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28th July 2016 @ 00:56

Procedure:

For details of synthesis of hydrazinylpyrazine, see Synthesis of 2-Chloro-6-hydrazinylpyrazine (AEW 85-7)

Hydrazinylpyrazine can also be purchased commercially.

Hydrazinylpyrazine (8.00g, 55.3mmol, 1 equiv.), triethyl orthoformate (16.40g 18.4 ml, 111 mmol, 2 equiv.), and tosylic acid (1.9g, 11.1mmol, 0.2 equiv.) were dissolved in toluene (158ml, 0.35 M with respect to Hydrazinylpyrazine) and heated at reflux for about 24 hours(using Dean Stark Aparatus to set up)

Volatiles were removed under reduced pressure, remaining orthoester was blown off under a gentle stream of nitrogen.

NMR of the crude showed that purification is needed. TLC showed that 6 fractions were spotted. The reaction mixture was dissolved in ethyl acetate and mixed with slica. The solvent (ethyl acetate) was evaporated under reduced pressure. Purified by column chromatography (30 to 100% ethyl acetate in hexanes). All fractions are yellow solid.

Strings:

ClC1=CN=CC(NN)=N1

and

CCOC(OCC)([H])OCC

to

ClC1=CN=CC2=NN=CN21

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

and  

InChI=1S/C7H16O3/c1-4-8-7(9-5-2)10-6-3/h7H,4-6H2,1-3H3  

to  

InChI=1S/C5H3ClN4/c6-4-1-7-2-5-9-8-3-10(4)5/h1-3H

HIRAC

HM 1-3.docx

Log

28th Jul 

Reaction started at 11:40

 

29th Jul 

There was no liquid collected in Dean Stark aparatus and solvent was not refluxing though the temperature of oil bath was 110℃.TLC was performed, showing SM was consumed and 4 product was formed. 

TLC also showed that there was impurity in SM. So I checked two batches of SM(The previous one and new-made one) by TLC. Both of them had two spots.

 

Reaction was switched of at 1:30. Toluene was removed.

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28th July 2016 @ 00:36

GitHub Issue #400 Resynthesised as part of "Frontrunner" campaign.

(xx mg, 0.xx mmol, xx% yield)

Starting material synthesis: 

Procedure:

JU 8 (310 mg, 1.17 mmol, 1 equiv.), potassium hydroxide (229 mg, 4.09 mmol, 3.5 equiv.) and 18-crown-6 (21.6 mg, 81.8 μmol, 0.07 equiv.) were stirred in toluene (11 mL) and 2-(3,4-difluorophenyl)ethanol (185 mg, 1.17 mmol, 1 equiv.) was added and the reaction mixture stirred at rt for 30 mins. TLC showed reaction complete (9:1 EtOAc/hex)


Water (20 mL) was added and the mixture was extracted with EtOAc (3 x 40 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried (MgSO4) filtered and evaporated to give a pale yellow solid which was purified by flash column chromatography using the Biotage IsoleraTM with handpacked 50 g column and EtOAc gradient. One fraction collected and evaporated to yield the desired product as a pearlescent cream solid (218 mg, 0.051 mmol, 44% yield).

 

Data:

 

AEW 302-1 200 MHZ.png
AEW 302-1 200 MHZ.mnova
AEW 302-1 200 MHZ.jcamp
AEW 302-1 200 MHz.zip

Hazard and Risk Assessment:

HIRAC AEW 296-1 .doc

Strings:

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

to

FC1=C(F)C=CC(CCOC2=CN=CC3=NN=C(C4=CC=C(Cl)C=C4)N32)=C1

InChI=1S/C11H5ClF3N5/c12-8-4-16-5-9-18-19-10(20(8)9)6-1-2-7(17-3-6)11(13,14)15/h1-5H

to

InChI=1S/C19H13ClF2N4O/c20-14-4-2-13(3-5-14)19-25-24-17-10-23-11-18(26(17)19)27-8-7-12-1-6-15(21)16(22)9-12/h1-6,9-11H,7-8H2


Attached Files
27th July 2016 @ 02:44

requires HRMS, IR and 19F NMR 

Crude AEW 102-11 was dissolved in MeOH (20 mL) and a few drops of H2SO4 was added and the reaction mixture stirred at 80 ˚C for 16 hours.

 Poured over water (40 mL) and extracted into EtOAc (30 mL x3). Combined organic layers were dried over MgSO4, filtered and evaporated to give a yellow oil. Crude material was filtered by flash column chromatography over silica (10% EtOAc in Petrol to EtOAc) to give a yellow oil (x g, x mmol, x% yield over three steps).

 

Data:

TLC (30% EtOAc in hexane)

 

Ref NMR from CRO:

Methyl ESTER NMR.pdf

 

Hazard and Risk Assessment:

HIRAC AEW 103-1.pdf

 

InChi:

InChI=1S/C8H6F2O3/c9-5-2-1-4(3-6(5)10)7(11)8(12)13/h1-3,7,11H,(H,12,13)

to

InChI=1S/C9H8F2O3/c1-14-9(13)8(12)5-2-3-6(10)7(11)4-5/h2-4,8,12H,1H3

Literature:

Possible useful paper for chiral HPLC of enantioenriched compounds: JACS, 2002, 124, 2870 (http://pubs.acs.org/doi/abs/10.1021/ja0255047?source=chemport)


27th July 2016 @ 02:32

Scaled up for the synthesis of left-hand side chain of some 'Frontrunner Molecules"

GitHub Issue #400

Outcome

Rationale

Attempt to couple 3-chloro-4-fluoroaniline to carboxylic acid for resynthesis.

Procedure

6-chloropyrazine-2-carboxylic acid (3.00 g, 18.9 mmol, 1 equiv.), 3-chloro-4-fluoroaniline (2.75 g, 18.9 mmol, 1 equiv.) and DIPEA (6.59 mL, 4.89 g, 37.9 mmol, 2 equiv.) were dissolved in DMF (30 mL) and cooled to 0 ˚ C. T3P (50% in EtOAc, 16.9 mL, 28.4 mmol, 1.5 equiv.) was added dropwise with stirring, and the reaction mixture was kept at 0 oC for 15 min, then stirred at rt overnight. 

The reaction mixture was diluted with EtOAc (60 mL), washed with a saturated aqueous solution of  (1M, 3 x 40 mL) to remove excess amine. The combined aqueous layers was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (2 x 20 mL), then brine (20 mL) and concentrated under reduced pressure to give the crude product as a cream solid (5.39 g, 99.6% crude yield) NMR shows that DMF is still present in crude sample but used in next reaction.

 

300 MHz NMR Data:

Crude

AEW 301-1 crude 300 MHz.png
AEW 301-1 crude 300.jcamp
AEW 301-1.mnova
AEW 301-1 crude.zip

Hazard and Risk Assessment:

HIRAC AEW 297-1.doc

Strings:

InChI=1S/C5H3ClN2O2/c6-4-2-7-1-3(8-4)5(9)10/h1-2H,(H,9,10)

to

InChI=1S/C11H6ClF3N4O/c12-9-5-16-4-7(19-9)10(20)18-6-1-2-17-8(3-6)11(13,14)15/h1-5H,(H,17,18,20)

ClC1=CN=CC(C(O)=O)=N1

to

ClC1=CN=CC(C(NC2=CC=NC(C(F)(F)F)=C2)=O)=N1


Attached Files
27th July 2016 @ 01:26

Synthesised for PfATP4  'Frontrunner Molecules"

GitHub Issue #400

 

Procedure:

Crude AEW 299-1 (~2.01 mmol, 1 equiv.) was suspended in CH2Cl2 (20 mL) and PhI(OAc)2 (647 mg, 2.01 mmol, 1 equiv.) was added. The reaction mixture was stirred at rt.

 

Product was purified by automated flash column chromatography using the Biotage Isolera.

 

Pure product obtained as a brown solid (94 mg, 0.20 mmol, 10% yield). 

Data:

TLC

AEW 300-1 EtOAc.JPG
6 hours EtoAc


Hazard and Risk Assessment:


Strings:

InChI=1S/C19H13F5N6O2/c20-18(21)32-13-3-1-11(2-4-13)8-27-30-16-10-25-9-14(29-16)17(31)28-12-5-6-26-15(7-12)19(22,23)24/h1-10,18H,(H,29,30)(H,26,28,31)/b27-8+

to

InChI=1S/C19H11F5N6O2/c20-18(21)32-12-3-1-10(2-4-12)16-29-28-15-9-25-8-13(30(15)16)17(31)27-11-5-6-26-14(7-11)19(22,23)24/h1-9,18H,(H,26,27,31)

O=C(NC1=CC=NC(C(F)(F)F)=C1)C2=NC(N/N=C/C3=CC=C(OC(F)F)C=C3)=CN=C2

to

FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C(C(NC4=CC=NC(C(F)(F)F)=C4)=O)=CN=C3

 

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