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26th July 2012 @ 06:16
This experiment uses the para isomer of the sulfonamide boronic acid ester to (hopefully) lead to the synthesis of the para isomer of the aminothienopyrimidine series lead target.

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Reaction start time: 11am, 26/07/2012
6-iodothieno[3,2-d]pyrimidin-4-amine (123 mg crude, approx. 70% pure, 86.1 mg pure, 0.31 mmol, 1 equiv.) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.014 mmol, 4.5 mol %) were dissolved in water (20 mL) and dioxane (40 mL) under a nitrogenous atmosphere, and stirred in these conditions for 10 min. After this time cesium fluoride (200 mg, 1.31 mmol, 4.2 equiv.), sodium bicarbonate (58 mg, 0.69 mmol, 2.2 equiv.) and 4-sulfamoylphenylboronic acid, pinacol ester (160.5 mg, 0.566 mmol, 1.8 equiv.) were added to the stirring solution. The nitrogenous atmosphere was maintained and the stirring solution was heated to reflux overnight. The reaction vessel was then allowed to cool to rt before being diluted with water (70 mL) and extracted with ethyl acetate (100 mL). The aqueous layer was extracted twice more with ethyl acetate (50 mL), before the combined organic layers were washed with brine (50 mL) and dried over anydrous magnesium sulfate. The solvent was removed and the product dried in vacuo to yield a brown solid (204 mg).

This brown solid was purified by flash chromatography by dry loading onto the column. The solid was eluted first with 50% EtOAc/hexane, followed by 70% EtOAc/hexane and finally by 100% EtOAc. The polarity was then increased to 1% MeOH/DCM increasing to 2%, 5% and finally 10%. Four fractions were collected.

Fraction 1 (EtOAc fractions): 18 mg
Fraction 2 (1-2% MeOH/DCM): 36 mg
Fraction 3 (5% MeOH/DCM): 63 mg

1H-NMR:
NEED NMR
Low res. mass spec.
Want: 306. Found: 307 (M+H).

Fraction 4 (10% MeOH/DCM): 78 mg

Total mass recovery from column: 195/204 (96%)

Fraction 3 was columned again for the purposes of purification. Four fractions were collected from the same regions as last time.

Fraction 1: 12 mg
Fraction 2: 33 mg
Fraction 3:
Fraction 4: 2.7 mg
Attached Files
25th July 2012 @ 05:30
This experiment aims to use the reaction conditions described in the JRC 14 series of reactions to replace the chlorine atom with an amine.

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Reaction start time: 11:30 am, 25/07/2012
To JRC 24-1 (111 mg containing 85.259 mg 4-chlorothieno[3,2-d]pyrimidine (0.287 mmol, 1 equiv.)) was added 28 % ammonium hydroxide solution (5.0 mL, 14.82 M, 74 mmol, 62 equiv.). The resultant suspension was stirred at 120 °C in an Ace 12 mL sealed tube for 4 hr. The reaction vessel was allowed to cool to rt before the reaction mixture was extracted with methanol (20 mL). The solvents were removed and the product dried in vacuo to yield a mixture of yellow/black solid (123.5 mg), which was then used without further purification in JRC 26-1.

Risk Assessment: As for JRC 14-1
Attached Files
23rd July 2012 @ 03:03
The experiment JRC 24-1 could not have a conclusion accurately drawn from it. This experiment is a repeat of that experiment, albeit with more starting material.

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Experiment start time: 1 PM, 23/07/2012
Recrystallised JRC 20-2 (355 mg, 1.27 mmol, 1 equiv.) was dissolved in phosphoryl oxychloride (1.5 mL, 16 mmol, 12.6 equiv.) with stirring. The stirring solution was heated to reflux under nitrogen and stirred at this temperature for 4 hr, before being allowed to cool ro rt. Once the reaction mixture had cooled it was quenched with water and neutralised with 4M sodium hydroxide solution until at ~pH 7. The solution was then extracted with diethyl ether (50 mL). The organic layer was washed with water (3 x 40 mL) and brine (40 mL) before being dried over anhydrous magnesium sulfate. The solvent was removed and the product dried in vacuo to yield a yellow solid (225 mg). 1H-NMR indicates that two products were formed.

1H-NMR:
1.zip
JRC24-2.pdf
Attached Files
20th July 2012 @ 01:37
This experiment aims to carry out the nucleophilic aromatic substitution reaction using POCl3 to replace the hydroxy group on the pyrimidine ring. This experiment assumes that the iodine is in the 6 position. This experiment is based upon the procedure outlined in the JRC 13-x series of experiments.

Conclusion: 1H-NMR had chemical shifts consistent with a new product. Significant amounts of product lost on the side of the flask. Mass spec. did not shed any light. The conclusion is that another experiment - properly carried out - needs to be attempted.

Experiment start time: 3:30 pm, 19/07/2012
4-chloro-6-iodothieno[3,2-d]pyrimidine (111 mg, 0.39 mmol, 1 equiv.) was dissolved in phosphoryl oxychloride (1.5 mL, 16 mmol, 16 equiv.) with stirring. The stirring solution was heated to reflux under nitrogen and stirred at this temperature for 20 hr, before being allowed to cool to rt. Material with a gel like consistency was found on the outside of the flask. Perhaps some material seeped out of the reaction vessel? The reaction mixture was neutralised with 5M aqueous sodium hydroxide. The reaction mixture was then extracted with diethyl ether (20 mL) and washed with water (3 x 20 mL) and brine (20 mL) before being dried over anhydrous magnesium sulfate. The solvent was removed and the product dried in vacuo to yield a yellow solid (43 mg). NMR showed chemical shifts consistent with a different product. Mass spec. did not show any peaks consistent with the product or starting material. Given the loss of product on the outside of the flask, the low yield, and the odd mass spec., this experiment is relegated to a failed experiment. Another will be attempted.
19th July 2012 @ 00:37
This is the third experiment in the series. It attempts an upscale of the previous reactions in this series.

Conclusion:

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Reaction start time: 10:30 am, 19/07/2012
Thieno[3,2-d]pyrimidin-4-ol (1.522 g, 10.00 mmol, 1 equiv.) was dissolved in dried THF (75 mL) with heating and sonification to form a very pale yellow solution, which was then stirred at -78 °C for 10 min. n-Butyllithium solution (1.481 M, 13.52 mL, 20.02 mmol, 2.0 equiv.) was added dropwise with stirring. Solution turned a more intense yellow upon addition. This reaction was stirred at -78 °C until bubbling in the cooling bath ceased. At +1 hr the reaction was allowed to warm to -40 °C. The reaction mixture was stirred at this temperature for 1 hr, before being cooled to -78 °C. After stirring at this temperature for 10 min a solution of elemental iodine (5.084 g, 20.00 mmol, 2 equiv.) in THF (45 mL) was added dropwise. The first ~half of the iodine solution was decolourised with stirring upon addition to the reaction mixture. The second ~half did not exhibit this behaviour. The reaction mixture was allowed to warm to rt and was stirred at this temperature for 20 hr. At +20 hr the reaction mixture was diluted with water (40 mL) and chloroform (100 mL). The two layers were washed together with saturated aqueous sodium thiosulfate solution until the solution became and remained a pale yellow colour. The organic layer was washed with water (3 x 70 mL) and brine (70 mL) before being dried over anhydrous magnesium sulfate. The magnesium sulfate was removed with filtration and the solvent removed, and the product dried in vacuo to yield a yellow solid (925 mg). 1H-NMR indicates this to be a mixture of the desired product along with some starting material.

This yellow solid was recrystallised from hot ethanol/water/acetone (2:2:1) to yield pure product (833.1 mg, 2.996 mmol, 30%).

1H-NMR: (recrystallised product):
1.zip
20-3recryst.pdf


m.p.= sublimes? at 257.7, mp at 274.2-275-0

2D NMR data does not shed much light on what position the iodonation occured at: only that it occured once. An X-ray crystal structure might be necessary.
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