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20th October 2014 @ 07:50

Summary:

Synthesis of Boronic Acid Pinacol Ester - MNR103-1 was repeated at a scale of X. This is a step towards the synthesis of Compound 24, as an effort to finish off the remaining Series 3 compounds.

Reaction Scheme:

 

Procedure:

3-bromobenzenesulfonamide (1.5 g, 6.35 mmol), potassium acetate (2.49 g, 25 .4 mmol) and bis(pinacolatodiborane) (2.42 g, 9.53 mmol) were dissolved in 1,4-dioxane (32 mL). Argon was bubbled through the suspension for ten minutes before [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.230g, 0.32 mmol) was added and the suspension heated at reflux with stirring for 22 h. The black solution was allowed to cool to room temperature and the filtered over celite being washed with MeOH (25 mL) and EtOAc (25 mL).  The filtrate was concentrated to yield a black sludge.  Recrystalisation was attempted using 50% EtOH/H2O (35 mL) but no crystals formed.  The mixture was contrantrated and ran through a coloumn.

Hazard and Risk Assessment:

RA 24 Part 3.doc

Data:

InChi:

Starting material

InChI=1S/C6H6BrNO2S/c7-5-2-1-3-6(4-5)11(8,9)10/h1-4H,(H2,8,9,10)

Product

InChI=1S/C12H18BNO4S/c1-11(2)12(3,4)18-13(17-11)9-6-5-7-10(8-9)19(14,15)16/h5-8H,1-4H3,(H2,14,15,16)

Attached Files
20th October 2014 @ 07:34

Summary:

This is the final step of the synthesis of the thienopyrimidine core component of Compound 24.

Reaction Scheme:

24 Part 2.png

Procedure:

4-chloro-6-bromo-7-methylthieno[3,2-d]pyrimidine (TF1-1) (100mg, 0.40 mmol), isopropanol (2.25 mL) and ammonia (aq, 28% (w/w), 4.5 mL) were added to a sealed tube, stirred and heated at 120 °C behind a blast shield for 2 hours. The reaction mixture was allowed to cool to room temperature and the solvent removed under vacuum to give a quantitative yield of white solid (~100mg).

Hazard and Risk Assessment:

RA TF2-1.doc

Data:

Product NMR:

OctIV-01033_10_1.pdf
TF2-1 Raw NMR.tar

InChi:

Attached Files
20th October 2014 @ 07:13

Summary

This is the first step towards the synthesis of Compound 24, as part of an effort to finish off the remaining compounds in Series 3.

Reaction Scheme

 

Procedure

Bromination of the thienopyrimidine core is analogous to the synthesis of AEW99-1.

To 4-chloro-7-methylthieno[3,2-d]pyrimidine (300 mg, 1.758 mmol, 1.0 equiv.) in THF (18 mL) at -78 C was added n-BuLi (1.056 mL, 2.640 mmol, 1.5 equiv.), dropwise with stirring at -78 C for 1 hour. Bromine (0.18 mL, 3.516 mmol, 2.0 equiv.) was added dropwise, and the reaction mixture warmed to RT and stirred for an hour.

The reaction mixture was diluted with an aqueous solution of 1M sodium thiosulfate (5 mL) and extracted into ethyl acetate and water (3 x 25 mL each). The combined organic extracts were dried with MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (5% ethyl acetate in heptane) to give the desired product as a yield of white crystals (253.9mg), and an additional fraction containing an as-of-yet undetermined product as a pale yellow solid (37.3mg).

Data:

Crude NMRs

TF1-1 Crude Product.pdf
TF1-1 SM.pdf
3ORProject6_TF1-1SM_201014_1H_av600_OctIV-00696.tar
3ORProject6_TF1-1C_201014_1H_av600_OctIV-00695.tar

NMR TF1-1 C1 (unidentified side product)

In Chloroform:

OctIV-01553_10_1.pdf
OctIV-01553_12_1.pdf
OctIV-01553_11_1.pdf
OctIV-01553_13_1.pdf
TF1-1 C1 Raw.tar

In DCM:

OctIV-01012_10_1.pdf
TF1-1 C1 DCM Raw.tar

NMR TF1-1 C2 (purified intended product)

In Chloroform:

OctIV-01554_13_1.pdf
OctIV-01554_11_1.pdf
OctIV-01554_10_1.pdf
OctIV-01554_12_1.pdf
TF1-1 C2 Raw.tar

Hazard and Risk Assessment:

RA 24 Part 1.doc

InChi:

Attached Files
14th October 2014 @ 12:02

Summary:

This is the final step of the synthesis of Compound 24. The chemistry of this reaction is analogous to this synthesis already performed by Patrick.

Hazard and Risk Assessment:

RA TF3-1.doc

Reaction Scheme:

 

Procedure:

The combination of the two above building blocks to form compound 24 is analogous to this synthesis alredy performed by Patrick. 

1-methyl-4-chlorothieno[3,2-d]pyrimidine [TF2] (84.9 mg, 0.3 mmol) was dissolved in isopropyl alcohol (6 mL). MNR103 (141 mg, 0.36 mmol, 3.6 eq) was added, followed by potassium carbonate solution (1M, 0.6 mL, 6 equivalents). The solution was degassed with nitrogen for 5 minutes, and Pd(dppf)2.CH2Cl2 (48 mg, 60 μmol, 20 mol%) was added.

The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel. 

 

Data:

 

InChi:

Attached Files
10th July 2014 @ 04:41

Resynthesised for hERG evaluation

AEW 100-6 (29 mg, 0.1 mmol) was dissolved in isopropyl alcohol (2 mL) and to this was added MNR 103 (34 mg, 0.12 mmol, 1.2 eq) followed by potassium carbonate solution (1M, 0.2 mL, 2 equivalents). The solution was degassed with Ar for 10 minutes and Pd(dppf)2.CH2Cl2 (16 mg, 20 umol, 20 mol%) was added and the red/pink reaction mixture was placed in the microwave reactor and heated to 85 ˚C. Originally, 200 W was applied as per optimised conditions but the temperature was unsteady. Found to be steady at 60 W and so heated to 85 ˚C at 60 W for 30 minutes. 

InChi:

InChI=1S/C6H4BrN3S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H,(H2,8,9,10)

and

InChI=1S/C12H18BNO4S/c1-11(2)12(3,4)18-13(17-11)9-6-5-7-10(8-9)19(14,15)16/h5-8H,1-4H3,(H2,14,15,16)

to

InChI=1S/C12H10N4O2S2/c13-12-11-9(15-6-16-12)5-10(19-11)7-2-1-3-8(4-7)20(14,17)18/h1-6H,(H2,13,15,16)(H2,14,17,18)

Attached Files