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30th September 2016 @ 04:23

(started on 9/28)

This time we are using more starting material for use in both continuation of the Nemesis synthesis outlined here and for synthesis of the triazolopyrazine core.

 

first step of nemesis synthesis

compound

MW (g/mol)

mol (mmol) g           density (g/mL) volume (mL) equivalents
[2,6] dichloropyrazine 148.98 26.8 4     1
hydrazine hydrate 32.045 26.8 0.88   1.78 1
ethanol         40  
2-Chloro-6-hydrazinylpyrazine 144.56  26.8  3.95g      1

 

[2,6]-Dichloropyrazine (4 g, 26.8 mmol) was stirred in ethanol (40 mL) and hydrazine hydrate (80% by volume, 1.78 mL). The mixture was refluxed at 80 ˚C  under Ar for ~24 hours. 

(9/29)

Solvent removed under reduced pressure. Resulting yellow solid dissolved in 30mL water and 40mL ethyl acetate. aqueous layer extracted 3x20mL etoac. combined organic layers washed with 20 mL brine, and then organic layer removed under reduced pressure. yield of 3.60g, 24.9mmol, 92% yield. 

30th September 2016 @ 02:39

 Started on 9/28

scheme

compound

MW (g/mol)

Mol (mmol)

g

Density (g/mL)

Volume (mL)

eqv

2 chloro 6 hydrazinylpyrazine

144.56

3.47

0.5084

 

 

1

toluene

 

 

 

 

15 mL

 

Triethyl orthoformate

148.20

6.94

1.22 g

0.891

1.14

2

TsOH

190.2

0.614

0.13g 

 

 

0.2

Product

 154.56

 3.47

 0.5136

 

 

 1

 

2-chloro-6-hydrazinylpyrazine (from Synthesis of 2-Chloro-6-hydrazinylpyrazine (MRLS 1-1) (0.5084 g, 3.47 mmol) was dissolved in dry toluene (15 mL). Dry Triethyl orthoformate (1.14 mL, 6.94 mmol) and TsOH (0.13g g, 10 mol %) were added, and the resulting reaction mixture was refluxed at 110 oC for 20 hours.

Procedure based on TM 37-14.

Log

9-27-16

Reaction was started at 3:00. 1-3 and triethyl orthoformate was added to toluene, but didn't dissolve until the toluene reaced about 60C. 

At about 3:45 once everything was dissolved, catalyst was added to prevent the insoluble black solid from forming (see HM1-5) 

9-28

11:00 am

A TLC was taken of the starting material, cospot, and reaction mixture. It showed very little starting material! This was in 60% etoac on sio2. 

Displaying FullSizeRender.jpg

The reaction was stopped, and the solvent removed under reduced pressure, resulting in a crusty black solid.

This solid was dissolved in DCM (quite soluble) and put into a Samplet (part of the biotage thing). The samplet was put into a dessicator to remove solvent, and then run on the biotage (settings: regular solvent ramp, 1.4L solvent, 50g KSIL column with samplet).

Fractions 33-67 contained the product, and the solvent was removed under reduced pressure. Pale yellow solid resulted. NMR done in DMSO. Proton NMR was great, 13C wasn't as good. GC/MS to come. 

Yield was 0.252g, 1.76mmol, for 50.4% yield. Bromination with NBS is the next step.

 

Attached Files
27th September 2016 @ 19:24

(started on 9/25)

Link to last attempt: Synthesis of 2-Chloro-6-hydrazinylpyrazine (MRLS 1-1). Synthesizing more to re-attempt the synthesis of the triazolopyrazine core with fresh reagents (p-tsoh catalyst had a worrying NMR). 

 

first step of nemesis synthesis

compound

MW (g/mol)

mol (mmol) g           density (g/mL) volume (mL) equivalents
[2,6] dichloropyrazine 148.98 13.4 2     1
hydrazine hydrate 32.045 13.4 0.680   0.66 1
ethanol         20  
2-Chloro-6-hydrazinylpyrazine 144.56  13.4  1.937     1

 

[2,6]-Dichloropyrazine (2.01 g, 13.4 mmol) was stirred in ethanol (22 mL) and hydrazine hydrate (80% by volume, 0.80 mL). The mixture was refluxed at 80 ˚C  under Ar for ~24 hours. 

(9/26)

Solvent removed under reduced pressure. Crude yellow solid was produced. This solid was dissolved in 15 mL deionized water and 20 mL EtOAc. Aqueous layer extracted with 3x10mL EtOAc. All organic layers combined and washed with 10mL Brine. Solvent removed under reduced pressure to yield pale yellow product (0.761g, 5.24 mmol, 39% yield). Yield was so bad because I failed to realize that the hydrazine was in fact 83% hydrazine, so there was a lot of unreacted starting material left over once the hydrazine was used up. 

Attached Files
22nd September 2016 @ 17:43

The synthesis of 2-1 seemed to go well, but the purification did not go well, we we're making another attempt using the hydrazinylpyrazine sythesized here.

scheme

2-chloro-6-hydrazinyl pyrazine (0.36g, 2.55 mmol, 1 equiv) was added to a round-bottom flask with triethyl orthoformate (0.85 mL, 5.11 mmol, 2 equiv) and p-toluenesulfonic acid (97mg, 0.5 mmol, 0.2 equiv) in 7.5ml of toluene. This was dissolved and then heated to reflux for 24

TLC after 24 hours showed a significant amount of starting material left in the reaction mixture, so it was put in a microwave reactor for 30 minutes at 150 degrees in an effort to speed things along. This did not change the reaction mixture appreciably. NMR was attempted, but someone else's NMR tube broke in the probe, so the machine is down for the forseeable future. 

16th September 2016 @ 06:57

Synthesis begun on 9/13

Reaction Scheme:

 

Compound

MW (g/mol)

Mol (mmol)

g

Density (g/mL)

Volume (mL)

eqv

2-chloro-6-hydrazinylpyrazine

(MRLS 1-2)

144.56

3.805 mmol

0.55

 

 

1

Tertbutyl 3-formylpiperidine-1-carboxylate

213.27

4 mmol

0.8531g

 

 

1

3% EtOH in H2O

60.05

 

 

 

0.7

 

Acetonitrile

41.05

 

 

 

10  ml

 

Product

339.82

3.805

1.293 g

 

 

 1

 MRLS 1-2 (0.5493 g, 3.805 mmol) was stirred in 3% EtOH (0.7 mL) and MeCN (10 mL). Tertbutyl 3-formylpiperidine-1-carboxylate (0.8519 g, 4 mmol) was added to the suspension and the reaction mixture was stirred at room temperature for 90 minutes. Once it appeared the starting material was consumed, the solvent was removed under reduced pressure to yield a yellow fluffy solid (1.1691 g, 3.44 mmol, 90% yield). The product was analyzed via NMR.

TLC: Silica gel plate, 30% EtOH/Hexanes

From bottom to top lanes: Starting material, cospot, product

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Attached Files