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20th July 2015 @ 06:38

Reaction was discarded. Desired product was made but hard to purify it. Too many byproducts.

Procedure: Reaction started at 16:30

For procedures of synthesis of the SM (6-chloro-pyrazine-2-amine), see TZ 1-3.

6-chloro-pyrazine-2-amine (500 mg,1 eq), phenacylchloride (716mg 1.2 eq), sodium hydrogen carbonate (324mg, 1 eq), Hydrobromic acid (33% in aqueous acetic acid, 0.70ml, 1eq), water (2ml) and IPA (2ml) were combined in a 25ml flask. The reaction mixture was heated at reflux (100 degrees celcius) for 17 hours.

The reaction mixture was slightly diluted with water. Sodium hydroxide solution (0.7M) was added to neutralise the reaction mixture. The reaction mixture was then diluted with ethyl acetate and water. The biphasic mixture was shaken in a separating funnel and the ogranic layers sperated. Aqueous layers were washed with ethyl acetate. The combined organic layers were dried with sodium sulfonate and filtered into a flask. The solvent was then removed under reduced pressure. 

Data :

TLC of the reaction mixture(ethyl acetate : petroleum = 7 : 3)









 

 

TLC of the reaction mixture (ethyl actetate : petroleum = 3 : 7 )

NMR data of crude:

TZ 3-1 crude ck.pdf

NMR data of starting material:

TZ 3-1 crude.pdf

NMR data of the fractions:

TZ 3-1 frac1.pdf
TZ 3-1 frac2.pdf
TZ 3-1 frac3+4.pdf
TZ 3-1 frac5.pdf
TZ 3-1 frac6.pdf
TZ 3-1 frac7.pdf

HIRAC:

HIRAC TZ 3-1.pdf

Strings:

ClC1=CN=CC(N)=N1
and
O=C(CCl)C1=CC=CC=C1
to
ClC1=CN=CC2=NC=C(C3=CC=CC=C3)N21
 
InChI=1S/C4H4ClN3/c5-3-1-7-2-4(6)8-3/h1-2H,(H2,6,8)
and
InChI=1S/C8H7ClO/c9-6-8(10)7-4-2-1-3-5-7/h1-5H,6H2
to
InChI=1S/C12H8ClN3/c13-11-7-14-8-12-15-6-10(16(11)12)9-4-2-1-3-5-9/h1-8H
Attached Files
16th July 2015 @ 05:42

Desired product was made (1.842 g, 84.7 % yield).

Scaled-up.

Procedures:

2,6-dichloropyrazine (2.50g,16.8 mmol, 1 eq) and ammona solution (12mL, 0.50 M, 28% aqueous) were combined in a sealed tube. The reaction mixture was stirred at 100 degrees celcius for 30 to 45 hours (heating switched off). 

The reaction mixture was diluted with EtOAc and a saturated aqueous solution of sodium hydrogen carbonate. The biphasic mixture was shaken in a separating funnel and then organic layers separated. Aqueous layers were washed with EtOAc and then combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered and evaporated to give a pale yellow crystalline solid, which was dried in vacuo (1.842 g, 84.7 % yield). No further purification.

Data:

reaction after 30 to 45 hours

TZ 1-3 mixture.jpg

TLC(EtOAc:Pretrol=50:50 )

TZ 1-3 TLC scaled-up.jpg

HIRAC:

HIRAC TZ 1-3.pdf

Literature:

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=WO&NR=2013068755A1&KC=A1&FT=D&ND=&date=20130516&DB=&&locale=en_EP

Strings:

ClC1=CN=CC(Cl)=N1

to

ClC1=CN=CC(N)=N1

 

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

to

InChI=1S/C4H4ClN3/c5-3-1-7-2-4(6)8-3/h1-2H,(H2,6,8)



Attached Files
15th July 2015 @ 23:46

AEW 245-1 (200 mg, 0.59 mmol, 1 equiv) was added to toluene (3.8 mL) along with AEW 221-1 (132 mg, 0.59 mmol, 1 equiv), potassium hydroxide (116 mg, 2.10 mmol, 3.5 equiv) and 18-crown-6 (11 mg, 0.04 mmol, 0.07 equiv).

The reaction was stirred at room temp for ten minutes and then heated to 40°C (bath temperature) for x

The sample was cooled to room temperature and diluted with 4 mL of water. The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with water (1 x 4 mL) until the aqueous layer became neutral followed by brine (3 mL) and dried over Na2SO4. The orange/yellow fluoro solution was filtered and dried under reduced pressure and in vacuo to yield an orange oil that was dried at the high vac.


Data:

 

Hazard and Risk Assessment:


Strings:

ClC1=CN=CC2=NN=C(C3CN(CCC3)C(OC(C)(C)C)=O)N21

and

OCC(OC1OCCCC1)C2=CC=CC=C2

to

CC(OC(N(CCC1)CC1C2=NN=C3N2C(OCC(OC4OCCCC4)C5=CC=CC=C5)=CN=C3)=O)(C)C

InChI=1S/C15H20ClN5O2/c1-15(2,3)23-14(22)20-6-4-5-10(9-20)13-19-18-12-8-17-7-11(16)21(12)13/h7-8,10H,4-6,9H2,1-3H3

and

InChI=1S/C13H18O3/c14-10-12(11-6-2-1-3-7-11)16-13-8-4-5-9-15-13/h1-3,6-7,12-14H,4-5,8-10H2

to

InChI=1S/C28H37N5O5/c1-28(2,3)38-27(34)32-14-9-12-21(18-32)26-31-30-23-16-29-17-24(33(23)26)36-19-22(20-10-5-4-6-11-20)37-25-13-7-8-15-35-25/h4-6,10-11,16-17,21-22,25H,7-9,12-15,18-19H2,1-3H3

Attached Files
14th July 2015 @ 03:10

Desired product was obtained (2.6g pure and 3.1g impure, yield 67% approximately).

Procedure:

For details of synthesis of hydrazinylpyrazine, see (AEW 85-7). Hydrazinylpyrazine can also be purchased commercially.

Hydrazinylpyrazine (8.01g, 55.3mmol, 1 equiv.), triethyl orthoformate (18.4 ml, 111mmol, 2 equiv.), and tosylic acid (476.1mg, 2.765mmol, 0.05 equiv.) were dissolved in toluene (to around 0.35 M) and heated at reflux for 24 h. Volatiles were removed under reduced pressure, remaining orthoester was blown off under a gentle stream of nitrogen.

NMR of the crude showed that purification is needed. TLC showed that 6 fractions were spotted. The reaction mixture was dissolved in ethyl acetate and mixed with slica. The solvent (ethyl acetate) was evaporated under reduced pressure. Purified by column chromatography (30 to 100% ethyl acetate in hexanes). All fractions are yellow solid. Desired product was obtained (2.6g pure and 3.1g impure, yield 67%). The desired pruduct with impurities was brominated directly in the next reaction without futher purification.

Data:

TLC(ethyl acetate: petrol=50: 50)

TZ 2-1 TLC.jpg

NMR (product)

NMR TZ 2-1 product dmso.pdf
NMR data TZ 2-1 product CDCl3.pdf

NMR (fractions)

TZ 2-1 Frac5.pdf
TZ 2-1 Frac1.pdf

Hazard and Risk Assessment:

HIRAC TZ 2-1.pdf

Strings:

ClC1=CN=CC(NN)=N1

and

CCOC(OCC)([H])OCC

to

ClC1=CN=CC2=NN=CN21


InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)
 
and
 
InChI=1S/C7H16O3/c1-4-8-7(9-5-2)10-6-3/h7H,4-6H2,1-3H3
 
to
 
InChI=1S/C5H3ClN4/c6-4-1-7-2-5-9-8-3-10(4)5/h1-3H


Linked Entries
Attached Files
12th July 2015 @ 15:12

SGS 7-1 and 7-2 were washed in with ethyl acetate and solvents were removed. Both samples were analysed with 1H NMR (300 MHz, CDCl3). The 7-1 sample was purified by column chromatography using ethyl acetate and petroleum eluent as some impurities were detected by TLC. The resulting fractions were combined to form 5 fractions.

Based on previous NMR results of this particular compound (AEW 94, DS 3, DS 8) it is likely that the product is present in fraction 1 and 2 only.

Data:

SGS 7-1 CDCl3

SGS 7-1 CDCl3 300 MHz AEW and PK.pdf
SGS 7-1 CDCl3 AEW and PK.zip

SGS 7-2 CDCl3

SGS 7-2 CDCl3 300 MHz AEW and PK.pdf
SGS 7-2 CDCl3 AEW and PK.zip

Column Fractions:

SGS 7-1 frac 1.pdf
SGS 7-1 frac 2.pdf
SGS 7-1 frac 3.pdf
SGS 7-1 frac 4.pdf
SGS 7-1 frac 5.pdf

Strings:

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

InChi: 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

Attached Files