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20th October 2014 @ 08:13

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 is added n-BuLi (1.056 mL, 2.640 mmol, 1.5 equiv.), dropwise with stirring at -78 C for 30 minutes. Bromine (0.18 mL, 3.516 mmol, 2.0 equiv.) is added dropwise, and the reaction mixture warmed to RT and stirred for an hour.

The reaction mixture is diluted with an aqueous solution of sodium thiosulfate (5 mL) and extracted into ethyl acetate (3 x 5 mL). The combined organic extracts are dried with MgSO4 and concentrated under reduced pressure. The residue is purified by flash column chromatography (7:1 hexanes:ethyl acetate) to give the desired product, and an additional fraction containing the starting material.

Data:

 

TF1-1 Crude Product.pdf
TF1-1 SM.pdf

Hazard and Risk Assessment:

RA 24 Part 1.doc

InChi:

Attached Files
10th July 2014 @ 05:41

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
9th July 2014 @ 09:27

Reaction scheme:

Procedure: Perfomed on 2 x 200 mg scale

AEW 99-1 (0.200 g, 0.80 mmol), isopropanol (4.5 mL) and ammonia (aq, 28% (w/w), 9 mL) were added to a sealed tube, stirred and heated at 120 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and the solvent was removed under vacuum.

2 batches of CT 3 were made (total 0.400 g starting material). CT 3-6 and CT 3-7 were purified together by column chromatography over silica (99:1 DCM:MeOH to 97:3 DCM:MeOH to 96.5:3.5:0.5 DCM:MeOH:NH3).

Data:


InChI strings:

InChI=1S/C6H2BrClN2S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H

to

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


9th July 2014 @ 02:40

See also AT 1-1

To MNR89-1 (1.50 g, 9.87 mmol, 1.0 equiv.) under argon was added phosphorus(V) oxychloride (15.1 g, 9.15 mL, 98.7 mmol, 10.0 equiv.) dropwise with stirring. The reaction mixture was heated to reflux and stirred for x h, before cooling to rt.

Ice (approx. 20 mL), an aqueous solution of NaHCO3 (approx. 600 mL) and solid NaHCO3 (approx. 5 g) were added sequentially until effervesence ceased and the reaction mixture was extracted with ethyl acetate (6 x 100 mL). The organic phases were combined, dried (MgSO4) and concentrated under reduced pressure to give the product as a yellow solid (xx%).  

  

HIRAC

See AT 1-1

 

InChi:

InChI=1S/C6H4N2OS/c9-6-5-4(1-2-10-5)7-3-8-6/h1-3H,(H,7,8,9)

to

InChI=1S/C6H3ClN2S/c7-6-5-4(1-2-10-5)8-3-9-6/h1-3H

Attached Files
3rd July 2014 @ 10:38

 

 

Conditions from Synthesis of 3-(7-aminothiazolo[4,5-d]pyrimidin-2-yl)-4-methyl-benzenesulfonamide (PT-22) were used on a 2x scale, to synthesise OSM-S-106.

 

PT-21-B1 (56.7 mg, 0.2 mmol) was dissolved in isopropyl alcohol (4 mL) and to this was added PT-18-D1 (68 mg, 0.24 mmol, 1.2 eq) followed by potassium carbonate solution (1M, 0.4 mL, 2 equivalents). The solution was degassed with nitrogen for 5 minutes and Pd(dppf)2.CH2Cl2 (32 mg, 40 umol, 20 mol%) was added. The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel, then evaporated to dryness. NMR (B1) indicated peaks consistent with a single major product, the title compound, plus misc. impurities (Reference spectrum):

PT-23-B1 1H NMR detail.png

The crude mixture was purified by dry flash column chromatography (gradient: 100% chloroform to 80% chloroform, 18% methanol, 2% sat. aq. ammonia) to give the title compound in two batches: 

C1, pale tan solid, 32.3 mg, 0.105 mmol, 52.8%

C2, tan solid, 23.1 mg, 0.075 mmol, 37.7%

Combined yield: 90.5%


Attached Files