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Pictet-Spengler route to Praziquantel
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27th July 2012 @ 02:34
START: 26/07/12
FINISH: 27/07/12




Hazard and Risk Assessment
HRA KAB26-18


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3/PyBOX catalysed asymmetric acyl-PS formation of KAB26-17

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (MNR42-1) - SMILES: O=[N+]([O-])C1=CC=C(/C=N/CCC2=CC(OC)=C(OC)C=C2)C=C1, InChI: InChI=1S/C17H18N2O4/c1-22-16-8-5-13(11-17(16)23-2)9-10-18-12-14-3-6-15(7-4-14)19(20)21/h3-8,11-12H,9-10H2,1-2H3/b18-12-, InChIKey: LMBMXYXQVBPKHJ-PDGQHHTCSA-N.
1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-18) - SMILES: O=[N+]([O-])C1=CC=C(C2N(C(C)=O)CCC3=CC(OC)=C(OC)C=C32)C=C1, InChI: InChI=1S/C19H20N2O5/c1-12(22)20-9-8-14-10-17(25-2)18(26-3)11-16(14)19(20)13-4-6-15(7-5-13)21(23)24/h4-7,10-11,19H,8-9H2,1-3H3, InChIKey: OIFIJKJQAGAGKY-UHFFFAOYSA-N.

Procedure
NOTE: All THF was dried over microwave activated 3 Å molecular sieves (2.0-2.5 mm) >72 h prior to use. All acetonitrile was dried over microwave 3 Å molecular sieves (2.0-2.5 mm) >24 h prior to use.[1] All glassware used was dried overnight at 115 °C.


Summary and Conclusion


References
[1] D. Bradley, G. Williams and M. Lawton, J. Org. Chem. 2010, 75, 8351. DOI: 10.1021/jo101589h Paper.
[2] H. Ishitani and S. Kobayashi, TetLett 1996, 37, 7357.
[3] S. Watanabe, Y. Kobayashi, T. Arai, H. Sasai, M. Bougauchi and M. Shibaski, TetLett 1998, 39, 7353.
[4] Rare-Earth Metal Triflates in Organic Synthesis, S. Kobayashi, M. Sugiura, H. Kitagawa and W. W.-L. Lam, Chem. Rev. 2002, 102, 2227–2302. DOI: 10.1021/cr010289i Paper.

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NOTES
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27th July 2012 @ 02:32
START: 26/07/12
FINISH: 26/07/12




Hazard and Risk Assessment
HRA KAB26-18


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3/PyBOX catalysed asymmetric acyl-PS formation of KAB26-17

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (MNR42-1) - SMILES: O=[N+]([O-])C1=CC=C(/C=N/CCC2=CC(OC)=C(OC)C=C2)C=C1, InChI: InChI=1S/C17H18N2O4/c1-22-16-8-5-13(11-17(16)23-2)9-10-18-12-14-3-6-15(7-4-14)19(20)21/h3-8,11-12H,9-10H2,1-2H3/b18-12-, InChIKey: LMBMXYXQVBPKHJ-PDGQHHTCSA-N.
1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-20) - SMILES: O=[N+]([O-])C1=CC=C(C2N(C(C)=O)CCC3=CC(OC)=C(OC)C=C32)C=C1, InChI: InChI=1S/C19H20N2O5/c1-12(22)20-9-8-14-10-17(25-2)18(26-3)11-16(14)19(20)13-4-6-15(7-5-13)21(23)24/h4-7,10-11,19H,8-9H2,1-3H3, InChIKey: OIFIJKJQAGAGKY-UHFFFAOYSA-N.
(R)-[1,1'-binaphthalene]-2,2'-diol ((R)-BINOL) - SMILES: OC1=[C@]([C@]2=C(C=CC=C3)C3=CC=C2O)C4=CC=CC=C4C=C1, InChI: InChI=1S/C20H14O2/c21-17-11-9-13-5-1-3-7-15(13)19(17)20-16-8-4-2-6-14(16)10-12-18(20)22/h1-12,21-22H, InChIKey: PPTXVXKCQZKFBN-UHFFFAOYSA-N.

Procedure
NOTE: All THF was dried over microwave activated 3 Å molecular sieves (2.0-2.5 mm) >72 h prior to use. All acetonitrile was dried over microwave 3 Å molecular sieves (2.0-2.5 mm) >24 h prior to use.[1] All glassware used was dried overnight at 115 °C.

Summary and Conclusion


References
[1] D. Bradley, G. Williams and M. Lawton, J. Org. Chem. 2010, 75, 8351. DOI: 10.1021/jo101589h Paper.
[2] H. Ishitani and S. Kobayashi, TetLett 1996, 37, 7357.
[3] S. Watanabe, Y. Kobayashi, T. Arai, H. Sasai, M. Bougauchi and M. Shibaski, TetLett 1998, 39, 7353.
[4] Rare-Earth Metal Triflates in Organic Synthesis, S. Kobayashi, M. Sugiura, H. Kitagawa and W. W.-L. Lam, Chem. Rev. 2002, 102, 2227–2302. DOI: 10.1021/cr010289i Paper.

------------------------------------------
NOTES
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27th July 2012 @ 01:20
PZQ was selected as a standard for monitoring the formation of MNR41 due to it's similarity to the product.

PZQ was initially investigated at different concentrations to show if it had a linear relationship between concentration and peak area.

Stock solution 1 was made by dissolving PZQ (0.006 g) in MeCN (1.8 mL) giving a concentration of 3333.33 ug/mL.

Stock solution 1 (0.2 mL) was then dissolved in (1.6 mL) giving stock 2 a concentration of 370.4 ug/mL.

Stock 2 (0.08 mL) + MeCN (0.4 mL) gave LCMS sample of 61.7 ug/mL.
Stock 2 (0.07 mL) + MeCN (0.4 mL) gave LCMS sample of 55.2 ug/mL.
Stock 2 (0.06 mL) + MeCN (0.4 mL) gave LCMS sample of 48.3 ug/mL.
Stock 2 (0.04 mL) + MeCN (0.4 mL) gave LCMS sample of 33.7 ug/mL.
Stock 2 (0.03 mL) + MeCN (0.4 mL) gave LCMS sample of 25.8 ug/mL.
Stock 2 (0.02 mL) + MeCN (0.4 mL) gave LCMS sample of 17.6 ug/mL.
Stcok 2 (0.01 mL) + MeCN (0.4 mL) gave LCMS sample of 9.0 ug/mL.

Running the samples in the LCMS with the method 0to50ov30 Water, 0.1 % formic acid, acetonitrile, 0.1% formic acid measuring at 210 nm produced the following calibration plot.

*This method was selected as it was the shortest run time where we could achieve baseline separation between the MNR41 and PZQ.

mnr41-7-PZQ_plot.PNG

Testing The Work Up Conditions.

Following the reaction by LCMS requires a mini workup. There is an area of doubt here as to how much standard and how much product is extracted in the single extraction. Therefore the following was conducted.

MNR41 (56 mg) and PZQ (5 mg) was dissolved in MeCN (5 mL). Three aliquots (0.1 ml) were taken.

Aliquot 1 - no further workup - just concentrated to dryness. MeCN (1.8 mL) added and 0.04 ml was taken and diluted with MeCN (0.3 mL)
Aliquot 2 - EtOAc (0.2 mL) add and sodium hydrogen carbonate (0.2 ml) added and organics extracted roughly by pipette then concentrated to dryness. MeCN (1.8 mL) added and 0.04 ml was taken and diluted with MeCN (0.3 mL)
Aliquot 3 - EtOAc (0.4 mL) add and sodium hydrogen carbonate (0.2 ml) added and organics extracted roughly by pipette then concentrated to dryness. MeCN (1.8 mL) added and 0.04 ml was taken and diluted with MeCN (0.3 mL)

Aliquot 1 - Product peak area 27,287,433 - 93.0%
PZQ peak area 2,044,010 - 7.0%

mnr41-7_Aliquot 1.pdf


Aliquot 2 - Product peak area 14,938,837 - 92.4%
PZQ peak area 1,235,799 - 7.6%

mnr41-7_Aliquot 2.pdf


Aliquot 3 - Product peak area 20,056,141 - 92.4%
PZQ peak area 1,642,434 - 7.6%

mnr41-7_Aliquot 3.pdf


Conclusion - A single extraction does not extract all of the product or PZQ but it does extract then at the same ratio therefore this procedure can be used to calculate yield.
Linked Posts
Attached Files
26th July 2012 @ 05:07
MNR43-1%20scheme.png
mnr43-1%20table.PNG

Yb(OTf)3 (0.050 g, 0.08 mmol) and R-iPr-box (0.049 g, 0.16 mmol) in THF (5 mL) in THF (5 mL) was stirred at room temperature for 10 minutes. The solution was then concentrated to about 0.5 mL volume and Et2O (5 mL) was added. A white precipitate appeared but had a very sticky consistency and was not crystalline. The mixture was concentrated to complete dryness
Attached Files
25th July 2012 @ 01:14
START: 25/07/12
FINISH:

Scheme%20KAB26-19.png
Table%20KAB26-19.png

Hazard and Risk Assessment
HRA KAB26-19


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3/PyBOX catalysed asymmetric acyl-PS formation of KAB26-17

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (MNR42-1) - SMILES: O=[N+]([O-])C1=CC=C(/C=N/CCC2=CC(OC)=C(OC)C=C2)C=C1, InChI: InChI=1S/C17H18N2O4/c1-22-16-8-5-13(11-17(16)23-2)9-10-18-12-14-3-6-15(7-4-14)19(20)21/h3-8,11-12H,9-10H2,1-2H3/b18-12-, InChIKey: LMBMXYXQVBPKHJ-PDGQHHTCSA-N.
1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-19) - SMILES: O=[N+]([O-])C1=CC=C(C2N(C(C)=O)CCC3=CC(OC)=C(OC)C=C32)C=C1, InChI: InChI=1S/C19H20N2O5/c1-12(22)20-9-8-14-10-17(25-2)18(26-3)11-16(14)19(20)13-4-6-15(7-5-13)21(23)24/h4-7,10-11,19H,8-9H2,1-3H3, InChIKey: OIFIJKJQAGAGKY-UHFFFAOYSA-N.

Procedure
NOTE: All THF was dried over microwave activated 3 Å molecular sieves (2.0-2.5 mm) >72 h prior to use. All acetonitrile was dried over microwave 3 Å molecular sieves (2.0-2.5 mm) >24 h prior to use.[1] All glassware used was dried overnight at 115 °C.

To a mixture of 3 Å molecular sieves (~1.5 g) in MeCN (16 mL) was dissolved MNR42-1 (100 mg, 0.318 mmol, 1 equiv.). The mixture was cooled in an acetone ice bath (-10 °C) before the addition of acetyl chloride (0.04 mL, 0.6 mmol, 1.8 equiv.) and 2,6-lutidine (0.06 mL, 0.5 mmol, 1.6 equiv.).
A solution of Yb(OTf)3 (10 mg, 0.016 mmol, 0.05 equiv.) and 2,2′-Isopropylidenebis[(4R)-4-phenyl-2-oxazoline (21 mg, 0.063 mmol, 0.2 equiv.) in THF (~1 mL) and acetonitrile (~0.5 mL) was prepared. Once dissolved, the Yb(OTf)3 was added to the cold MNR42-1 mixture. The reaction mixture was allowed to warm to 25 °C and stirred under argon from 10:15.
After 2 hours, the reaction mixture was diluted with EtOAc (15 mL). The mixture was washed with saturated sodium bicarbonate solution (15 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure to yield crude KAB26-19 (159 mg, 140%).
The crude product was purified by silica gel column chromatography (60-70% EtOAc/hexane, v/v) to yield KAB26-19 as a yellow solid (93 mg, 82%).

Summary and Conclusion

References
[1] D. Bradley, G. Williams and M. Lawton, J. Org. Chem. 2010, 75, 8351. DOI: 10.1021/jo101589h Paper.
[2]
[3] Rare-Earth Metal Triflates in Organic Synthesis, S. Kobayashi, M. Sugiura, H. Kitagawa and W. W.-L. Lam, Chem. Rev. 2002, 102, 2227–2302. DOI: 10.1021/cr010289i Paper.

------------------------------------------
NOTES
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Attached Files