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9th July 2013 @ 23:40

Bromination of MJT 7-2, using same process as MJT 9-1 but with more (2.5) equivalents of n-BuLi to account for deprotonation on the amine hydrogen as well as deprotonation at the N-6 position to improve the yield compared to MJT 9-1. This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

***

Reaction proceeded to give a mixture of the desired product and one other product brominated at the other carbon of the thiene bond. It was discovered that column chromatography is able to separate these products.

The reaction was repeated in an attempt to synthesise just the desired product - see MJT 9-3.


Procedure

11AM 11-07-2013

MJT 7-2 (0.200 g, 1.21 mmol, 1.0 equiv.) was dissolved in THF (25 mL) under an atmosphere of argon and cooled to -78 °C. To the stirring solution was added n-BuLi (2.5 M in hexane, 1.2 mL, 3.0 mmol, 2.5 equiv.) and the stirring was continued for 30 minutes. Bromine (0.12 mL, 2.4 mmol, 2.0 equiv.) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 3.5 hours, it is now an orange solution. TLC shows some SM remains and two new product spots of which one is feint and one is sharp. The reaction mixture was quenched with a saturated sodium thiosulphate solution on ice (70 mL). From this the product was extracted with ethyl acetate (3 x 50 mL). The combined organic extract was washed with brine, dried with MgSO4 and concentrated to a brown sludge (0.200 g, 0.82 mmol, "68%"). NMR analysis of this crude product showed the desired product (major) was formed along with a byproduct (minor) and that some SM remained and that there is grease contaminant in this crude product.

In future the aqueous wash would be basified during extraction to ensure all SM and products are collected and don't remain in aqueous phase as a salt (see MJT 16-1 first vs second extraction NMR). This was completed on a small scale and analysis of the resulting organic layer revealed that the duplicate peaks were not caused by the presence of a salt; rather they were more likely caused by the two possible monobrominated products.

Flash column chromatography (50% ethyl acetate in hexane; 40-60 micron silica particles) was used to isolate a single spot fraction (0.060 g after concentration) which NMR showed  contained a mix of isomers of the monobrominated product. A further fraction containing a mixture of spots (0.030 g) was also isolated but NMR showed that it contained one of the monobrominated species along with a small amount of product dimer. Salt remained on the column and was washed off with 10% methanol in DCM to give 0.020 g of brown sludge which was discarded.

 

 

 

Hazard and Risk Assessment

HIRAC MJT 9-1.pdf

Data


TLC

MJT 9-2 post workup

H NMR

crude produt:

MJT 9-2 crude.pdf

single product spot from column:

MJT 9-2 pure from column.pdf

two spot mix from column:

MJT 9-2 column mix.pdf

after basic workup:

MJT 9-2 after basic workup.pdf

H NMR of SM, MJT 7-2

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9th July 2013 @ 08:07

See also: Synthesis of Boronic Acid Pinacol Ester - MNR103-1

White solid 230 mg, 0.77 mmol, 79% yield

Requires m.p.,  IR and HRMS

Procedure

AEW 68-1 (~0.98 mmol, 1 equiv.), potassium acetate (380 mg, 3.92 mmol, 4 equiv.) and bis(pinacolatodiborane) (370 mg, 1.47 mmol, 1.5 equiv.) were dissolved in anhydrous 1,4-dioxane (5 mL). Argon was bubbled through the suspension for ten minutes before [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40 mg, 0.05 mmol, 0.05 equiv.) was added and the suspension heated at reflux with stirring overnight. Stirrer switched off at some point overnight. Reaction mixture re-heated to reflux and stirred for 6 hours. Reaction mixture allowed to cool and then filtered through a pad of Celite and washed with EtOAc and MeOH to give a black mixture. 1H NMR indicates complete transformation to a compound consistent with the desired product.

Crude Mixture was purified by flash column chromatography over silica (EtOAc/Hexane, 20–80%) to give two fractions. Top spot = desired product, white solid 230 mg, 0.77 mmol, 79% yield. Lower spot brown oil.

Product is a known compound contained within two patents, data not found so need to fully characterise: US2009/12129 A1, 2009 and WO2005/108352 A1, 2005.

m.p. 1H NMR (300 MHz, CDCl3): δ 8.29 (1H, s), 8.00 (1H, app d, J 7.4), 7.98–7.92 (1H, m), 7.52 (1H, t, J 7.6), 4.70 (1H, q, J 5.2), 2.65 (3H, d, J 5.2), 1.35 (12H, s);  13C NMR (75 MHz, CDCl3) δ: 139.3, 138.8, 133.6, 130.2, 128.9, 84.9, 75.5, 29.8, 25.3;  IR νmax (neat) /cm-1 HRMS (ESI+) found xxx [M+H]+, xxxx requires xxx.

 

TLC

Product could not be visualised in the UV. Anisaldehyde stain revealed a green and a blue spot.

AEW 69-1 col prep, EtOAc, vanillin.JPG
AEW 69-1 col prep, EtOAc:Hex 50:50 vanillin.jpg
 

Data:

Crude NMR:

crude 1H.pdf

Pure Product:

AEW 69-1 proton.pdf
AEW 69-1 carbon.pdf

Raw Data:

AEW 69-1 A.zip

 

Hazard and Risk Assessment:

See: Synthesis of Boronic Acid Pinacol Ester - MNR103-1

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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

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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
8th July 2013 @ 09:32

Repeat of See Synthesis of 4-(4-Methylpiperazin-1-yl)thieno[3,2-d]pyrimidine (AEW 55-1)

Procedure:

To MNR 99-3 (500 mg, 2.93 mmol, 1 equiv) in THF (3.5 mL) (ethanol (2.5 mL added to get the starting material into solution) was added 1-methylpiperazine (0.49 mL, 4.40 mmol, 1.5 equiv) at 0 ˚C and the reaction mixture was stirred overnight at room temperature. Volatiles were removed in vacuo and then the white suspension was dissolved in EtOAc, washed with a saturated aqueous solution of sodium hydrogen carbonate, brine, dried (MgSO4) and evaporated to give a yellow oil which solidified at the high vac to give a yellow solid 

Data:

AEW 55-2, EtOAc.jpg

Hazard and Risk Assessment:

See Synthesis of 4-(4-Methylpiperazin-1-yl)thieno[3,2-d]pyrimidine (AEW 55-1)

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