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13th October 2016 @ 19:48

Synthesis begun on 10/3

Reaction Scheme:

 

Compound

MW (g/mol)

Mol (mmol)

g

Density (g/mL)

Volume (mL)

eqv

2-chloro-6-hydrazinylpyrazine

(MRLS 1-2)

144.56

1.435

0.2075

 

 

1

Tertbutyl 3-formylpiperidine-1-carboxylate

213.27

1.48

.3157

 

 

1

EtOH (190 proof)

60.05

 

 

 

5

 

   

 

 

 

 

 

Product

339.82

1.435

0.488 

 

 

 1

Procedure

MRLS 1-3 (0.2075 g, 1.435 mmol)) was stirred in EtOH (190 proof, 5 mL). Note that the MRLS 1-3 was added slowly to make sure it all went into the mixture.

Tertbutyl 3-formylpiperidine-1-carboxylate (0.3157 g, 1.48 mmol) was added to the suspension and the reaction mixture was stirred at room temperature for 12 hours. Once it appeared the starting material was consumed, the solvent was removed under reduced pressure to yield a yellow pale solid. Dried under high vac, and the product was analyzed via NMR (0.25 g, 51% yield).

(Compared to the MRLS 3-1, this product was much paler and drier, resembling the 3-2. However, the NMRs look similar. I'm having difficulties analyzing using GC-MS, as no peaks appear on the TIC. Will update if I make any progress. Reminder: The only difference between the procedures for the 3-1 and 3-3 was the addition of acetonitrile as a solvent.)

 

Attached Files
13th October 2016 @ 19:25

Synthesis begun on 9/29

Bringing through more material to continue primary synthesis. This time, we are not using acetonitrile, and instead just using 3% EtOH.

Reaction Scheme:

 

Compound

MW (g/mol)

Mol (mmol)

g

Density (g/mL)

Volume (mL)

eqv

2-chloro-6-hydrazinylpyrazine

(MRLS 1-4)

144.56

3.46 mmol

0.5

 

 

1

Tertbutyl 3-formylpiperidine-1-carboxylate

213.27

3.5 mmol

0.746 g

 

 

1

3% EtOH in H2O

60.05

 

 

 

10

 

   

 

 

 

 

 

Product

339.82

3.46

1.176 g

 

 

 1

Procedure: 

MRLS 1-4 (0.5 g, 3.46 mmol) was stirred in 3% EtOH (10 mL). After stirring for 1 hour, the MRLS 1-4 had yet to completely dissolve. 

Tertbutyl 3-formylpiperidine-1-carboxylate (0.8519 g, 4 mol) was added to the suspension and the reaction mixture was stirred at room temperature under Argon for 90 minutes. Unlike the last attempt (MRLS 3-1), an orange, sticky material formed that gathered on the stir bar. The stir bar was removed and cleaned, and the reaction was left stirring under Argon for another 48 hours. 

10/1

Checked reaction via TLC, but the starting material had yet to be consumed (perhaps some of the undissolved MRLS 1-4 from earlier). I decided to rotovap what was left, but the spinning of the round bottom caused the reaction mixture to foam up and collect in the bump trap. Although rotovapping had worked for MRLS 3-1, the solvent had not evaporated. Instead, proceeded with vacuum filtration. Collected 0.3448 g of material (yield: 29.3%). Unlike the yellow fluffy solid from the last attempt, the product was a pale, peach color.

10/3

Filtered the solution that was in the filter flask from 10/1. Collected 0.2683 g of material (yield:22.8%). Verified via TLC that this material was identical to product from 10/1, so the two were combined (total:0.6131 g, 52 % yield). Prepared NMR sample (will update).

10/4

After checking NMR of MRLS 1-4, we noticed a strange peak around 2 ppm (also seen in NMR below). I decided to run this reaction once more with MRLS 1-3, which had a cleaner NMR. 

Attached Files
12th October 2016 @ 05:09

Started 10-6-2016

This is different than previous attempts in that we're using polymer bound p-tsoh in hopes of having a cleaner reaction mixture. We also used a microwave reactor to run the reaction at 140C.

scheme

compound

MW (g/mol)

Mol (mmol)

g

Density (g/mL)

Volume (mL)

eqv

2 chloro 6 hydrazinylpyrazine

144.56

4.80

0.70g

 

 

1

toluene

 

 

 

 

19 mL

 

Triethyl orthoformate

148.20

9.70

1.42 g

0.891

1.60

2

TsOH (poly bound)

190.2

0.614

0.33g 

 

 

0.2

Product

 154.56

 3.47

 0.74

 

 

 1

 

2-chloro-6-hydrazinylpyrazine (from Synthesis of 2-Chloro-6-hydrazinylpyrazine (MRLS 1-1) (0.70 g, 4.80 mmol) was dissolved in dry toluene (19 mL). Dry Triethyl orthoformate (1.60 mL, 6.94 mmol) and polymer bound TsOH (0.33g g, 2.5-3 mmol active ingredient/1g material) were added, and the resulting reaction mixture was put into a microwave reaction vial and run at 140C for 3.5 hours.

Procedure based on HM 1-1.

Log

10-6 3:55 pm

Starting material dissolved in toluene, which didn't dissolve until about 60C as expected. Triethyl orthoformate added after starting material was dissolved, along with 0.33g polymer bound p-TsOH. This mixture was added to a 20 mL microwave reaction flask and put into the microwave reactor for 3.5 hours at 140C. Pressure did not exceet 2.23 bar. 

8:50 pm

flask was removed from reactor and taken back to the hood to cool. TLC tomorrow.

10-7

TLC performed, 60% etoac. product is believed to be the bottom spot that shows up under long-wave UV. s=starting mat, c=co-spot, p=product

image

 

Reaction mixture after reaction, p-TsOH polymer filtered off. very clear.

Displaying IMG_1424.JPG

The reaction mixture was filtered off and left an oil. NMR was performed on this oil, and the lines we want are definitely there (8. 26, 9.42, 9.68ppm) Column will be run after break.

10-18

Oil dissolved in DCM and put into a samplet to use in the biotage. 4 fractions were spotted. The fourth fraction was isolated and the solvent was removed under reduced pressure. TLC and NMR (calling it 2-4-1 was performed on this, which showed it to indeed be the core, but a very small amout (about 40 mg). 

In the crude NMR, it was noted that there seemed to be a lot of this compound in the reaction mixture:

 intermediate

It was thought that isolating this and submitting it back to acidic conditions would force the ring to close, so the solvent from this fraction was removed under reduced pressure and the resulting oil was dissolved in toluene, and 0.25g of polymer bound p-tsoh was added after it was dissolved. This was brought to reflux for 24 hours, after which most of the unclosed structure was gone from the TLC. 

Displaying IMG_1443.JPG

10-19

The toluene was removed under reduced pressure, which again left an oil. This oil was dissolved in DCM and submitted to the biotage. Four fractions were spotted, and the fourth was the probable product. Unfortunately, when the solvent was removed under reduced pressure, an oil resulted (not the crystal from the previous procedures). TLC was performed on this oil, which certainly seemed to be the core. NMR will be performed on this oil tomorrow.

.Displaying IMG_1442.JPG

Attached Files
11th October 2016 @ 18:56

(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 13.4 2     1
hydrazine hydrate 32.045 13.4 0.88   0.88 1
ethanol         25  
2-Chloro-6-hydrazinylpyrazine 144.56  13.4  1.90     1

 

[2,6]-Dichloropyrazine (2 g, 13.4 mmol) was stirred in ethanol (25 mL) and hydrazine hydrate (80% by volume, 0.84mL). 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 1.12g, 57% yield. 

Attached Files
4th October 2016 @ 20:30

Starting material, MRLS 2-3 (0.14g, 0.921 mmol), was added to a round bottom flask, and NBS (0.145g, 0.81 mmol, 0.9 eq) was added along with 10 ml of chloroform. Brought to reflux for 48 hours, then allowed to cool overnight. 

Workup: reaction mixture diluted with 20 mL more chloroform, then washed with 10 mL potassium carbonate. Aqueous layer washed with 2x10 mL chloroform and combined with the other organic layers. Solvent removed under reduced pressure. 

 

Log

10-1, 8:45p 

Reaction started. Everything was very soluble in chloroform as expected. Turned a dark wine color once everything was dissolved. Brought to reflux over about 20 minutes.

10-2

Took TLC of the reaction mixture (60% EtOAc) which showed a good bit of starting material left, so another 0.5 eq NBS was added. I noticed that it seemed like there was less chloroform than we'd started with, so I greased the joints of the reflux condenser and added 4 more mL chloroform to be on the safe side.

10-3

All of the chloroform is gone! It's kind of a mystery, because the argon balloon is still full. very hard solid was left in the flask. More chloroform added in hopes of salvaging the reaction. Most of the solid was soluble in chloroform, but there was some stuck to the stir bar that was insoluble. I took it off of the heat and let it cool over night, still stirring. 

10-4

Workup done as described above. Nothing good resulted. The aqueous and organic layers were quite difficult to distinguish, and there was a gooey slab in the aqueous layer. Organic layers concentrated anyways, giving a thick black oil. NMR was done in DMSO, which looked nothing like expected. Product scrapped.

Attached Files