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12th July 2013 @ 00:18

Bromination of MJT 14-1. This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

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Reaction proceeded to give product in 45 % yield, some of which was taken forward in suzuki coupling with MNR 103-1 to give MJT 18-1, a target compound.

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


Procedure

 MJT 14-1 (0.360 g, 1.61 mmol, 1.0 equiv.) was dissolved in THF (32 mL) under an atmosphere of argon and cooled to -78 °C over ten minutes. To the stirring solution was added n-BuLi (2.5 M in hexane, 1.0 mL, 2.4 mmol, 1.5 equiv.) and the stirring was continued for 30 minutes to give a yellow solution. Bromine (0.2 mL, 3.2 mmol, 2.0 equiv.) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 2 hours, it is now an orange solution. TLC shows some SM remains and several new products have formed. To the reaction saturated sodium thiosulfate solution on ice (75 mL) was added and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with brine and dried over MgSO4. After concentration crude product was obtained as a brown sludge (0.113 g, 0.37 mmol, 23%). NMR analysis indicated that this extraction isolated a dimer of the desired product and was contaminated with grease.

A TLC of the aqueous wash showed it still contained SM and / or products; it had a pH of 4 and so it was basified with sodium hydrogen carbonate to pH 10 before a further extraction using ethyl acetate (3 x 40 mL), brine wash and drying over MgSOto give crude product / SM (0.29 g, 0.96 mmol, 60 %; total yield now 83 %) as a yellow oil. TLC showed aqueous washings no longer contained SM or product. NMR analysis of this second crude extract shows that it consists mainly of the desired product, with a small amount of SM. This second extraction was purified by column chromatography (10% MeOH in DCM, 40-60 micron silica particles) to give three fractions. In order of elution these were: one fraction as a white solid (0.020 g) shown to be byproduct by NMR, one with a single spot by TLC as a white solid (0.088 g, 0.29 mmol, 18 %) which NMR showed was pure and one with two spots by TLC as a light brown solid (0.129 g, 4.27 mmol, 27 %), again fairly clean by NMR. Both of the later fractions will be taken forward in suzuki couplings.

Hazard and Risk Assessment

HIRAC MJT 16-1.pdf

Data


TLC

 TLC after workup

TLC after workup.JPG

Stained TLC after workup

stained tlc after workup.JPG

H NMR

Of first extraction: dimer of desired product

MJT 16-1 crude first extraction pdf

Of second (basified) extraction: desired product

MJT 16-1 crude second extraction pdf

From column:

byproduct

MJT 16-1 column frac 40- 60.pdf

single product spot fraction

MJT 16-1 column single spot.pdf

mix product fraction

MJT 16-1 mix spot fraction.pdf

H NMR of SM, MJT 14-1

Characterisation Data

1H NMR


MJT 16-1 proton.pdf
MJT 16-1 H NMR raw data

13C NMR


MJT 16-1 carbon.pdf
MJT 16-1 C NMR raw data

Mpt. 49-50 ˚C

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Attached Files
HIRAC MJT 16-1.pdf
amounts table MJT 16-1
TLC after workup.JPG
stained tlc after workup.JPG
MJT 16-1 reaction scheme.png
MJT 16-1 crude first extraction raw data
MJT 16-1 crude first extraction pdf
MJT 16-1 crude second extraction pdf
MJT 16-1 crude second extraction raw data
MJT 16-1 column frac 40- 60.pdf
MJT 16-1 column single spot.pdf
MJT 16-1 mix spot fraction.pdf
byproduct NMR raw data
single spot product NMR raw data
mix spots fraction NMR raw data
MJT 16-1 proton.pdf
MJT 16-1 carbon.pdf
MJT 16-1 H NMR raw data
MJT 16-1 C NMR raw data