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30th April 2015 @ 22:41

Reaction performed by Jason Chami, Evan Hockings, Alex Su and James Kalas 

First step in the synthesis (below) to prepare four chloroarylpyrazine cores.

 

2,6-dichloropyrazine (40.2 g, 270 mmol) was dissolved in 120 mL EtOH and hydrazine hydrate (27.2 mL, 540 mmol) was added. The mixture was stirred under reflux for 7 h.   The cooled, crude mixture was allowed to stand overnight.

The solvent was then removed from the crude mixture in vacuo, giving an orange mixture of oil and solid to which EtOAc (200mL) and  water (150mL) was added. The aqueous layer was removed and washed with EtOAc (3x 100mL). The combined organic layers were concentrated in vacuo to produce an orange crystalline solid. 

64.3 g of orange crude was produced. Tlc (DCM) showed the presence of a new material (Rf =0.6). 

 

TLC

30th April 2015 @ 04:49

 



Procedure:

Crude AEW 229-1 (~0.34 mmol) was dissolved in dioxane (1 mL) and then HCl (1 mL, 1 M aqueous solution) was added and the reaction mixture stirred at room temperature but was't soluble so DCM (0.5 mL) was added. Stirred for 36 hours. TLC showed SM still present. Reaction was dissolved in DCM (10 mL), washed with a saturated aqueous solution of sodium hydrogen carbonate (5 mL x 3), water (5 mL), brine (5 mL) and then dried (MgSO4) filtered and evaporated. The black crude material was then dissolved in DCM (0.5 mL) and ice cold 4M HCl in dioxane (3 mL) was added and the reaction stirred for 1 h. TLC showed no starting material. The reaction mixture was neutralised by the addition of an aqueous solution of 3 M NaOH and then partioned with EtOAc (20 mL), and the organic layer was collected and washed with water (10mL), brine (5 mL) and then dried (MgSO4) filtered and evaporated to give a black tar.

Purified by column chromatography using the biotage isolera (25g initial EtOAc/hexane system and then 10-20% MeOH in DCM to remove product from the column)

Product collected in two fractions:

Black gum frac one: NMR shows product but impure and poorly shimmed sample.

AEW 231-1 frac 1.pdf

Frac two: shows product not completely pure

AEW 231-1 frac 2.pdf
Data:

Crude 300 MHz NMR:

AEW 214 proton 300.pdf

Strings:

InChI=1S/C25H25F2N5O4/c1-25(2,3)36-24(33)29-19(16-7-5-4-6-8-16)15-34-21-14-28-13-20-30-31-22(32(20)21)17-9-11-18(12-10-17)35-23(26)27/h4-14,19,23H,15H2,1-3H3,(H,29,33)

to

InChI=1S/C20H17F2N5O2/c21-20(22)29-15-8-6-14(7-9-15)19-26-25-17-10-24-11-18(27(17)19)28-12-16(23)13-4-2-1-3-5-13/h1-11,16,20H,12,23H2/t16-/m0/s1

CC(OC(N[C@H](C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32)=O)(C)C

to

N[C@H](C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32

Reference

http://onlinelibrary.wiley.com/doi/10.1034/j.1399-3011.2001.00935.x/epdf

Attached Files
30th April 2015 @ 04:23

Started 9.30 am posted 13.25 due to lack of internet connectivity.


Procedure:

Crude AEW 128-1 (~0.43 mmol, 1 equiv.) was dissolved in MeOH (1.5 mL) and PPTS (11 mg, 0.043 mmol, 0.1 equiv.) was added and the reaction mixture stirred at room temperature for ten minutes.

Disaster: clamp broke and the flask fell into oil bath. 

Rescue: Tried to extract into DCM (20 mL), didn't work so shook with HCl (1 M, 10 mL) for ten minutes in separating funnel then washed organic layer with water (10 mL), brine (5 mL) and dried (MgSO4), filtered and evaporated to give a brown oily product surrounded with silca oil. Carefully pipetted of majority of oil and then resubmitted to the same reaction conditions and stirred for 2 hours. Some new product but mainly SM. Stirred with monitoring for 2 days. Still SM. Added 0.2 mL of 4 M HCl in dioxane and stirred overnight - reaction complete.

Added EtOAc (10 mL) and neutralised with a concentrated solution of sodium hydrogen carbonate (~10 mL). Separated organic from aqueous and washed aqueous with EtOAc (3 x 10 mL). Washed combined organic layers with water (10 mL), brine (5 mL) and then dried over MgSO4, filtered and evaporated to yield a red oil. Crude mixture was purified prior to NMR owing to silica oil present in sample. Purified using biotage isolera (25 g column, re-packed and product loaded in toluene) First ran a gradient of hexane to remove silica oil and then EtOAc in hexane. Product obtained as a fluffy yellow solid (46 mg, 32% over two steps).

 

Data:

 200 MHZ nmr final product - probably needs further purification but nearly there.

AEW 230-1.pdf

Hazard and Risk Assessment:


Strings:

InChI=1S/C24H24N4O3/c1-3-9-18(10-4-1)20(31-23-13-7-8-14-29-23)17-30-22-16-25-15-21-26-27-24(28(21)22)19-11-5-2-6-12-19/h1-6,9-12,15-16,20,23H,7-8,13-14,17H2

to

InChI=1S/C19H16N4O2/c24-16(14-7-3-1-4-8-14)13-25-18-12-20-11-17-21-22-19(23(17)18)15-9-5-2-6-10-15/h1-12,16,24H,13H2

C12=NN=C(C3=CC=CC=C3)N1C(OCC(OC4OCCCC4)C5=CC=CC=C5)=CN=C2

to

OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=CC=C4)N32

Attached Files
29th April 2015 @ 13:29

GitHub Issue #276 and #275 previously (#235 and #236)

See related attempts: Synthesis of methyl 2-(3,4-difluorophenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)acetate (AEW 109-1) and Synthesis of methyl 2-(3,4-difluorophenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)acetate (AEW 109-2)

Procedure:

AEW 173-1 (5 g, 30 mmol, 1 equiv.) and DHP (4.65 mL, 51 mmol, 1.7 equiv.) were dissolved in anhydrous CH2Cl2 (36 mL) under Argon at 0 ˚C. PPTS (185 mg, 0.75 mmol, 0.03 eq.) was added and the reaction mixture was stirred at 0 ˚C for and then allowed to reach room temperature.

CH2Cl(80 mL) was added and the resulting solution was shaken with portions of ice-cold water (3 x 10 mL) and once with saturated NaHCO(10 mL). The organic phase was dried (MgSO4) and filtered, and the solvent was removed under reduced pressure.

 

Hazard and Risk Assessment:

Strings:

Reference:

New Symmetrical Chiral Dibenzyl- and Diphenyl-Substituted Diamido-,Dithionoamido-, Diaza-, and Azapyridino-18-crown-6 Ligands
Peter Huszthy, Masatoshi Oue, Jerald S. Bradshaw, Cheng Y. Zhu, Ting

J. Org. Chem., Vol. 57, No. 20, 1992 5383-5394

http://pubs.acs.org/doi/pdf/10.1021/jo00046a020?source=chemport

29th April 2015 @ 09:34

Procedure:

SM (100 mg, 0.34 mmol, 1 equiv) was added to toluene (2 mL) along with AEW 180-1 (80 mg, 0.43 mmol, 1 equiv), potassium hydroxide (67 mg, 1.18 mmol, 3.5 equiv) and 18-crown-6 (6 mg, 0.02 mmol, 0.07 equiv). The reaction was stirred at room temperature for ten minutes (homogeneous mixture) and then heated to 40°C (bath temperature) for 30 minutes black solution. After 30 minutes still SM - stirred for a further 30 minutes. Reaction complete by TLC.

The sample was cooled to room temperature and diluted with 4 mL of water. The mixture was extracted with EtOAc (3 x 10 mL). Fluorescent yellow solution. The combined organic layer was washed with water (1 x 4 mL) until the aqueous layer became neutral followed by brine (3 mL) and dried over Na2SO4. The orange/yellow fluoro solution was filtered and dried under reduced pressure and in vacuo to yield a black/green oil that was dried at the high vac.

Crude NMR looks promising. Subjected crude directly to deprotection AEW 231-1.

Data:

TLC 60% EtOAc in Hex, 30 then 60 mins

AEW 229-1 60% EtOAc in Hex 30 mins.JPG
AEW 229-1 60% EtOAc in Hex 1 h.JPG

Crude NMR 300 MHz

AEW 229-1.pdf
AEW 229-1 crude.zip

Hazard and Risk Assessment:

Strings:

InChI=1S/C12H7ClF2N4O/c13-9-5-16-6-10-17-18-11(19(9)10)7-1-3-8(4-2-7)20-12(14)15/h1-6,12H

and

InChI=1S/C13H19NO3/c1-13(2,3)17-12(16)14-11(9-15)10-7-5-4-6-8-10/h4-8,11,15H,9H2,1-3H3,(H,14,16)

to

InChI=1S/C25H25F2N5O4/c1-25(2,3)36-24(33)29-19(16-7-5-4-6-8-16)15-34-21-14-28-13-20-30-31-22(32(20)21)17-9-11-18(12-10-17)35-23(26)27/h4-14,19,23H,15H2,1-3H3,(H,29,33)

 

ClC1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21

and

OCC(NC(OC(C)(C)C)=O)C1=CC=CC=C1

to

CC(OC(NC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32)=O)(C)C

Attached Files