1=CN=CC(NN)=N1

and

[H]C(C1=CC2=C(OCO2)C=C1)=O

to

ClC1=CN=CC(N/N=C/C2=CC=C(OCO3)C3=C2)=N1

 

 

This series of molecule synthesised are part of a first year TSP (talented students program) under OSM Series 4 research group, working with a certain triazolopyrazine target. More specifically, synthesising a molecule with  a 1,3 benzodioxole on the north east of the triazolopyrazine core.  Previous posts on this analog may be viewed here.

Other students’ works may be viewed here and here.

Attached Files