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20th August 2012 @ 02:13
Synthesised pure MD 5-1 (0.15 g, 0.5 mmol, 47% yield) which was found to be pure by H1NMR and elemental analysis and has been sent for biological testing.

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Synthesis of OSDD desired synthetic compound, 1-amino-2-methyl-1-oxopropan-2-yl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate.

3040.png

Reaction start time: 1:32 PM EST 20/8/12

MD 2-1 (0.24 g, 1 mmol, 1 equiv) and 2-Bromo-2-methylpropionamide (0.32 g, 2 mmol, equiv) were dissolved in a acetonitrile and water mixture (4.2 mL, 95:5). Silver Oxide (0.46 g, 2 mmol, 2 equiv) was added and the reaction was left at room temperature covered in aluminium foil.

At 4:30 PM TLC showed starting product had been consumed and a second TLC showed that starting product had not just turned into a salt with the silver. The reaction was filtered through cellite with methanol and left in the fridge overnight.

The mixture was then concentrated to give the crude product (0.34 g) which included the expected product MD 5-1 by H1NMR . The crude product was then columned (50:50 EtOAc:Hexane)to give the final pure product (0.15 g, 0.5 mmol, 47% yield) which was found to be pure by H1NMR and elemental analysis.

See also:
A direct functionalization of tertiary alkyl bromides with O-, N-, and C-nucleophiles
Hyrdolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (MD 2-1)

Risk and Hazard assessment:
MD 5-1 RA
Linked Posts
Attached Files
13th August 2012 @ 07:07
Synthesis of 1-ethoxy-2-methyl-1-oxopropan-2-yl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate using silver oxide prepared using silver nitrate and sodium hydroxide.

2956.png

Reaction start time: 4:43 PM EST 13/8/12


See also:

Risk and Hazard assessment:
MD 3-3 RA
Linked Posts
Attached Files
13th August 2012 @ 06:20
Reaction of Silver oxide with 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid to identify if any unexpected side reactions are taking place.

2948.png

Reaction start time: 3:20 PM EST 13/8/12
MD 2-1 (0.24 g, 1 mmol, 1 equiv) was dissolved in a acetonitrile and water mixture (4.2 mL, 95:5). Silver Oxide (0.46 g, 2 mmol, 2 equiv) was added and the solution was heated to 90°C. The reaction was stopped at 2 PM the next day. Silver was found to have deposited on the flask. The reaction mixture was filtered through cellite and washed with EtOAc (40 mL) then HCl (2 M, 80 mL) and finally EtOAc (40 mL) again. The three washes were investigated with HNMR.

It was found in the first EtOAc wash that acetamide was being formed. It was found in the literature that acetonitrile with a silver catalyst would form acetamide but the reaction was said to require high temperatures which was not the case in this experiment. I guessed it was the light decomposing the silver oxide to silver which was then somehow reacting with the solvent to form the acetamide. MD 5-1 and MD 3-4 were then done exactly the same as previous attempts but this time with the reaction flask covered in foil to keep out light.

See also:
Synthesis of 1-ethoxy-2-methyl-1-oxopropan-2-yl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (MD 3-3)
Synthesis of 1-ethoxy-2-methyl-1-oxopropan-2-yl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (MD 3-4)
Synthesis of 1-amino-2-methyl-1-oxopropan-2-yl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate MD (5-1)

Risk and Hazard assessment:
Same as MD 3-2
Attached Files
9th August 2012 @ 06:26
Desired product was not obtained. Acidification of the silver residue freed MD 2-1 starting material (0.11 g, 0.45 mmol, 45% yield), corresponding to the hypothesis that the carboxylic acid was making a salt with silver.

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Synthesis of 1-ethoxy-2-methyl-1-oxopropan-2-yl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate from MD 2-1 for conversion into TDMC-123812 analogues.

2942.gif

Reaction start time: 4:40 PM EST 9/8/12
MD 2-1 (0.24g, 1.0 mmol, 1 equiv) was dissolved in an acetonitrile/water mixture (95:5, 5 mL). Methyl 2-bromo-2-methylpropionate (0.26 mL, 2.0 mmol, 2 equiv) was then added to the mixture followed by Ag2O (0.45 g, 1.9 mmol, 2 equiv). The reaction was heated to 90°C and left over night.

The reaction was stopped 16 hours later and allowed to cool to room temperature, then filtered over cellite with ethanol. The filtrate was concentrated under reduced pressure to give what seemed like black silver oxide residue (0.19 g) H1NMR of the residue showed the presence of tertiary alkyl bromide and acetamide. To make sure it was acetamide being formed, pure acetamide was mixed with the filtrate and NMRed again to confirm it was acetamide in the ethanol wash. A methanol wash had nothing in it.

To see if MD 2-1 starting material was making a salt with the silver, the cellite residue was acidified with HCl (30 mL, 2 M). This caused the black residue to change to an orange colour. The residue was then washed with methanol and concentrated under reduced pressure giving MD 2-1 starting material (0.11 g, 0.45 mmol, 45% yield) by H1NMR.

See also:
Synthesis of 1-ethoxy-2-methyl-1-oxopropan-2-yl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (MD 3-1)

Risk and Hazard assessment:
MD 3-1 RA.pdf

Same as MD 3-1 except elevated temperature and increased ratio of alkyl bromide relative to acid starting material.
Attached Files
8th August 2012 @ 03:32
Desired product was not obtained, starting material was not retained, experiment repeated as (MD 3-2).

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Synthesis of 1-ethoxy-2-methyl-1-oxopropan-2-yl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate from MD 2-1 for conversion into TDMC-123812 analogues.

2942.gif

Reaction start time: 2:40 PM EST 8/8/12

MD 2-1 (0.24g, 1 mmol, 1 equiv) was dissolved in an acetonitrile/water mixture (95:5, 5 mL). Methyl 2-bromo-2-methylpropionate (65 μL, 0.5 mmol, 0.5 equiv) was then added to the mixture followed by Ag2O (0.45 g, 2 mmol, 2 equiv). TLC at 4:15 PM showed that mostly starting material was present. The reaction was left stirring overnight.

After 19 hours the reaction was filtered through cellite with ethanol. The filtrate was then concentrated under reduced pressure gave 4 mg (2% yield) of what seemed to be silver contamination. The residue on the cellite was washed with methanol, yielding nothing.

Tertiary alkyl bromide was H1NMRed, it was found to not have degraded. Starting material was not retained, hypothesised the causes as formation of a salt between the carboxylic acid starting material and silver getting stuck on the cellite. Experiment was repeated as (MD 3-2).

TLC (25% ethyl acetate/hexane in vanilin):
Vanilin TLC at 4:15 PM


See also:
A direct functionalization of tertiary alkyl bromides with O-, N-, and C-nucleophiles Hyrdolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (MD 2-1)

Risk and Hazard assessment:
MD 3-1 RA
Linked Posts
Attached Files