Amino-thienopyrimidine Series

Procedure:

AEW 55-1 (1.25 g, 5.33 mmol) was dissolved in THF (107 mL) and cooled to –78 ˚C. To the stirring solution was added n-BuLi (2.5 M in hexanes, 3.2 mL, 8.00 mmol) and stirring was continued for 30 minutes. Bromine (0.55 mL, 10.7 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature and stirred for 2 hours.

Data:

Hazard and Risk Assessment:

Procedure:

AEW 58-1 (270 mg, 1.21 mmol) was dissolved in THF (24 mL) and cooled to –78 ˚C. To the stirring solution was added n-BuLi (2.5 M in hexanes, 0.73 mL, 1.82 mmol) and the stirring was continued for 30 minutes. Bromine (0.12 mL, 2.43 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature and stirred for

Data:

Hazard and Risk Assessment:

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

Analysis

TLC

1H NMR

 Crude NMR, after celite filtration

After work up

Fraction 1

Fraction 2

Bromination of MJT 8-1. This 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

Analysis

TLC 2.5h, 50% hexane / ethyl acetate

Characterisation Data

1H NMR

13C NMR

Mpt. 123-124 ˚C

Bromination of MJT 7-1. This 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

Analysis

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

1H NMR