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31st July 2014 @ 07:48

Repeat of TM 37, using straight triethyl orthoformate assolvent/reagent, plus catalytic TsOH, together with a longer reaction time. For the first time an isolatable quantity of the desired chlorotriazolopyrazine was obtained (by proton NMR and LCQ-MS: further characterisation in progress), in 16 % yield (with substantial loss of material to charring/tar due to the long and hot reaction).

scheme

2-chloro-6-hydrazinylpyrazine (from Resynthesis of 2-chloro-6-hydrazinylpyrazine (TM 34-2): assume pure, 300 mg, 2.07 mmol) and tosylic acid (60 mg, 35 mmol, .15 eq) were added to triethyl orthoformate (3 mL), and stirred at reflux (bath temperature 145 oC) for 18 h with an air condenser, under a gently flowing stream of nitrogen. The reaction mixture was then concentrated under a stream of nitrogen, to give a thick dark oil, together with some insoluble black charcoal-looking residue. This was diluted with EtOAc, filtered to remove solid gunk, re-concentrated under reduced pressure, and purified by automatic column chromatography (loaded neat).

Three fractions were obtained, in 40 mg, 80 mg, and 50 mg yield (the loss of mass can likely be attributed to the degraded material discarded earlier, presumably from the high reaction temperature). Fractions one and two were somewhat overlapping, so neither can be considered pure.

Isolera report:

TM 37-5_arch.pdf

 

Fraction 1, 40 mg:

NMR (1H, DMSO, 200 MHz):

TM 37-5 f1 1H DMSO 200 MHz.pdf

TM 37-5 f1 DMSO.zip

This is a real mess. I'm not really sure what's going on here.

 

Fraction 2, 80 mg:

NMR (1H, DMSO, 200 MHz):

TM 37-5 f2 1H DMSO 200 MHz.pdf

TM 37-5 f2 DMSO.zip

LCQ-MS (MeOH, ESI +ve)

TM 37-5 f2 POS dil.pdf

This fraction looks to be largely the uncyclised hydrazone species observed in Synthesis of 5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (TM 37-3) ([M+H]+ = 201, δH = 10.01 s, 8.26 s, 7.90 s, 6.97 s, 4.17 2H q, 1.29 3H t), along with some other species.

 

Fraction 3, 50 mg:

NMR (1H, DMSO, 200 MHz):

TM 37-5 f3 1H DMSO 200 MHz.pdf

TM 37-5 f3 DMSO.zip

LCQ-MS (MeOH, ESI +ve)

TM 37-5 f3 POS dil.pdf

This fraction appears to be the desired triazolopyrazine product, for the first time obtained in isolatable quantities. [M+H]+155.07, predicted 155.01. δH= 9.70, 9.45, 8.17 ppm.

 

HIRAC: See TM 37-1

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31st July 2014 @ 02:43

GitHub Issue #237

Procedure:

Lithium aluminium hydride (1.9 g, 49.4 mmol, 1.5 equiv.) was dissolved in anhydrous THF (33 mL) and cooled to 0 ˚C. Crude AEW 176-1 (~32.9 mmol) was dissolved in anhydrous THF (33 mL) and added dropwise at 0 ˚C. Reaction mixture stirred at 0 ˚C for 15 min and then removed from the ice bath and stirred whilst reaching rt

 

Data:

 

Hazard and Risk Assessment:

HIRAC AEW 179-1.pdf

 

InChi Key:

InChI=1S/C10H22O3Si/c1-8(9(11)12-5)13-14(6,7)10(2,3)4/h8H,1-7H3

to

InChI=1S/C9H22O2Si/c1-8(7-10)11-12(5,6)9(2,3)4/h8,10H,7H2,1-6H3

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31st July 2014 @ 02:26

Conclusions: Successful, the correct product was obtained. I will use these conditions in future syntheses of the hydrazinylpyrazine. 

Repeat synthesis of JU 1-15 as more starting material is needed. Conditions from TM 34-2 were tested, i.e. reflux at 100°C and 3 equiv of hydrazine hydrate.  

Reaction Scheme

Procedure

Started 12pm

2,6-Dichloropyrazine (Aldrich, 1.00 g, 6.8 mmol) was dissolved in ethanol (10 mL) to give a clear solution. Hydrazine hydrate (1.0 mL, 1.0 g, 20.4 mmol, 3 equiv) was added resulting in a pale yellow solution. The resulting mixture was heated at reflux (bath temperature 100˚C) for 3.25 h. Analysis by TLC showed the reaction was complete, although the rf of the product was higher than expected.

TLC JU 1-20 30:70 EtOAc:Hex 3.25 h.jpg

The solution was left to cool to room temperature, then cooled briefly in an ice bath before the solvent was removed by rotary evaporation at 40°C. The crude product (fluffy yellow crystals, 1.562 g, 10.81 mmol, >100% yield, likely a hydrate) was analysed by 1H NMR and found to be the correct product. 

1H NMR, crude, DMSO, 200 MHz

JU 1-20 crude 200 MHz.pdf
JU 1-20 crude.zip

 

HIRAC & Risk Assessment

See JU 1-1

InChI strings

InChI=1S/C4H2Cl2N2/c5-3-1-7-2-4(6)8-3/h1-2H

to

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

SMILES

ClC1=CN=CC(Cl)=N1

to

ClC1=CN=CC(NN)=N1

Attached Files
31st July 2014 @ 02:10

Investigation of benzyl ethers since there is little data on them currently (see wiki). I have chosen to attached the difluorophenyl methanol to the triazolopyrazine core with the chloro substituent on the phenyl ring to compare the effect of the ether chain length directly with MMV 639565, which is one CH2 group longer. 

Literature reference: 10.1021/jo901707x

GitHub link: #248

Reaction Scheme

Procedure

Started 12:30pm

JU 16-1 (0.08 mL, 100 mg, 0.69 mmol, 1.2 equiv) was added to 1.5 mL toluene along with JU 8 (154 mg, 0.58 mmol, 1 equiv), potassium hydroxide (110 mg, 2 mmol, 3.4 equiv) and 18-crown-6 (18 mg, 0.07 mmol, 0.12 equiv). The reaction mixture turned a dark red-brown on addition of the 18-crown-6. The reaction was stirred at 40°C for 1.25 h. Analysis by TLC showed that the reaction was complete.

TLC JU 17-1 50:50 EtOAc:Hex 1.25 h.jpg

The reaction was stopped and cooled before diluting with water (6 mL). The aqueous layer was extracted with EtOAc (4 x 4.5 mL). The combined organic layers were washed with water (2 x 6 mL) until neutral, then with brine (4.5 mL). The organic layers were dried over Na2SO4 and the solvent removed by rotary evaporation. The crude product (259 mg, >100% yield) was dried in vacuo and analysed by 1H NMR.

1H NMR, crude, CDCl3, 200 MHz

JU 17-1 crude 200 MHz.pdf
JU 17-1 crude.zip
 

The crude product was purified using the biotage isolera, see run details below.

JU 17-1_arch.pdf

The pure product (fluffy, white, 103 mg, 48%) was analysed by 1H NMR.

1H NMR, pure, CDCl3, 200 MHz

JU 17-1 pure green frac 200 MHz.pdf
JU 17-1 green frac pure.zip
 

1H NMR, impure frac, CDCl3, 200 MHz

JU 17-1 pure blue frac 200 MHz.pdf
JU 17-1 blue frac pure.zip
 

1H NMR, pure, DMSO, 200 MHz - the pure fraction was run again in DMSO to obtain a clearer NMR.

JU 17-1 pure DMSO 200 MHz.pdf
JU 17-1 pure DMSO.zip

A second purification was performed on the biotage isolera and the product was analysed by 1H NMR, see run details below.

JU 17-1 2_arch.pdf

1H NMR, pure, DMSO, x MHz

JU 17-1 pure 3.zip

 

HIRAC

HIRAC JU 17-1.pdf

InChI strings

InChI=1S/C11H6Cl2N4/c12-8-3-1-7(2-4-8)11-16-15-10-6-14-5-9(13)17(10)11/h1-6H

and 

InChI=1S/C7H6F2O/c8-6-2-1-5(4-10)3-7(6)9/h1-3,10H,4H2

to

InChI=1S/C18H11ClF2N4O/c19-13-4-2-12(3-5-13)18-24-23-16-8-22-9-17(25(16)18)26-10-11-1-6-14(20)15(21)7-11/h1-9H,10H2

SMILES

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

and

OCC1=CC(F)=C(F)C=C1

to

ClC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4=CC=C(F)C(F)=C4)N32

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31st July 2014 @ 00:39

GitHub Issue #235 and #236


  

 

Procedure:

Lithium aluminium hydride (1.9 g, 49.4 mmol, 1.5 equiv.) was dissolved in anhydrous THF (33 mL) and cooled to 0 ˚C. Crude AEW 176-1 (~32.9 mmol) was dissolved in anhydrous THF (33 mL) and added dropwise at 0 ˚C. The reaction mixture was then stirred for 2 h whilst reaching rt. On completion, an aqueous solution of NaOH (2M, 10 mL) was added dropwise to the mixture at 0 ˚C. The formation of a gluggy white aluminium suspension meant that the mixture was extrememly difficult to filter. A saturated aqueous solution of Rochelle's salt (150 mL) was added and the reaction mixture was stirred at room temperature for 2 hours and then extracted with a large amount of diethyl ether (4 x 125 mL). Combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated to give a viscous yellow oil that solidified at the high vac to give a flaky white solid ( x g).

 

1H NMR indicated that the reduction was successful but that the TBS group had also been removed...GAH!

Data:

 

AEW 178-1 crude.pdf
AEW 178-1.zip

Hazard and Risk Assessment:

HIRAC AEW 178-1.pdf

InChi Key:

InChI=1S/C15H24O3Si/c1-15(2,3)19(5,6)18-13(14(16)17-4)12-10-8-7-9-11-12/h7-11,13H,1-6H3

to

InChI=1S/C14H24O2Si/c1-14(2,3)17(4,5)16-13(11-15)12-9-7-6-8-10-12/h6-10,13,15H,11H2,1-5H3

Attached Files