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27th June 2013 @ 05:54

Repeat synthesis of MNR 103-1, ortho sulfonamide boronic acid ester to couple with MJT 9-1 and MJT10-1 via suzuki reaction (e.g. MJT 17-1) to synthesise compounds discussed in the May 2013 Open Consultation.

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Reaction did not give desired products - see NMR of product fractions from column, peaks in the range 6-7 ppm rather than 8-9ppm (shown by MNR 103-1) indicate that something went wrong - likely due to the wet, syrupy KOAc used. SM was not recovered.

 

Procedure


3-bromobenzenesulfonamide (0.6056 g, 2.57 mmol, 1 equiv.), potassium acetate (1.01 g, 10.3 mmol, 4 equiv.) andbis(pinacolatodiborane) (0.98 g, 3.85 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (13 mL) giving a yellow solution with some undissolved white solids. Argon was bubbled through the suspension for ten minutes before [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.094 g, 0.13 mmol, 0.05 equiv.) was added. Argon was bubbled through the solution for 5 minutes and then the suspension was heated at reflux with stirring for 16 hours. Reaction is now a black solution with white solid.

TLC (50% and 30% hexane / EtOAc) showed the reaction had not gone to completion and a single product spot. The reaction was filtered through celite and washed with methanol (100 mL) and EtOAc (40 mL) giving a yellow solution which was concentrated to a beige solid (2.684 g). NMR analysis showed no product signals in the aromatic region (compared to JRC 29-4).

Reaction was separated between water and ethyl acetate, organic layer was separated off, washed with brine, dried over Na2SO4 and solvent removed to give a beige sold (2.008 g). TLC against MNR 103-1 did not co spot => product is not MNR 103-1 as intended. H NMR analysis showed no SM or product signals.

Flash column chromatography (30 %, 50 %, 100 % EtOAc in hexane) was completed and gave two fractions - see NMR analysis below

Hazard and Risk Assessment


HIRAC MJT 11-1.pdf

Analysis

TLC

TLC 17h 30 and 50% hexane / EtOAc

IMG_2086.JPG

1H NMR

 Crude NMR, after celite filtration

 

MJT 11-1 H NMR after celite filter 200 MHz.pdf

After work up

MJT 11-1 post workup.pdf

Fraction 1

MJT 11-1 bottom spot.pdf

Fraction 2

MJT 11-1topspot.pdf
Attached Files
26th June 2013 @ 06:38

Bromination of MJT 8-1This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

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Product was synthesised in 57 % yield. and taken forward in a suzuki coupling with MNR 103 - see MJT 17-1.

This is a novel compound; data to be collected: IR, LRMS, HRMS

 

 

 

 



Procedure

MJT 8-1 (0.2386 g, 1.33 mmol, 1 equiv.) was dissolved in THF (27 mL) and cooled to -78 °C.  To the stirring solution was added n-BuLi (2.5 M in hexane, 0.80 mL, 2.00 mmol, 1.5 equiv.) and the stirring was continued for 30 minutes.  Bromine (0.14 mL, 2.66 mmol, 2 equiv.) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 2.5 hours, it is now an orange solution. TLC analysis showed reaction did not go to completion. The reaction was stirred for 1h more, then saturated sodium thiosulfate solution (30 mL) was added - a precipitate formed. The resulting solution was washed with ethyl acetate (30 mL) x 3. The organic layer was collected and washed with brine (20 mL) in to which the precipitate dissolved, then dried with Na2SO4 and concentrated to an orange solid (0.394 g, >100 %). Column chromatography (50 % hexanes / ethyl acetate) was used to isolate the product (0.1934 g, 0.75 mmol, 57 %) as a white solid.

Hazard and Risk Assessment

HIRAC MJT 10-1.pdf

Analysis

TLC 2.5h, 50% hexane / ethyl acetate

MJT 10-1 TLC.JPG

Characterisation Data

1H NMR

MJT_10-1_H.pdf
 
MJT 10-1 H NMR raw data

13C NMR

MJT_10-1_Carbon.pdf
 
MJT 10-1 carbon NMR raw data

Mpt. 123-124 ˚C

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Attached Files
26th June 2013 @ 02:44

Bromination of MJT 7-1This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

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Reaction gave mixed products and lots of SM remained unreacted. Crude product was discarded since TLC showed it had degraded. SM was not recovered; reaction was repeated in MJT 9-2.

 

 

 

Procedure

MJT 7-1 (0.2377 g, 1.44 mmol, 1 equiv.) was dissolved in THF (29 mL) and cooled to -78 °C.  To the stirring solution was added n-BuLi (2.5 M in hexane, 0.86 mL, 2.16 mmol, 1.5 equiv.) and the stirring was continued for 30 minutes.  Bromine (0.14 mL, 2.88 mmol, 2 equiv.) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 2.5 hours. The reaction is an orange solution and TLC shows the reaction is not completed. The reaction was left to stir for 1.5h more before sodium thiosulfate solution (30 mL) was added, an aqueous and an organic layer formed. The crude product was collected by washing with ethyl acetate (30 mL) x 3. The organic layer was washed with brine (20 mL), dried with Na2SO4 and solvent removed to give MJT 9-1 (0.175 g, 0.717 mmol, 50 %) as an orange oil.

Hazard and Risk Assessment


HIRAC MJT 9-1.pdf

Analysis


TLC 2.5h, 30% and 50% hexane in ethyl acetate

TLC MJT 9-1.JPG

1H NMR

MJT_9-1_crude.pdf
 
MJT 9-1 crude H NMR raw data

MJT_9-1_crude_degraded.pdf
 
MJT 9-1 degraded crude product H NMR raw data
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Attached Files
24th June 2013 @ 10:26

Amination of MNR 99-3 with dimethylamine to give N,N-dimethylthieno[3,2-d]pyrimidin-4-amine. This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

***

Reaction was completed  in 91 % yield; product was taken forward in MJT 10-1.

Novel compound, data to be collected:IR, LRMS, HRMS

Procedure

1715PM 24-06-2013

Dimethylamine (33% in EtOH, 2.2 mL, 9.5 mmol, 6 equiv.) was added dropwise to MNR 99-3 (0.2696 g, 1.58 mmol, 1 equiv.), a white solid. A vapour was emitted and the solid dissolved immediately to give a yellow solution, a minute later a solid precipitated out of solution. The mixture was then heated to 85oC, the solid dissolved to give a yellow solution. The mixture was left at 85oC with stirring for 16 hours, giving a white solid with brown stains which was cooled. TLC showed no remaining SM and a single product spot. The product was dried under high vacuum to give N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (0.4101 g, 2.29 mmol, "145 %"). NMR shown below - shows dimethylamine remains, signal at 2.7ppm. This was washed with hexane though NMR showed dimethylamine SM persisted, again peak at 2.7 ppm. 

Reaction was partitioned between water and ethyl acetate, NaHCO3 (2 mL) was added too as the solid did not dissolve initially. Organic layer was extracted, washed with brine and solvent removed to give N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (0.257 g, 1.44 mmol, 91 %). NMR analysis showed no remaining dimethylamine.

 

Hazard and Risk Assessment

HIRAC MJT 8-1

Data

TLC

TLC 16h EtOAc
 

H1 NMR

300MHz

MJT8-1 nmr.pdf

200 MHz, after hexane wash

1H NMR PDF 200 MHZ MJT 8-1 POST HEXANE WASH

clean, after aqueous work up

1H NMR MJT 8-1 clean.pdf

 

Characterisation Data

1H NMR

MJT_8-1_H.pdf
 
MJT 8-1 proton NMR raw data

13C NMR

MJT_8-1_carbon.pdf
 
MJT 8-1 Carbon NMR raw data

Mpt. 120-121 ˚C

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Attached Files
24th June 2013 @ 09:43

Amination of MNR 99-3 with methylamine to give N-methylthieno[3,2-d]pyrimidin-4-amine. This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

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Reaction was completed  in 90 % yield; product was taken forward in MJT 9-1.

Reaction was repeated to bring through more product - see: Synthesis of N-methylthieno[3,2-d]pyrimidin-4-amine (MJT 7-2).

Novel compound, data to be collected - see MJT 7-2 for data

 

Procedure

1715PM 24-06-2013

Methylamine (24% w/v in H2O, 2.1 mL, 11.6 mmol, 6 equiv.) was added to MNR 99-3 (0.3010 g, 1.8 mmol, 1 equiv.), insoluble. On heating to 85oC MNR 99-3 dissolved to give a pale yellow solution. The solution was heated at 85oC for 16 hours to give a yellow solution which was cooled to room temperature. A white solid precipitated out on cooling. TLC (EtOAc) showed no SM remained, one strong and one feint new product spots.

The reaction was partitioned between water and ethyl acetate, organic layer isolated and solvent removed to give N-methylthieno[3,2-d]pyrimidin-4-amine as a white solid (0.261 g, 1.58 mmol, 90 %). 1H NMR shown below.

 Hazard and Risk Assessment

HIRAC MJT 7-1

Data

TLC

TLC 16h MJT 7-1

NMR

See MJT 7-2 for characterisation data

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Attached Files