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2nd April 2013 @ 01:13
Mnr: MNR91-100

Starting material - Synthesis of thienopyrimidine MNR89-3

As for Chlorination of MNR89 To Give MNR99-2

 

Hazard Assessment

HIRAC MNR99.pdf

Procedure


Reaction carried out in two lots due to scale and volume of POCl3 required.

A

To MNR89-3 (3.95 g, 25.96 mmol) at room temperature was added POCl3 (24 mL, 259 mmol) under argon and the mixture was heated to reflux for 2 hours during which time the reaction turned a dark brown colour.  The the reaction was then allowed to reach room temperature and was slowly added dropwise to ice ice (400 mL) in a large beaker.  The mixture was then slowly neutralised with sodium bicarbonate.  A pale brown solid also began to precipitate out during the quencing.  Once the reaction was fully quenched it was extracted with EtOAc (400 mL x 2), the organics were combined and washed with brine (100 mL) then dried with anhydrous magnesium sulfate, filtered and concentrated to give a pale orange solid.

B as above and quenched in the same ice bath, starting material (4.10 g, 26.9 mmol)

Column 40-80% EtOAc/Hex

Fracs 1-5 - 8.269 g, 48.5 mmol, 92% as a white crystaline solid

NMR

 

mnr99-3_frac1-5_1H.pdf
mnr99-3_frac1-5.zip

Conclusion

Clean porduct in good high yield.

Strings

Starting material

InChI=1S/C6H4N2OS/c9-6-5-4(1-2-10-5)7-3-8-6/h1-3H,(H,7,8,9)

Product

InChI=1S/C6H3ClN2S/c7-6-5-4(1-2-10-5)8-3-9-6/h1-3H

 

 

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Attached Files
25th February 2013 @ 22:49
Mnr: MNR91-100

Starting material - JRC13-6

As for compound 10a here and MNR100-1

Hazard Assessment

MNR100-1.pdf

Procedure

A suspension of JRC13-6 (0.70 g, 4.10 mmol) in morpholine (3.5 mL, 041.0 mmol) was gently heated under reflux for 3 hours and then allowed to cool to room temperature.  EtOAC was then added to the mixture to rinse the magnetic stirrer and on doing so a white precipitate formed.  More EtOAc (10 mL) was added and the mixture was filtered and the solid washed with hexane.  

 

Col 80% EtOAc/Hex

 

Frac 7-19 - 0.805 g, 3.63 mmol, 89% as pale yellow, fluffy solid

 

NMR

Starting Material

jrc13-6_1H.pdf
mnr_jrc13-6.zip

Product

 

mnr100-2_frac7-19_1H.pdf
mnr100-2_frac7-19_13C.pdf
mnr100-2_frac7-19.zip

Conclusion

 Good clean high yielding reaction

Strings

 Starting material

InChI=1S/C6H3ClN2S/c7-6-5-4(1-2-10-5)8-3-9-6/h1-3H

Product

InChI=1S/C10H11N3OS/c1-6-15-9-8(1)11-7-12-10(9)13-2-4-14-5-3-13/h1,6-7H,2-5H2

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Attached Files
20th February 2013 @ 04:41
Mnr: MNR91-100

Starting material - MNR99-1

As for compound 10a here

Hazard Assessment

MNR100-1.pdf

Procedure

A suspension of MNR99-1 (0.15 g, 0.88 mmol) in morpholine (0.75 ml) was gently heated under reflux for 90 minutes (I had to leave the lab ) and then allowed to cool to room temperature overnight (should have been worked up earlier).  EtOH (2 mL) was added to the mixture but everything went into solution.  The mixture was concentrated and columned.

 

Column - 20-100% EtOAc/Hex

 

Fracs 1-25      0.005 g, 0.03 mmol, 3%  - starting material

Fracs 36-63    0.169 g, 0.76 mmol, 87%  - product

Fracs 64-flush 0.125 g - not clean whatever it is

 

NMR

Product

mnr100-1_frac36-63_1H.pdf
mnr100-1_frac36-63_13C.pdf
mnr100-1_frac36-63.zip

Conclusion

Successful reaction to yield the desired product.  This can now be tested and also taken on to substitute at the 6 postion either via halogenation followed by suzuki coupling or by direct arylation 

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Attached Files
18th February 2013 @ 23:47
Mnr: MNR91-100

Starting material MNR89-1 - 2nd crop

As for JRC13-2 and MNR99-1

Hazard Assessment

HIRAC MNR99.pdf

Procedure

To MNR89-1 (2.94 g, 19.32 mmol) at room temperature was added POCl3 (18 mL, 193 mmol) under argon and the mixture was heated to reflux for 90 minutes during which time the reaction turned a dark brown colour.  The the reaction was then allowed to reach room temperature and was cooled in an ice bath and slowly queched with some ice followed by saturated sodium bicarbonate solution.  During the quenching the mixture was transferred to a 1 L beaker due to volume of solution required.  A pale brown solid also began to precipitate out during the quencing.  Once the reaction was fully quenched (almost 800 mL aq required) it was extracted with EtOAc (400 mL x 2), the organics were combined and washed with brine (100 mL) then dried with anhydrous magnesium sulfate, filtered and concentrated to give a pale orange solid (2.47 g,  14.5 mmol, 75%)

 

NMR

 

mnr99-2_crude_1H.pdf
mnr99-2_crude.zip

 

NMR showed approx 10% impurities, possibly starting material.  No further purification was carried out at this pint.

Strings

Starting material

InChI=1S/C6H4N2OS/c9-6-5-4(1-2-10-5)7-3-8-6/h1-3H,(H,7,8,9)

Product

InChI=1S/C6H3ClN2S/c7-6-5-4(1-2-10-5)8-3-9-6/h1-3H

 

 

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Attached Files
17th February 2013 @ 23:37
Mnr: MNR91-100

Starting material MNR89-1 - 2nd crop

As for JRC13-2

Hazard Assessment

HIRAC MNR99.pdf

Procedure

To MNR89-1 (1.0 g, 6.57 mmol) at room temperature was added POCl3 (6.13 mL, 65.7 mmol) under argon and the mixture was heated to reflux for 90 minutes during which time the reaction turned a dark brown colour.  The the reaction was then allowed to reach room temperature and was cooled in an ice bath and slowly queched with some ice followed by saturated sodium bicarbonate solution.  During the quenching the mixture was transferred to a 500 mL conical flask due to volume of solution required.  A pale brown solid also began to precipitate out during the quencing.  Once the reaction was fully quenched (almost 500 mL aq required) it was extracted with EtOAc (200 mL x 2), the organics were combined and washed with brine (75 mL) then dried with anhydrous magnesium sulfate, filtered and concentrated to give a pale orange solid (1.196 g, 7.01 mmol, >100%)


NMR

 

mnr99-1_crude_1H.pdf
mnr99-1_crude.zip

 

1H NMR showed product and only slight traces on impurities.  No further purification required.

 

Strings

Starting material

InChI=1S/C6H4N2OS/c9-6-5-4(1-2-10-5)7-3-8-6/h1-3H,(H,7,8,9)

Product

InChI=1S/C6H3ClN2S/c7-6-5-4(1-2-10-5)8-3-9-6/h1-3H

 

 

Attached Files