All Notebooks | Help | Support | About
31st March 2014 @ 08:07

Conclusion: The reaction was successful with an 88% crude yield if the product is a hydrate. The product was used in JU 2-3 without purification.

Repeat of JU 1-1 for synthesis of key starting material.

Reaction Scheme

Procedure

Started 7pm

2,6-Dichloropyrazine (Aldrich, 2.007 g, 13.4 mmol) was dissolved in ethanol (20 mL) to give a clear solution. Hydrazine hydrate (0.70 mL, 680 mg, 13.4 mmol) was added dropwise resulting in a pale yellow solution. The resulting mixture was heated at reflux (bath temperature 80˚C) for 16 h. Analysis by TLC showed the reaction was complete.

TLC JU 1-4 30:70 EtOAc:Hex.jpg

The reaction was cooled to room temperature, the solvent was removed by rotary evaporation and the product dried in vacuo. The crude product (1.918 g, 99% yield, 88% if hydrate) was analysed by 1H NMR.

1H NMR, crude, DMSO, 200 MHz

JU 1-4 crude DMSO 200 MHz.pdf
JU 1-4 crude DMSO.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

Linked Posts
This post is linked by:
Attached Files
31st March 2014 @ 06:52

Following the method used in Synthesis of 6-chloropyrazine-2-carboxylic acid (IT 4-1)

scheme

TM 5-2 (9.4 g, 55 mmol) dissolved in ethanol (100 mL). NaOH (125 mL, 250 mmol, 2M aq) was added, and the reaction left stirring for 18 hours (note: previous runs of this reaction were left for 2 hours, but I ran it overnight. As the product is obviously thermodynamic and (I suspect) not prone to degradation, this seemed unlikely to hurt yields. This was a bad idea. See below.).

The reaction mixture contained pale yellow chunks floating in solution. HCl (2M, ~150 mL) was added until the reaction mixture was acidic (~pH 2), causing the solid product to dissolve to give a pale orange liquid. The solution was then diluted with water (700 mL), and then extracted with EtOAc (nominally 4 x 500 mL, but as we had no >1 L separation funnels, the reaction mixture was divided into two portions of ~500 mL and each extracted with 4 x 250 mL). The combined organic fractions were washed with brine (nominally 1 x 500 mL but in reality two 500 mL organic portions washed with  2 x 250 mL; see above), recombined, and dried over MgSO4. The solvent was removed under vacuum, giving crude TM 10-1 as beige flakes. Crude yield: 7.1 g.

 

1H NMR:

TM 10-1 crude 1H CDCl3 200 MHz.pdf

As well as the desired product (at 9.31, 8.87 ppm), there are significant quantities of other pyrazine species (as well as the ever-present chlorobenzoic acid). It is theorised that the long reaction time led to displacement of the pyrazinyl chlorine by ethanol, giving an ethoxy product with these peaks: CH s 8.97, CH s 8.49, CH2 q 4.48, CH3 t 1.48. There also appears to be some of the methyl ester remaining.

 

As at the time it was thought that incomplete hydrolysis was the only problem (and than an ethyl ester had formed), the reaction was rerun in THF following DOI: 10.1039/c2nj40791d.

The crude product was stirred in THF (200 mL), and NaOH (2M, ~50 mL) added. The reaction mixture was stirred for 4 hours.

 

 

 

 

HIRAC: See IT 4-1.

Linked Posts
Attached Files
26th March 2014 @ 13:13

According to literature procedure DOI: 10.1002/anie.201001999

Github Tag: Issue #155

 

Procedure:

Crude AEW 119-2 (65 mg, ~0.125 mmol, q equiv.) was combined with Chloramine-T (42 mg, 1.5 mmol, 1.2 equiv.) in 2-methyltetrahydrofuran (1 mL) and the reaction mixture was heated to 60 ˚C for 1.5 hours (in line with above procedure).

The TLC was inconclusive but looked like there could be more spots so the work-up procedure from the referenced publication was followed. The reaction mixture was cooled to room temperature and then the organic phase was diluted with 2-methyltetrahydrofuran (8 mL) and then washed with 10 wt% aq. sodium sulfite solution (4 mL), 1 M sodium hydroxide solution (2 x 4 mL) and then evaporated to dryness to give a brown oil/solid. Crude NMR 300 showed possible product and starting aldehyde, no SM.

Purified by flash column chomatography over silica (30% EtOAc in hexane --> EtOAc). Collected aldehyde and second spot...NMR 400 indicates product.

Data:

TLC:

AEW 120-2.jpg
AEW 120-2 80% EtOAc in Hexane.jpg
AEW 120-2 column 20% hex in EtOAC TLC.jpg

1HNMR Crude:

Purified 400 MHz Proton NMR:

AEW 120-2 400 NMR picture.jpg

Hazard and Risk Assessment:

HIRAC AEW 120-1.pdf

InChi:

InChI=1S/C21H13F8N5O2/c22-19(23)36-15-3-1-11(2-4-15)8-31-34-17-10-30-9-16(33-17)18(35)32-14-6-12(20(24,25)26)5-13(7-14)21(27,28)29/h1-10,19H,(H,32,35)(H,33,34)/b31-8-

to 

InChI=1S/C21H11F8N5O2/c22-19(23)36-14-3-1-10(2-4-14)17-33-32-16-9-30-8-15(34(16)17)18(35)31-13-6-11(20(24,25)26)5-12(7-13)21(27,28)29/h1-9,19H,(H,31,35)

Attached Files
26th March 2014 @ 00:04

Conclusions: The reaction was successful with a 44% yield of the pure product. This is comparable to JU 3-6 with a 43% yield.

Resynthesis of JU 3-6

Github Tag: Issue #158

Reaction Scheme

Procedure

Started 11:40am

JU 2-2 (1.005 g, 3.88 mmol) was stirred into CH2Cl2 (60 mL). PhI(OAc)2 (1.255 g, 3.88 mmol) was added and the resulting solution was stirred at room temperature for 5.5 h. Analysis by TLC showed the reaction was incomplete.

TLC JU 3-7 EtOAc:Hexane 50:50 5.5 h.jpg

The reaction was stirred for a further 16.5 h. Analysis by TLC showed the reaction was incomplete.

TLC JU 3-7 EtOAc:Hexane 50:50 22 h.jpg

The reaction was stirred for a further 8 h. Analysis by TLC showed the reaction was incomplete.

TLC JU 3-7 EtOAc:Hexane 50:50 30 h.jpg

The reaction was stirred for a further 16 h. Analysis by TLC showed the reaction was incomplete. The reaction was stopped and worked up because it couldn;t be left over the weekend.

TLC JU 3-7 EtOAc:Hexane 50:50 46 h.jpg

The reaction mixture  was washed with 120 mL of saturated sodium hydrogen carbonate solution. The NaHCO3 layer was extracted with DCM (6 x 120 mL), dried over MgSO4 and filtered. The solvent was removed by rotary evaporation and dried in vacuo. The crude product was purified by flash column chromatography over silica. The column was first eluted with 50:50 EtOAc and Pet Benzine followed by 70:30 EtOAc:PB, and 100% EtOAC. The pure product was a pale yellow solid (437 mg, 44% yield) and was analysed by 1H NMR as were the impure fractions.

1H NMR, pure, DMSO, 200 MHz

JU 3-7 pure DMSO 200 MHz.pdf
JU 3-7 pure DMSO.zip

1H NMR, frac 10-96, DMSO, 200 MHz

This sample looks to be the starting material plus something else.

JU 3-7 frac 10-96 DMSO 200 MHz.pdf
JU 3-7 frac 10-96 DMSO.zip

 

HIRAC - see JU 3-1

InChI strings

InChI=1S/C12H8ClN5/c13-11-7-15-8-12(17-11)18-16-6-10-3-1-9(5-14)2-4-10/h1-4,6-8H,(H,17,18)/b16-6+

to

InChI=1S/C12H6ClN5/c13-10-6-15-7-11-16-17-12(18(10)11)9-3-1-8(5-14)2-4-9/h1-4,6-7H

SMILES

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

to

ClC1=CN=CC2=NN=C(C3=CC=C(C#N)C=C3)N21


Linked Posts
This post is linked by:
Attached Files
25th March 2014 @ 22:23

Github Tag: Issue #155

Filtered AEW 118-2 (165 mg, ~0.45 mmol) was sirred in AcOH (0.05 mL) in MeCN (1.7 mL) and 4-(difluoromethoxy)benzaldehyde (59 microL, 0.45 mmol, 1 equiv.) and the resulting mixture stirred at room temperature for 

 

Data:

 

Hazard and Risk Assesment:

InChi:

InChI=1S/C13H9F6N5O/c14-12(15,16)6-1-7(13(17,18)19)3-8(2-6)22-11(25)9-4-21-5-10(23-9)24-20/h1-5H,20H2,(H,22,25)(H,23,24)

and

InChI=1S/C8H6F2O2/c9-8(10)12-7-3-1-6(5-11)2-4-7/h1-5,8H

to

InChI=1S/C21H13F8N5O2/c22-19(23)36-15-3-1-11(2-4-15)8-31-34-17-10-30-9-16(33-17)18(35)32-14-6-12(20(24,25)26)5-13(7-14)21(27,28)29/h1-10,19H,(H,32,35)(H,33,34)/b31-8-