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30th April 2013 @ 08:09
Mnr: mnr121-130

Using 4-bromobenzenesulfonamide as a test system as it's a lot cheaper than 3-bromobenzenesulfonamide.

As for - Synthesis of N,N-dimethyl-3-bromobenzenesulfonamide - MNR109-1

 

 

Hazard Assessment


Procedure

To a solution of 4-bromobenzenesulfonyl chloride (5.2 g, 20.35 mmol) in EtOH  (18mL) at 0 °C (THF (10 mL) was added as not all the starting material went into the EtOH solution) was added dimethylamine (33% in EtOH, 18.2 mL).  The resulting solution was allowed to warm to room temperature and stirred overnight.  In the morning TLC showed complete consumption of starting material.  The mixture was concentrated then washed with HCl (1M) (20 mL) and extracted with CHCl3 (4 x 50 mL).  The organic fractions were combined, dried, filtered and concentrated to give the crude at a off white solid.

TLC

50% EtOAc/Hexane

2013-05-01 12.19.27.jpg

 NMR

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30th April 2013 @ 06:05
Mnr: mnr121-130

Starting material from commercially purchased 4-chloroethieno[3,2-d]pyrimidine

As for Nucleophilic Displacement of MNR99 with Morpholine to give MNR100-1

 

Hazard Assessment


Procedure

To 4-chloroethieno[3,2-d]pyrimidine (2.0 g, 11.72 mmol) was added dimethylamine in absolute alcohol (4.2 mL, 23.44 mmol) at room temperature.  The mixture gave off some white gas and was stirred.  The solid quickly went into solution then almost instantly as solid started to precipitate out of the mixture.  The mixture was not heated as planned and was left to stir for 20 minutes.  TLC after 20 minutes showed complete consumption of starting material and one new, lower running spot.  The mixture was concentrated and crude NMR showed what looked like product but with a 1:1 ratio of dimethylamine still present.

TLC


TLC 50% EtOAc/Hex 

2013-04-30 11.56.14.jpg

TLC 100% EtOAc

2013-04-30 12.07.53.jpg


Crude NMR

mnr122-1_crude_1H.pdf
mnr122-1_crude_13C.pdf
mnr122-1_crude.zip

 

The crude was dissolved in CHCl3 (25 mL) and washed with sodium hydrogen carbonate (20 mL) and then extracted with CHCl3 (25 mL x 2).  The organic layers were combined, dried, filtered and concentrated to give an off white/pale yellow solid (1.94 g, 10.82 mmol, 92%)

 

Workup NMR

mnr122-1_workup_1H.pdf
mnr122-1_workup_13C.pdf
mnr122-1_workup.zip

Conclusion

Product obtained clean and in high yeild after workup, no need for further purification.  Taken on to the next step MNR124-1

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23rd April 2013 @ 04:54

Scale up for more material.

 

To a degassed solution of isopropanol (10 mL) and potassium carbonate (1 M, 0.870 mL, 0.870 mmol, 2.0 equiv.) was added AT-6 (0.100 g, 0.43 mmol, 1.0 equiv.), 3-sulfamoylphenyl boronic acid pinacol ester (0.148 mg, 0.52 mmol, 1.2 equiv.) and PdCl2dppf (0.064 g, 0.087 mmol, 0.2 equiv.) and the reaction mixture heated to 90 C in a microwave reactor (200 W) and stirred for 1 h.

Reaction incomplete after 1 h. Heated to 90 C under the same conditions again. 

Reaction mixture diluted with methanol (50 mL), filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (90:9:1 dichloromethane:methanol:ammonia) to give the product as a brown solid (0.077 g, 50%).

 

NMR

AT-11-4-1H-DMSOMeOD.pdf
1H NMR in MeOD/DMSO-d6.

 

HIRAC

AT-Suzuki.pdf

 

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23rd April 2013 @ 04:47

 

A solution of AT-18-1 (0.030 g, 0.12 mmol, 1.0 equiv.), 3-sulfamoylphenyl boronic acid pinacol ester (0.042 g, 0.15 mmol, 1.2 equiv.) and PdCl2dppf (0.018 g, 0.024 mmol, 0.2 equiv.) in isopropanol (2 mL) and K2CO3 (1 M, 0.26 mL, 0.26 mmol, 2.0 equiv.) was heated to 90 C in a microwave reactor (200 W) for 30 minutes. 

Immediate colour change upon addition of catalyst to reaction mixture. Hydrazyl group doesn't like palladium?? 

Complex mixture of products observed by TLC. Reaction mixture not purified.  

HIRAC

AT-Suzuki.pdf
Attached Files
9th April 2013 @ 01:40
Mnr: MNR111-120

Starting material - Bromination of MNR89 at the 7 position - MNR118-1

As for Chlorination of MNR89 To Give MNR99-3

NMR reference  WO2011093684  (A2) ― 2011-08-04 - page 19 step 3

 

Hazard Assessment

HIRAC MNR99.pdf

Procedure

To MNR118-1 (0.180 g, 0.78 mmol) at room temperature was added POCl3 (0.73 mL, 7.79 mmol) under argon and the mixture was heated to reflux for 3 hours during which time the reaction turned a dark brown colour.  The the reaction was then allowed to reach room temperature and was slowly added dropwise to ice (20 mL) in a beaker.  The mixture was then slowly neutralised with sodium bicarbonate.  Once the reaction was fully quenched it was filtered and washed with water to give a pale brown soild (0.086g) 

NMR

 

mnr119-2_filter_1H.pdf
mnr119-2_filter_13C.pdf
mnr119-2_filter.zip

Conclusion

NMR showed mainly starting material with less than 5% product.  The reaction has therefore started to go but has not had long enough.  Reaction needs repeated possibly at a higher temperature and for a longer period of time.

 

The new peaks in the 1H NMR at 9.17 and 8.80 are of different shifts to that of AT-5-6 (9.02 and 8.06) therefore suggesting that the Br substitution has occurred at the 7 position.


AT-5-6-DMSO.pdf

Strings

Starting material

InChI=1S/C6H3BrN2OS/c7-3-1-11-5-4(3)8-2-9-6(5)10/h1-2H,(H,8,9,10)

Product

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

 

 

Attached Files