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9th July 2013 @ 05:36

Amination of MNR 99-3 with 1,3-diaminopropane to give N1-(thieno[3,2-d]pyrimidin-4-yl)propane-1,3-diamin. This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

***

None of desired product was isolated or characterised; NMR of crude product indicated dimer formation. Scum collected during separation showed peaks of the aminothienopyrimidine core; LRMS gave 343 as m/z of molecular ion peak.

Procedure

1,3-diaminopropane (1.5 mL, 18 mmol, 6.0 equiv.) was added dropwise to MNR 99-3 (0.501 g, 2.94 mmol, 1.0 equiv.), with emission of puffs of vapour leaving a yellow solution and white solid. Ethanol (1 mL) and THF (2 mL) were added to give a suspension of the solid in the solution. This solution was heated to 85oC and left at this temperature with stirring for 3 hours. TLC analysis showed all MNR 99-3 had been consumed and formation of new, more polar product(s). The resulting yellow suspension was cooled to room temperature. Water (10 mL) was added to the solution and the crude product was extracted with ethyl acetate (3 x 20 mL), the combined extracts were washed with brine (15 mL) and then dried using anhydrous Na2SO4, the solution of crude product in ethyl acetate was left in the fridge for 14 hours before concentration under reduced pressure to give a yellow oily solid (0.14 g, 0.71 mmol, 34 %). NMR analysis showed presence of desired product and its dimer.

A further extraction of aqueous washings was completed. This gave 0.070 g, NMR shown below - consists mainly of ethyl acetate and CDCl3, all product signals are negligible.

During extractions a scum gathered between the aqueous and organic phases, and collected on the sides of separating funnel once extraction was complete. This was collected (soluble in methanol) and concentrated to a pale yellow solid (0.075 g) NMR showed this scum was a compound with the thienopyrimidine core. The scum was again washed with water and basified to pH 12 using NaOH (1M), the organic products were collected, dried and concentrated to a pale yellow solid (0.035 g).


Hazard and Risk Assessment

HIRAC MJT 15-1


Data

TLC 

TLC MJT 15-1.png

H NMR of first wash

MJT 15-1 first extraction.pdf

H NMR of second wash

MJT 15-1 second extraction.pdf

H NMR of scum

MJT 15-1 scum.pdf


H NMR of MNR 99-3 

H NMR of 1,3-diaminopropane

Attached Files
9th July 2013 @ 02:24

Nucleophilic displacement of the chlorine of MNR 99-3 for 2-dimethylaminoethanol. As effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

 ***

Reaction completed and gave 59 % yield after purification by column chromatography. Product taken forward in to bromination (MJT 16-1).

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

Procedure

2-dimethylaminoethanol (1.7 mL, 17 mmol, 6.0 equiv.) was added to MNR 99-3 (0.496 g, 2.91 mmol, 1.0 equiv.) to give a yellow solution. This solution was heated to 85oC and left at this temperature with stirring for 3 hours. TLC analysis showed all MNR 99-3 had been consumed and formation of new, more polar product(s). The solution was cooled to room temperature, a white solid precipitated out of solution. Ethyl acetate (2 mL) was added and the reaction mixture was left stirring at room temperature in a sealed vessel for 14 hours. Water (10 mL) was added to the solution and the white solid dissolved. The crude product was extracted with ethyl acetate (3 x 20 mL), the combined extracts were washed with brine (10 mL) and then dried using anhydrous Na2SO4 before concentration under reduced pressure to give a pale yellow oil (0.529 g, 2.4 mmol, 81 %). NMR analysis showed presence of the desired product though it was wet and contained some amine still. The crude product was dissolved in ethyl acetate, washed with water (20 mL) and then brine (20 mL) before drying over anhydrous Na2SOand concentration to give a yellow oil (0.529 g, 2.4 mmol, 81%). NMR analysis after this second wash showed product was contaminated with some impurities - it had extra signals in the aromatic region. The crude product was purified by column chromatography (2%, 5%, 7.5%, 10% methanol in DCM) over silica (40-60 micron particles) to give 2 fractions: the top spot as a white solid (0.03 g) and a bottom spot as a pale yellow oil (0.381 g, 1.7 mmol, 59%); the bottom spot is pure product by NMR.


Hazard and Risk Assessment

MJT 14-1 HIRAC


Data

TLC 

TLC MJT 14-1

H NMR

 after column:

MJT_14-1_purified_by_column.pdf

before column:

MJT 14-1 after second wash.pdf

 

H NMR of MNR 99-3 

H NMR of 2-dimethylaminoethanol

Characterisation Data

1H NMR


MJT 14-1 proton.pdf
MJT 14-1 proton nmr raw data

13C NMR

MJT 14-1 carbon.pdf
MJT 14-1 carbon nmr raw data

Mpt. < RT, MJT 14-1 is an oil

Attached Files
5th July 2013 @ 01:13

Repeat of Synthesis of N-methylthieno[3,2-d]pyrimidin-4-amine (MJT 7-1) (amounts of SM doubled), nucleophilic aromatic substitution of chlorine for methylamine to bring through more material to allow repeat of Synthesis of 6-bromo-N-methylthieno[3,2-d]pyrimidin-4-amine (MJT 9-1) using more equivalents of BuLi in the hope of a better 

***

Reaction completed in 97 % yield, product was pure after extraction. 200 mg of product taken forward in MJT 9-2.

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


Procedure

Methylamine (24% w/v in H2O, 4.2 mL, 22 mmol, 6 equiv.) was added to MNR 99-3 (0.590 g, 3.46 mmol), insoluble. The mixture was heated to 100oC, MNR 99-3 dissolved to give a pale yellow solution, the heat was reduced to 85oC and maintained for 6 hours by which time the reaction was a slurry of white solid in yellow solution. TLC (EtOAc) showed reaction had gone to completion. The reaction mixture was cooled to room temperature before the reaction was worked up with water (20 mL) and the product was extracted with ethyl acetate (3 x 20 mL). The combined ethyl acetate extracts were washed with brine before drying over Na2SO4 and removal of solvent to give MJT 7-2 (0.552 g, 3.34 mmol, 97 %) as a white powder. NMR matched MJT 7-1 and showed product was pure.

Hazard and Risk Assessment

HIRAC MJT 7-1

Data

TLC 6h EtOAc

 

TLC 6h EtOAc.JPG

Characterisation Data

1H NMR

MJT_7-2_H.pdf
 
MJT 7-2 Proton NMR raw data

13C NMR

MJT_7-2 Carbon.pdf
 
MJT 7-2 Carbon NMR raw data

Mpt. 156-160 ˚C

Linked Posts
Attached Files
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