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23rd March 2012 @ 00:35
JRC 8-1 lead to a crude yield of only 15% (m/m), and JRC 8-2 gave a crude yield of 28% (m/m). The column purification step of JRC 8-1 lead did not give good separation, and the column purification step of JRC 8-2, while yet to be analysed by 1H-NMR, does not look promising. This synthesis aims to synthesise the desired compound with greater yield than JRC 8-1 and JRC 8-2.

This procedure is adapted from Dhanoa (2011, p. 4) and is summarised below.

2095.png

Part I

Sub-conclusion: Reaction did not lead to desired product, but instead to methyl 3-formamidothiophene-2-carboxylate (pictured below) in 60% yield.

Reaction start time: 10:30 am, 23/03/2012
Methyl-3-aminothiophene-2-carboxylate (0.300 g, 2.110 mmol, 1 equiv.) and ammonium acetate (0.226 g, 2.932 mmol, 1.4 equiv.) were dissolved in formic acid (1 mL, 26 mmol, 12 equiv.) and left stirring at a gentle reflux for 7 hr. Following this the reaction was cooled to rt and a pale brown granular solid appeared in the reaction vessel (no appreciable quantity of liquid visible in the vessel after it was cooled to rt), which was tipped onto ice, filtered and washed with water to yield a very light brown powder (0.575 g). TLC at this point (+6.5 hr) shows a mixture of the ester starting material, and new product.

TLC at +6.5 hr in 10% ethyl acetate/hexane, visualised with UV/vanillin
JRC9-1(23rd 5pm).png


This powder was recrystallised from 50% acetone/water (approx. 4 mL), which was not a good solvent system since both a brown impurity (suspected to be starting material) and the fluffy white crystals (suspected to be product) crashed out at the same time. Product was recrystallised from hot ethanol/water, where a single drop of water was added for each approx. 10 drops of ethanol. This successfully dissolved the suspected product and left the brown material undissolved. The hot liquid was pipetted out and the ethanol/water removed under reduced pressure to yield fluffy, white crystals (237 mg, 1.27 mmol, 60%).

1H-NMR did not show the desired product and, instead, showed the following as a product:

JRC9-1halfwaystructure.png

methyl 3-formamidothiophene-2-carboxylate

1H-NMR:
1.zip
JRC9-1.pdf


The solvent (formic acid) had evaporated from the reaction earlier, so it was reasoned that perhaps more formic acid and ammonium acetate would drive the reaction to completion.

Part II:

Sub-conclusion: The desired product was, again, not synthesised and the half-cyclised heterocycle, methyl 3-formamidothiophene-2-carboxylate, was synthesised in 76% yield.

The remains of the previous reaction (236 mg, 1.27 mmol, 1 equiv.) and ammonium acetate (300 mg, 3.89 mmol, 3.8 equiv.) were dissolved in formic acid (1.5 mL, 39 mmol, 39 equiv.) and stirred at reflux for 4 hr. The reaction mixture was cooled (solvent did not evaporate and remained a liquid) and as this liquid was poured over ice a light brown solid crashed out of solution. This solid was filtered and washed with ice water. The resultant brown powder was dried and evaluated by 1H-NMR, indicating the presence of starting material (179 mg, 0.96 mmol, 76%).

1H-NMR:
2.zip
JRC9-1(Excess).pdf


In a last ditch effort to drive this reaction to the intended product, it was reasoned that harsher conditions might be a possible method of driving this reaction to formation of the intended product.

Part III

Reaction start time: 4pm, 13/04/2012
The remains of the previous reaction (179 mg, 0.96 mmol, 1 equiv.) and ammonium formate (363 mg, 5.75 mmol, 6 equiv.) were dissolved in formic acid (1.5 mL, 39 mmol, 39 equiv.) and heated to 140 °C for 66 hr. The reaction mixture was cooled and water (5 mL) was added before this solution was poured onto ice water. Too much of the product dissolved in the water (probably too much ice water) so the water was removed under reduced pressure to yield X (304 mg, x mmol, x %)

Risk Assessment: Paper copy signed
JRC 9-1 RA.pdf


Linked posts:
Synthesis of Thieno[3,2-d]pyrimidine-4(3H)-one (JRC 8-1)
Re-synthesis of Thieno[3,2-d]pyrimidine-4(3H)-one (JRC 8-2)

References:

Dhanoa, D.J. (Del Mar, CA, US.). Deuterium-enriched pyrimidine compounds and derivatives and pharmaceutical use. United States Patent Application Publication 20110028496 A1, 2011; SciFinder Scholar AN 2011:149048 (accessed 19/03/2012).
Linked Posts
Attached Files
19th March 2012 @ 00:07
This experiment is a repeat of JRC 8-1, with longer heating periods, to obtain a higher yield than was given in JRC 8-1. As with JRC 8-1, this experiment is based on one described by Son et al. (2011).

1945.png

Reaction start time: 10am 14/03/2012
Methyl-3-aminothiophene-2-carboxyate (0.301 g, 1.91 mmol, 1 equiv.) was dissolved in formamide (1 mL, 25 mmol, ~25 equiv.) and stirred at 180°C for eight hr, followed by stirring at rt for 18 hr. The reaction mixture was extracted with ethyl acetate (2 x 20 mL), before being washed with water (2 x 20 mL) and brine (20 mL). Solvent was removed in vacuo to yield 0.086 g product. This crude product was purified by column chromatography using 10% EtOAc/hexane as an eluent. Results as follows:

DCM (used to dissolve the crude product) went through the column. Yield = 0.010 g
Fraction 1. Yield = 0.043 g
Fraction 2. Yield = 0.001 g

The remainder of the fractions were combined and the solvent reduced under pressure to yield 0.05 g of material

Risk Assessment:
As for JRC 8-1

References:
Son, J.B.; Jung, S. H.; Choi, W.I.; Jung, Y.H.; Choi, J.Y.; Song, J.Y.; Lee, K.H.; Lee, J.C.; Kim, E.Y.; Ahn, Y.G.; Kim, M.S.; Choi, HG.; Sim, T.B.; Ham, Y.J.; Park, D.; Kim, H.; Kim, D. (Hanmi Holdings Co., Ltd., S. Korea; Korea Institute of Science and Technology; Catholic University Industry Academic Cooperation Foundation). Preparation of thienopyrimidine derivatives for use as protein kinase inhibitors. World Intellectual Property Organisation 2011093684 A2, 2011; SciFinder Scholar AN 2011:971406 (accessed 3/2/2012).
Linked Posts
15th March 2012 @ 05:09
This experiment, identical to JRC 7-1, is being repeated in dry conditions. The reaction is based upon the work of Deshmukh et al. (2006), and is summarised below.

2101.png

Reaction start time: ~ 2pm 15/03/2012
1M Titanium tetrachloride in toluene (1.00 mL, 0.99 mmol, 1 equiv.) was cooled in an ice/sodium chloride bath and JRC 4-2 (0.20 mL, 0.99 mmol, 1 equiv.) in dried DCM (5 mL) was added dropwise. This mixture was left for 20 min before triethylamine (0.30 mL, 2.17 mmol, 2.2 equiv.) was added dropwise. As for JRC 7-1, when the first drop was added the mixture immediately turned a dark violet colour, and white gas was evolved. Further evolution of thick white gas occured as further triethylamine was added. When 1 mL (0.71 mmol) of triethylamine was left to be added no further fuming took place (perhaps all of the protons had been removed at this point?). Reaction mixture caked high up on the walls indicates a fairly exothermic reaction even when conducted carefully at -10°C.

After 2 hr the mixture was poured into a 10% aqueous sodium chloride mixture (10 mL) and made basic with triethylamine (~pH 10). This mixture was left overnight. TLC at this point (+19.5 hr) showed several, probably 2, new products formed in the reaction (with corresponds to literature indications of an aromatic product, and 2 stereoisomers of a non-aromatic product formed.).

TLC +19.5 hr, 10% ethyl acetate/hexane, visualised with UV/potassium permanganate
JRC 7-2 930am 16th.JPG


The precipitate was removed via filtration and the solid washed with DCM (20 mL). This mixture was then extracted with further DCM (20 mL) and the organic layer was washed with water (3 x 10 mL) and brine (3 x 10 mL). In an attempt to overcome the signifiant levels of emulsion present, an aqueous solution of 0.18 M potassium sodium tartrate (6 x 5 mL) was added with each water and brine extraction, though it made seemingly little impression on the levels of emulsion. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield 0.163 g of crude product (which, as a side note, doesn't seem to smell half as bad as the starting material).

1H-NMR indicated that the desired product was present in mainly keto form, though some enol form was observed.

7-2.zip
JRC7-2crude.pdf


Crude product was purified over a flash silica column (5% ethyl acetate/hexane).

Fraction 1 (0.004 g)
Fraction 2 (0 g)
Ethyl acetate wash (0.012 g)
Methanol wash (0.010 g)

The remaining fractions were combined and solvent removed to yield 0.015 g material.

Risk Assessment: As for JRC 7-1

Linked Posts:
Synthesis of 2-Ethoxycarbonylthiolan-3-one using titanium (IV) chloride (JRC 7-1)

References:
M. N. Deshmukh, K. K. Gangakhedkar, U. S. Kumar, Synthetic Communications 1996, 26, 1657-1661.
Attached Files
11th March 2012 @ 07:32
This synthesis is based off one put forth by Son et al. (p. 17), and is summarised below:

1945.png

Conclusion: methyl 3-formamidothiophene-2-carboxylate was recovered along with starting material with a combined mass of 0.057 g.

Reaction start time: 11am 07/03/2012
Ethyl-3-aminothiophene-2-carboxylate (0.376 g, 2.39 mmol, 1 equiv.) was dissolved in formamide (1 mL, 25.15 mmol, ~10 equiv.) and heated to 180 °C. TLC at +6.5 hr showed some new products being formed.

TLC (10% ethyl acetate/hexane): + 6.5 hr, visualised with UV/vanillin
JRC8-1(530pm).JPG


Reaction was cooled to rt and left for 36 hr. The mixture was filtered, with no solid product recovered. The mixture was extracted once with ethyl acetate (10mL) and the organic layer was washed twice with water (10mL) and twice with brine (10mL) before being dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield 0.057 g red solid, and 1H-NMR was taken, revealing a mixture of starting material and a product consistent with the following structure:

2163.png
methyl 3-formamidothiophene-2-carboxylate

1H-NMR:

This red soild was purified by column chromatography using 60% ethyl acetate/hexane as the eluent. Three fractions were collected:

Fraction 1: 0.037 g 1H-NMR showed this to be mostly starting material
1H-NMR:
1.zip
JRC8-1f1.pdf


Fraction 2: 0.004 g 1H-NMR revealed this to be methyl 3-formamidothiophene-2-carboxylate.

1H-NMR:
2.zip
JRC8-1f2.pdf


Fraction 3: 0.056 g 1H-NMR revealed this to be a mixture of solvents and a very small amount of methyl 3-formamidothiophene-2-carboxylate.

1H-NMR:
3.zip
JRC8-1f3.pdf


An accurate yield was not obtained due to a column that did not give good separation, and due to the low crude yield.

Risk Assessment: (paper copy signed)
JRC8-1RA.pdf


References:
Son, J.B.; Jung, S. H.; Choi, W.I.; Jung, Y.H.; Choi, J.Y.; Song, J.Y.; Lee, K.H.; Lee, J.C.; Kim, E.Y.; Ahn, Y.G.; Kim, M.S.; Choi, HG.; Sim, T.B.; Ham, Y.J.; Park, D.; Kim, H.; Kim, D. (Hanmi Holdings Co., Ltd., S. Korea; Korea Institute of Science and Technology; Catholic University Industry Academic Cooperation Foundation). Preparation of thienopyrimidine derivatives for use as protein kinase inhibitors. World Intellectual Property Organisation 2011093684 A2, 2011; SciFinder Scholar AN 2011:971406 (accessed 3/2/2012).
Linked Posts
Attached Files
5th March 2012 @ 06:54
This procedure is intended aas an improvement upon JRC 5-1 and JRC 5-2, using titanium (IV) chloride and triethylamine in place of sodium ethoxide (or methoxide). This procedure is adpapted from that which is described by Deshmukh et al. (2006), and it is summarised below.

2101.png

Reaction start time: 5pm (5/3/2012)
A solution of 1M TiCl4 in toluene (1.148 mL, 1.148 mmol, 0.85 equiv.) was stirred under a nitrogenous atmosphere and to this, JRC 4-2 (0.344 mL, 1.36 mmol, 1 equiv.) in dried DCM (5 mL) was added dropwise. After 15 stirring at this temperature, triethylamine (0.188 mL, 2.992 mmol, 2.2 equiv.) was added dropwise. Solution became a dark violet colour with intense fuming upon addition. Reaction was then left for 1.5 hr. TLC at this point showed very little starting material remaining.

TLC (+1.5 hr): 10% ethyl acetate/hexane (visualised with UV/vanillin):
JRC 7-1.JPG


Reaction was quenched after 2 hr with 10% sodium chloride in water (15 mL). The violet organic layer separated easily from the aqueous layer. The entire mixture went orange and afforded an orange/cream precipitate upon basification (~pH 9-10) with triethylamine.

The following morning the precipitates were filtered off and washed with DCM (30 mL). The filtrate was washed with additional DCM (30mL), which produced white fumes upon addition to the reaction mixture. The combined organic layers were dried with MgSO4 before the solvent was removed in vacuo to yield a brown oil (0.337g). 1H-NMR revealed starting material along with triethylamine.

Risk Assessment (paper copy signed):
JRC 7-1.pdf


Linked Posts:
Upscaled synthesis of ethyl β-(carbethoxymethylthio)propionate (JRC 4-2)
Synthesis of 2-Ethoxycarbonylthiolan-3-one (JRC 5-1)
Synthesis of 2-Ethoxycarbonylthiolan-3-one (JRC 5-2)

References:
Deshmukh, M. N.; Gangakhedkar, K. K.; Kumar, U. S., Regioselective Titanium Tetrachloride Mediated Five Membered Hetero-Cyclisations. Synthetic Communications 1996, 26 (9), 1657-1661.
Linked Posts
Attached Files