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15th December 2014 @ 06:08

AEW 205-1 (100 mg, 0.36 mmol, 1.00 equiv.) and AEW 212-1 (54 mg, 0.36 mmol, 1.00 equiv.) were added to toluene (1.5 mL) followed by potassium hydroxide (70 mg, 1.26 mmol, 3.5 equiv.) and 18-crown-6 (6 mg, 0.025 mmol, 0.07 equiv.). The reaction mixture was stirred at 40°C (bath temperature) for 50 min. Heating had failed but TLC recorded and SM found to have been consumed at RT.

The reaction was stopped and cooled before diluting with water (2 mL). The aqueous layer was extracted with EtOAc (4 x 40 mL). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL), dried (MgSO4) and evaporated to yield an orange brown gum.

Purified by flash column chromatography over silica using Biotage Isolera (10 g, pre-packed column, crude loaded in DCM).

Gave two major factions: NMR of second fraction showed desired product x mg.

Data:

AEW 214-1 9:1 DCM:MeOH.jpg

AEW 214-1 crude 300 MHz.pdf

Purified product: 

AEW 214 proton 300.pdf

Hazard and Risk Assessment:

 

Strings:

InChI=1S/C12H8ClFN4O/c13-10-5-15-6-11-16-17-12(18(10)11)8-1-3-9(4-2-8)19-7-14/h1-6H,7H2

and 

InChI=1S/C9H13NO/c1-10-9(7-11)8-5-3-2-4-6-8/h2-6,9-11H,7H2,1H3

to

InChI=1S/C21H20FN5O2/c1-23-18(15-5-3-2-4-6-15)13-28-20-12-24-11-19-25-26-21(27(19)20)16-7-9-17(10-8-16)29-14-22/h2-12,18,23H,13-14H2,1H3

 

ClC1=CN=CC2=NN=C(C3=CC=C(OCF)C=C3)N21

and

OC[C@H](NC)C1=CC=CC=C1

to

FCOC(C=C1)=CC=C1C2=NN=C3N2C(OC[C@H](NC)C4=CC=CC=C4)=CN=C3

Attached Files
12th December 2014 @ 04:32

AEW 211-1 (80 mg, 0.17 mmol, 1 equiv) was dissolved in anhydrous CH2Cl2 (0.5 mL) and TFA (0.5 mL) was added and the reaction mixture was stirred for 30 mins. Still SM monitored over next 2 hours. TLC shows spot at same Rf as SM in the product but not as bright in UV. Stirred for a further 30 mins.

Excess reagent and solvent were removed under vacuum. The resulting red oil was neutralisedd by 2N
KOH (4 mL) extracted with DCM (5× 5 mL), dried over MgSO4, filtered and evaporated to give an orange/brown oil that was purified using the Isolera. 10 g column, repacked and product adsorbed onto silica and dry loaded. (DCM/MeOH gradient see: attached PDF). 

Detector failed and fraction 3 was not collected (should be according to UV trace) so collect all was started.

Two distinct spots Frac A contained in tube 4 was highly UV visible top spot (10 mg brown oil)

and

Frac A lower spot thought to be product (10 mg).

Both dissolved in CDCl3 for NMR evaluation.

 

Data:

 TLC 9:1 DCM/MeOH

AEW 213-1 (DCM:MeOH 9:1).jpg
AEW 213-1 (DCM:MeOH 9:1, 9h ruler view).jpg

 

2.5 h

AEW 213-1 TLC (9:1 DCM:MeOH).jpg

Isolera Reports:

aew 213-1_arch.pdf
aew 213-1_frac.pdf

Hazard and Risk Assessment:

Literature Reference:

http://pubs.acs.org/doi/pdf/10.1021/ol048771l

Highly Efficient Stereoconservative Amidation and Deamidation of alpha-Amino Acids
Deepak M. Shendage, Roland Fröhlich, and Günter Haufe

Org. Lett., Vol. 6, No. 21, 2004, 3675-3678

Strings:

InChI=1S/C25H26FN5O4/c1-25(2,3)35-24(32)28-20(17-7-5-4-6-8-17)15-33-22-14-27-13-21-29-30-23(31(21)22)18-9-11-19(12-10-18)34-16-26/h4-14,20H,15-16H2,1-3H3,(H,28,32)

to

InChI=1S/C20H18FN5O2/c21-13-28-16-8-6-15(7-9-16)20-25-24-18-10-23-11-19(26(18)20)27-12-17(22)14-4-2-1-3-5-14/h1-11,17H,12-13,22H2/t17-/m0/s1

FCOC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC[C@H](NC(OC(C)(C)C)=O)C4=CC=CC=C4)N32

to

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

Attached Files
11th December 2014 @ 06:27

 

To a stirred suspension of LiAlH4 (2.0 g, 53.3 mmol, 8 equiv.) in  anhydrous THF ( 8 mL) was added dropwise at 0 ˚C AEW 210-1 (1.3 g, 6.66 mmol, 1 equiv.) dissolved in anhydrous THF (30 mL). The reaction mixture was stirred at 0 ˚C for 30 min, at rt for 3 h, and at reflux temperature for 12 h. TLC not conclusive (see below). So refluxed for a further few hours.

The reaction mixture was cooled to 0 ˚C and 15% aqueous NaOH (4 mL) was slowly added. Formed a slurry that was a mixture of grey powder and white ppt, not stirring (no pic). The mixture was stirred for 48 hours whilst reaching rt and a clear solution and white ppt resulted (see pic).

The liquid was diluted with THF (30 mL) and the ppt was sonicated and then filtered and washed with THF. The combined filtrate and washing solutions were evaporated (forgot the MgSO drying step detailed in literature) and the residue was dried invacuo to give a pale orange oil (510 mg, 3.37 mmol, 51% yield) no further purification and used in AEW 214-1.

For ref: literature purification: distilled under reduced pressure to give 10.8 g (80%) of 13 as a clear oil: bp 90-92 "C/0.4 mmHg].

~30% lower yield than predicted so solid was sonicated with THF (2 x 50 mL) for ten minutes and filtered to give



Data:


TLC after stirring at reflux o/n

AEW 212-1 (9:1 DCM:MeOH then Pot Mang).jpg
AEW 212-1 (EtOAc then Pot Mang).jpg

 

 

Hazard and Risk Assessment:

HIRAC AEW 212-1.pdf

 

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

Strings:

InChI=1S/C9H9NO4/c11-8(12)7(10-9(13)14)6-4-2-1-3-5-6/h1-5,7,10H,(H,11,12)(H,13,14)

to

InChI=1S/C9H13NO/c1-10-9(7-11)8-5-3-2-4-6-8/h2-6,9-11H,7H2,1H3

OC([C@H](NC(O)=O)C1=CC=CC=C1)=O

to

OC[C@H](NC)C1=CC=CC=C1

Attached Files
10th December 2014 @ 05:39

Resynthesis of SGS 1-1.

Reaction performed by Trent Wallis.

Reaction scheme for synthesis of 2-chloro-6-hydrazinylpyrazine

2,6-dichloropyrazine (20 g, 134 mmol) was suspended in 100 mL EtOH and hydrazine hydrate (14.5 mL, 270 mmol) added. The mixture was stirred under reflux overnight.  

Photos:

20 s after hydrazine addition

SGS-1-2-start.jpg
 

30 min after hydrazine addition

SGS-1-2-30min.jpg

55 min after hydrazine addition

SGS-1-2-55min.jpg

17.5 hours after hydrazine addition

IMG_20141211_120207.jpg

The ethanol was then removed from the crude mixture in vacuo at 60°C, giving an orange oil to which EtOAc (200mL) and  water (150mL) was added. The aqueous layer was removed and washed with EtOAc (3x 100mL). The combined EtOAc layers were concentrated in vacuo at 60°C to produce an orange oil that solidified upon slight cooling. 

The crude product was recrystallised from ethanol/water; 6.865 g of a crystalline orange solid were obtained.

Photos:

Product mixture after removing the ethanol

IMG_20141211_143658.jpg

Crude product after water wash, extraction into EtOAc and removal of EtOAc

IMG_20141211_163800.jpg

No, Mr Hydrazine, I expect you to die!

IMG_20141211_153503.jpg

Recrystallised product.

IMG_20141212_163808.jpg

TLC (3:7 EtOAc:hexane) revealed a new spot at Rf = 0.68, SM at Rf = 0.85).

IMG_20141212_170409.jpg

S = starting material, P = recrystallised product, Co = both S and P co-spotted.

Conclusion: Looks like some starting material is still present...

SMILES

ClC1=CN=CC(Cl)=N1 to

ClC1=CN=CC(NN)=N1

InChI

InChI=1S/C4H2Cl2N2/c5-3-1-7-2-4(6)8-3/h1-2H to

InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)

Attached Files
10th December 2014 @ 04:04

Repeat of AEW 182-1 using -OCHF2 starting material rather than -CN in the hope that this will improve solubility issues. CLogP is ~3 and LogP ~4, but this compound is being synthesised to explore the importance of the benzyl amino functional group on potency.


AEW 205-1 (200 mg, 0.72 mmol, 1.00 equiv.) and AEW 180-1 (170 mg, 0.72 mmol, 1.00 equiv.) were added to toluene (3 mL) followed by potassium hydroxide (141 mg, 2.51 mmol, 3.5 equiv.) and 18-crown-6 (13 mg, 0.050 mmol, 0.07 equiv.). The reaction mixture was stirred at 40°C (bath temperature) for 30 min. TLC showed SM and new lower spot (data can't be uploaded right now but will be later). The reaction mixture was stirred for a further hour and TLC showed SM consumed (data can't be uploaded right now but will be later).

The reaction was stopped and cooled before diluting with water (2- mL). The aqueous layer was extracted with EtOAc (4 x 40 mL). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL), dried (MgSO4) and evaporated. The crude black product was dried in vacuo and then a crude NMR was measured.

Data:

 

Hazard and Risk Assessment:

 

Strings:

InChI=1S/C12H8ClFN4O/c13-10-5-15-6-11-16-17-12(18(10)11)8-1-3-9(4-2-8)19-7-14/h1-6H,7H2

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/C25H26FN5O4/c1-25(2,3)35-24(32)28-20(17-7-5-4-6-8-17)15-33-22-14-27-13-21-29-30-23(31(21)22)18-9-11-19(12-10-18)34-16-26/h4-14,20H,15-16H2,1-3H3,(H,28,32)

 

ClC1=CN=CC2=NN=C(C3=CC=C(OCF)C=C3)N21

and

OC[C@H](NC(OC(C)(C)C)=O)C1=CC=CC=C1

to

FCOC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC[C@H](NC(OC(C)(C)C)=O)C4=CC=CC=C4)N32

Attached Files