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24th May 2012 @ 03:52
This experiment aims to synthesise the aforementioned product using the method devised in JR 15-2. The method is based loosely upon one described by Mitchell et al. (2005, pp.67-68), and it described below.

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Reaction start time: 12:45 pm, 24/05/2012
To methyl-3-aminothiophene-2-carboxylate (2.531 g, 16.10 mmol, 1 equiv.) was added ammonium formate (1.102 g, 17.47 mmol, 1.08 equiv.) and formic acid (0.64 mL, 16.96 mmol, 1.05 equiv.). The slurry was dissolved in formamide (3.4 mL, 85 mmol, 5.2 equiv.) and heated to 140 °C. The reaction was cooled to rt and then filtered and washed with water, before being dried in vacuo to yield 2.027 g (13.32 mmol, 83%) of brown powder.

This brown powder was recrystallised from boiling 50% ethanol/water, filtered and dried in vacuo to yield the desired product as fluffy brown crystals (1.297 g, 8.523 mmol, 53%).

m.p. 218.9 &degC - 220.3 &degC

Risk Assessment: As for JRC 15-2

References:
Mitchell, I.S.; Spencer, K.L.; Stengel, P.; Han, Y.; Kallan, N.C.; Munson, M.; Vigers, G.P.A.; Blake, J.; Piscopio, A.; Josey, J.; Miller, S.; Xiao, D.; Xu, R.; Rao, C.; Wang, B.; Bernacki, A.L (Array Biopharma, CO, US.). AKT Protein Kinase Inhibitors for use in treatment of hyperproliferative diseases. World Intellectual Property Organisation 2005051304 A2, 2005; SciFinder Scholar AN 2005:490266 (accessed 24/04/2012).
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23rd May 2012 @ 00:37
JRC 14-3 lead to the successful synthesis of thieno[3,2-d]pyrimidin-4-amine. This procedure is a repeat of that experiment, and it is based on a procedure described by Baykal et al. (2006, p. 7523). It is summarised below.

Conclusion: Desired product synthesised. Accurate yield not obtained (133%).

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Reaction start time: 9:15 am, 23/05/2012
4-chlorothieno[3,2-d]pyrimidine (283 mg, 1.66 mmol, 1 equiv.) and 28 % ammonium hydroxide solution (5.0 mL, 14.82 M, 74 mmol, 45 equiv.) were mixed in a 12 mL Ace sealed tube and heated at 120 °C for 5 hr. The reaction pressure vessel was then cooled to rt before the reaction mixture was extracted with methanol (12 mL). The solvent was removed in vacuo to yield the desired compound (336 mg, 2.22 mmol) as shown by 1H-NMR.

1H-NMR:
1.zip
JRC14-3.pdf

(note: though the name suggests JRC14-3, this is the NMR for JRC14-4)

Risk Assessment: As for JRC 14-2

References:
A. T. Baykal, L. Kakalis, F. Jordan, Biochemistry 2006, 45, 7522-7528.
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22nd May 2012 @ 02:28
JRC 13-2 lead to the successful synthesis of the 4-chlorothieno[3,2-d]pyrimidine in good yield. This experiment is an upscale of the previous one, and is adapted from a procedure described by Benish, Lawless & Budde (2004, p. 19).

Conclusion: Desired product synthesised in 67% yield.

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Reaction start time 11:00 am 22/05/2012
To thieno[3,2-d]pyrimidine-4(3H)-one (1.093 g, 7.182 mmol, 1 equiv.) was added phosphoryl chloride (5.0 mL, 53.6 mmol, 7.5 equiv.) dropwise under a nitrogenous atmosphere. This mixture was stirred at heated to reflux for 2 hr. The mixture was cooled and quenched/neutralised with ice (20 mL) and saturated aqueous sodium bicarbonate (300 mL). The organic products were extracted with diethyl ether (50 mL) and washed with water (2 x 40 mL) and brine (2 x 40 mL). The organic layer was dried with anhydrous magnesium sulfate and the solvent removed in vacuo to yield a yellow powder, which in turn was dried in vacuo to yield the desired product (569 mg, 3.33 mmol, 46%) as shown by 1H-NMR.

1H-NMR:
2.zip
JRC13-3.pdf


Some product remained in the seperation flask. The combined aqueous layers were extracted with DCM (40 mL). The organic layer was washed with water (2 x 20 mL) and brine (2 x 20 mL) before the organics were dried with anhydrous magnesium sulfate. The solvent was removed in vacuo to yield a light orange powder (255 mg, 1.49 mmol, 21%).

Total yield is 824 mg desired product (4.82 mmol, 67%).

mp: 124.4-125.5

Risk Assessment: As for JRC 13-2

References:
Benish, M.A.; Lawless, M.; Budde, R.J. (Fulbright & Jaworski, TX, US.). Preparation pf thienopyrimidine based inhibitors of the SRC family. United States Patent Application Publication 20040077663 A1, 2004; SciFinder Scholar AN 2007:1197581 (accessed 24/04/2012).
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18th May 2012 @ 00:36
JRC 14-2 was successful in synthesising thieno[3,2-d]pyrimidin-4-amine in a near quantitative yield. This procedure is a repeat of that experiment, and it is based on a procedure described by Baykal et al. (2006, p. 7523). It is summarised below.

Conclusion: Desired product formed, though an accurate yield was not obtained (124%).

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Reaction start time: 9:30 am, 18/05/2012
4-chlorothieno[3,2-d]pyrimidine (205 mg, 1.20 mmol, 1 equiv.) and 28 % ammonium hydroxide solution (5.0 mL, 14.82 M, 74 mmol, 62 equiv.) were mixed in a 12 mL Ace sealed tube and heated to 120 °C for 4 hr. The reaction was cooled and extracted with methanol (8 mL). Solvent was removed in vacuo to yield a yellow powder, which in turn was dried in vacuo to yield a yellow powder (226 mg, 1.49 mmol, 124%).

Risk Assessment: As for JRC 14-2

References:
A. T. Baykal, L. Kakalis, F. Jordan, Biochemistry 2006, 45, 7522-7528.
16th May 2012 @ 04:30
JRC 14-1 did not lead to formation of the desired product. This experiment is a repeat, albeit at higher temperatures and pressures. The procedure is adapted from one described by Baykal et al. (2006, p. 7523) and is described below.

2350.png


Conclusion: The desired product was synthesised in 94% yield.

Reaction start time: 1:30 pm, 16/05/2012
4-chlorothieno[3,2-d]pyrimidine (274 mg, 1.61 mmol, 1 equiv.) and 28 % ammonium hydroxide solution (5.0 mL, 14.82 M, 74 mmol, 74 equiv.) were mixed in a 12 mL Ace sealed tube and heated to 120 °C for 4 hr, at which point the reaction was cooled and left to sit at room temperature for 15 hr. At this point methanol (5 mL) was added to the reaction vessel with shaking, and the solid dissolved instantly. All solvent was removed in vacuo to yield a yellow powder (247 mg, 1.59 mmol, 94%), which was shown by 1H-NMR to be the desired product.

TLC indicated disappearance of starting material.

TLC (10% methanol/DCM), visualised with UV/vanillin
TLC 14-2 930am.JPG


1H-NMR:
1.zip
JRC14-2.pdf


Risk Assessment: (paper copy signed)
JRC15-2.pdf


References:
A. T. Baykal, L. Kakalis, F. Jordan, Biochemistry 2006, 45, 7522-7528.
Attached Files