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9th May 2013 @ 10:43
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 @ 10:38
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 @ 02:26
Mnr: MNR101-110

Synthesis of 1-(4-fluorobenzyl)piperazine as a coupling partner to make TCMDC-132385

Following procedure from DOI: 10.1021/jm900722z - General Procedure for 1-Benzylpiperazines 35-36  

 

As for Synthesis of 1-(4-fluorobenzyl)piperazine - MNR107-1

Hazard Assessment

 

HIRAC MNR107.pdf

Procedure

Anhydrous piperazine (4.32 g 50.2 mmol) was added to THF (17 mL) and the mixture was heated to reflux until the piperazine was fully dissolved. To the solution was added 4-fluorobenzyl chloride (1.0 mL, 8.37 mmol) dropwise.  A white precipitate was formed immediately.  The reaction mixture was refluxed for 1 hour and then allowed to cool to room temperature.  The excess piperazine was filtered off and washed with EtOAc (30 mL). The organic layer was concentrated.  The crude white sollid was washed with KOH solution (pH >12) (40 mL) and the the aqueous layer was extracted with DCM (3 x 50mL).  The organic layers were combined, dried, filtered concentrated to give a cloudy white oil (1.759 g, >8.37 mmol, >100%) 

NMR

mnr107-2_crude_1H.pdf
mnr107-2_crude.zip
- contains traces of DCM and EtOAc

Conclusion

Reaction proceeded as before and crude 1H NMR was consistent as before.  Crude product was dried further under hi-vac before being taken on to the next step without further purification.  


Strings


Starting Material

InChI=1S/C7H6ClF/c8-5-6-1-3-7(9)4-2-6/h1-4H,5H2

InChI=1S/C4H10N2/c1-2-6-4-3-5-1/h5-6H,1-4H2

Product

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

Attached Files
2nd May 2013 @ 08:24
Mnr: mnr121-130

Starting material from commercially purchased 4-chloroethieno[3,2-d]pyrimidine

As for Nucleophilic Displacement of MNR99 with Morpholine to give MNR100-1 and Nucleophilic Displacement of MNR99 with Dimethylamine to give MNR122-1

 

 

Hazard Assessment


Procedure

To 4-chloroethieno[3,2-d]pyrimidine (1.0 g, 5.86 mmol) in THF (7 mL) (ethanol (5 mL added to get the starting material into solution) was added ethyl 1-piperazinecarboxylate (1.72 mL, 11.72 mmol at 0 C.  Stirring was contiued overnight (due to having other things on).  In the morning the mixture was washed with HCl (1M), (10 mL) and extracted with EtOAc (4 x 15 mL).  The organic fractions was combined, dried, filtered and concentrated to give the crude as an orange oil (0.107 g).  The aqueous fraction was then concentrated.

2013-05-03 11.22.17.jpg

 

mnr126-1_crude_1H.pdf

Thinking that there was a solubiltiy probelm with the product the aqueous layer was concentrated to give a yellow solid.  1H NMR of this showed product and the excess piperazine. All the material was then washed with sodium hydrogen carbonate solution (30 mL) and extraced with EtOAc (40 ml x 3).  The organic fractions were combined, dried, filtered and concentrated to yeild (1.679 g, as a pale yellow solid.   1H NMR showed that the crude still contained 25% ethyl 1-piperazinecarboxylate.  Therefore product = (1.421 g, 4.86 mmol, 83%)

NMR

mnr126-1_crude_1H.pdf
 - 1H NMR crude HCl extraction

mnr126-1_pH12_1H.pdf
mnr126-1_pH12.zip
 - 1H NMR or organic layer after making pH12

Conclusion

If repeating this reaction the reaction mixture should just be washed with sodium hydrogen carbonate solution and extracted.  Probelms arrose by making the HCl salt by mistake.

 

 

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Attached Files
2nd May 2013 @ 08:19
Mnr: mnr121-130

Starting material from commercially purchased 4-chloroethieno[3,2-d]pyrimidine

As for Nucleophilic Displacement of MNR99 with Morpholine to give MNR100-1 and Nucleophilic Displacement of MNR99 with Dimethylamine to give MNR122-1

 

 

Hazard Assessment


Procedure

To 4-chloroethieno[3,2-d]pyrimidine (1.0 g, 5.86 mmol) in THF (7 mL) (ethanol (5 mL added to get the starting material into solution) was added 1-methylpiperazine (1.3 mL, 11.72 mmol at 0 C.  Stirring was contiued for 6 hours.  HCl (1M) (10 mL) was added and extracted with EtOAC (20 mL x 3).  The organic fractions were combined, dried, filtered and concentrated to yeild 20 mg of and orange oil that slowly solidifed on standing.  

2013-05-03 11.22.17.jpg

Thinking that there was a solubiltiy probelm with the product the aqueous layer was concentrated to give a yellow solid.  1H NMR of this showed product and the excess piperazine.  Attempts to recrystalise this in Methonal/Hexane gave a white sold but most of this was lost on washing.  NMR showed clean product although it was thought this was the HCl.  All the material was then washed with sodium hydrogen carbonate solution (30 mL) and extraced with EtOAc (40 ml x 3).  The organic fractions were combined, dried, filtered and concentrated to yeild (1.186 g, 5.06 mmol, 86%) as a pale yellow solid. 

NMR

 

mnr125-1_aq_1H.pdf
- 1H NMR aqueous layer

mnr125-1_aq_recrystal1_1H.pdf
- 1H NMR recrystallisationof the HCl salt

mnr125-1_pH12_1H.pdf
mnr126-1_pH12.zip
- 1H NMR or organic layer after making pH12

Conclusion

If repeating this reaction the reaction mixture should just be washed with sodium hydrogen carbonate solution and extracted.  Probelms arrose by making the HCl salt by mistake.

 

Linked Posts
Attached Files