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23rd April 2013 @ 01:07
Mnr: 11-20
As for
Synthesis of MNR11-17
and
Synthesis of MNR11-16

Starting material from
Preparation of the dimethoxy Ugi-intermediate (MNR8-5)

MNR11-18%20scheme.png

MNR11-18%20table.PNG

Hazard and Risk Assessment:
HIRAC MNR11.pdf


Procedure:
To a solution of MNR8-5 (4.88 g, 10.5 mmol) in toluene (35 mL) at room temperature was added methanesulfonic acid (1.47 mL, 22.58 mmol) and the mixture was refluxed for 1 hour. The reaction was allowed to cool to room temperature and was quenched with saturated sodium carbonate and extracted with EtOAc (50 mL x 3). The organic fractions were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as a thick orange oil.

Crude - 3.965 g, 101 %

TLC
100% EtOAc. Starting material, co=spot, reaction mixture after work up
2013-04-22 16.41.25.jpg


NMR
mnr11-18_crude_vs_mnr11-17.pdf
mnr11-18_crude_1H.pdf
mnr11-18_crude.zip


Conclusion
Crude product taken on to the next step without further purification.

Hydrolysis of MNR11-18 to give MNR26-7

Strings
Starting material
InChI=1S/C25H40N2O6/c1-5-32-24(33-6-2)18-27(25(29)20-10-8-7-9-11-20)17-23(28)26-15-14-19-12-13-21(30-3)22(16-19)31-4/h12-13,16,20,24H,5-11,14-15,17-18H2,1-4H3,(H,26,28)
Product
InChI=1S/C21H28N2O4/c1-26-18-10-15-8-9-23-17(16(15)11-19(18)27-2)12-22(13-20(23)24)21(25)14-6-4-3-5-7-14/h10-11,14,17H,3-9,12-13H2,1-2H3
Linked Entries
Attached Files
24th August 2012 @ 07:24
Mnr: 11-20
*Duplicate lab book entry to allow data upload

Original post - TfOH catalysed PS* reactions to give the dimethoxy PZQ analogues (KAB8-14 & KAB1-5)

Acetal MNR10 (0.300 g, 0.66 mmol) was dissolved in toluene (30 mL) at room temperature. TfOH (2.92 μL, 0.03 mmol) was added and the reaction was heated to reflux for 3.5 hours. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (50 mL) then quenched with saturated sodium bicarbonate solution (50 mL), the organic layer was separated and the aqueous fraction was extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried over magnesium sulfate and filtered to give the crude as an orange semi-solid which was recrystallised from EtOAc/Hexane to give the KAB8 as an off white solid (0.211 g, 0.567 mmol, 87 %)

Characterisation

kab08-16_1H.pdf
kab8-16.zip



1H NMR (500 MHz, CDCl3): d = 7.56-7.39 (m, 5H), 6.81 (br, 1H), 6.65 (s, 1H), 5.20 (br, 1H), 4.98-4.75 (m, 2H), 4.34 (br, 1H), 4.17-4.02 (m, 1H), 3.87 (br, 6H), 3.06 (br, 1H), 2.97-2.79 (m, 2H), 2.73-2.64 (m, 1H).

kab08-16_13C.pdf
kab8-16.zip


13C NMR (125 MHz, CDCl3): d = 170.3, 164.2, 148.4, 148.1, 134.2, 130.7, 128.7, 127.4, 127.1, 124.4, 111.8, 108.2, 56.2, 55.9, 54.5, 51.4, 46.1, 39.1, 28.3.


*lab book page closed, MNR
Attached Files
5th June 2012 @ 09:51
Mnr: 11-20
test reaction to see if the purity of MNR8-5 is effectiong the PS reaction.

MNR11-1%20scheme.png

MNR11-16%20table.PNG

Hazard and Risk Assessment:
HIRAC MNR11.pdf


Procedure:
To a solution of MNR8-5 (0.6 mg, 1.29 mmol) in toluene (10 mL) at room temperature was added methanesulfonic acid (0.18 mL, 2.77 mmol) and the mixture was refluxed for 30 minutes. The reaction was quenched with saturated sodium carbonate and extracted with EtOAc (20 mL x 3). The organic fractions were dried over magnesium sulfate, filtered and concentrated under reduced pressure.

column chromatography on silica gel (60-100 % EtOAc:hexane) to give MNR11 as an off white solid (0.467 g, 1.25 mmol, 97 %)

mnr11-16_crude.pdf


Characterisation


kab01-2_1H.pdf
kab1-2.zip


As a 50:50 mixture of rotamers. Peaks not fully resolved at 300 K

1H NMR (500 MHz, CDCl3): d = 6.73 (s, 1H), 6.64 (s, 1H), 5.11 (dd, J = 13.3, 2.6 Hz, 1H), 4.90-4.81 (m, 1H), 4.76-4.68 (m, 1H), 4.48 (s, 0.5H), 4.45 (s, 0.5H), 4.10 (s, 0.5), 4.06 (s, 0.5H), 3.87 (s, 3H), 2.98-2.75 (m, 3H), 2.70 (s, 0.5H), 2.67 (s, 0.5H), 2.53-2.43 (m, 1H), 1.91-1.67 (m, 5H), 1.62-1.48 (m, 2H), 1.36-1.22 (m, 3H).

kab01-2_13C.pdf
kab1-2.zip


13C NMR (125 MHz, CDCl3): d = 174.9, 164.4, 148.3, 148.1, 126.9, 124.4, 111.7, 108.1, 56.1, 55.9, 54.8, 49.0, 45.4, 40.8, 39.2, 29.3, 29.0, 28.3, 25.7, 25.7, 25.7

Lit mp 98-100°C - Sadhu, P. S.; Kumar, S. N.; Chandrasekharam, M.; Pica-Mattoccia, L.; Cioli, D.; Rao, V. J. Bioorganic & Medicinal Chemistry Letters 2012, 22, 1103

Lit m.p. 91-92°C - Kim, C. S.; Min, D. Y. Arch. Pharm. Res. 1998, 21, 744

See also

Acid-mediated PS cyclisation to give racemic PZQ (KAB3-3), the dimethoxy N-benzoyl PZQ analogue (KAB8-1), the dimethoxy PZQ analogue (KAB1-2) and the N-benzoyl PZQ analogue (KAB7-1)
Linked Posts
Attached Files
18th May 2012 @ 04:02
Mnr: 11-20

MNR10-1 (0.18 g, 0.38 mmol) in toluene (2 mL) was treated with methanesulfonic acid (0.002 mL, 0.38 mmol) and the reaction was stirred at room temperature for 5 hours by which time TLC had shown complete consumption of SM. The reaction was neutralised with sat. sodium hydrogen carbonate solution, the organic fraction extracted and the aqueous fraction was washed with EtOAc (10 mL x 3). The organic layers were combined, dried, filtered and concentrated to give a white foam.

**after 1 hour it does not look like everything has gone into solution. First TLC at 90 minutes.

TLC after 5 hours in 100% EtOAc

MNR12-6 5 hours

Crude - 0.162 g

FCC - 50-100% EtOAc/Hexane

frac 54-80 0.114 g, 0.31 mmol, 82 % as a white solid

-------------------------------------------------------------- 19/09/12

repeating the conditions but using crude MNR10-3 to see if we can potentially save on doing a 50 g column.

Preparation of the dimethoxy Ugi-intermediate (MNR10-2 and MNR10-3)

MNR10-3 (1.3 g, 2.84 mmol) in toluene (14 mL) was treated with methanesulfonic acid (0.18 mL, 2.84 mmol) and the reaction was stirred at room temperature for 2 hours by which time TLC had shown complete consumption of SM. The reaction was neutralised with sat. sodium hydrogen carbonate solution (15 mL), the organic fraction extracted and the aqueous fraction was washed with EtOAc (20 mL x 3). The organic layers were combined, dried, filtered and concentrated to give a white foam.

TLC of the crude reaction after workup, ran in 75% EtOAc/Hex. Rows, SM, co-spot, Reaction mixture.

MNR12-7_75%EtOA_Hex.JPG

Column - 75-100 EtOAc/Hex

Fracs 11-27 as a of white foam/solid 0.528 g, 1.44 mmol, 51%

test recryst using EtOAc:Hex (10:15 mL)

 

IR 

1d rac IR MNR12-6 dont include.jpg
Attached Files