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16th May 2013 @ 04:23

1.35 g, 4.11 mmol, 99% crude yield

Scheme AEW 53-1

Repeat of Nucleophilic Displacement of 4-chlorothienopyrimidine with Piperazine MNR107-1 to give MNR113-1 but using 1.5 equiv of amine rather than 2.

Procedure:

A mixture of MNR 99-4 (710 mg, 4.16 mmol, 1 equiv.) and MNR 107-1 (1.21 g, 6.24 mmol, 1.5 equiv) in EtOH (20 mL) was heated to reflux for 4 hours. Reaction complete by TLC. 

Reaction mixture was allowed to cool to room temperature and the resulting heterogeneous mixture was evaporated and then partitioned between EtOAc and a saturated solution of sodium hydrogen carbonate and then extracted with EtOAc, combined organic layers washed with brine, dried (MgSO4), filtered and evaporated to yield an off white solid (1.35 g, 4.11 mmol, 99% yield).

1H NMR (300 MHz, CDCl3) δ: 8.58 (1H, s), 7.71 (1H, d, J 5.5), 7.42 (1H, d, J 5.5), 7.37–7.23 (2H, m), 7.09–6.97 (2H, m), 4.04 (2H, t, J 4.9), 3.53 (2H, s), 2.58 (2H, t, J 4.9).

Data:

AEW 53-1 40% EtOAc in Hexane.png

AEW 53-1 crude 1H 200MHz.pdf

Hazard and Risk Assessment:

See: Nucleophilic Displacement of 4-chlorothienopyrimidine with Piperazine MNR107-1 to give MNR113-1

InChi

InChI=1S/C6H3ClN2S/c7-6-5-4(1-2-10-5)8-3-9-6/h1-3H

and

InChI=1S/C11H15FN2/c12-11-3-1-10(2-4-11)9-14-7-5-13-6-8-14/h1-4,13H,5-9H2

to

InChI=1S/C17H17FN4S/c18-14-3-1-13(2-4-14)11-21-6-8-22(9-7-21)17-16-15(5-10-23-16)19-12-20-17/h1-5,10,12H,6-9,11H2

Attached Files
16th May 2013 @ 01:18

231 mg, 1.39 mmol, 42%

needs HRMS, m.p. and IR


Scheme AEW 52-1 

 

Procedure:

MNR 89-2 (500 mg, 3.29 mmol, 1 equiv) was dissolved in DMF (3.5 mL) and K2CO3 (500 mg, 3.61 mmol, 1.1 equiv.) was added. The reaction mixture was stirred at room temperature for 10 minutes and then methyl iodide (205 mL, 3.29 mmol, 1 equiv.) was added and the reaction mixture stirred at room temperature for 4 hours. Still appears to be some SM on TLC so reaction mixture was heated to 50 ˚C for 1 h. No change to TLC so reaction was stopped.

Reaction mixture taken up in EtOAc and washed with water (x3), brine, dried (MgSO4), filtered and evaporated to give a yellow solid. Low mass recovery so the aqueous layers were re-extracted.

Crude 1H NMR indicates desired product has been formed.

Crude yellow solid was purified by flash column chromatography over silica (60% EtOAc in hexane to 100% EtOAc) to give the desired product as a white powder (231 mg, 1.39 mmol, 42%).

Comment: may have lost some product to DMF as reaction seemed pretty clean.

1H NMR (300 MHz, CDCl3) δ: 8.10 (1H, s), 7.76 (1H, d, 5.3), 7.31 (1H, d, 5.3), 3.62 (3H, s);  13C NMR (75 MHz, CDCl3) δ: 158.2, 157.5, 148.4, 134.7, 125.5, 124.0, 34.3;

Known compound no NMR data, instead elemental analysis, m.p. (105 ˚C) and IR 3070, 3085, 1110.

Data:

AEW 52-1 1H Crude 200.pdf

AEW 52-1 40% EtOAc in DCM.png

AEW 52-1 proton.pdf
AEW 52-1 carbon.pdf
aew 52-1.zip

Hazard and Risk Assessment:

HIRAC AEW 52-1.pdf

InChi

InChI=1S/C6H4N2OS/c9-6-5-4(1-2-10-5)7-3-8-6/h1-3H,(H,7,8,9)

to

InChI=1S/C7H6N2OS/c1-10-7-6-5(2-3-11-6)8-4-9-7/h2-4H,1H3

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Attached Files
9th May 2013 @ 09:43
Mnr: mnr121-130

Starting material from - Nucleophilic Displacement of MNR99 with ethyl 1-piperazinecarboxylate to give MNR126-1

As for - Bromination of MNR100-2 to give MNR101-2

Hazard Assessment

 

Procedure

MNR126-1 (1.42 g, 4.86 mmol) was dissolved in THF (100 mL) and cooled to -78 °C.  To the stirring solution was added n-BuLi (2.5 M in hexanes, 2.91 mmol, 7.29 mmol) and the stirring was continued for 30 minutes.  Bromine (0.5 mL, 9.71 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 2 hours.  Sodium thiosulfate solution (100 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL).  The organic layers were commbined, dried and filteres then concentrated in vacuo to yield the crude as pale yellow solid.

Attached Files
9th May 2013 @ 09:38
Mnr: mnr121-130

Starting material from - Nucleophilic Displacement of MNR99 with 1-Methylpiperazine to give MNR125-1

As for - Bromination of MNR100-2 to give MNR101-2

Hazard Assessment

 

Procedure

MNR125-1 (1.18 g, 5.04 mmol) was dissolved in THF (100 mL) and cooled to -78 °C.  To the stirring solution was added n-BuLi (2.5 M in hexanes, 3.02 mL, 7.55 mmol) and the stirring was continued for 30 minutes.  Bromine (0.52 mL, 10.07 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 2 hours.  Sodium thiosulfate solution (100 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL).  The organic layers were commbined, dried and filteres then concentrated in vacuo to yield the crude as yellow solid (0.666 g, (100% = 1.57 g)

Poor crude recovery

Attached Files
7th May 2013 @ 10:16

Repeat of AT-26-1.

To a solution of isopropanol (4 mL) and potassium carbonate (0.24 mL, 1 M, 0.24 mmol, 2.0 equiv.) degassed with argon was added AT-5 (0.030 g 0.12 mmol, 1.0 equiv.), 4-sulfamoylphenyl boronic acid pinacol ester (0.037 g, 0.13 mmol, 1.1 equiv.) and PdCl2dppf (0.0088 g, 0.012 mmol, 0.1 equiv.) and the reaction mixture heated to 90 C in a microwave reactor (200 W) for 30 minutes. 

The reaction mixture was diluted with methanol (50 mL), filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (95:4.5:0.5 dichloromethane:methanol:ammonia).

Attached Files